A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Haemophilia A
Phase: PHASE1
Conditions: Severe Haemophilia A
Sponsor: BioMarin Pharmaceutical

 
 
 
 
    
 
 
 
 
 
 
Official Title:  A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene 
Transfer of Human Factor VIII in Patients with Severe Haemophilia A 
 
NCT Number: NCT02576795 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 24 Aug 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Proprietary and Confidential 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene 
Transfer of Human Factor VIII in Patients with Severe Haemophilia A 
Protocol Number: 
270-201 
Active Investigational Product: 
AAV5-hFVIII-SQ 
IND/European Union Drug 
Regulating Authorities Clinical 
Trials (EudraCT) Number: 
2014-003880-38 
Indication: 
Haemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 1/2 
Sponsor's Responsible Medical 
Monitor: 
 MD, PhD 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive Novato, CA 94949 
Duration of Subject 
Participation: 
Approximately 368 weeks 
Dose: 
Varied 
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
10 February 2015 
Date of Amendment 1:
06 March 2015
Date of Amendment 2:
26 May 2015
Date of Amendment 3:
06 November 2015
Date of Amendment 4:
02 September 2016 
Date of Amendment 5:
14 February 2017 
Date of Amendment 6:
21 December 2017
Date of Amendment 7:
10 October 2018
Date of Amendment 8:
31 January 2019
Date of Amendment 9:
19 June 2020 
Date of Amendment 10: 
24 August 2021
Property of BioMarin 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin. 
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code 
of Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving 
of essential documents 
PI
PI

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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 10 
Date: 24 August 2021 
RATIONALE AND SUMMARY OF MAJOR CHANGES
A summary of major changes covered by Amendment 10 to the 270-201 protocol is provided 
below.   
1.
Changes have been made to enhance screening for potential malignancies (including 
hepatic cancers) after dosing with BMN 270. 
Rationale: The changes made include: 
 Including a targeted liver ultrasound at the End of Year visits after Year 4 to screen 
for HCC (additional interim liver ultrasounds may be performed at the discretion of 
the Investigator); 
 Recommending genomic analyses for any malignancy (except non-melanoma skin 
cancer) diagnosed during the course of the study. 
Year-end liver ultrasounds are being implemented to assess the theoretical risk of HCC. 
While no cases of HCC have been reported in the Sponsor's AAV gene therapy non-clinical 
or clinical trials (more than 150 patients dosed, with some dosed more than 5 years ago), 
these assessments will further inform this theoretical risk. 
2. Malignancy (except non-melanoma skin cancer) has been added as an Event of Special 
Interest (EOSI). 
Rationale: The occurrence of malignancy (as above) was added as an EOSI for purposes of 
expedited safety reporting and additional safety monitoring. 
3. Language has been added concerning the use of the SARS-CoV-2 vaccines. 
Rationale: Due to the current worldwide SARS-CoV-2 pandemic and evolving availability 
and types of vaccines, language has been added to assist with timing and planning for 
vaccine administration. The Sponsor's recommendations reflect the risk assessment 
conducted on the currently available vaccines and guidance from multiple health agencies, 
and include information regarding different types of SARS-CoV-2 vaccines. 
4. Guidance concerning the use of reactive corticosteroids for ALT elevations has been 
updated. 
Rationale: The guidance suggests that subjects who are seeing ALT elevations more than 
52 weeks after BMN 270 dosing should be started on reactive corticosteroids only after 
discussion between the Investigator and the Medical Monitor. Corticosteroids may be 

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delayed if elevations in ALT are clearly not related to BMN 270 (eg, elevated with 
concurrent increase in CPK due to intensive exercise).  
5. The definition of treatment failure has been changed.  
Rationale: The previous definition required either a failure to achieve FVIII activity 
 5 IU/dL by Week 52 or an inability to maintain independence from prophylactic FVIII 
replacement therapy due to joint bleeding episodes; the revised definition requires both of 
these conditions to be present before a subject may be considered a treatment failure. The 
revision reflects the data seen as of the 52-week data cut for 270-301, where some subjects 
were still able to remain off of prophylactic FVIII replacement therapy (due to an absence of 
treated bleeding events) despite lower FVIII levels 1 or more years after BMN 270 infusion. 
6. Frequency of several laboratory assessments after Year 1 has been decreased. These 
changes include: 
 Reducing FVIII Antigen BDD Assay to Q12W after Year 1 through Year 5, and 
Q26W in Years 6-7 
Rationale: Robust characterization is already available from Year 1 data, and more 
frequent sampling is not needed to understand long-term protein to activity ratios
 Reducing AAV5 TAb to End of Year Visits only after Year 1 
Rationale: Antibody response is high and does not change much over time. Yearly 
testing should be sufficient to understand longer term responses, as little change is 
expected.
 Reducing FVIII TAb to End of Year Visits only after Year 1 
Rationale: FVIII Bethesda Inhibitor is the main safety assessment. After 3 years, if 
there is a need in specific instances for data more frequent than once a year, backup 
plasma from another assay may be used for testing. 
7. The identity of the Medical Monitor has been updated. 
8. The summary of risks and benefits (Section 7) has been updated. 
9. Minor administrative changes have been made for consistency and clarity. 
Specific changes included in this amendment, including the Synopsis, since 
Amendment 9 (approved 19 June 2020) are outlined in Section 24. 

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2
SYNOPSIS 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
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TITLE OF STUDY: 
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of BMN 270, an 
Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients 
with Severe Haemophilia A 
PROTOCOL NUMBER: 
270-201 
STUDY SITES:
Approximately 6-10 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 1/2 
STUDY RATIONALE: 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an 
essential cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to 
a new mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 
1-5% of wild type activity and the mild form is 5-40% activity. The clinical manifestations of 
severe HA remain frequent spontaneous bleeding episodes, predominantly in joints and soft 
tissues, with a substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life for 
FVIII (12 to 18 hours for most approved products) necessitates frequent infusions, and although a 
major advance in the treatment of HA, it remains common for severe HA patients to continue to 
have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up 
to 30 to 50 episodes/year for on demand treatment). The consequence of multiple bleeding events 
is the development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death. Chemical modification (eg, direct conjugation 
of polyethylene glycol (PEG) polymers) and bioengineering of FVIII (eg, FVIII-Fc fusion 
proteins) improve half-life by approximately 50%, and thus, show promise in reduced dosing and 
maintaining activity levels above 1% trough. However, these longer acting FVIIIs remain 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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dependent on multiple infusions to maintain critical levels of FVIII activity in severe HA patients. 
There is therefore a strong unmet need for a fully preventive treatment of HA to give patients a 
FVIII level compatible with a normal and haemorrhage-free life. 
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach because 
clinical manifestations are attributable to the lack of a single gene product (FVIII) that circulates in 
minute amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not 
essential, and modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml 
induces an increase in activity of 1%) can ameliorate the severe form of the disease.  Thus, 
relatively small changes in endogenous FVIII activity results in clinically relevant improvements 
in disease phenotype. Finally, the response to gene transduction can be assessed using validated 
quantitative rather than qualitative endpoints that are easily assayed using established laboratory 
techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific 
tissues such as the liver (for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy 
clinical trial for a related disorder, haemophilia B, has established that stable (>36 months) 
expression of human factor IX at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
administration of AAV-8 vector. Several participants in this trial have been able to discontinue 
factor prophylaxis without suffering spontaneous haemorrhages, even when they undertook 
activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a liver-selective promoter (Figure 1).
Figure 1. hFVIII-SQ Vector Genome and Encoded Protein

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
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Legend –Note that schematic is not to scale; aa = amino acids; ITR = inverted terminal repeat; HLP = human 
liver promoter; Kozak = Kozak concensus sequence (GCCACC); SpA = Synthetic poly(A) signal 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from vector-transduced 
liver tissue. The clinical study 270-201 is a first-in-human study designed to assess the relationship 
of vector dose to the augmentation of residual FVIII activity, and whether these levels are 
sufficient to alter the clinical phenotype. The relationship of dose to safety will be correlated to the 
activity of hFVIII in patients with severe HA. 
Liver Biopsy Substudy Rationale 
The pattern of response in hFVIII activity observed so far after administration of BMN 270 
demonstrates peak expression levels during the first 6-12 months post-treatment followed by a 
decline to a steady-state level of expression in the second year of follow-up, with mean hFVIII 
activity levels remaining above the lower limit of normal (50 IU/dL).  One of the explanations may 
lie in the kinetics of vector genome processing which involves a series of steps such as DNA 
degradation and repair, annealing, and circularization that can result in the formation of stable 
double-stranded circularized transgene DNA forms, and it is these circularized DNA species that 
are thought to be associated with long-term, persistent expression of the gene product in target 
cells.  Examination of transduced hepatocytes from subjects treated with BMN 270 in the 270-201 
study will help to establish whether DNA circularization may occur and could account for the 
long-term hFVIII expression observed in humans. 
Additionally, health of the liver after gene transduction has been monitored indirectly by periodic 
assessments of hepatic enzymes released into the blood stream.  Transient post-treatment 
elevations in ALT levels have been observed in some subjects, as well as inter-subject variability 
in post-therapy hFVIII levels. Neither the reasons for, nor the significance of, the ALT elevations 
or variations in response to FVIII gene therapy are known. Moreover, the effects of BMN 270 on 
hepatic tissue structure and function are also currently unknown.  
The purpose of this exploratory substudy is to provide a better understanding of the long-term gene 
expression related to circularized genomes, health of the liver, and variation in hFVIII levels 
observed after gene therapy with BMN 270. Whilst consenting subjects may not derive any direct 
benefit themselves by participating in the substudy, the overall findings could aid future patients 
by helping to characterize the means by which long-term efficacy is achieved and the safety of 
liver-directed gene therapy.  

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
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OBJECTIVES:  
The primary objectives of the study are: 
 
To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
 
To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of 
normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose. 
The secondary objectives of the study are: 
 
To describe the immune response to the FVIII transgene and AAV capsid proteins 
following systemic administration of AAV5-hFVIII-SQ 
 
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during 
the study 
 
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study 
The exploratory objectives of the liver biopsy substudy are: 
 
To examine the histopathology of the liver following BMN 270 therapy, including 
assessing for possible safety findings (eg, fibrosis, fatty liver disease, lymphocytic 
invasion) 
 
To quantify FVIII DNA, RNA, and protein expression within hepatocytes 
 
To determine which forms of rAAV vector DNA are present at the time of biopsy. 
 
To determine the transduction pattern of BMN 270 in humans (ie, peri-portal hepatocytes, 
central vein hepatocytes) 
STUDY DESIGN AND PLAN:  
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will be 
taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed 
for approximately 7 years. 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
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Patients who provide written informed consent, meet the entry criteria definition of severe HA, and 
do not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. 
Participants will be enrolled into one of up to four cohorts according to dose level:  
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv) 
Cohort 2:  2E13 vg per kilogram, iv 
Cohort 3:  6E13 vg per kilogram, iv 
Cohort 4:  4E13 vg per kilogram, iv 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies 
of mice and monkeys. The starting dose has a 10-fold safety margin from no observed adverse 
effect level (NOAEL) in non-human primates.  
Cohorts 1-3  
The first 3 cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between 
cohorts. Dose escalation may occur after a single subject has been safely dosed if the resulting 
FVIII activity at the Week 3 visit is < 5 IU/dL in both the one-stage clotting and chromogenic 
substrate assays. Three weeks is expected to be the time the expression will be close to the 
maximum.  This escalation paradigm is intended to minimize the subject numbers exposed to 
subtherapeutic doses. 
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study, the Data Review Board (DRB).  
If the FVIII 
IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects. 
Subject 1 will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram of 
IU/dL at the Week 3 visit in both assays, 
then no further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with 
Subject 2 at the next dose (2E13 vg/kg).  
If the FVIII 
 IU/dL at the 
Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and enrollment into 
Cohort 3 (6E13) will initiate with the next subject. If the FVIII activity level in the first subject 
Review Board (DRB) will recommend whether to continue to add subjects to the cohort and/or 
whether to continue the study. 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
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For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
5 IU/dL and 
no safety issue is found, then up to four subjects will be enrolled in the Cohort, though, the 
adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts based 
on activity levels of FVIII and safety signals.  
Cohort 4 
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects is 
 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in this 
cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB.  The adaptive nature of this trial allows the DRB to recommend allocating 
subjects to the cohorts based on activity levels of FVIII and safety signals. 
As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding consideration of 
FVIII activity levels by themselves or subjects in the reporting of bleeding episodes and FVIII 
usage. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will 
discuss whether to resume prior FVIII prophylaxis. Subjects who do not respond to BMN 270 
52 and inability to maintain independence from prophylactic FVIII replacement therapy due to 
joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion 
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, 
as applicable and at the discretion of the Investigator. Because subjects develop neutralizing 
immunity upon exposure to the capsid, re-challenge of vector is not a likely treatment option and 
these subjects have effectively a single opportunity for therapy using this AAV capsid. Efficacy 
will be determined by FVIII activity at 16 weeks post dose. Safety will be evaluated for 
approximately 7 years after dosing.  Any safety signal may trigger a review of the data and 
possible additional immunogenicity studies that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMC). 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
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At applicable sites, certain study assessments designated in the Schedule of Events may be 
performed by a mobile nursing (MN) professional at the subject’s home or another suitable 
location, such as their school or office, to improve access and convenience for subjects 
participating in the study. The Sponsor may select a healthcare company that will be responsible 
for providing MN services for participating sites (the MN vendor). The MN vendor is responsible 
for ensuring that all MN professionals are licensed, qualified, and in good standing, as per 
applicable regulations, and that appropriate background checks have been performed. If the 
investigator at a participating site determines that MN services are appropriate for a subject and the 
subject gives written informed consent to participate in MN visits, the MN network will 
communicate with the subject and the subject’s site.  
Liver Biopsy Substudy Design 
All subjects enrolled in 270-201 and who are at least one year post-BMN 270 infusion are eligible 
for the optional liver biopsy substudy. Subjects who consent to participate in the substudy will 
have a liver biopsy via either the transjugular or percutaneous (ultrasound-guided) route, according 
to the standard procedures of the institution. Participation in the substudy may include liver 
biopsies at one or more time points. To enhance safety, all subjects will have an ultrasound 
examination of the liver within 3 months prior to the procedure (to ensure there are no pathological 
findings such as bile duct obstruction that might interfere with the safe performance of the liver 
biopsy) and a FibroScan of the liver within one week before the liver biopsy (to correlate with any 
potential histopathologic findings of fibrosis on the biopsy).  
Subjects who consent should have their FVIII levels monitored/adjusted by the Investigator to 
enable the procedure to be performed safely.  This may require the administration of exogenous 
FVIII replacement products in order to achieve the desired FVIII activity.  The target FVIII 
activity level within 24 hours prior to the liver biopsy is at the discretion of the Investigator and/or 
according to local guidelines, but at a minimum should be at the lower limit of the normal range 
(ie, at least 50 IU/dL). 
NUMBER OF SUBJECTS PLANNED:  
Up to 15 subjects may enroll into the study; the actual number of subjects will depend on the FVIII 
activity levels seen in each Cohort. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe haemophilia A as evidenced by 
their medical history.  Patients will be considered as severe if their base FVIII level is 
1 IU/dL or less 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
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2.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs)
3.
Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 
12 months 
6. Sexually active patients must be willing to use an acceptable method of contraception such 
as double barrier, including hormonal contraception for at least 6 months post-treatment.  
After 6 months, subjects may stop contraception use only if they have had 3 consecutive 
semen samples below the limit of detection of the test. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition or AAV5 total antibodies 
2. Any evidence of active infection or any immunosuppressive disorder.   
3. HIV positive 
4. Significant liver dysfunction as defined by abnormal elevation of: 
 
ALT (alanine transaminase) to 3 times the upper limit of normal; 
 
Bilirubin above 3 times the upper limit of normal; 
 
Alkaline phosphatase above 3 times the upper limit of normal; or 
 
 1.4 
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if they 
had significant fibrosis of 3 or 4 as rated on a scale of 0-4 
6. Evidence of any bleeding disorder not related to Haemophilia A 
7. Platelet count of < 100 x 109/L 
8. Creatinine  1.5 mg/dL 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
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9.
Liver cirrhosis of any etiology as assessed by liver ultrasound 
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive 
12. Treatment with any IP within 30 days prior to the end of the screening period 
13. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study including possible corticosteroid 
treatment outlined in the protocol.  The physician may exclude patients unwilling or 
unable to agree on not using alcohol for the 16-week period following the viral infusion. 
14. Prior treatment with any vector or gene transfer agent 
15. Major surgery planned in the 16-week period following the viral infusion 
16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral 
infusion 
Individuals eligible to participate in the liver biopsy substudy must meet all of the following 
criteria: 
1. Currently enrolled in 270-201 
2. Received BMN 270 infusion at least 1 year prior to enrollment in the substudy 
3. Able to sign informed consent and comply with requirements of the substudy 
4. FVIII activity at least >50 IU/dL (or higher, depending on local guidelines and/or 
Investigator discretion) within 24 hours prior to the liver biopsy being performed.  (FVIII 
levels should be assessed at the local laboratory.)  Subjects may be treated with additional 
exogenous FVIII replacement products in order to increase their FVIII levels to an 
appropriate level, under the supervision/instruction of the Investigator. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the liver biopsy substudy: 
1. Assessed by the investigator or a hepatologist as having a medical condition such that 
undergoing a liver biopsy would be contraindicated. These conditions could include (but 
are not limited to): 
 
Significant thrombocytopenia (platelet count < 100 x 109/L) 
 
Evidence of significant ascites 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
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Abnormalities detected on liver ultrasound (performed within 90 days of procedure) 
that would preclude safe performance of the biopsy. 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
The study is open label with comparison of FVIII activity to baseline values. No reference therapy 
will be evaluated in this study. 
DURATION OF TREATMENT: 
BMN 270 is given as a single dose by intravenous infusion. 
CRITERIA FOR EVALUATION: 
Safety: 
The following safety outcome measurements will be assessed: 
 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
 
Change in clinical laboratory tests (serum chemistry and haematology) 
 
Change in vital signs 
 
Change in physical examination  
 
Vector shedding 
 
Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, alkaline phosphatase) 
 
Immune response to FVIII transgene and AAV capsid proteins 
No major toxicity is expected based on preclinical studies in mice and monkeys. Each subject will 
have comprehensive surveillance monitoring of LTs (at local labs, once per week for Weeks 1-36, 
then once every 2 weeks from Week 37-52) during Year 1. LTs will be monitored every 4 weeks 
during Year 2, every 6 weeks for Years 3-5, and every 26 weeks for Years 6-7 post-dose in the 
safety extension; the frequency and duration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator and review of subject data. 
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Efficacy:  
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the 
study is to establish the dose relationship to FVIII a
 weeks post BMN 270 
administration. 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Subjects will be 
asked to keep a subject diary to record the details in these areas.   
Pharmacodynamics: 
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage 
clotting and/or chromogenic substrate assay (activity level), will be used for plasma profiles; FVIII 
activity will be used to determine PD parameters.  Traditional PK analysis is not applicable. 
If supported by the FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), 
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.   
Liver Biopsy Substudy: 
The following exploratory assessments will be performed as part of the optional liver biopsy 
substudy: 
 
Morphologic/pathogenic changes after FVIII gene transduction or any change that may be 
associated with sustained ALT rise  
 
Determine quantities of liver FVIII-SQ DNA/RNA 
 
Determine forms of vector DNA in liver at the time of biopsy 
 
Determine percentage of hepatocytes expressing FVIII protein  
 
Determine percentage of hepatocytes staining positive for vector DNA  
 
Determine hepatic liver transcriptome at single nuclei level if sufficient material is 
obtained 
 
Identify the forms of vector DNA in the liver  
 
Examination of potential stress inducing cellular pathways 
 
Other exploratory assessment to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer 
STATISTICAL METHODS:  
The sample size is based upon clinical considerations and could detect a strong clinical efficacy 
signal. Up to 15 subjects may be dosed in the study.  The subjects will be followed in a 
longitudinal manner and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature but data collected in a longitudinal manner may be analyzed using 
longitudinal methods such as mixed effect model which takes into account the correlation among 
the observation taken at various time points within a participant. Efficacy is a secondary endpoint, 
defined as biological
 5 IU/dL by chromogenic substrate assay and/or one-stage 
clotting assay at 16 weeks following study treatment. We can only assess the true steady state of 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
FVIII protein produced from BMN 270 after a minimum of 72 hours has elapsed since the last 
infusion of FVIII protein concentrates. 
Analysis of neutralizing antibody response and other immunological parameters as well as vector 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses. 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2
2
SYNOPSIS...........................................................................................................................4
3
TABLE OF CONTENTS ...................................................................................................16
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................21
5
ETHICS..............................................................................................................................23
5.1
Independent Ethics Committee .................................................................................23
5.2
Ethical Conduct of Study ..........................................................................................24
5.3
Subject Information and Informed Consent ..............................................................24
6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................26
7
INTRODUCTION .............................................................................................................27
7.1
Nonclinical Studies ...................................................................................................27
7.2
Previous and Ongoing Clinical Studies ....................................................................29
7.3
Study Rationale .........................................................................................................30
7.3.1
Liver Biopsy Substudy Rationale ................................................................32
7.4
Summary of Overall Risks and Benefits ...................................................................33
7.4.1
Optional Liver Biopsy Substudy Risks and Benefits ..................................35
8
STUDY OBJECTIVES ......................................................................................................36
9
INVESTIGATIONAL PLAN ............................................................................................37
9.1
Overall Study Design and Plan .................................................................................37
9.2
Discussion of Study Design, Including Choice of Control Group ............................54
9.3
Selection of Study Population ...................................................................................54
9.3.1
Inclusion Criteria .........................................................................................54
9.3.2
Exclusion Criteria ........................................................................................55
9.3.3
Liver Biopsy Substudy Inclusion and Exclusion Criteria ...........................56
9.3.4
Removal of Subjects from Treatment or Assessment .................................56
9.3.5
Subject Identification and Replacement of Subjects ...................................58
9.3.6
Duration of Subject Participation ................................................................58
9.4
Treatments .................................................................................................................58
9.4.1
Treatments Administered ............................................................................58

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9.4.2
Identity of Investigational Product ..............................................................59
9.4.3
Storage .........................................................................................................59
9.4.4
Directions for Administration .....................................................................59
9.4.5
Method of Assigning Subjects to Treatment Groups ..................................60
9.4.6
Selection of Doses Used in the Study .........................................................60
9.4.7
Blinding .......................................................................................................61
9.4.8
Prior and Concomitant Medications ............................................................61
9.4.9
Treatment Compliance ................................................................................65
9.5
Investigational Product Accountability .....................................................................66
9.5.1
Return and Disposition of Clinical Supplies ...............................................66
9.6
Dietary or Other Protocol Restrictions......................................................................66
9.7
Safety and Efficacy Variables ...................................................................................66
9.7.1
Safety and Efficacy Measurements Assessed .............................................67
9.7.2
Primary Efficacy Variables .........................................................................67
9.7.3
Secondary Efficacy Variables .....................................................................68
9.7.4
Immunogenicity ...........................................................................................68
9.7.5
Pharmacodynamics ......................................................................................68
9.7.6
Exploratory Assessments ............................................................................69
9.7.7
Haemo-QoL-A Quality of Life Assessment ................................................69
9.7.8
Liver Biopsy Substudy ................................................................................69
9.7.9
Safety Variables ..........................................................................................70
10 REPORTING ADVERSE EVENTS .................................................................................77
10.1 Safety Parameters and Definitions ............................................................................77
10.1.1 Adverse Events ............................................................................................77
10.2 Serious Adverse Events ............................................................................................77
10.2.1 Events of Special Interest (EOSI) ...............................................................78
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................78
10.3.1 Adverse Event Reporting Period .................................................................78
10.3.2 Eliciting Adverse Events .............................................................................79
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................79
10.4 Procedures for Recording Adverse Events ...............................................................82

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10.4.1 Recording Adverse Events on an eCRF ......................................................82
10.5 Reporting Requirements ...........................................................................................85
10.5.1 Expedited Reporting Requirements .............................................................85
10.5.2 Ethics Committee Reporting Requirements ................................................85
10.6 Follow-up of Subjects after Adverse Events .............................................................86
10.7 Post-Study Adverse Events .......................................................................................86
10.8 Urgent Safety Measures ............................................................................................86
10.9 BioMarin Pharmacovigilance Contact Information ..................................................87
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................88
12 STUDY PROCEDURES ...................................................................................................89
12.1 Prestudy .....................................................................................................................89
12.2 Screening Visit ..........................................................................................................89
12.2.1 “Smart Rescreening” Visit ..........................................................................90
12.3 Baseline Visit ............................................................................................................91
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................91
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................92
12.5.1 Once per week (Weeks 1 through 16) .........................................................92
12.5.2 Week 1 – Day 2 and Day 4 ..........................................................................93
12.5.3 Week 1 – Day 8 ...........................................................................................93
12.5.4 Every 2 Weeks .............................................................................................94
12.5.5 Weeks 4, 8, 12, and 16 ................................................................................94
12.5.6 Week 16 .......................................................................................................94
12.5.7 Weeks 8 and 16 ...........................................................................................94
12.5.8 Weeks 2, 3, 4, and 16 ..................................................................................95
12.5.9 Week 13 .......................................................................................................95
12.6 Safety Follow-Up – Weeks 17-36 .............................................................................95
12.6.1 Once per week (Weeks 17 through 36) .......................................................95
12.6.2 Once per week (Weeks 17 through 20) .......................................................96
12.6.3 Every 2 weeks (Weeks 21 through 36) .......................................................96
12.6.4 Every 4 Weeks .............................................................................................96
12.6.5 Every 8 Weeks .............................................................................................96

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12.6.6 Week 26 .......................................................................................................96
12.6.7 Week 28 .......................................................................................................97
12.7 Safety Follow-Up – Weeks 37-52 .............................................................................97
12.7.1 Once per visit ...............................................................................................97
12.7.2 Every 4 Weeks .............................................................................................98
12.7.3 Every 8 Weeks .............................................................................................98
12.7.4 Week 38 and 52 ...........................................................................................98
12.7.5 Week 52 .......................................................................................................98
12.8 Safety Follow-Up – Years 2-5 ..................................................................................99
12.8.1 Year 2 – Every 4 Weeks (not required for treatment failure) .....................99
12.8.2 Years 3-5 – Every 6 Weeks (not required for treatment failure) ...............100
12.8.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)................................................................................................101
12.9 Safety Follow-Up – Years 6-7 ................................................................................103
12.9.1 Years 6-7 – Every 13 Weeks .....................................................................103
12.9.2 Years 6-7 – Every 26 Weeks and End of Year Visits ...............................104
12.10Liver Biopsy Substudy - Years 1-7 ........................................................................105
12.11Early Termination Visit ..........................................................................................106
12.12End of Study ...........................................................................................................108
13 DATA QUALITY ASSURANCE ...................................................................................109
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................110
14.1 Statistical and Analytical Plans ...............................................................................110
14.1.1 Interim Analyses ........................................................................................110
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........110
14.2 Primary and Secondary Efficacy Analysis..............................................................110
14.3 Liver Biopsy Substudy Analysis .............................................................................110
14.4 Immunogenicity ......................................................................................................110
14.5 Pharmacodynamic Analyses ...................................................................................111
14.6 Safety Analysis .......................................................................................................111
14.7 Determination of Sample Size ................................................................................111
14.8 Analysis Populations ...............................................................................................111

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14.9 Changes in the Conduct of the Study or Planned Analyses ....................................112
15 DATA REVIEW BOARD ...............................................................................................113
16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................114
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................115
18 STUDY MONITORING AND AUDITING ...................................................................117
19 RETENTION OF RECORDS .........................................................................................118
20 USE OF INFORMATION AND PUBLICATION .........................................................119
21 REFERENCES ................................................................................................................120
22 INVESTIGATOR RESPONSIBILITIES ........................................................................123
22.1 Conduct of Study and Protection of Human Patients .............................................123
23 SIGNATURE PAGE .......................................................................................................124
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................125
LIST OF TABLES 
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................41
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) ............................43
Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) .....................................45
Table 9.1.4:  Schedule of Events – Safety Follow-Up (Week 33-52) .....................................47
Table 9.1.5:  Schedule of Events – Safety Follow-Up (Years 2-7) .........................................49
Table 9.1.6:  Schedule of Events – Reactive Corticosteroids for LT Elevations .....................52
Table 9.1.7:  Schedule of Events – Liver Biopsy Substudy.....................................................53
Table 9.4.8.2.1.1:  Management of ALT Elevations with Reactive Corticosteroids ...............64
Table 9.4.8.2.1.2:  Viral and Autoimmune Hepatitis Testing ..................................................65
Table 9.7.9.2.1:  Clinical Laboratory Tests .............................................................................72
Table 9.7.9.3.1:  Liver Tests ....................................................................................................74
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................80
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................81
LIST OF FIGURES 
Figure 7.3.1:  hFVIII-SQ Vector Genome and Encoded Protein .............................................32
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3...............................38 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations 
AAV 
adeno-associated virus 
ADL 
activities of daily living 
ADR
adverse drug reaction
AE 
adverse event 
ALT 
alanine transaminase 
APTT
activated partial thromboplastin time
AST 
aspartate aminotransferase 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DRB 
Data Review Board 
eCRF 
electronic case report form 
ED 
exposure days 
EOSI 
events of special interest 
ETV
early termination visit
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FIH
first-in-human
FVIII 
coagulation factor VIII 
FXa 
coagulation factor Xa 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HA 
Haemophilia A 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 

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ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6
IEC
independent ethics committee
IND 
Investigational New Drug (application) 
INR
international normalized ratio
IP
investigational product
IV 
intravenous 
LT
liver test
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL 
no-observed-adverse-effect level 
PBMC
peripheral blood mononuclear cells
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
ULN 
upper limit of normal 
vg 
vector genomes 
VWF:Ag 
von Willebrand factor Antigen 
Definition of Terms: 
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol.

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5
ETHICS
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1
Independent Ethics Committee
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
independent ethics committee (IEC) is properly constituted and compliant with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IEC will be 
provided to BioMarin or its designee. The Investigator will provide the IEC with all 
appropriate material, including the protocol, Investigator’s Brochure (IB), the Informed 
Consent Form (ICF) including compensation procedures, and any other written information 
provided to the subjects, including all ICFs translated to a language other than the native 
language of the clinical site. The study will not be initiated and Investigational Product (IP) 
supplies will not be shipped to the site until appropriate documents from the IEC confirming 
unconditional approval of the protocol, the ICF and all subject recruitment materials are 
obtained in writing by the Investigator and copies are received at BioMarin or its designee. 
The approval document should refer to the study by protocol title and BioMarin protocol 
number (if possible), identify the documents reviewed, and include the date of the review and 
approval. BioMarin will ensure that the appropriate reports on the progress of the study are 
made to the IEC and BioMarin by the Investigator in accordance with applicable guidance 
documents and governmental regulations. 

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5.2 
Ethical Conduct of Study
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability. 
This study will be conducted in accordance with the following: 
 European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
 US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable
 ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6)
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IEC and will be conducted by scientifically and medically qualified persons. The benefits of 
the study are in proportion to the risks. The rights and welfare of the subjects will be 
respected and the investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each subject will provide written informed consent before any 
study-related tests or evaluations are performed, as well as when updates to the ICF are 
made. Where it is not feasible for the Investigator to receive the signed, written ICF from the 
subject prior to beginning new or changed study-related procedures contained in such an ICF 
update (for example, due to COVID-19-related restrictions), the Investigator will ask the 
subject to verbally confirm during an informed consent interview that the subject has signed 
and dated the ICF. The Investigator should document this verbal confirmation on the 
Investigator's copy of the ICF and, when it is possible to do so, receive the informed consent 
signed by the subject and archive the original(s) in the record file of the subject. 
5.3 
Subject Information and Informed Consent
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IEC approval. BioMarin and the IEC must approve the documents 
before they are implemented. A copy of the approved ICF, and if applicable, a copy of the 

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approved subject information sheet and all ICFs translated to a language other than the native 
language of the clinical site must also be received by BioMarin or designee prior to any 
study-specific procedures being performed. 
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject. 

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INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of subjects in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 
Liver tests (LTs) will be performed at the local laboratories associated with the study sites.  
Local laboratory results of LTs will be used to trigger corticosteroid treatment as needed 
(refer to Section 9.4.8.2).  In case of discrepant results between local and central laboratories, 
the Investigator and Medical Monitor will decide further action.  Safety labs evaluations 
(including LTs) will be performed at the central lab, while bioanalytical samples will be 
performed at the appropriate specialty lab.  Refer to the Laboratory Manual for more details. 

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7
INTRODUCTION 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Iorio 2019). It is caused by mutations in the factor VIII (FVIII) gene that 
codes for FVIII protein, an essential cofactor in the coagulation cascade. Clinical 
manifestations of severe FVIII deficiency are frequent unprovoked bleeding episodes in 
joints and soft tissues causing permanent disability and occasionally death mostly after brain 
haemorrhage. Treatment in Western (Berntorp 2012) countries consists of intravenous 
injection of plasma derived or recombinant FVIII protein concentrates at the time of a bleed,
or prophylactically, to prevent bleeding episodes. The short half-life for FVIII (~8-12 hours) 
necessitates frequent infusions and makes this treatment prohibitively expensive for the 
majority of the world’s haemophilia A patients. These individuals develop debilitating 
arthropathy and have a substantially increased risk of death from haemorrhage in life 
(Stonebraker 2010). Chemical modification or bioengineering of FVIII may improve half-life 
to 18-19 hours (Kaufman 2013). However, these long acting FVIII variants do not eliminate 
the need for lifelong FVIII protein administration (Hay 2012).  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of human FVIII following a single administration of vector. Haemophilia A is 
well suited for this approach because its clinical manifestations are attributable to the lack of 
a single gene product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. 
Tightly regulated control of gene expression is not essential and a modest increase in the 
level of FVIII (a plasma level of 2 ng/ml protein leads to a 1% expression) can ameliorate the 
severe phenotype (Srivastava 2020); thus the therapeutic goal for gene therapy is a modest 
increase in hFVIII. Finally, the consequences of gene transfer can be assessed using simple 
quantitative rather than qualitative endpoints that can be easily assayed in most clinical 
laboratories. 
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 
7.1 
Nonclinical Studies 
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 
nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 

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pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints. 
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in FVIII KO x Rag2 mice given matched IU 
levels of Refacto®.   
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.   
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed. 
The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 
the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 

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toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence closely matching that of 
the protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Nathwani 2006). Despite distribution 
to non-liver organs, no expression of Factor IX was detected in these tissues.  Additionally, 
distribution to the testis was observed in another study in monkeys given an 
AAV5-codon-optimized human porphobilinogen deaminase; however, vector genomes in the 
semen were only transiently observed within one week but not thereafter (Paneda 2013).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents 10-fold safety factor from the 
no observed adverse effect level (NOAEL) in the GLP enabling nonclinical toxicology study 
in mice.  
7.2 
Previous and Ongoing Clinical Studies 
This is the first clinical study for BMN 270. 
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno 2003) and an AAV8 vector (Nathwani 2011; Nathwani 2014). The large size 
of the FVIII cDNA was shortened and a preclinical validation of this approach was 
performed with an AAV8 vector (McIntosh 2013). 
AAV serotype 5 is being tested in other clinical trials and was reportedly well tolerated 
without treatment-related serious adverse events in a recent phase 1 study for treatment of 
Acute Intermittent Porphyria (D'Avola 2014). In addition, AAV using other serotypes have 
been used in 105 clinical studies to date and no safety issue specific to the vector was ever 
reported.   

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Ongoing clinical studies for BMN 270 include: 
270-203, a phase 2 study in patients with severe HA who have anti-AAV5 antibody 
titers
270-205, a phase 1/2 study in patients with severe HA who have active or prior FVIII 
inhibitors 
270-301, the pivotal phase 3 study in patients with severe HA who receive BMN 270 
at the 6E13 vg/kg dose level 
 270-302, a phase 3 study in patients with severe HA who receive BMN 270 at the 
4E13 vg/kg dose level 
 270-303, a phase 3 study in patients with severe HA who received BMN 270 at the 
6E13 vg/kg dose level along with prophylactic corticosteroids 
A comprehensive review of safety, efficacy, and immunogenicity results as of the latest data 
cut is contained in the IB supplied by BioMarin. Investigators are to review this document 
prior to initiating this study. 
7.3 
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Iorio 2019).  It is caused by deficiency in the activity of coagulation factor 
VIII (FVIII), an essential cofactor in the intrinsic coagulation cascade. This disorder can be 
either inherited, due to a new mutation or an acquired immunologic process, leading to 
insufficient quantities of FVIII or a dysfunctional FVIII, but all are characterized by a 
defective coagulation process. The clinical phenotype of HA patients is largely governed by 
the level of residual expression. Severe HA is classified as FVIII activity less than 1% of 
wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild type activity and the mild 
form is 5-40% activity. The clinical manifestations of severe HA remain frequent 
spontaneous bleeding episodes, predominantly in joints and soft tissues, with a substantially 
increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-4 times per 
week, and at the time of a bleed, to prevent or control bleeding episodes, respectively. The 
half-life for FVIII (12-18 hours for most approved products) necessitates frequent infusions, 
and although a major advance in the treatment of HA, it remains common for severe HA 
patients to continue to have multiple bleeding events on treatment (mean of 
1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year for on demand 
treatment) (Nagel 2011). The consequence of multiple bleeding events is the development of 
an underlying pathology that contributes to debilitating multiple-joint arthropathy and 

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substantially increased risk of death (Nagel, 2011, Haemophilia).  Chemical modification 
(eg, direct conjugation of polyethylene glycol (PEG) polymers) and bioengineering of 
FVIII (eg, FVIII-Fc fusion proteins) improve half-life by approximately 50%, and thus, show 
promise in reduced dosing and maintaining activity levels above 1% trough 
(Stonebraker 2010; Mahlangu 2014). However, these longer acting FVIIIs remain dependent 
on multiple infusions to maintain critical levels of FVIII activity in severe HA patients. There 
is therefore a strong unmet need for a fully preventive treatment of HA to give patients a 
FVIII level compatible with a normal and haemorrhage-free life. 
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Mannucci 2001). 
They have an excellent and well defined safety profile, and can direct long term transgene 
expression with tropism for specific tissues such as the liver (Nathwani 2005) for serotypes 
2, 5 and 8 among others.  Indeed, an on-going gene therapy clinical trial for a related 
disorder, haemophilia B, has established that stable (>36 months) expression of human factor 
IX at levels that are sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild is achievable following a single peripheral vein administration of AAV-8 
vector (Nathwani 2014).  Several participants in this trial have been able to discontinue factor 
prophylaxis without suffering spontaneous haemorrhages, even when they undertook 
activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life (Nathwani 2014). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a liver-selective promoter (Figure 7.3.1).  

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Figure 7.3.1:  hFVIII-SQ Vector Genome and Encoded Protein
Legend –Note that schematic is not to scale; aa = amino acids; ITR = inverted terminal repeat; HLP = human 
liver promoter; Kozak = Kozak concensus sequence (GCCACC); SpA = Synthetic poly(A) signal
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active FVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study 270-201 is a first-in-human study designed 
to assess the relationship of vector dose to the augmentation of residual FVIII activity, and 
whether these levels are sufficient to alter the clinical phenotype. The relationship of dose to 
safety will be correlated to the activity of FVIII in patients with severe HA.
7.3.1
Liver Biopsy Substudy Rationale 
The pattern of response in hFVIII activity observed so far after administration of BMN 270 
demonstrates peak expression levels during the first 6-12 months post-treatment followed by 
a decline to a steady-state level of expression in the second year of follow-up, with mean 
hFVIII activity levels remaining above the lower limit of normal (50 IU/dL).  One of the 
explanations may lie in the kinetics of vector genome processing which involves a series of 
steps such as DNA degradation and repair, annealing, and circularization that can result in 
the formation of stable double-stranded circularized transgene DNA forms. It is these 
circularized DNA species that are thought to be associated with long-term, persistent 
expression of the gene product in target cells.  Examination of transduced hepatocytes from 
subjects treated with BMN 270 in the 270-201 study will help to establish whether DNA 
circularization may occur and could account for the long-term hFVIII expression observed in 
humans. 
Additionally, health of the liver after gene transduction has been monitored indirectly by 
periodic assessments of hepatic enzymes released into the blood stream.  Transient 
post-treatment elevations in ALT levels have been observed in some subjects, as well as 

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inter-subject variability in post-therapy hFVIII levels. Neither the reasons for, nor the 
significance of, the ALT elevations or the variations in response to FVIII gene therapy are 
known.  Moreover, the effects of BMN 270 on hepatic tissue structure and function are also 
currently unknown. Finally, a call to incorporate liver biopsy substudies into gene therapy 
trials for hemophilia has been issued by medical and scientific leaders in the field to help 
illuminate these and other questions (National Hemophilia Foundation 2019).  
The purpose of this exploratory substudy is to provide a better understanding of the 
long-term gene expression related to genome circularization, health of the liver, and variation 
in hFVIII levels observed after gene therapy with BMN 270.  Whilst consenting subjects may 
not derive any direct benefit themselves by participating in the substudy, the overall findings 
could aid future patients by helping to characterize the means by which long-term efficacy is 
achieved and the safety of liver-directed gene therapy.  
7.4 
Summary of Overall Risks and Benefits 
BMN 270 has an acceptable safety and tolerability profile that supports a positive 
benefit-risk assessment. Single infusions have been generally well tolerated by treated 
subjects across all investigated doses. All subjects have successfully completed their 
full-dose infusion of BMN 270, with no infusions requiring permanent termination prior to 
completion due to AEs. No deaths have been reported in any of the BMN 270 studies, and no 
participants discontinued from studies as a result of an AE. Frequency of adverse events 
decreased over time with no delayed adverse drug reactions.
Infusion reactions associated with BMN 270 administration included symptoms such as 
maculopapular rash, urticaria, nausea, diarrhea, watery eyes, rigors, chills, myalgia, fever, 
tachycardia and hypotension emerging within 24 hours of receiving BMN 270. All of these 
events subsided without clinical sequela within 48 hours following medical management 
Infusion-related reactions were effectively mitigated by managing infusion rate and 
medications. 
Transient, asymptomatic ALT elevation (grade 1 to 3 in severity) was observed in most 
subjects administered BMN 270 shortly after dosing, with no symptoms or sequelae 
suggestive of clinically significant hepatocyte injury or liver dysfunction. Across the 
6E13 vg/kg cohort of 270-201 and 270-301, subjects enrolled in 270-201 developed ALT 
elevation about 5.5 weeks later than subjects in 270-301, generally once the first course of 
corticosteroids was being tapered, and experienced lower peak elevations in ALT (75.7 U/L) 
than subjects in 270-301 (112.5 U/L). The difference in the ALT profile seen between the 
6E13 vg/kg subjects in 270-201 and the subjects in 270-301 could be attributed to the 
difference in the protocol-specified corticosteroid regimens in place in those studies, 

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including the early use of corticosteroids (ie, by Week 3 post-BMN 270 infusion). While the 
majority of ALT elevations responded rapidly to corticosteroids, given current interest in the 
field of AAV gene therapy for the use of non-steroidal approaches to managing or preventing 
ALT elevations, alternate non-steroidal systemic immunosuppressive agents have also been 
used to manage hepatic reactions where corticosteroids have proven to be ineffective or 
where high doses/and or prolonged exposure to corticosteroids have led to unwanted side 
effects. Overall, the literature and clinical experience with BMN 270 suggests that transient 
elevations in liver enzymes are expected following AAV-based gene therapy for the 
treatment for hemophilia A or B without any long-term concerns of hepatic injury 
(Manno 2006; Nathwani 2011; George 2016; Miesbach 2016; Pasi 2020). 
At the highest dose tested in 270-201 (6E13 vg/kg), the majority of subjects achieved FVIII 
levels above 50 IU/dL at 52 weeks post-infusion.  Subjects in that cohort also reported 
markedly decreased bleeding compared with pre-study rates and the ability to discontinue 
prophylactic FVIII infusions. Subjects at all dose levels continue to be followed.  
In 270-301, an interim analysis has shown increased FVIII activity in the majority of subjects 
to mild HA or normal levels at 26 weeks post-infusion, also with markedly decreased 
bleeding compared with pre-study rates and the ability to discontinue prophylactic FVIII 
infusions. All subjects who were included in the 1-year analysis have been dosed with 
6E13 vg/kg and continue to be followed. 
The current data available has shown an established positive benefit-risk profile for 
BMN 270 at the 6E13 vg/kg dosing level. Given the monitoring measures in place in the 
clinical protocol(s) to minimize the risk to subjects participating in the existing studies, the 
identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-301 will have a comprehensive surveillance plan that monitors LTs 
during the study, and elevations in LTs will be addressed according to the guidelines set forth 
in the protocol. Safety will be assessed by adverse event reporting and clinical laboratory 
assessments.
For additional information on safety findings from clinical studies, refer to current version of 
the Investigator’s Brochure. 
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose 
that maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the 
possibility of a sub-therapeutic effect. With this consideration in mind, the starting dose 
6E12 vg/kg was selected using overall data from the pre-clinical studies conducted in mice 
(normal and disease model, Rag2 -/- x FVIII -/-) and monkey. A detectable pharmacological 
response based on activity was observed at 6E12 vg/kg. A 10-fold safety margin based upon 

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the NOAEL was observed in the GLP 13-week study in normal mouse at the highest dose 
administered. A 30-fold safety margin in an 8-week dose response study in disease model 
mice based on histology was observed at the highest dose administered. No BMN 270-related 
changes in clinical observations or chemistry was observed in the monkey at doses up to 
6E13 vg/kg, a 10-fold safety margin after 8-weeks. Overall, no BMN 270-related findings, 
except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model 
mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to subjects with the best chance of 
benefiting the subject therapeutically. 
7.4.1 Optional Liver Biopsy Substudy Risks and Benefits 
Liver biopsy is considered a safe procedure, with serious complications occurring less than 
once in every 10,000 procedures (Grant 2004). Although the theoretical risks of significant 
complications are extremely small, the main complications would include bleeding and bile 
leakage. Another theoretical complication is infection at the needle insertion site; the sterile 
technique used makes this risk extremely small.  
The most common problems include mild pain and a minor decrease in blood pressure. More 
serious complications, such as bleeding, infection, and injury to nearby organs, are very rare, 
but the subject will be monitored appropriately to ensure correct management should any of 
these occur. Any complications related to the liver biopsy should be reported as adverse 
events, as outlined in Section 10. The liver biopsy is a standard investigation, and will be 
explained more fully by the experienced clinician performing the biopsy.  
Each subject who participates in this optional substudy will have a comprehensive 
pre-/post-biopsy surveillance plan according to the standard procedures at the institution. 
Safety will be assessed by adverse event reporting and clinical laboratory assessments. Per 
the Investigator's discretion and/or according to local guidelines, the subject may be kept in 
overnight following the liver biopsy for additional safety monitoring; such an overnight stay 
would not be considered a hospitalization for serious adverse event (SAE) reporting purposes 
(refer to Section 10.4.1.7).  
There is no direct benefit from participating in this study other than contributing to 
understanding the mechanism of action of BMN 270. Consenting into this specific substudy 
is optional and will not have any effect on the subject’s continued participation in 270-201. 

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8
STUDY OBJECTIVES 
The primary objectives of the study are: 
 To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
 To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII 
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270
dose. 
The secondary objectives of the study are: 
 To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of AAV5-hFVIII-SQ
 To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study 
 To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study 
The exploratory objectives of the liver biopsy substudy are: 
 To examine the histopathology of the liver following BMN 270 therapy, including 
assessing for possible safety findings (eg, fibrosis, fatty liver disease, lymphocytic 
invasion) 
 To quantify FVIII DNA, RNA, and protein expression within hepatocytes 
 To determine which forms of rAAV genomic DNA (eg, concatemers) are present at 
the time of biopsy 
 To determine the transduction pattern in humans (ie, peri-portal hepatocytes, central 
vein hepatocytes) 

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9
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 7 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled into one of up to four cohorts according to dose level:  
 Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv) 
 Cohort 2:  2E13 vg per kilogram, iv 
 Cohort 3:  6E13 vg per kilogram, iv 
 Cohort 4:  4E13 vg per kilogram, iv 
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys.  The starting dose has a 10-fold safety margin from no 
observed adverse effect level (NOAEL) in mice.  
Cohorts 1-3  
The first three cohorts will be enrolled sequentially, allowing a period of 3 weeks or more 
between cohorts. Dose escalation may occur after a single subject in a cohort has been safely 
dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both assays. 
Three weeks is expected to be the time the expression will be close to the maximum.  
This escalation paradigm is intended to minimize the subject numbers exposed to 
subtherapeutic doses.  The decision to escalate to the next dose level will be made based on 
the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study.  
If the 
IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects. 

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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3 
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1) 
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in 
 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.  
If the FVIII activity level in the first subject treated in Co
 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
 IU/dL and no safety issue is found, then up to four subjects will be enrolled in the Cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals. 
Cohort 4   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the Data Review Board (DRB).  The adaptive nature of this trial allows the DRB 

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to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals. 
As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not 
respond to BMN 270 treatment (ie, treatment failure, manifesting as failure to achieve FVIII 
activity 
by Week 52 and inability to maintain independence from prophylactic 
FVIII replacement therapy due to joint bleeding episodes, in the judgment of the 
Investigator) may, at the Investigator’s discretion and after discussion with the Medical 
Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the 
discretion of the Investigator.  
At applicable sites, certain study assessments designated in the Schedule of Events may be 
performed by a mobile nursing (MN) professional at the subject’s home or another suitable 
location, such as their school or office, to improve access and convenience for subjects 
participating in the study. The Sponsor may select a healthcare company that will be 
responsible for providing MN services for participating sites (the MN vendor). The MN 
vendor is responsible for ensuring that all MN professionals are licensed, qualified, and in 
good standing, as per applicable regulations, and that appropriate background checks have 
been performed. If the investigator at a participating site determines that MN services are 
appropriate for a subject and the subject gives written informed consent to participate in MN 
visits, the MN network will communicate with the subject and the subject’s site.  
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity 
for therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 7 years after dosing. Any safety signal 
may trigger a review of the data and possible additional immunogenicity studies that include 
an assessment of cellular immune responses using collected PBMC. Additionally, if any of 
the events listed in Section 9.3.4.1 occur, enrollment into the trial will be halted to complete 
an extensive safety analysis. Notification of the study enrollment halt will be sent by the 
Sponsor to the participating sites via telephone and email immediately after becoming aware 
of a safety concern. This will ensure no additional subjects are dosed until the signal has been 
completely evaluated. If, following safety review by the DRB and the Sponsor, it is deemed 

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appropriate to restart dosing, a request to restart dosing with pertinent data will be submitted 
to the health authority. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3, Table 9.1.4, and Table 9.1.5 for Safety Follow-up. 
Table 9.1.6, dealing with reactive corticosteroid use in the event of elevated LTs, is discussed 
in Section 9.4.8.2. 
Liver Biopsy Substudy Design 
All subjects enrolled in 270-201 and who are at least one year post-BMN 270 infusion are 
eligible for the optional liver biopsy substudy. Subjects who consent to participate in the 
substudy will have a liver biopsy via either the transjugular or percutaneous 
(ultrasound-guided) route, according to the standard procedures of the institution. To enhance 
safety, all subjects will have an ultrasound examination of the liver within 3 months prior to 
the procedure (to ensure there are no pathological findings such as bile duct obstruction that 
might interfere with the safe performance of the liver biopsy) and a FibroScan of the liver 
within one week before the liver biopsy (to correlate with any potential histopathologic 
findings of fibrosis on the biopsy).  
Subjects who consent should have their FVIII levels monitored/adjusted by the Investigator 
to enable the procedure to be performed safely.  This may require the administration of 
exogenous FVIII replacement products in order to achieve the desired FVIII activity.  
The target FVIII activity level within 24 hours prior to the liver biopsy is at the discretion of 
the Investigator and/or according to local guidelines, but at a minimum should be at the lower 
limit of the normal range (ie, at least 50 IU/dL).
Table 9.1.7 presents the schedule of assessments for participation in the liver biopsy 
substudy. 
 

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Table 9.1.1: Schedule of Events – Screening and Infusion 
Assessment 
Prior to BMN 270 Infusion
BMN 270 
Infusion 
Visit (Day 1)k
Screeningi 
(Day -28 to Day -1) 
Smart Rescreeningi  
(Day -28 to Day -1) 
Baseline (Day -7 
to Day -1)h
Informed consent 
X 
 
 
 
Medical History 
X 
 
 
 
Physical Examinationa 
X
X
X
Height and Weighta
X
Vital Signs 
X 
X
 
X
Assessment of Adverse Events and Concomitant Medications
X
X
X
X
Documentation of bleeding episodes and FVIII usage (by either subject or 
clinical information)
X
X
X
Distribution of subject diaries and training in their use
X
Electrocardiogram 
X 
 
 
 
Chest X-ray
X
Liver Ultrasound
X
hFVIII Assaysb
X 
Xj 
 
 
AAV5 Assaysc
X
X
X
Screen for Hepatitis B, Hepatitis C, HIVd
X
Blood chemistry, haematology, coagulation screen, and CRPe
X
X
X
Urine Testse
X
X
X
Liver Testse
X
X
X
PBMC collection for CTL baseline
X
Von Willebrand Factor Antigen (VWF:Ag)
X
Direct Thrombin Test
X
PCR of vector DNA in blood, saliva, urine, semen, and stools
X
Biomarker testingf
X
Exploratory biomarker assessmentsg
X
Haemo-QoL-A Quality of Life (QoL) assessment
X
BMN 270 Infusion
X

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a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height will be 
recorded at Screening only.  Weight will be recorded at Screening and then every 6 months thereafter. 
b Includes baseline hFVIII activity (chromogenic substrate assay and one-stage clotting assay), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level 
(Bethesda assay with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).   
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction 
inhibition, in vitro transduction inhibition and AAV5 total antibody assays).  Sample collection on the day of the infusion visit must be performed before the BMN 270 
infusion is given. 
d Patients with documented negative results within the last 30 days do not need to be retested.
e Refer to Table 9.7.9.2.1 for laboratory assessments to be included, and to Table 9.7.9.3.1 for liver tests. 
f Includes HLA genotyping, FVIII genotyping, TNF
and IL10a single nucleotide polymorphisms.
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for Direct Thrombin Activity test and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
h Should the screening visit occur within 7 days of the drug infusion, physical examination, blood chemistry, LTs, haematology, urine tests, coagulation screen, and CRP 
do not need to be repeated at Baseline. 
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion 
prior to the closing of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion 
within 90 days of signing the original consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures. 
Subjects may not undergo smart rescreening more than once. 
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening.
k Assessments on the day of infusion must be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, 
during the infusion every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 
4 hour intervals (± 15 minutes). 

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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) 
Assessment
Follow-Up After BMN 270 Administration – Weeks* 
Week 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
D2
D4
D8
Physical examinationa 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary 
for bleeding and FVIII use) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation 
screen, and CRPb     
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Urine Testsb 
X 
X 
X 
X 
Liver Tests (local)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Tests (central)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer
X 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolse
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
X 
X 
X 
X 
AAV5 antibody titer
X 
X 
Testing for reactivation of hepatitis B and 
hepatitis C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg
PBMC collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
Direct Thrombin test
X 
X 
* Visit windows are ± 48 hours (and include the Day 4 visit)

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a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.9.5. 
b Refer to Table 9.7.9.2.1 for laboratory assessments to be included, and to Table 9.7.9.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular 
when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least 
 1.5 ULN during the study may undergo additional evaluations (eg, imaging 
studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any 
study week may be performed if: (1) the ALT has increased to above ULN; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII 
activity level; or after a discussion between the Medical Monitor and the Investigator based on a review of subject data.  If FVIII levels and/or ALT values are stable 
over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting assay and chromogenic substrate assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects 
who have a
 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are 
elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. 
A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.   
d Includes hFVIII activity level (one-stage clotting assay and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, 
hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be 
made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have 
eeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or 
stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer 
may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.   
e Collection to occur on Day 2 and 4 following BMN 270 infusion, and then until at least 3 consecutive negative results are obtained.  Collection and testing of semen 
samples must continue through Week 12, even if 3 consecutive negative samples in that compartment have already been recorded. 
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for Direct Thrombin Activity test and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
g Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of Hepatitis B or Hepatitis C prior to study entry, should be 
performed only in subjects who have not received reactive corticosteroids prior to Week 16; subjects who have received reactive corticosteroids will have hepatitis B and 
hepatitis C testing at the time points indicated in Table 9.1.6. 

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Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) 
Assessment
Follow-Up After BMN 270 Administration – Weeks*
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary for 
bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, 
and CRPb     
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urine Testsb 
X 
X 
X 
X 
Liver Tests (local)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Tests (central)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, 
and stoolse
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
AAV5 antibody titer
X 
X 
X 
X 
PBMC collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
Direct Thrombin test
X 
* Visit windows are ± 48 hours
a Brief physical examination should be done at all weekly visits.  Refer to Section 9.7.9.5.

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b Refer to Table 9.7.9.2.1 for laboratory assessments to be included, and to Table 9.7.9.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular 
when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least 
rgo additional evaluations (eg, imaging 
studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any 
study week may be performed if: (1) the ALT has increased to above ULN; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII 
activity level; or after a discussion between the Medical Monitor and the Investigator based on a review of subject data.  If FVIII levels and/or ALT values are stable 
over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay). If a subject has used FVIII within 72 hours of a measurement day, all efforts should 
be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who 
have achieved 
 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated 
or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A 
d-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.   
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII 
coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved 
L at 16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over 
the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be 
considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.   
e Collection for each matrix to occur until at least 3 consecutive negative results are obtained.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for Direct Thrombin Activity test and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 

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Table 9.1.4:  Schedule of Events – Safety Follow-Up (Week 33-52) 
Assessment
Year 1 – Weeks* 
33
34
35
36
38
40
42
44
46
48
50
52
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta 
 
 
 
 
 
 
 
 
 
 
 
X 
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, and CRPb
X 
X 
X 
X 
X 
Urine Testsb 
X 
X 
X 
X 
X 
Liver Tests (local)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Tests (central)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AAV5 antibody titer
X 
X 
X 
X 
X 
FVIII antibody titer 
 
 
 
X 
 
 
X 
 
 
 
X 
PBMC Collection (for determination of FVIII and Capsid specific CTL 
activity) 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
X 
Direct Thrombin Test
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and stoolse
X 
X 
X 
X 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52.
a Complete physical examination should be performed at Week 52; brief physical examination may be performed at other study visits.  Refer to Section 9.7.9.5.
b Refer to Table 9.7.9.2.1 for laboratory assessments to be included, and to Table 9.7.9.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular 
when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least 

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twice weekly during periods wh
studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any 
study week may be performed if: (1) the ALT has increased to above ULN or increased by > 10 U/L from prior assessment; (2) Increases in ALT values from prior 
assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the Investigator based on a review of subject 
data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion 
between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay). If a subject has used FVIII within 72 hours of a measurement day, all efforts should 
be made to obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who 
 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated 
or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A 
d-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.   
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII 
coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved 
 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over 
the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be 
considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for Direct Thrombin Activity test and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 

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Table 9.1.5:  Schedule of Events – Safety Follow-Up (Years 2-7) 
Assessment 
Years 
2-5* 
Year 
2* 
Years 
3-5* 
Years 6-7 
End of Year Visits
ETV
Q12W 
Q4Wh 
Q6Wh,j 
Q13W 
(Remote)i 
Q26W 
Year 
2
Year 
3
Year 
4
Year 
5
Year 
6
Year 
7
W104 
W156
W208
W260
W312
W364 
Physical examinationa
Xa
Xa
X 
X 
X 
Weighta 
Xa 
 
 
 
 
Xa
X 
X 
X 
Assessment of Adverse Events and Concomitant 
Medications (including review of subject diary for 
bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, 
and CRPb 
X 
 
 
 
X 
X 
X 
X 
X 
Urine Testsb 
X 
X 
X 
Liver Tests (local)b 
X 
X 
X 
X 
X 
FVIII assays (local)c 
X 
X 
X 
X 
X 
Liver Tests (central)b 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X 
X 
X 
X 
X 
X 
X 
X 
FVIII Antigen assay
X 
X 
X 
X 
X 
X 
AAV5 antibody titer
X 
X 
X 
X 
FVIII antibody titer
X 
X 
X 
X 
PBMC Collection (for determination of FVIII and 
Capsid specific CTL activity) 
X 
 
 
 
 
X 
 
 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
PCR of vector DNA in semene
Xe
Xe
Xe
Xe
Xe
Xe
Xe
X 
PRC of vector DNA in blood, saliva, urine, stoolse 
Xe
Xe
Xe
Xe
Xe
X 
Exploratory biomarker assessmentsg
X 
X 
X 
X 
X 

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Assessment
Years 
2-5* 
Year 
2* 
Years 
3-5* 
Years 6-7 
End of Year Visits
ETV
Q12W 
Q4Wh 
Q6Wh,j 
Q13W 
(Remote)i 
Q26W
Year 
2
Year 
3
Year 
4
Year 
5
Year 
6
Year 
7
W104
W156
W208
W260
W312
W364
Haemo-QoL-A QoL assessment
Xf 
Xf
Xf
Xf 
Xf 
X 
Liver ultrasoundk 
 
 
 
 
Xk (Year 5 only) 
Xk
Xk
X 
ETV: Early Termination Visit 
* Visit windows are ± 2 weeks for visits in Years 2-5 and ± 4 weeks for visits in Years 6-7. The Q6W visits during Years 3-5 should restart after each End of Year visit 
(eg, the first Q6W visit during Year 3 should be ~6 weeks after the End of Year 2 visit). 
a Complete physical examination should be performed at the End of Year visits (genitourinary examination may be deferred unless the subject has genitourinary-related 
complaints); brief physical examination may be performed at other study visits. Weight should be recorded at the second Q12W visit each year during Years 2-5, and at 
every End of Year visit during Years 2-7. 
b Refer to Table 9.7.9.2.1 for laboratory assessments to be included, and to Table 9.7.9.3.1 for liver tests.  LTs may be assessed more frequently when ALT values are 
 1.5x ULN or based upon discussion between the Medical Monitor and the Investigator. Subjects with ALT  
  1.5x ULN during the study may undergo additional 
evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII 
and LTs during any study week may be performed if: (1) the ALT has increased to above ULN or increased by > 10 U/L from prior assessment;; or (2) after a discussion 
between the Medical Monitor and the Investigator based on a review of subject data. If ALT values are stable over the course of several weeks, assessment of FVIII 
activity and ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator. During Years 2-5 of the Post-Infusion Follow-Up 
period, urine tests and blood, chemistry, and coagulation tests should be performed at the second Q12W visit each year and at every End of Year visit. During Years 6-7, 
these tests should be performed at the Q26W and End of Year visits.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should 
be made to obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who 
 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated 
or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A 
d-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen modification) during Years 3-5, a fresh sample should be collected within 4 weeks of 
the initial visit that had a positive result.  
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, and hFVIII 
coagulation activity exploratory assay.  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 

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measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out per
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of 
several weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests 
positive in the Bethesda assay (with Nijmegen modification) in Years 3-5, a fresh sample should be collected within 4 weeks of the initial visit that had a positive result. 
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.  Subjects who have not 
had 3 consecutive negative semen samples by Week 52 should continue to have PCR testing every 4 weeks (during Year 2), every 6 weeks (during Years 3-5), and/or 
every 26 weeks (during Years 6-7) until 3 consecutive samples below the limit of detection are documented (or upon consultation between the Investigator and Medical 
Monitor). 
f Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at the second Q12W visit each year and at every End of Year visit. During 
Years 6-7, the Haemo-QoL-A assessment should be performed at the Q26W visits and the End of Year visits. 
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
h Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 may omit the Q4W and Q6W visits during Years 2-5, and must attend only the 
Q12W and End of Year visits. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in semen must still provide samples Q4W 
(during Year 2), Q6W (during Years 3-5), or Q26W (during Years 6-7), until vector shedding has been cleared (but do not need to do other scheduled assessments at 
those visit dates), either by reporting to the site to provide samples or by providing those samples to an MN professional. 
i For every 13 week remote visits during Years 6-7, the site should contact the subject to collect data on adverse events, new or changed concomitant medications, and 
diary entries (FVIII usage and bleeding events). 
j At applicable sites, certain study assessments designated in the Schedule of Events may be performed by a mobile nursing (MN) professional at the subject’s home or 
another suitable location, such as their school or office. Refer to Section 9.7.9.2 for details. 
k Additional liver ultrasounds may be performed at interim timepoints (ie, between the End of Year visits) at the discretion of the Investigator.
 

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Table 9.1.6:  Schedule of Events – Reactive Corticosteroids for LT Elevations 
 
Steroid Treatment Periodd
Post-Steroid Periodc
Week 
1 
Week 
2 
Week 
3 
Week 
4
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11b 
Week 
1
Week 
2
Week 
3
Week 
4 
Week 
13 
Reactive 
corticosteroids 
(dose in 
mg/day) a  
60 mg 
60 mg 
40 mg 
40 
mg 
30 mg 
30 mg 
20 
mg 
20 mg 
15 mg 
10 mg 
5 mg 
 
 
 
 
 
FVIII activity 
testing 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Liver testing 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Hepatitis B 
testinge 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
HCV Viral 
Loade 
X 
X 
X 
a
enzyme data after consultation between the 
Investigator and the Medical Monitor. 
b Following initiation or completion of steroid regim
Investigator and Medical Monitor.  Modification of the steroid regimen may take into consideration timing of the ALT elevation (after Week 52), as well as possible 
confounders for the ALT elevation and adverse events related to corticosteroid dosing. Guidance for tapering oral corticosteroids can be found in Section 9.4.8.2. 
c After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values. If these 
assessments are already being done as part of normal study follow-up, they do not need to be duplicated. 
d Regardless of the assessments listed in the Schedule of Assessments (Table 9.1.2, Table 9.1.3, or Table 9.1.4), subjects initiated on corticosteroids will only be required 
to have laboratory evaluations on a weekly basis. 
e Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry.
 
 

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Table 9.1.7:  Schedule of Events – Liver Biopsy Substudy
 
Within 28 Days 
Before Biopsy Day 
Within 7 Days 
Before Biopsy Day 
1 Day Before Biopsy 
Day d 
Biopsy Day (BD) 
Informed Consent
X 
Liver Ultrasounda 
X 
 
 
 
Brief Physical Examination 
X 
 
X 
X 
Hematology, Coagulation, Chemistry Assessmentsb 
X 
 
X 
 
Liver Testsb
X 
X 
X 
FibroScan 
 
X 
 
 
Local FVIII Activity Level Assessment
X 
X 
X 
Pre-Biopsy Consultationc
X 
Liver Biopsye 
 
 
 
X 
a Liver ultrasound must be performed within 28 days prior to the scheduled biopsy, unless an ultrasound result from the prior 3 months is already available.
b Refer to Table 9.7.9.2.1 for laboratory assessments to be included, and to Table 9.7.9.3.1 for liver tests.  
c Subjects will undergo a pre-biopsy consultation with the investigator (treating hematologist). 
d Subjects may need to repeat/extend this visit if their FVIII activity levels need adjustment before the biopsy, at the discretion of the investigator (treating hematologist).
e Biopsy will be a percutaneous or transjugular biopsy under ultrasound guidance, performed according to the standard procedure of the institution. If only a small amount 
of tissue (< 2 cm) is obtained at the time of the biopsy, the subject may be asked to consent for a second pass. In this case, the original < 2 cm sample should still be 
retained and handled according to the instructions for handling biopsy specimens in the Laboratory Manual. Following completion of the biopsy, the subject should 
remain in the hospital under observation for at least 4-6 hours. Overnight post-procedure observation may be done at the investigator’s discretion. 
 
 

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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Four doses of BMN 270 will be evaluated and the dose 
escalation decision tree for Cohorts 1-3 is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and the DRB. 
There will be no control group. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy).  
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3 
Selection of Study Population 
Up to 15 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation.  
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe Haemophilia A as evidenced 
by their medical history.  Patients will be considered as severe if their base FVIII 
level is 1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs) 
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less 
than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within 
the past 12 months 
6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment.  After 6 months, subjects may stop contraception use only if they have 
had 3 consecutive semen samples below the limit of detection of the test. 

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9.3.2 Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition or AAV5 total antibodies 
2. Any evidence of active infection or any immunosuppressive disorder.   
3. HIV positive 
4. Significant liver dysfunction as defined by abnormal elevation of: 
 ALT (alanine transaminase) to 3 times the upper limit of normal; 
 Bilirubin above 3 times the upper limit of normal; 
 Alkaline phosphatase above 3 times the upper limit of normal; or 
 
 
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if 
they had significant fibrosis of 3 or 4 as rated on a scale of 0-4 
6. Evidence of any bleeding disorder not related to Haemophilia A 
7. Platelet count of < 100 x 109/L 
8. Creati
 
9. Liver cirrhosis of any etiology as assessed by liver ultrasound  
10. Hepatitis B if surface antigen is positive 
11. Hepatitis C if RNA is positive 
12. Treatment with any IP within 30 days prior to the end of the screening period 
13. Any disease or condition at the physician’s discretion that would prevent the patient 
from fully complying with the requirements of the study including possible 
corticosteroid treatment outlined in the protocol.  The physician may exclude 
patients unwilling or unable to agree on not using alcohol for the 16-week period 
following the viral infusion. 
14. Prior treatment with any gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion 
16. Use of immunosuppressive agents or live vaccines within 30 days before the viral 
infusion 

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9.3.3 Liver Biopsy Substudy Inclusion and Exclusion Criteria 
Individuals eligible to participate in the liver biopsy substudy must meet all of the following 
criteria:
1. Currently enrolled in 270-201 
2.
Received BMN 270 infusion at least 1 year prior to enrollment in the substudy 
3.
Able to sign informed consent and comply with requirements of the substudy 
4. FVIII activity at least >50 IU/dL (or higher, depending on local guidelines and/or 
Investigator discretion) within 24 hours prior to the liver biopsy being performed.  
(FVIII levels should be assessed at the local laboratory.)  Subjects may be treated 
with additional exogenous FVIII replacement products in order to increase their FVIII 
levels to an appropriate level, under the supervision/instruction of the Investigator. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the liver biopsy substudy: 
1. Assessed by the investigator or a hepatologist as having a medical condition such that 
undergoing a liver biopsy would be contraindicated. These conditions could include 
(but are not limited to): 
 Significant thrombocytopenia (platelet count < 100 x 109/L)
 Evidence of significant ascites 
 Abnormalities detected on liver ultrasound (performed within 90 days of 
procedure) that would preclude safe performance of the biopsy. 
9.3.4 Removal of Subjects from Treatment or Assessment
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 
BioMarin must be notified of all subject withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 

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Reasons for which the Investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following: 
 Subject requires medication or medical procedure prohibited by the protocol 
Subject does not adhere to study requirements specified in the protocol 
Subject was erroneously admitted into the study or does not meet entry criteria 
Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
Subjects may be considered lost to follow-up if the site has documented at least 4 attempted 
contacts by key research personnel to reach the subject without success in the following 
manner: 
 2 attempts by telephone or email (if possible); then 
 If telephone/email contacts are unsuccessful, 2 attempts must be made by certified 
letter or by appropriate local process.
Where communication has been made by phone, this should be documented in the subject 
source notes. 
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IEC. It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study. 
9.3.4.1
Study Safety Evaluation Criteria 
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis 
per Section 9.1. 
 
Any ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of 
BMN 270, in the absence of a definitive alternate etiology for the increase   

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The occurrence of Grade 3 or higher adverse events (excluding ALT elevation)
assessed as related to study drug, including liver failure and clinical hepatitis
The detection of neutralizing antibodies to hFVIII following BMN 270 infusion
The detection of AAV vector DNA in the semen of a participant in 3 consecutive
samples (which are at least 2 weeks apart) more than 52 weeks after BMN 270
infusion, as discussed in Section 9.7.9.
The occurrence of a malignancy excluding skin cancers at any point after BMN 270
infusion
If the following event occurs in a subject in the study who has received BMN 270 infusion, a 
DRB review and analysis of safety data will be undertaken to determine whether the 
enrollment into the trial will be put on halt: 
Grade 2 adverse event assessed as related to study drug that persists for at least 7 days
9.3.5 Subject Identification and Replacement of Subjects 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Subjects who withdraw from the study will not be replaced. 
9.3.6 Duration of Subject Participation 
The duration of this study will be approximately 368 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 348 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks. 
9.4 
Treatments 
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 

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9.4.2 Identity of Investigational Product 
9.4.2.1
Product Characteristics and Labeling 
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 
stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4 Directions for Administration 
After a physical examination performed by the PI or designee, participants will be admitted 
on the day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral 
vein (eg, the median cubital vein) and flushed with saline. FVIII replacement therapy will not 
be given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 ml/min while monitoring the vital signs (pulse, blood pressure, respiration 
rate and temperature) at 15 minute (± 5 minutes) intervals. The anticipated maximum interval 
from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, although the 
IP has been shown to be stable at room temperature for 6 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard protocol 
for infusing FVIII concentrates. Subjects will remain in the clinic for 24 hours to observe for 
any immediate toxicity of the procedure. After 24 hours, participants will be discharged from 
the clinic unless toxicity has been observed in which case the stay in the clinic may be 

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extended or the subject may transfer to a separate facility based on the evaluation and 
judgment of the Principal Investigator after consultation with the Medical Monitor. 
9.4.5 Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study subject. Upon their enrollment into the study, subjects will be assigned a unique subject 
number and dose level by the Sponsor.
Cohorts 1 to 3 are enrolled serially and their dose is defined in Section 9.4.6.2 below. 
Escalation is based on FVIII activity 3 weeks after injection. Cohorts may receive the next 
higher dose if subjects in the previous cohort does not meet the activity criteria, or the same 
dose if subjects in the previous cohort meets the activity criteria. Subjects in Cohort 4 will all 
be enrolled at a single dose. 
9.4.6 Selection of Doses Used in the Study 
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in mice. The dose escalation is half-logs based.    
9.4.6.1 
Selection of Timing of Dose for Each Subject 
A minimum of three weeks are required between subjects, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next subject will be made as described below.  
9.4.6.2 
Selection of Dose for Each Subject 
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus potentially decreasing the risk of immune response), and a new 
evaluation of the titer (PCR performed after hairpin removal). 
For Cohorts 1 to 3, approximately three weeks after an injection, the decision to escalate to 
the next dose level will be made based on the review of safety parameters and FVIII activity 
by the Sponsor and the DRB.  
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1) 
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 

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If the FVIII activity level in the first sub
 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject. 
If the FVIII activity level in the first subje
 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
 IU/dL and no safety issue is found, then up to four subjects will be enrolled in that cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
bjects may be enrolled in 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB.  The adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals. 
Refer to Figure 9.1.1 for a visual representation of the study design for Cohorts 1-3 
9.4.7 Blinding 
This is an open-label study. 
9.4.8 Prior and Concomitant Medications 
All prescription and over-the-counter medications (including dietary and herbal supplements) 
taken by a subject for 30 days before Screening will be recorded on the designated CRF. The 
Investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF. 
The following medications are prohibited starting 30 days before Screening: 
 Live vaccines 
 Systemic immunosuppressive agents 
 Emicizumab 

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 Fitusiran 
Concizumab
Efavirenz
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their 
participation in 270-201 must have their antiretroviral medication regimen approved by the 
Investigator and Medical Monitor prior to starting antiretroviral treatment.
Medications which are predominately metabolized by the liver (eg, acetaminophen) and 
alcohol should, whenever possible, be avoided for the first 52 weeks of the study, and 
particularly within 48 hours prior to lab work. 
Administration of SARS-CoV-2 vaccine after BMN 270 infusion may occur after 
consultation between Investigator and Medical Monitor. Investigators should use clinical 
judgment, taking into consideration local factors, individual risk factors, and the benefit/risk 
related to timing of vaccine administration. 
9.4.8.1 
Concomitant Haemophilia Treatments 
Subjects on “episodic” therapy for FVIII will continue their treatment at will.  Subjects on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and 
switch to an “episodic” schedule. FVIII can always be taken as needed by the subject, who 
will carefully record his treatment and bleeding episodes in his diary.  In addition, 
information on FVIII usage by medical history will be collected (if available) from subjects 
for the 6 month period immediately preceding study enrollment. 
9.4.8.2 
Glucocorticoid Treatment of Elevated Hepatic Transaminases 
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject 
will have comprehensive surveillance plan monitoring of LTs (at local labs, once per week 
for Weeks 1-36, then once every 2 weeks from Week 37-52).  LTs may be monitored more 
or less frequently (and in particular when ALT values are >1.5x ULN) based on discussion 
between the Medical Monitor and the Investigator and review of subject data.  
9.4.8.2.1 Reactive Corticosteroids 
In general, reactive corticosteroids may be initiated when a subject’s ALT value is 
 1.5x ULN, or based on review of FVIII and liver enzyme data after consultation between 
the Medical Monitor and the Investigator. Corticosteroids may be delayed, upon discussion 
with the Medical Monitor, if elevations in ALT are clearly not related to BMN 270 (eg, 
elevated ALT with concurrent increase in CPK due to intensive exercise) and in particular for 
elevations occurring more than 52 weeks after BMN 270 dosing.  

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Repor
medical monitor within 30 minutes of the lab value being available.  Local laboratory results 
of LTs will be used to trigger corticosteroid treatment as needed.  In case of discrepant 
results between local and central laboratories, the Investigator and Medical Monitor will 
decide further action.  
Following initiation or completion of reacti
 1.5x ULN 
is reported, steroid management decisions will based on discussions between the Investigator 
and Medical Monitor. Modification of the steroid regimen may take into consideration 
possible confounders for the ALT elevation and impact on FVIII expression.   
Unless otherwise indicated, treatment with reactive corticosteroids should be initiated at a 
dose of 60 mg per day and then gradually tapered if the ALT level remains stable or declines 
after 2 weeks (60 mg daily for the first 2 weeks, then 40 mg the next 2 weeks, then 30 mg the 
next two weeks, then 20 mg the next two weeks, then 15 mg for the next week, then 10 mg 
for the next week, then 5 mg for the next week, then stop, for a total treatment of 11 weeks) 
(refer to Table 9.1.6).  
Should a scenario arise in which differences from the minimum recommended dose and/or 
duration of reactive corticosteroids may be clinically indicated, a discussion should take 
place between the Investigator and Medical Monitor regarding corticosteroid dose 
adjustments. Management of ALT elevations with reactive corticosteroids, including tapering 
of doses and managing worsening and/or recurrent ALT elevations, should be guided by the 
following (Table 9.4.8.2.1.1):

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Table 9.4.8.2.1.1:  Management of ALT Elevations with Reactive Corticosteroids 
Baseline or > ULN 
 
Repeat LTs and FVIII within 24-72 hours 
Continue to monitor LTs until ALT is stable or not increasing
 
Investigate for alternative etiologies (eg, concomitant medications, viral or 
autoimmune hepatitis, alcohol use, recreational drug use, special diets, strenuous 
exercise, prior and/or concurrent illnesses, exposure to environmental and/or 
industrial chemicals, etc.) 
If no alternative etiology is found, contact the Medical Monitor to discuss the 
initiation of reactive corticosteroids with the following tapering schedule: 60 mg 
x 2 weeks; 40 mg x 3 weeks; 30 mg x 1 week; 20 mg x 1 week; 10 mg x 1 week 
upon consultation with the Medical Monitor
 
Consider evaluation with additional liver tests (including but not limited to ALT, 
AST, bilirubin, and alkaline phosphatase) 
 
Consider obtaining other possibly relevant laboratory evaluations (albumin, 
PT/INR, CRP, etc.) 
 
Consider obtaining complete blood count with differential to assess for 
eosinophilia 
 
Consider obtaining PBMC, C3, C3a, Bb, and sC5b-9 to evaluate potential 
immune response (prior to starting reactive oral corticosteroids) 
 
Continue to taper as long as subject’s ALT is not increasing. Decisions 
regarding regimen modification may be made based upon Investigator 
judgement and discussion with the Medical Monitor 
 
For any ALT elevations that begin after 52 weeks on study, please consult the 
Medical Monitor prior to initiating corticosteroids unless there is an imminent 
safety concern 
Worsening ALT 
If after 2 weeks ALT levels have worsened with corticosteroid dose of 60 mg/day, the 
following is recommended: 
 
Investigate for alternative etiologies including labs noted above, if not 
previously checked 
Increase corticosteroid dose up to a maximum of 1.2 mg/kg for no more than 2 
weeks 
 
For subjects who are refractory to the maximum dose of corticosteroids, or 
intolerant to use of corticosteroids, consider use of alternative 
immunosuppressants (tacrolimus or mycophenolate) 
 
Consider gastroenterology and/or hepatology consult, abdominal workup, 
imaging (including MRI or ultrasound), and/or liver biopsy as appropriate 
Any concerns should be discussed between the Investigator and the Medical Monitor 
Recurrent ALT 
elevations 
here are no 
safety concerns, the decision regarding management may be made at the discretion of the 
Investigator after discussion with the Medical Monitor 
For any scenarios that are not accounted for in the above table, a discussion should take place between the 
Investigator and Medical Monitor regarding corticosteroid dose adjustments. 
When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT 
workup, the following tests should be performed (Table 9.4.8.2.1.2): 

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Table 9.4.8.2.1.2:  Viral and Autoimmune Hepatitis Testing 
Viral Hepatitis Workup Testing
Autoimmune Hepatitis Workup Testing
Hepatitis A
Smooth muscle antibody
Hepatitis B 
Mitochondrial antibody 
Hepatitis C
Liver/kidney microsomal antibodies
Hepatitis E
Antinuclear antibody (ANA) HEP-2 
Cytomegalovirus (CMV) 
Epstein-Barr virus (EBV)
Herpes simplex virus (HSV) 1 & 2
After discontinuation of reactive corticosteroids, weekly labs for ALT and FVIII levels will 
be measured once a week for 4 weeks to ensure stability in values. 
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. 
This includes the contraindicated use of NSAIDs during corticosteroid treatment, and 
specific monitoring not already covered by the schedule of events. The use of COX-2 
inhibitors, while not contraindicated during corticosteroid treatment, should be limited, if 
possible.  Practical management to prevent complications related to oral corticosteroid 
therapy may be undertaken at the discretion of the Investigator (eg, evaluation of glucose 
intolerance, hyperlipidemia etc.). For the subjects with a past medical history of hepatitis B 
or hepatitis C prior to study entry, Hepatitis B status and HCV viral load will be rechecked 
6 weeks after the start of corticosteroid treatment, and then 1 week and 13 weeks after the 
completion of corticosteroid treatment. All adverse events should be reported as outlined in 
Section 10 of the protocol. 
Subjects on corticosteroids should receive appropriate counselling and support regarding side 
effects from the Investigator or the treating institution (eg, listings of side effects and when to 
notify carers, wallet card for emergencies if on steroids, etc.). Additional management, 
including the co-prescription of additional medications to prevent complications related to 
corticosteroid therapy, may be undertaken at the discretion of the investigator, including, 
but not limited to, prophylaxis against the occurrence of gastric ulcers, osteoporosis, and 
infections. 
9.4.9 Treatment Compliance 
Study drug will be administered to subjects at the study site by a qualified professional.  
The quantity dispensed, returned, used, lost, etc. must be recorded on a dispensing log.  Sites 
will be instructed to return or destroy all used and unused study drug containers. 

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9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data, if allowed by local SOPs. 
9.5.1
Return and Disposition of Clinical Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials (or must be referenced in their institution 
SOPs). 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a study drug return form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions
There are no dietary or other protocol restrictions for this study. 
Subjects should be advised to abstain from any blood or sperm donation after BMN 270 
infusion, until there is no further evidence of vector shedding from PCR analysis of samples.  
9.7 
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.9. 
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
 5 IU/dL at 16 weeks post 
BMN 270 administration.  

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9.7.1 Safety and Efficacy Measurements Assessed 
The Schedule of Events (Table 9.1.1 through Table 9.1.5) describes the timing of required 
evaluations.
9.7.2 Primary Efficacy Variables
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to expression of FVIII at 5 IU/dL or above, 
(ie, a mild severity). This is associated in natural history studies with clinically superior long 
term outcomes (Den Ujil 2011). 
The following assays (assessed by the central laboratory) will be used to measure the primary 
efficacy variable: 
 FVIII activity (chromogenic substrate assay) 
 FVIII activity by one-stage clotting assay
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made 
to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 
The 72-hour wash-out period is only intended for subjects who have achieved FVIII 
 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care 
FVIII replacement therapy. 
The FVIII activity level in both assays and the number of subjects with FVIII activity 
 5 IU/dL in at least one of the two assays will be summarized. 
FVIII activity assays will also be performed at the local laboratory at the time points 
indicated in Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5 but will be used in 
conjunction with local lab LT assessments to monitor subject safety and need for initiation of 
reactive corticosteroid dosing; local laboratory FVIII activity assessments will not be used to 
assess efficacy or to measure the primary efficacy outcome of the study. 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
failure to a
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable 
and at the discretion of the Investigator.  
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, Table 9.1.4, 
and Table 9.1.5.  Details on performing the assays are included in the Laboratory Manual. 

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9.7.3 Secondary Efficacy Variables
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Subjects will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the subject’s diary or 
other subject records. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. 
9.7.4 Immunogenicity 
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
5-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to a retrospective immunogenicity assessment to determine 
anti-FVIII and capsid specific CTL. Anti-FVIII and capsid specific CTL assays will be 
performed on collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4. 
9.7.5 Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage clotting and/or chromogenic substrate assay (activity).  Individual antigen and 
activity plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity 
measurements will be used to determine PD parameters.
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), 
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology. 
Sample collection times are indicated in Table 9.1.2, Table 9.1.3, Table 9.1.4, and 
Table 9.1.5. 

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9.7.6 Exploratory Assessments 
Blood samples will be collected at the time points indicated in Table 9.1.1, Table 9.1.2, 
Table 9.1.3, Table 9.1.4, and Table 9.1.5 to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations.  Subjects may choose to opt out of the 
exploratory genetic/genomic research being done to study or try to discover genes that are 
not yet known to be associated with hemophilia A.  
Liver biopsy samples collected as part of the exploratory substudy may also be tested to 
evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer.  Subjects participating in the substudy 
may choose to opt out of the exploratory genetic/genomic research being done to study or try 
to discover genes that are not yet known to be associated with hemophilia A. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes may be used for exploratory use once the 
primary use has been completed. 
On an exploratory basis, samples may be fractionated prior to shedding analysis in order to 
better characterize the presence and location of vector DNA and/or vector capsid within each 
matrix. The fractionation may be performed with samples collected specifically for shedding 
analysis (saliva, blood, semen, urine, faeces), or by using exploratory samples, such as 
plasma, PBMCs, and red blood cells, collected under the study protocol. 
9.7.7 Haemo-QoL-A Quality of Life Assessment 
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to 
assess subject quality of life (QoL) during the study.  Assessments will occur at the time 
points listed in the Schedules of Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual. 
9.7.8 Liver Biopsy Substudy 
The objectives of the liver biopsy substudy are considered exploratory. 
Subjects who consent to the procedure will have a liver biopsy via either the transjugular or 
percutaneous (ultrasound-guided) route, according to the standard procedures of the 
institution. To enhance safety, all subjects will have an ultrasound exam of the liver within 
28 days prior to the procedure (to ensure there is no obstruction to the liver that would 
interfere with the liver biopsy) and a FibroScan of the liver within one week before the liver 

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biopsy (to correlate any histopathologic findings on the biopsy). Subjects will also undergo a 
pre-biopsy consultation with the investigator (treating hematologist). 
Within 24 hours prior to the biopsy being performed, subjects must have a FVIII activity 
level of at least 50 IU/dL (or higher, depending on local guidelines and/or investigator 
discretion). FVIII activity levels for this purpose should be assessed at the local laboratory 
within 7 days before the biopsy, and again the day before the biopsy. As needed, subjects 
may be treated with additional exogenous FVIII replacement products in order to increase 
their FVIII activity levels to an appropriate level, under the supervision/instruction of the 
investigator, to ensure the safety of the subject during the procedure. This exogenous FVIII 
usage (if performed) should be recorded in the eCRF FVIII infusion pages under the category 
“Surgery/Procedure”. 
The liver biopsy should be performed in the morning, and the biopsy procedure and 
follow-up care should be done according to the local standard of care. Additional details for 
handling the biopsy specimens are provided in the Laboratory Manual. 
Following completion of the biopsy, the subject should remain in the hospital under 
observation for at least 4-6 hours. Overnight post-procedure observation may be done at the 
investigator’s discretion and/or according to local guidelines. 
Participation in the substudy may include liver biopsies at one or more time points. 
Safety findings arising from the histopathological analysis of the biopsy sample are subject to 
Adverse Event reporting (Section 10), and such findings should be further assessed and 
followed-up as clinically appropriate and in order to safeguard the subject’s ongoing medical 
care (this should be done in consultation with a hepatologist and/or other specialist clinicians 
if required).  In the event fibrotic changes being observed on the biopsy sample, additional 
follow-up Fibroscans may be considered (with the frequency of subsequent scans at the 
discretion of the Investigator and/or hepatologist). 
Where a biopsy has been taken for safety-related reasons (rather than as part of the liver 
biopsy substudy) or was available from a past procedure, the Sponsor may want to see that 
biopsy information to help evaluate the impact of BMN 270 on the liver. The Sponsor may 
request that slides from a liver biopsy not performed as part of the substudy be made 
available for additional histopathological review. 
9.7.9 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 

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9.7.9.1
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the subject signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1, 
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5. 
9.7.9.2 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5. The scheduled clinical 
laboratory tests are listed in Table 9.7.9.2.1. Refer to the Study Reference Manual for 
instructions on obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant.
All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF. 

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Table 9.7.9.2.1:  Clinical Laboratory Tests 
Blood Chemistry
Haematology
Urine Tests
Other
Albumin
Haemoglobin 
Appearance
CRP
BUN
Haematocrit 
Color 
 
Calcium
WBC count
pH
Coagulation Screen
including:
Chloride
RBC count
Specific gravity
Total cholesterol 
Platelet count 
Ketones 
APTT 
CO2
Differential cell count 
Protein 
PT/INR
CPK
Glucose 
TT
Creatinine 
 
Bilirubin 
 
Glucose 
 
Nitrite 
Other Tests:
Phosphorus 
 
Urobilinogen 
ABO blood typing*
Potassium 
 
Haemoglobin 
 
Total protein
 
 
 
Sodium
 
 
 
Uric Acid 
 
 
 
BUN, blood urea nitrogen; CO2, carbon dioxide; CRP, C-reactive protein; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; INR, 
international normalized ratio. 
* ABO blood typing assessment should be completed at the next regularly scheduled study visit (or at least prior 
to the end of the subject’s participation in the study). 
 
At applicable sites, certain study assessments designated in the Schedule of Events may be 
performed by a mobile nursing (MN) professional at the subject’s home or another suitable 
location, such as their school or office, to improve access and convenience for subjects 
participating in the study. The Sponsor may select a healthcare company that will be 
responsible for providing MN services for participating sites (the MN vendor). The 
MN vendor is responsible for ensuring that all MN professionals are licensed, qualified, and 
in good standing, as per applicable regulations, and that appropriate background checks have 
been performed. If the investigator at a participating site determines that MN services are 
appropriate for a subject and the subject gives written informed consent to participate in MN 
visits, the MN network will communicate with the subject and the subject’s site. 
9.7.9.3
Malignancies
Liver ultrasounds will be performed annually at each End of Year visit starting at Year 5 
(Week 260) through the end of the study to screen for HCC. Additional liver ultrasounds may 
be performed between the End of Year visits at the discretion of the Investigator. 

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Any development of a malignancy (except non-melanoma skin cancers) during the course of 
the study will be considered an EOSI (refer to Section 10.2.1) and is subject to expedited 
reporting. In addition, it is recommended that genomic analyses be performed on any 
malignancy (except non-melanoma skin cancers) diagnosed during the course of the study. 
The study site will coordinate sending samples from the malignancy for genomic analyses, if 
available.
9.7.9.4
Liver and Hepatitis Testing
Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening. Subjects with documented results showing an absence of active hepatitis B or 
hepatitis C infection (as measured by positive surface antigen for hepatitis B or positive RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to be 
screened again. 
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with a 
history of hepatitis B or hepatitis C will be asked for information about the treatments 
received as part of their medical history assessment at Screening. 
Subjects with a history of hepatitis B or hepatitis C infection prior to study entry will be 
tested for hepatitis B and hepatitis C reactivation at Week 16. Subjects who receive reactive 
corticosteroids prior to Week 16 do not need to complete the Week 16 reactivation 
assessment; instead, they will be tested for hepatitis B and hepatitis C reactivation at the time 
points listed in Table 9.1.6. 
A liver ultrasound and LTs at Screening will identify any significant hepatic dysfunction, 
which is defined as: 
 More than 3x the normal ALT level 
 More than 3x the normal bilirubin level 
 More than 3x the normal Alkaline phosphatase level. 
 INR > 1.4.  
 Thrombocytopenia under 100 x 109/L
 Liver ultrasound results indicative of a liver cirrhosis  
Liver tests will be monitored on a regular basis, at the time points indicated in Table 9.1.1, 
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5.  At each time point, the following LTs 
should be assessed: 

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Table 9.7.9.3.1:  Liver Tests 
Liver Tests (LTs)
Alkaline Phosphatase 
AST (SGOT) 
Total Bilirubin 
LDH
ALT (SGPT) 
Direct Bilirubin 
GGT 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, 
lactate dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic 
transaminase 
Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, 
imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at 
the discretion of the investigator. 
9.7.9.5
HIV Testing
HIV testing will be performed at Screening. Subjects with documented negative results 
within the last 30 days prior to screening do not need to be retested. 
9.7.9.6
Vital Signs, Physical Examinations and Other Observations Related to Safety
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE. 
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored prior to infusion, during the infusion every 15 minutes 
(± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours 
(± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).  
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 
and at the End of Years visits thereafter. A complete physical examination will include 
general appearance (head, eyes, ears, nose, and throat), cardiovascular, dermatologic, 
lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic 
systems. The genitourinary examination may be deferred for visits after Year 1 unless the 
subject has genitourinary-related complaints. 
At other visits, brief physical examinations may be performed at the discretion of the 
investigator based on the subject’s clinical condition. A brief physical examination will 
include general appearance, cardiovascular, respiratory, neurologic, dermatologic, 

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musculoskeletal, and gastrointestinal assessments. Particular attention should be given to 
signs of bleeding, as well as assessing possible hemarthroses. 
Height will be recorded at Screening only. Weight will be recorded at Screening, at Weeks 
26 and 52 during Year 1, and then at the second Q12W visit each year during Years 2-5 and 
at every End of Year visit during Years 2-7. 
9.7.9.7
Vector Shedding 
Vector shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani 2014; Manno 2006; Schenk-Braat 2007; Croteau 2004). In the literature 
referenced above, including Haemophilia B clinical studies utilizing AAV2 and AAV8, 
vector was no longer detectable after 40 days in blood, saliva, urine or stool, but in one study 
was detected in the seminal fluid but not in motile sperm (Manno 2006).  In these studies, the 
amount of vector present in these bodily fluids involved an extremely small fraction of the 
infused dose.  More recent data from an ongoing AAV-FIX study demonstrates persistence 
of the vector in both the blood and the semen for at least 39 weeks (Miesbach 2016). 
During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily 
samples to look for evidence of vector shedding for possible viral transmission.  Bodily 
fluids will be tested by PCR at the time points indicated in Table 9.1.2, Table 9.1.3, 
Table 9.1.4, and Table 9.1.5.  Fluids tested will include: 
 Blood 
 Saliva 
 Semen 
 Urine 
 Stool 
Vector shedding will also be extensively studied in the present clinical trial, every other week 
between Weeks 4-16, then every 4 weeks to Week 52 until at least 3 consecutive negative 
results are obtained. Testing of semen will continue through Week 12, even if 3 consecutive 
negative results have been recorded in that compartment prior to that timepoint.  Subjects 
who have not had 3 consecutive negative semen samples by Week 52 should continue to 
have PCR testing every 4 weeks (during Year 2), every 6 weeks (during Years 3-5), and 
every 26 weeks (during Years 6-7) until 3 consecutive semen samples below the limit of 
detection of the test are documented (or upon consultation between the Investigator and 
Medical Monitor). Subjects who meet the definition of treatment failure and wish to follow 
an abbreviated schedule (refer to Section 12.5.3 but who have not cleared vector shedding 
from semen must still provide samples for assessment until vector shedding has cleared: 

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every 4 weeks (during Year 2), every 6 weeks (during Years 3-5), or every 26 weeks (during 
Years 6-7), either by reporting to the site to provide samples or by providing those samples to 
an MN professional. 
Contraception use may need to be extended beyond 26 weeks in individual subjects based on 
observed vector shedding in semen. After 6 months, subjects may stop contraception use 
only if they have had 3 consecutive semen samples below the limit of detection (upon 
consultation between the Investigator and Medical Monitor). 
Details for sample collection and storage are provided in the Laboratory Manual. 

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10 
REPORTING ADVERSE EVENTS
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(eg, sign, symptom, illness, disease or injury) in a subject administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
 AEs not previously observed in the subject that emerge during the course of the 
study. 
 Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
 Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
10.1.1.1 
Bleeding and Suspected Bleeding Events
All bleeding events and suspected bleeding events, regardless of the need for exogenous 
FVIII therapy as treatment, should be captured in subject diaries and recorded on the 
designated bleeding eCRF.  Bleeding events and suspected bleeding events should not be 
reported as adverse events, with the following exception: 
 All bleeding events and suspected bleeding events which meet one or more of the 
criteria for being serious (refer to Section 10.2) should be reported as serious adverse 
events (whether or not they are bleeding events that are normal sequelae of 
hemophilia, and whether or not they required exogenous FVIII as treatment).
10.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 

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 Is fatal
Is life threatening 
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
Requires or prolongs inpatient hospitalization.   
Results in persistent or significant disability or incapacity
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of  the above 
consequences (eg, anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs. 
10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
 Elevation of ALT 1.5x ULN, regardless of whether that triggers an initiation or 
modification of  corticosteroid treatment 
 Events meeting the crite
 
 Thromboembolic event 
 Development of anti-FVIII inhibitory antibodies (inhibitors) 
 Any new diagnosis of malignancy (except non-melanoma skin cancer)
10.3 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.3.1 Adverse Event Reporting Period 
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported. After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
7 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.1.1.1.  

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10.3.2 Eliciting Adverse Events
Investigators will seek information on AEs, SAEs, and EOSI at each subject contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the subject’s medical record and on the AE Case Report 
Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.1.1.1
for SAE definitions).  These assessments must be made by a study clinician with the training 
and authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.3.3.1
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.1.1.  Seriousness serves as a guide for 
defining regulatory reporting obligations. 
10.3.3.2
Severity
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1. 
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 

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Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade
Description
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated
Grade 4 and 5 AEs 
should always be 
reported as SAEs
5 
Death related to AE
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden. 
10.3.3.3
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1. 

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Table 10.3.3.3.1:  Causality Attribution Guidance 
Relationship
Description
Not Related 
Exposure to the IP has not occurred 
 
OR 
 
The administration of the IP and the occurrence of the AE are not reasonably 
related in time  
 
OR 
 
The AE is considered likely to be related to an etiology other than the use of 
the IP; that is, there are no facts, evidence, or arguments to suggest a causal 
relationship to the IP. 
Related 
The administration of the IP and the occurrence of the AE are reasonably 
related in time 
AND 
 
The AE could possibly be explained  by factors or causes other than exposure 
to the IP 
OR 
 
The administration of IP and the occurrence of the AE are reasonably related 
in time  
AND 
 
The AE is more likely explained by exposure to the IP than by other factors 
or causes. 
Factors suggestive of a causal relationship could include (but are not limited to): 
 Plausible temporal relationship 
 Absence of alternative explanations
 Rarity of event in a given patient or disease state 
 Absence of event prior to study drug exposure 
 Consistency with study product pharmacology 
 Known relationship to underlying mechanism of study drug action 
 Similarity to adverse reactions seen with related drug products 
 Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 

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cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on an eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.4.1.1 
Diagnosis versus Signs and Symptoms
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE (or SAE, as appropriate) eCRF, replacing the original 
entries where appropriate.
10.4.1.2 
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3
Persistent or Recurrent Adverse Events
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 

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10.4.1.4
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF. Any laboratory result abnormality of CTCAE Grade 4 
or 5 should be recorded as an SAE in the AE eCRF, unless the abnormal laboratory results 
has been reported or captured as part of an underlying diagnosis. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met: 
 Accompanied by clinical symptoms 
 Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless there is an impact to clinical outcomes 
(eg, increased rate of bleeding, worsening of joint disease). 
10.4.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 

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A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.4.1.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.4.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.1.1). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
 Perform a protocol-mandated procedure or assessment 
 Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
 Insert an in-dwelling IV catheter (such as a Port-a-Cath or other brand) for 
administration of study drug or FVIII replacement therapy. 
 Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 

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Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event. The Investigator must make every effort to 
follow the subject’s partner (with that partner’s consent) through resolution of the pregnancy 
(delivery or termination) and to report the resolution on the Pregnancy Follow-up eCRF. In 
the event of pregnancy in the partner of a study subject, the Investigator should make every 
reasonable attempt to obtain the woman’s consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5 
Reporting Requirements 
10.5.1 Expedited Reporting Requirements
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF and submitting to BPV within 24 hours of the site becoming 
aware of the event. Investigators should not wait to collect information that fully documents 
the event before notifying BPV of an SAE. BioMarin may be required to report certain SAEs 
to regulatory authorities within 7 calendar days of being notified about the event; therefore, it 
is important that Investigators submit any information requested by BioMarin as soon as it 
becomes available.
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations. 
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF.
10.5.2 Ethics Committee Reporting Requirements 
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required. 

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10.6 
Follow-up of Subjects after Adverse Events
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the subject is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the subject’s medical record to facilitate source data verification.
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.7 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment.
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study.  
10.8 
Urgent Safety Measures 
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IEC is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 

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events which may require the implementation of urgent safety measures to BioMarin within 
24 hours of becoming aware of the event. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
 Immediate need to revise the IP administration (eg, modified dose amount or 
frequency not defined in protocol) 
 Lack of study scientific value, or detrimental study conduct or management 
Discovery that the quality or safety of the IP does not meet established safety 
requirements 
10.9 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:
, MD, PhD
Address:
Biomarin Pharmaceutical Inc.
105 Digital Drive 
Novato, CA  94949 
Phone 
 
E-mail: 
 
PI
PI
PI
PI
PI

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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic substrate assay and the one-stage clotting assay are both validated and 
utilize CE marked reagents.  The exploratory FVIII activity assay will be used for 
exploratory purposes only. 

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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed. 
12.2 
Screening Visit 
Screening assessments will be performed within 28 days (+ 14 days) of BMN 270 infusion 
while baseline assessments will take place within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LTs, haematology, urine tests, coagulation screen, and CRP do 
not need to be repeated at Baseline.  
The following procedures will be performed during the Screening Period: 
 Full medical history, including haemophilia A history, hepatitis B, hepatitis C, and 
HIV. 
o Subjects with a history of hepatitis B or hepatitis C will be asked for 
information about the treatments received. Any prior pharmacokinetics 
information obtained while the subject was receiving prophylactic or 
on-demand FVIII therapy prior to the study should also be collected. For 
subjects who have already enrolled in 270-201, this information should be 
collected at the next regularly scheduled study visit (or at least prior to the 
subject’s completion of study participation). 
 Complete Physical Examination  
 Height and weight 
 Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature) 
 Assessment of Adverse Events and Concomitant Medications 
 Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
 Electrocardiogram 
 Chest X-ray
 Liver Ultrasound 
 Samples for hFVIII Assays
o Baseline hFVIII activity – chromogenic substrate (plasma) 
o Baseline hFVIII activity level – one-stage clotting assay

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o hFVIII coagulation activity exploratory assay 
o hFVIII inhibitor level (Bethesda assay with Nijmegen modification)
o hFVIII total antibody assay 
o hFVIII antigen (ELISA) 
 Blood sample for AAV5 Assays 
o AAV5 antibody titer 
o AAV5 transduction inhibition assay 
 Screen for hepatitis B, hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested) 
 Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
 Urine Tests (refer to Table 9.7.9.2.1) 
 Liver Tests (refer to Table 9.7.9.3.1) 
 Von Willebrand Factor Antigen (VWF:Ag)  
 Blood samples for Biomarker testing (including HLA genotyping, FVIII genotyping 
status, TNF  and IL10a single nucleotide polymorphisms) 
12.2.1 “Smart Rescreening” Visit 
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study: 
 
Vital signs
 
Assessment of Adverse Events and Concomitant Medications 
 
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
 
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification) 
 Blood sample for AAV5 Assays 

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o AAV5 antibody titer 
o AAV5 transduction inhibition assay 
 Blood chemistry, haematology, coagulation screen, and CRP (refer to 
Table 9.7.9.2.1) 
 Urine Tests (refer to Table 9.7.9.2.1) 
 Liver Tests (refer to Table 9.7.9.3.1) 
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
 Physical examination 
 Assessment of Adverse Events and Concomitant Medications 
 Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
 Distribution of subject diaries and training in diary completion 
 Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
 Urine Tests (refer to Table 9.7.9.2.1) 
 Liver Tests (refer to Table 9.7.9.3.1) 
 PBMC collection for CTL baseline 
 Direct Thrombin test 
 PCR of vector DNA in blood, saliva, urine, semen, and stools 
Exploratory biomarker assessments
 Haemo-QoL-A QoL assessment 
12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each subject.  Subjects will remain in the clinic for 
24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
 Physical examination 
 Assessment of Adverse Events and Concomitant Medications 
 Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
o AAV5 antibody titer 
o AAV5 transduction inhibition assay 

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 BMN 270 Infusion 
Vital Signs
o
Vital signs will be recorded prior to BMN 270 infusion and then every 
15  minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the subject’s stay in 
the clinic. 
12.5 
BMN 270 Infusion Follow-Up Visits
After BMN 270 has been infused, subjects will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Once per week (Weeks 1 through 16)  
The following procedures will be performed at one visit per week from Weeks 1 through 16: 
 Physical examination 
 Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
 Vital Signs 
 Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment 
o LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
 Samples for FVIII Assays – central laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved.  The 72-hour wash-out period is only 
intended 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy.

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o Central assessment of FVIII activity level should be performed 1x/week 
from Week 1 through Week 16 
 Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment 
o LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
 FVIII activity level – local laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
 PBMC collection 
12.5.2 Week 1 – Day 2 and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed: 
 
PCR of vector DNA in blood, saliva, urine, semen, and stools (Day 2 and Day 4) 
 Samples for FVIII Assays (Day 4 only) – central laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved.  The 72-hour wash-out period is only 
intended for subjects wh
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy. 
 Liver Tests (refer to Table 9.7.9.3.1) (Day 4 only) – central laboratory assessment 
 Liver Tests (refer to Table 9.7.9.3.1) (Day 4 only) – local laboratory assessment
 FVIII activity level (Day 4 only) – local laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
12.5.3 Week 1 – Day 8 
On Day 8, the following procedures will be performed: 

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PCR of vector DNA in blood, saliva, urine, semen, and stools 
 
Direct Thrombin test
 
Haemo-QoL-A QoL assessment
12.5.4 Every 2 Weeks 
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedures will be 
performed: 
 Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
(not assessed at Week 14)
 PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at 
Week 2) 
o Collection to occur until at least 3 consecutive negative results are 
obtained.  Semen samples should continue to be collected and tested 
through Week 12, even if 3 consecutive negative results in that 
compartment have been recorded prior to that timepoint. 
12.5.5 Weeks 4, 8, 12, and 16 
At Weeks 4, 8, 12, and 16, the following procedures will be performed: 
 Urine Tests (refer to Table 9.7.9.2.1) 
 VWF:Ag
 FVIII antibody titer 
 Exploratory biomarker assessments 
12.5.6 Week 16 
At Week 16, the following procedures will be performed: 
 Test for hepatitis B and hepatitis C reactivation (in subjects with a history of hepatitis 
B or hepatitis C infection prior to study entry) 
o Subjects who receive reactive corticosteroids prior to Week 16 do not 
need to complete the Week 16 reactivation assessment; instead, they will 
be tested for hepatitis B and hepatitis C reactivation at the time points 
listed in Table 9.1.6. 
12.5.7 Weeks 8 and 16 
At Weeks 8 and 16, the following procedures will be performed:
 AAV5 antibody titer 

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12.5.8 Weeks 2, 3, 4, and 16 
At Weeks 2, 3, 4, and 16, the following procedure will be performed: 
 Haemo-QoL-A QoL assessment
12.5.9 Week 13 
At Week 13, the following procedure will be performed: 
 Direct Thrombin test 
12.6 
Safety Follow-Up – Weeks 17-36 
After the Post-Infusion Follow-Up visits are complete, subjects will return to the study site 
for Safety Follow-Up visits from Weeks 17 through Week 36 (± 48 hours), when the 
following procedures will be completed: 
12.6.1 Once per week (Weeks 17 through 36) 
Once per week from Week 17 through Week 36, the following procedures will be performed: 
 Physical examination 
 Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
 Vital Signs 
 Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
 FVIII Assays – central laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved. The 72-hour wash-out period is only 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy. 

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 Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment 
o LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
 FVIII activity level – local laboratory assessment
o FVIII activity level (one-stage clotting assay)
o FVIII activity level (chromogenic substrate assay) 
12.6.2 Once per week (Weeks 17 through 20) 
Once per week from Week 17 through Week 20, the following procedures will be performed: 
 PBMC collection 
12.6.3 Every 2 weeks (Weeks 21 through 36) 
Every 2 weeks (Weeks 22, 24, 26, 28, 30, 32, 34, and 36), the following procedures will be 
performed: 
 PBMC collection 
12.6.4 Every 4 Weeks  
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed: 
 Exploratory biomarker assessments 
 Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
 Urine Tests (refer to Table 9.7.9.2.1)  
 VWF:Ag 
 AAV5 antibody titer 
 PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period. 
12.6.5 Every 8 Weeks  
Every 8 weeks (Weeks 20, 28, and 36), the following procedure will be performed: 
 FVIII antibody titer 
12.6.6 Week 26 
At Week 26, the following procedure will be performed: 
 Direct Thrombin test 

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 Weight 
12.6.7 Week 28  
At Week 28, the following procedure will be performed: 
Haemo-QoL-A QoL assessment
12.7
Safety Follow-Up – Weeks 37-52 
Subjects will return every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) from 
Week 37-52 (± 1 week), when the following procedures will be completed:
12.7.1 Once per visit 
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed: 
 Physical examination 
 Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
 Vital Signs 
 Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment 
o LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
 FVIII activity level – local laboratory assessment
o FVIII activity level (one-stage clotting assay)
o FVIII activity level (chromogenic substrate assay)
 Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment
o LTs may be monitored more or less frequently based (and in particular when 
ALT values are >1.5x ULN) on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
 FVIII Assays – central laboratory assessment 
o FVIII activity level (one-stage clotting assay)
o FVIII activity level (chromogenic substrate assay)
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level

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o FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
 5 IU/dL at 16 weeks after 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy. 
12.7.2 Every 4 Weeks  
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed: 
 Exploratory biomarker assessments 
 Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
 Urine Tests (refer to Table 9.7.9.2.1)  
 AAV5 antibody titer 
 VWF:Ag 
 PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period.  
Subjects who have not had 3 consecutive negative samples by Week 52 
should continue to have PCR testing every 4 weeks until 3 consecutive 
negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor). 
12.7.3 Every 8 Weeks  
Every 8 weeks (Weeks 44 and 52), the following procedure will be performed: 
 PBMC collection 
 FVIII antibody titer 
12.7.4 Week 38 and 52 
At Week 38 and Week 52, the following procedure will be performed: 
 Direct Thrombin test 
12.7.5 Week 52  
At Week 52, the following procedure will be performed: 
 Haemo-QoL-A QoL assessment 
 Weight 

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12.8 
Safety Follow-Up – Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by 
attending only the Q12W and End of Year visits during Years 2-5. 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from semen must still provide samples 
for assessment every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
vector shedding has cleared (but do not have to perform other scheduled assessments at those 
study visits). 
At applicable sites, certain study assessments designated in the Schedule of Events may be 
performed by a mobile nursing (MN) professional at the subject’s home or another suitable 
location, such as their school or office, to improve access and convenience for subjects 
participating in the study. 
During Years 2-5 of Safety Follow-up, the following procedures will be completed: 
12.8.1 Year 2 – Every 4 Weeks (not required for treatment failure)
During Year 2, every 4 weeks (± 2 weeks), the following procedures will be performed: 
 Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
 Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
 FVIII activity level – local laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
 Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 

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 FVIII Assays – central laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy. 
 PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Year 2 is not required if at least 3 consecutive samples 
are negative during the Post-Infusion Follow-Up period in Weeks 1-52.  
Subjects who have not had 3 consecutive negative semen samples by Week 52 
should continue to have PCR testing of semen every 4 weeks during Year 2 
until 3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor). 
o Subjects who meet the definition of treatment failure and wish to follow an 
abbreviated schedule but who have not cleared vector shedding from all fluids 
must still provide samples for assessment every 4 weeks during Year 2 until 
vector shedding has cleared (in such a case, these subjects do not need to 
perform other assessments except for PCR sample delivery scheduled at these 
timepoints). 
12.8.2 Years 3-5 – Every 6 Weeks (not required for treatment failure)
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
 Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
 Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment
o LTs may be assessed more frequently when ALT values are >1.5x ULN or 
based upon discussion between the Medical Monitor and the Investigator and 
review of subject data. 
 FVIII activity level – local laboratory assessment
o FVIII activity level (one-stage clotting assay)
o FVIII activity level (chromogenic substrate assay)

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 Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment 
o LTs may be assessed more frequently when ALT values are >1.5x ULN or 
based upon discussion between the Medical Monitor and the Investigator and 
review of subject data.
 FVIII Assays – central laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o FVIII activity level (chromogenic substrate assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
fter 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy. 
 PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Years 3-5 is not required if at least 3 consecutive 
samples are negative during the Post-Infusion Follow-Up period in 
Weeks 1-52 and/or Year 2.  Subjects who have not had 3 consecutive negative 
semen samples by the end of Year 2 should continue to have PCR testing of 
semen every 6 weeks during Years 3-5 until 3 consecutive samples below the 
limit of detection are documented (or upon consultation between the 
Investigator and Medical Monitor). 
o Subjects who meet the definition of treatment failure and wish to follow an 
abbreviated schedule but who have not cleared vector shedding from semen, 
must still provide samples for assessment every 6 weeks during Years 3-5 
until vector shedding has cleared (in such a case, these subjects do not need to 
perform other assessments except for PCR sample delivery scheduled at these 
timepoints). 
12.8.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects)
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks (± 2 weeks):
 Year 2 – Week 64, Week 76, Week 88, Week 100, Week 104 
 Year 3 – Week 116, Week 128, Week 140, Week 152, Week 156 
 Year 4 – Week 168, Week 180, Week 192, Week 204, Week 208 
 Year 5 – Week 220, Week 232, Week 244, Week 256, Week 260 

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For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and 
Week 260) will serve as an End of Year visit. 
At the every 12 week and End of Year visits, the following procedures will be performed: 
 Brief physical examination (at every 12 week visits) or complete physical 
examination (at End of Year visits) (genitourinary examination may be deferred 
unless the subject has genitourinary-related complaints)
 Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
 Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
 Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment
o LTs may be assessed more frequently when ALT values are >1.5x ULN or 
based upon discussion between the Medical Monitor and the Investigator and 
review of subject data. 
 FVIII activity level – local laboratory assessment
o FVIII activity level (one-stage clotting assay)
o FVIII activity level (chromogenic substrate assay)
 Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment
o LTs may be assessed more frequently when ALT values are >1.5x ULN or 
based upon discussion between the Medical Monitor and the Investigator and 
review of subject data. 
 FVIII Assays – central laboratory assessment 
o FVIII activity level (one-stage clotting assay)
o FVIII activity level (chromogenic substrate assay)
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved FV
at 16 weeks after 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy. 
 Vital Signs 

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 Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
o ABO blood typing assessment should be performed at the next regularly 
scheduled study visit (or at least prior to the end of the subject’s participation 
in the study) 
 Urine Tests (refer to Table 9.7.9.2.1) 
 FVIII antigen (ELISA) 
 AAV5 antibody titer (at End of Year visits only) 
FVIII antibody titer (at End of Year visits only) 
PBMC collection
VWF:Ag
 Exploratory biomarker assessments 
Haemo-QoL-A QOL assessment (at Week 76, Week 128, Week 180, Week 232, and 
End of Year visits only) 
 Liver ultrasound (at End of Year 5 visit only) 
o Additional liver ultrasounds may be performed at interim time points (ie, 
between the End of Year visits) at the discretion of the Investigator.
 PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o
Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are negative during the Post-Infusion Follow-Up period in 
Weeks 1-52.  Subjects who have not had 3 consecutive negative semen 
samples by Week 52 should continue to have PCR testing of semen every 
4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
3 consecutive samples below the limit of detection are documented (or 
upon consultation between the Investigator and Medical Monitor). 
12.9 
Safety Follow-Up – Years 6-7 
If the investigator at a participating site determines that MN services are appropriate for a 
subject and the subject gives written informed consent to participate in MN visits, the MN 
network will communicate with the subject and the subject’s site. 
During Years 6-7 of Safety Follow-up, the following procedures will be completed: 
12.9.1 Years 6-7 – Every 13 Weeks 
Every 13 weeks (± 4 weeks) during Years 6-7, the site should contact the subject remotely to 
collect the following data: 
 Adverse events 

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 New or changed concomitant medications 
Diary entries (FVIII usage and bleeding events) 
12.9.2 Years 6-7 – Every 26 Weeks and End of Year Visits 
During Years 6-7, the following assessments will be performed at a site visit every 26 weeks 
(±4 weeks) (Week 286 and Week 338) and at the End of Year Visits (±4 weeks) (Week 312 
and Week 364): 
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
Complete Physical Examination (genitourinary examination may be deferred unless 
the subject has genitourinary-related complaints) (Week 312 and Week 364 only)  
Weight (Week 312 and Week 364 only) 
 Vital signs (Week 312 and Week 364 only) 
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment
o LTs may be assessed more frequently when ALT values are >1.5x ULN or 
based upon discussion between the Medical Monitor and the Investigator and 
review of subject data. 
 FVIII Assays – central laboratory assessment 
o FVIII activity level (one-stage clotting assay)
o FVIII activity level (chromogenic substrate assay)
o FVIII coagulation activity exploratory assay
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy. 
 FVIII antigen (ELISA) 
 AAV5 antibody titer (Week 312 and Week 364 only) 
 FVIII antibody titer (Week 312 and Week 364 only) 
 Exploratory biomarker assessments (Week 312 and Week 364 only) 
 Haemo-QoL-A QOL assessment 

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 Liver ultrasound (Week 312 and Week 364 only) 
o Additional liver ultrasounds may be performed at interim time points at the 
discretion of the Investigator. 
 PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Years 6-7 is not required if at least 3 consecutive 
samples are below the limit of detection as of the end of Year 5.
12.10 Liver Biopsy Substudy - Years 1-7 
For the optional liver biopsy substudy (refer to Table 9.1.7), the following procedures will be 
performed at the following times: 
 Within 28 days before Biopsy Day 
o Informed consent 
o Liver ultrasound 
Liver ultrasound does not need to be performed if an ultrasound 
result from the prior 3 months is already available 
o Brief physical examination 
o Hematology, Coagulation, and Chemistry Assessments (refer to 
Table 9.7.9.2.1) 
o Liver Tests (refer to Table 9.7.9.3.1) 
 Within 7 Days before Biopsy Day 
o FibroScan
o Local laboratory FVIII activity level assessment 
o Pre-biopsy consultation with investigator (treating hematologist).  This 
may need to be repeated/extended if the subject’s FVIII activity levels 
need adjustment before the biopsy, at the discretion of the investigator 
(treating hematologist). 
 1 Day before Biopsy Day 
o Hematology, Coagulation, and Chemistry Assessments (refer to 
Table 9.7.9.2.1) 
o Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment 
o Brief physical examination 

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o Local laboratory FVIII activity level assessment 
 Subjects must have a FVIII activity level of at least 50 IU/dL (or 
higher, depending on local guidelines and/or investigator 
discretion). As needed, subjects may be treated with additional 
exogenous FVIII replacement products in order to increase their 
FVIII activity levels to an appropriate level, under the 
supervision/instruction of the investigator, to ensure the safety of 
the subject during the procedure. This exogenous FVIII usage (if 
performed) should be recorded in the eCRF FVIII infusion pages 
under the category “Surgery/Procedure”. 
 Biopsy Day 
o Brief physical examination 
o Local laboratory FVIII activity level assessment (performed pre-biopsy) 
Subjects must have a FVIII activity level of at least 50 IU/dL (or 
higher, depending on local guidelines and/or investigator 
discretion). As needed, subjects may be treated with additional 
exogenous FVIII replacement products in order to increase their 
FVIII activity levels to an appropriate level, under the 
supervision/instruction of the investigator, to ensure the safety of 
the subject during the procedure. This exogenous FVIII usage (if 
performed) should be recorded in the eCRF FVIII infusion pages 
under the category “Surgery/Procedure”. 
o Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment 
(pre-biopsy) 
o Liver Biopsy (refer to Laboratory Manual for guidelines for biopsy 
procedure and handling of biopsy samples) 
If only a small amount of tissue is obtained at the time of the 
biopsy, the subject may be asked to consent for a second pass. 
Following completion of the biopsy, the subject should remain in the hospital under 
observation for at least 4-6 hours. Overnight post-procedure observation may be done at the 
investigator’s discretion. 
Participation in the substudy may include liver biopsies at one or more time points. 
12.11 Early Termination Visit 
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 

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If a subject leaves the study prior to the Week 364 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
 Physical examination 
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
Vital Signs
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.9.2.1) 
Urine Tests (refer to Table 9.7.9.2.1) 
Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment
 FVIII activity level – local laboratory assessment 
o FVIII activity level (one-stage clotting assay) 
o
FVIII activity level (chromogenic substrate assay)
Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment
 FVIII Assays – central laboratory assessment 
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
BMN 270 infusion and who have not resumed standard of care FVIII replacement 
therapy. 
 FVIII antigen (ELISA) 
 AAV5 antibody titer 
 FVIII antibody titer 
 PBMC collection 
 VWF:Ag 

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 Liver ultrasound 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
o
Sample testing at the ETV is not required if at least 3 consecutive samples 
are below the limit of detection prior to the ETV. 
Exploratory biomarker assessment 
Haemo-QoL-A QOL assessment
12.12 End of Study
The study will end after the last subject completes the last Safety Follow-Up visit 
(Week 364). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study subjects may be 
compromised. 

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13 
DATA QUALITY ASSURANCE
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all subjects having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16). 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
Missing data will not be imputed.  
14.2 
Primary and Secondary Efficacy Analysis 
The subjects will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of subjects, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined. 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
IU/dL by chromogenic substrate assay and/or one-stage 
clotting assay as measured by the central laboratory at 16 weeks following study treatment.  
We can only assess the true steady state of hFVIII protein produced from BMN 270 after a 
minimum of 72 hours has elapsed since the last infusion of FVIII protein concentrates.   
14.3 
Liver Biopsy Substudy Analysis 
A separate report presenting and discussing analyses of the exploratory objectives for the 
optional liver biopsy substudy will be prepared. 
14.4 
Immunogenicity 
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons   

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14.5 
Pharmacodynamic Analyses 
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by a 
one-stage clotting assay and/or chromogenic substrate assay (activity level), will be used for 
plasma profiles; FVIII activity will be used to determine PD parameters.  Traditional PK 
analysis is not applicable. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics.  
14.6 
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of subjects who report hepatitis will be presented. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided.  
Detailed statistical methods will be provided in the SAP. 
14.7 
Determination of Sample Size 
No formal sample size calculations based on statistical power were performed.
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 15 subjects may be dosed in the study; the actual number of 
subjects will depend on the criteria for dose escalation.  
14.8 
Analysis Populations 
The Safety analysis population is defined as all enrolled subjects who receive any study drug. 
The analysis of safety data will be performed on Safety Set.

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The Full Analysis Set (FAS) is defined as all enrolled subjects who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis.
14.9 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IEC must be sought, and the 
Investigator should inform BioMarin and the full IEC within 2 working days after the 
emergency occurs.  
With the exception of minor administrative or typographical changes, the IEC must review 
and approve all protocol amendments. Protocol amendments that have an impact on subject 
risk or the study objectives, or require revision of the ICF, must receive approval from the 
IEC prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the IEC, and all 
active subjects must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 

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15 
DATA REVIEW BOARD 
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established. 
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available subject safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene 
for further assessment of subject safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites. 

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COSTS, COMPENSATION, AND SUBJECT INJURY 
BioMarin will pay the full costs of the study-related tests, procedures, and treatments set 
forth in this protocol. In addition, after IEC approval, BioMarin may reimburse the 
reasonable cost of travel for study-related visits in accordance with BioMarin’s travel and 
reimbursement policy. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. BioMarin 
or the institution may pay for reasonable and necessary medical services to treat the injuries 
caused by the IP or study procedures. In some jurisdictions, BioMarin is obligated by law to 
pay for study-related injuries. If this is the case, BioMarin will comply with the law. 
BioMarin will not pay for any hospitalizations, tests, or treatments for medical problems of 
any sort related solely to the study subject’s primary disease or any concurrent disease and 
that are unrelated to this study. 

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CASE REPORT FORMS AND SOURCE DOCUMENTS
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy.
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to 
their medical records, and subjects will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
subject records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification. 
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a subject’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. 

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Upon completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 

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STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas AND to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. When in person site 
monitoring or source data verification cannot be conducted, remote site monitoring and/or 
source data verification will be conducted where allowed by country and local health 
authorities and IECs. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 

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RETENTION OF RECORDS 
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained.

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USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  

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REFERENCES 
Bainbridge, JW, Smith, AJ, Barker, SS, Robbie, S et. al. Effect of gene therapy on visual 
function in Leber's congenital amaurosis. N Engl J Med 358[21], 2231-2239. 2008. 
Berntorp, E, Peake, I, Budde, U, Laffan, M et. al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia 18 Suppl 6, 1-13. 2012. 
Croteau, GA, Martin, DB, Camp, J, Yost, M et. al. Evaluation of exposure and health care 
worker response to nebulized administration of tgAAVCF to patients with cystic fibrosis. 
Ann Occup Hyg 48[8], 673-681. 2004. 
D'Avola, D. Phase 1 Clinical Trial of Liver Directed Gene Therapy with rAAV5-PBGD in 
Acute Intermittent Porphyria: Preliminary Safety Data. J Hepatol 60[S58]. 2014. 
Den Ujil, Mauser Bunschoten, Roosendaal, Schutgens et. al. Clinical Severity of haemophilia 
A: does the classification of the 1950s still stand? Haemophilia 17, 849-853. 2011. 
George LA, Sullivan S, Teitel J, Cuker A et al.  Preliminary results of a phase 1/2 trial of 
SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent 
factor IX activity levels at the lowest dose cohort.  Haemophilia. 2016;22(S4):151-152. 
Grant A, Neuberger J, Day C, Saxseena S. British Society of Gastroenterology Guidelines on 
the use of Liver Biopsy in Clinical Practice. 2004. Available at: 
https://www.bsg.org.uk/resource/bsg-guidelines-on-the-use-of-liver-biopsy-in-clinical-practi
ce.html (last visited 1 December 2018). 
Hay, CR, DiMichele, DM. The principal results of the International Immune Tolerance 
Study: a randomized dose comparison. Blood 119[6], 1335-1344. 2012. 
Iorio A, Stonebraker JS, Chambost H, et al, for the Data and Demographics Committee of the 
World Federation of Hemophilia. Establishing the Prevalence and Prevalence at Birth of 
Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med. 
2019;171(8):540-546. 
Kaufman, RJ, Powell, JS. Molecular approaches for improved clotting factors for hemophilia 
1. Blood 122[22], 3568-3574. 2013. 
Maguire, AM, High, KA, Auricchio, A, Wright, JF et. al. Age-dependent effects of RPE65 
gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 
374[9701], 1597-1605. 2009. 

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Mahlangu, J, Powell, JS, Ragni, MV, Chowdary, P et. al. Phase 3 study of recombinant factor 
VIII Fc fusion protein in severe hemophilia A
8. Blood 123[3], 317-325. 2014. 
Manno, CS, Chew, AJ, Hutchison, S, Larson, PJ et. al. AAV-mediated factor IX gene 
transfer to skeletal muscle in patients with severe hemophilia B
1. Blood 101[8], 2963-2972. 2003. 
Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006. 
Mannucci, PM, Tuddenham, EG. The hemophilias--from royal genes to gene therapy 
1. N Engl J Med 344[23], 1773-1779. 2001. 
McIntosh, J, Lenting, PJ, Rosales, C, Lee, D et. al. Therapeutic levels of FVIII following a 
single peripheral vein administration of rAAV vector encoding a novel human factor VIII 
variant. Blood 121[17], 3335-3344. 2013. 
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016. 
Nagel, K, Walker, I, Decker, K, Chan, AK et. al. Comparing bleed frequency and factor 
concentrate use between haemophilia A and B patients. Haemophilia 17[6], 872-874. 2011. 
Nathwani, AC, McIntosh, J, Davidoff, AM. An update on gene therapy for hemophilia. Curr 
Hematol Rep 4[4], 287-293. 2005. 
Nathwani, AC, Gray, JT, Ng, CY, Zhou, J et. al. Self-complementary adeno-associated virus 
vectors containing a novel liver-specific human factor IX expression cassette enable highly 
efficient transduction of murine and nonhuman primate liver. Blood 107[7], 2653-2661. 
2006. 
Nathwani, AC, Rosales, C, McIntosh, J, Rastegarlari, G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011. 
Nathwani, AC, Tuddenham, EG, Rangarajan, S, Rosales, C et. al. Adenovirus-associated 
virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365[25], 2357-2365. 
2011. 
Nathwani, AC, Reiss, UM, Tuddenham, EG, Rosales, C et. al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014. 

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National Hemophilia Foundation. MASAC recommendation for liver biopsies in gene 
therapy trials for hemophilia. Available at https://hemophilia.org/sites/default/files/ 
document/files/256.pdf. 2019. MASAC Recommendation #256. Last accessed 20 July 2021. 
Paneda, A, Lopez-Franco, E, Kaeppel, C, Unzu, C et. al. Safety and liver transduction 
efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute 
intermittent porphyria. Hum Gene Ther 24[12], 1007-1017. 2013. 
Pasi KJ, Rangarajan S, Mitchell N, Lester W et al. Multiyear Follow-up of AAV5-hFVIII-SQ 
Gene Therapy for Hemophilia A. N Engl J Med. 2020;382(1):29-40. 
Schenk-Braat, EA, van Mierlo, MM, Wagemaker, G, Bangma, CH et. al. An inventory of 
shedding data from clinical gene therapy trials. J Gene Med 9[10], 910-921. 2007. 
Simonelli, F, Maguire, AM, Testa, F, Pierce, EA et. al. Gene therapy for Leber's congenital 
amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18[3], 
643-650. 2010. 
Srivastava A, Santagostino E, Dougall A, Kitchen S et. al. WFH guidelines for the 
management of hemophilia, 3rd edition. Haemophilia. 2020;26(Suppl 6):1-158. 
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010. 

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INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Patients  
In accordance with FDA Form 1572 and/or principles of ICH E6 R2 GCP, the Investigator 
will ensure that: 
 He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
 He or she will personally conduct or supervise the study. 
 He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or ICH E6 
R2 Sections 2.9 and 4.8 are met. As well, he or she will ensure that IEC review and 
approval in 21 CFR Part 56 and/or ICH E6 R2 Section 2.6 are met.  
 He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 R2 Section 4.11. 
 He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
 His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments. 
 Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 R2 
Section 4.9 are kept, and those records are available for inspection in accordance with 
21 CFR 312.68 and/or ICH E6 R2 Section 4.9.7. 
 The IEC complies with the requirements of 21 CFR Part 56, ICH E6 R2 Section 3.0, 
and other applicable regulations, and conducts initial and ongoing reviews and 
approvals of the study. He or she will also ensure that any change in research activity 
and all problems involving risks to human patients or others are reported to the IEC. 
Additionally, he or she will not make any changes in the research without IEC 
approval, except where necessary to eliminate apparent immediate hazards to human 
patients.
 He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6 R2. 

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SIGNATURE PAGE
Protocol Title: A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII in Patients with Severe Haemophilia A
Protocol Number: 270-201 Amendment 10
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
ICH E6 R2, as stated in the protocol, and other information supplied to me. 
Investigator Signature
Date
Printed name _______________________________________________________________ 
Accepted for the Sponsor:
Medical Monitor Signature
Date
Printed name: 
 MD, PhD, 
, Clinical Sciences
PI
PI
PI
PI
PI

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PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See page 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font. 
Section No./Title 
Revision 
Rationale
2/Synopsis (Study 
Design and Plan) 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume 
prior FVIII prophylaxis. Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either 
failure to a
 5 IU/dL by Week 52 orand inability to maintain independence from prophylactic FVIII 
replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion 
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the 
discretion of the Investigator. 
… 
Liver Biopsy Substudy Design 
Participation in the sub-study may include liver biopsies at one or more time points. 
1, 5, 9
5.1/Institutional Review 
Board or Independent 
Ethics Committee 
Prior to initiating the study, the Investigator will obtain written confirmation that the institutional review board (IRB) or 
independent ethics committee (IEC) [for Canadian protocols, Research Ethics Board (REB)] is properly constituted and 
compliant with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) and Good Clinical Practice (GCP) requirements, applicable laws and local regulations. A copy of the 
confirmation from the IRB/IEC/REB will be provided to BioMarin or its designee. The Investigator will provide the 
IRB/IEC/REB with all appropriate material, including the protocol, Investigator’s Brochure (IB), the Informed Consent Form 
(ICF) including compensation procedures, and any other written information provided to the subjects, including all ICFs 
translated to a language other than the native language of the clinical site. The study will not be initiated and Investigational 
Product (IP) supplies will not be shipped to the site until appropriate documents from the IRB/IEC/REB confirming 
unconditional approval of the protocol, the ICF and all subject recruitment materials are obtained in writing by the Investigator 
and copies are received at BioMarin or its designee. The approval document should refer to the study by protocol title and 
BioMarin protocol number (if possible), identify the documents reviewed, and include the date of the review and approval. 
BioMarin will ensure that the appropriate reports on the progress of the study are made to the IRB/IEC/REB and BioMarin by 
the Investigator in accordance with applicable guidance documents and governmental regulations.
9 
5.2/Ethical Conduct of 
Study 
Specifically, this study is based on adequately performed laboratory and animal experimentation. The study will be conducted 
under a protocol reviewed and approved by an IRB/IEC/REB and will be conducted by scientifically and medically qualified 
persons.
9 

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Section No./Title 
Revision 
Rationale 
5.3/Subject Information 
and Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United States Code of Federal Regulations 
(CFR) 21 CFR §50, European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and 
other applicable local regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior to submission to the 
IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve the documents before they are implemented. 
9 
7/Introduction 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males (Nathwani, 
1992Iorio 2019). 
… 
Tightly regulated control of gene expression is not essential and a modest increase in the level of FVIII (a plasma level of 2 
ng/ml protein leads to a 1% expression) can ameliorate the severe phenotype (Srivastava, 2013 2020); thus the therapeutic 
goal for gene therapy is a modest increase in hFVIII. 
9 
7.2/Previous and 
Ongoing Clinical 
Studies 
Ongoing clinical studies for BMN 270 include:
 
270-203, a phase 2 study in patients with severe HA who have anti-AAV5 antibody titers 
270-205, a phase 1/2 study in patients with severe HA who have active or prior FVIII inhibitors
270-301, the pivotal phase 3 study in patients with severe HA who receive BMN 270 at the 6E13 vg/kg dose level
270-302, a phase 3 study in patients with severe HA who receive BMN 270 at the 4E13 vg/kg dose level
270-303, a phase 3 study in patients with severe HA who received BMN 270 at the 6E13 vg/kg dose level along with 
prophylactic corticosteroids
A comprehensive review of safety, efficacy, and immunogenicity results as of the latest data cut is contained in the IB 
supplied by BioMarin. Investigators are to review this document prior to initiating this study.
9 
7.3/Study Rationale
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males (Mannucci, 
2001Iorio 2019).
9 
7.4/Summary of Risks 
and Benefits 
Transient, asymptomatic ALT elevation (grade 1 to 3 in severity) was observed in most subjects administered BMN 270 
shortly after dosing, with no symptoms or sequelae suggestive of clinically significant hepatocyte injury or liver dysfunction. 
In almost all subjects, ALT elevations decreased quickly following corticosteroid treatment. There were differences inAcross 
the use6E13 vg/kg cohort of corticosteroids across studies. Subjects in 270-201, who received corticosteroids an average of 8 
weeks earlier following BMN 270 infusion than the mITT population and 270-301, subjects enrolled in 270-301, were more 
likely to avoid a significant decline in FVIII activity concurrently with an201 developed ALT elevation, and saw a more 
robust recovery of FVIII activity upon about 5.5 weeks later than subjects in 270-301, generally once the first usecourse of 
8, 9

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corticosteroids, was being tapered, and experienced lower peak elevations in ALT (75.7 U/L) than did the subjects in 270-301 
(112.5 U/L). The difference in the mITT population in 270-301. Despite the clinical response to steroids, no associationsALT 
profile seen between safety parameters (transient ALT rises), or efficacy as measuredthe 6E13 vg/kg subjects in 270-201 and 
the subjects in 270-301 could be attributed to the difference in the protocol-specified corticosteroid regimens in place in those 
studies, including the early use of corticosteroids (ie, by FVIII activity levels were foundWeek 3 post-BMN 270 infusion). 
While the majority of ALT elevations responded rapidly to corticosteroids, given current interest in the field of AAV gene 
therapy for the use of non-steroidal approaches to be temporally associated with anti-AAV5 antibodymanaging or preventing 
ALT elevations, alternate non-steroidal systemic immunosuppressive agents have also been used to manage hepatic reactions 
where corticosteroids have proven to be ineffective or cellular immune responses.where high doses/and or prolonged exposure 
to corticosteroids have led to unwanted side effects. Overall, the literature and clinical experience with BMN 270 suggests that 
transient elevations in liver enzymes are expected following AAV-based gene therapy for the treatment for hemophilia A or B 
without any long-term concerns of hepatic injury (Manno 2006; Nathwani 2011; George 2016; Miesbach 2016; Pasi 2020). 
9.1/Overall Study 
Design and Plan 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume 
prior FVIII prophylaxis. Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either 
failure to achieve FVIII activ
orand inability to maintain independence from prophylactic FVIII 
replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion 
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the 
discretion of the Investigator.  
5 
Table 9.1.5/Schedule of 
Events Years 2-7 
Table 9.1.5 has been updated consistent with changes made in the footnotes and elsewhere in the protocol. 
1, 6, 9 
Table 9.1.5 footnotes
ETV: Early Termination Visit
a Complete physical examination should be performed at the End of Year visits; (genitourinary examination may be deferred 
unless the subject has genitourinary-related complaints); brief physical examination may be performed at other study visits. 
Weight should be recorded at the second Q12W visit each year during Years 2-5, and at every End of Year visit during Years 
2-7.
b Refer to Table 9.7.9.2.1 for laboratory assessments to be included, and to Table 9.7.9.3.1 for liver tests.  LTs may be 
monitoredassessed more or less frequently (and in particular 
 1.5x ULN) or based onupon discussion 
between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice 
. Subjects with ALT 
1.5x ULN during the study may 
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undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) 
at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the 
ALT has increased to above ULN or increased by > 10 U/L from prior assessment; (2) Increases in ALT values from prior 
assessment are accompanied by declines in FVIII activity level; or;; or (2) after a discussion between the Medical Monitor 
and the Investigator based on a review of subject data. If FVIII levels and/orIf ALT values are stable over the course of 
several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical
Monitor and the Investigator. During Years 2-5 of the Post-Infusion Follow-Up period, urine tests and blood, chemistry, and 
coagulation tests should be performed at the second Q12W visit each year and at every End of Year visit. During Years 6-7, 
these tests should be performed at the Q26W and End of Year visits. 
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen 
modification) for hFVIII inhibitor level, and hFVIII coagulation activity exploratory assay and hFVIII antigen (ELISA).   
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion 
Follow-Up period.  Subjects who have not had 3 consecutive negative semen samples by Week 52 should continue to have 
PCR testing every 4 weeks (during Year 2), every 6 weeks (during Years 3-5), and/or every 26 weeks (during Years 6-7) 
until 3 consecutive samples below the limit of detection are documented (or upon consultation between the Investigator and 
Medical Monitor). 
h Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 may omit the Q4W and Q6W visits 
during Years 2-5, and must attend only the Q12W and End of Year visits. Such subjects following the abbreviated schedule 
who have not yet cleared vector shedding in a fluidsemen must still provide samples Q4W (during Year 2), Q6W (during 
Years 3-5), or Q26W (during Years 6-7), until vector shedding has been cleared (but do not need to do other scheduled 
assessments at those visit dates), either by reporting to the site to provide samples or by providing those samples to an MN 
professional. 
k Additional liver ultrasounds may be performed at interim timepoints (ie, between the End of Year visits) at the discretion of
the Investigator.
Table 9.1.6/Therapeutic
Reactive Corticosteroids
Table 9.1.6 has been update consistent with changes made elsewhere in the protocol and in the footnotes.
4, 9
Table 9.1.6 footnotes
a TherapeuticReactive
and liver enzyme data after consultation between the Investigator and the Medical Monitor.
b
decisions will based on discussions between the Investigator and Medical Monitor.  Modification of the steroid regimen may 
4, 9 

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take into consideration timing of the ALT elevation (after Week 52), as well as possible confounders for the ALT elevation 
and adverse events related to corticosteroid dosing impact on FVIII expression.. Guidance for tapering oral corticosteroids 
can be found in Section 9.4.8.2.
9.4.8/Prior and 
Concomitant 
Medications 
Administration of SARS-CoV-2 vaccine after BMN 270 infusion may occur after consultation between Investigator and 
Medical Monitor. Investigators should use clinical judgment, taking into consideration local factors, individual risk factors, 
and the benefit/risk related to timing of vaccine administration. 
3 
9.4.8.1/Concomitant 
Hemophilia Treatments 
Subjects on “on demandepisodic” therapy for FVIII will continue their treatment at will.  Subjects on prophylactic FVIII 
therapy will discontinue their treatment starting the day of infusion and switch to an “on demandepisodic” schedule. 
9 
9.4.8.2.1/Therapeutic
Reactive Corticosteroids 
In general, therapeuticreactive 
 1.5x ULN, or based on review 
of FVIII and liver enzyme data after consultation between the Medical Monitor and the Investigator. Corticosteroids may be 
delayed, upon discussion with the Medical Monitor, if elevations in ALT are clearly not related to BMN 270 (eg, elevated 
ALT with concurrent increase in CPK due to intensive exercise) and in particular for elevations occurring more than 52 weeks 
after BMN 270 dosing.
… 
Following initiation or completion of therapeuticreactive 
 1.5x ULN is reported, steroid 
management decisions will based on discussions between the Investigator and Medical Monitor. Modification of the steroid 
regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression.   
Unless otherwise indicated, treatment with prednisolone willreactive corticosteroids should be initiated at a dose of 60 mg per 
day and then gradually tapered if the ALT level remains stable or declines after 2 weeks (60 mg daily for the first 2 weeks, 
then 40 mg the next 2 weeks, then 30 mg the next two weeks, then 20 mg the next two weeks, then 15 mg for the next week, 
then 10 mg for the next week, then 5 mg for the next week, then stop, for a total treatment of 11 weeks) (refer to Table 9.1.6).  
Should a scenario arise in which differences from the minimum recommended dose and/or duration of reactive corticosteroids 
may be clinically indicated, a discussion should take place between the Investigator and Medical Monitor regarding 
corticosteroid dose adjustments. Management of ALT elevations with reactive corticosteroids, including tapering of doses and 
managing worsening and/or recurrent ALT elevations, should be guided by the following (Table 9.4.8.2.1.1):
4, 9
Table 9.4.8.2.1.1/ 
Management of ALT 
Elevations with 
Corticosteroids
Table 9.4.8.2.1.1 and its footnotes have been added.
4 

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9.4.8.2.1/Therapeutic 
Reactive Corticosteroids 
(cont.) 
When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT workup, the following tests should be 
performed (Table 9.4.8.2.1.2): 
4 
Table 9.4.8.2.1.2/Viral 
and Autoimmune 
Hepatitis Testing 
Table 9.4.8.2.1.2 has been added 
4 
9.4.8.2.1/Therapeutic 
Reactive Corticosteroids 
(cont.) 
After discontinuation of reactive corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 
weeks to ensure stability in values. 
Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in 
consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid 
treatment, and specific monitoring not already covered by the schedule of events. The use of COX-2 inhibitors, while not 
contraindicated during corticosteroid treatment, should be limited, if possible.  Practical management to prevent complications 
related to oral corticosteroid therapy may be undertaken at the discretion of the Investigator (eg, evaluation of glucose 
intolerance, hyperlipidemia etc.). For the subjects with a past medical history of hepatitis B or hepatitis C prior to study entry, 
Hepatitis B status and HCV viral load will be rechecked 6 weeks after the start of corticosteroid treatment, and then 1 week 
and 13 weeks after the completion of corticosteroid treatment. All adverse events should be reported as outlined in Section 10 
of the protocol. 
Subjects on corticosteroids should receive appropriate counselling and support regarding side effects from the Investigator or 
the treating institution (eg, listings of side effects and when to notify carers, wallet card for emergencies if on steroids, etc.). 
Additional management, including the co-prescription of additional medications to prevent complications related to 
corticosteroid therapy, may be undertaken at the discretion of the investigator, including, but not limited to, prophylaxis 
against the occurrence of gastric ulcers, osteoporosis, and infections.
4, 9
9.7.2/Primary Efficacy 
Variables 
FVIII activity assays will also be performed at the local laboratory at the time points indicated in Table 9.1.2, Table 9.1.3, 
Table 9.1.4, and Table 9.1.5 but will be used in conjunction with local lab LT assessments to monitor subject safety and need 
for initiation of therapeuticreactive corticosteroid dosing; local laboratory FVIII activity assessments will not be used to assess 
efficacy or to measure the primary efficacy outcome of the study.
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
orand inability to maintain independence from prophylactic FVIII replacement therapy due to 
4, 5

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joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the discretion of the Investigator.  
9.7.8/Liver Biopsy 
Substudy 
Participation in the substudy may include liver biopsies at one or more time points. 
1, 9 
9.7.9.3/Malignancies
Liver ultrasounds will be performed annually at each End of Year visit starting at Year 5 (Week 260) through the end of the 
study to screen for HCC. Additional liver ultrasounds may be performed between the End of Year visits at the discretion of the 
Investigator. 
Any development of a malignancy (except non-melanoma skin cancers) during the course of the study will be considered an 
EOSI (refer to Section 10.2.1) and is subject to expedited reporting. In addition, it is recommended that genomic analyses be 
performed on any malignancy (except non-melanoma skin cancers) diagnosed during the course of the study. The study site 
will coordinate sending samples from the malignancy for genomic analyses, if available.
1 
9.7.8.6/Vital Signs and 
Physical Exams 
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 and at the End of Years visits 
thereafter. A complete physical examination will include general appearance (head, eyes, ears, nose, and throat), 
cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. 
The genitourinary examination may be deferred for visits after Year 1 unless the subject has genitourinary-related complaints. 
9 
9.7.9.7/Vector Shedding
Vector shedding will also be extensively studied in the present clinical trial, every other week between Weeks 4-16, then every 
4 weeks to Week 52 until at least 3 consecutive negative results are obtained. Testing of semen will continue through Week 
12, even if 3 consecutive negative results have been recorded in that compartment prior to that timepoint.  Subjects who have 
not had 3 consecutive negative semen samples by Week 52 should continue to have PCR testing every 4 weeks (during Year 
2), every 6 weeks (during Years 3-5), and every 26 weeks (during Years 6-7) until 3 consecutive semen samples below the 
limit of detection of the test are documented (or upon consultation between the Investigator and Medical Monitor). Subjects 
who meet the definition of treatment failure and wish to follow an abbreviated schedule (refer to Section 12.5.3 but who have 
not cleared vector shedding from all fluidssemen must still provide samples for assessment until vector shedding has cleared: 
every 4 weeks (during Year 2), every 6 weeks (during Years 3-5), or every 26 weeks (during Years 6-7), either by reporting to 
the site to provide samples or by providing those samples to an MN professional. 
9 
10.2.1/EOSI
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, irrespective of seriousness, severity 
or causality: 
2 

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Any new diagnosis of malignancy (except non-melanoma skin cancer)
10.8/Urgent Safety 
Measures 
The reporting period for these events which may require the implementation of urgent safety measures is the period from the 
time of signing of the ICF through the completion of the last study visit or at the Early Termination Visit (ETV). Investigators 
are required to report any events which may require the implementation of urgent safety measures to BioMarin within 
24 hours of becoming aware of the event. 
9 
10.9/Contact 
Information 
The medical monitor contact information has been updated 
7 
12.8/Safety Follow-Up 
Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
orand inability to maintain independence from prophylactic FVIII replacement therapy due to 
joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of 
Year visits during Years 2-5. 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule but who have not cleared 
vector shedding from a fluidsemen must still provide samples for assessment every 4 weeks (during Year 2) or every 6 weeks 
(during Years 3-5) until vector shedding has cleared (but do not have to perform other scheduled assessments at those study 
visits). 
5, 9 
12.8.2/Years 3-5 Every 
6 Weeks 
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment
o
LTs may be monitoredassessed more or less frequently (and in particular when ALT values are >1.5x 
ULN) or based onupon discussion between the Medical Monitor and the Investigator and review of 
subject data.
Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment
o
LTs may be monitoredassessed more or less frequently (and in particular when ALT values are >1.5x 
ULN) or based onupon discussion between the Medical Monitor and the Investigator and review of
subject data.
FVIII Assays – central laboratory assessment
o
FVIII antigen (ELISA)
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PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule but 
who have not cleared vector shedding from fluidsemen, must still provide samples of that fluid for 
assessment every 6 weeks during Years 3-5 until vector shedding has cleared (in such a case, these 
subjects do not need to perform other assessments except for PCR sample delivery scheduled at these 
timepoints). 
12.8.3/Years 3-5 Every 
12 Weeks and End of 
Year Visits 
At the every 12 week and End of Year visits, the following procedures will be performed:
Brief physical examination (at every 12 week visits) or complete physical examination (at End of Year visits)
(genitourinary examination may be deferred unless the subject has genitourinary-related complaints) 
 
Liver Tests (refer to Table 9.7.9.3.1) – local laboratory assessment 
o
LTs may be monitoredassessed more or less frequently (and in particular when ALT values are >1.5x 
ULN) or based onupon discussion between the Medical Monitor and the Investigator and review of 
subject data. 
Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment
o
LTs may be monitoredassessed more or less frequently (and in particular when ALT values are >1.5x 
ULN) or based onupon discussion between the Medical Monitor and the Investigator and review of 
subject data.
FVIII Assays – central laboratory assessment
o
FVIII antigen (ELISA)
FVIII antigen (ELISA)
 
AAV5 antibody titer (at End of Year visits only) 
 
FVIII antibody titer (at End of Year visits only) 
 
Liver ultrasound (at End of Year 5 visit only) 
o
Additional liver ultrasounds may be performed at interim time points (ie, between the End of Year 
visits) at the discretion of the Investigator.
1, 4, 6, 9 
12.9.2/Years 6-7 Every 
26 Weeks and End of 
Year 
During Years 6-7, the following assessments will be performed at a site visit every 26 weeks ( ± 4 weeks) (Week 286 and 
Week 338) and at the End of Year Visits ( ± 4 weeks) (Week 312 and Week 364):
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Complete Physical Examination (genitourinary examination may be deferred unless the subject has 
genitourinary-related complaints) (Week 312 and Week 364 only) 
 
Liver Tests (refer to Table 9.7.9.3.1) – central laboratory assessment 
o
LTs may be monitoredassessed more or less frequently (and in particular when ALT values are >1.5x ULN) 
or based onupon discussion between the Medical Monitor and the Investigator and review of subject data. 
 
FVIII Assays – central laboratory assessment 
o
FVIII antigen (ELISA)
FVIII antigen (ELISA)
 
Liver ultrasound (Week 312 and Week 364 only) 
o
Additional liver ultrasounds may be performed at interim time points at the discretion of the Investigator.
12.10/Liver Biopsy 
Substudy 
Participation in the substudy may include liver biopsies at one or more time points.
1, 9 
12.11/ETV
At the Early Termination visit, as many of the following assessments as possible should be done:
 
FVIII Assays – central laboratory assessment 
o
FVIII antigen (ELISA)
FVIII antigen (ELISA)
Liver ultrasound
1, 6
14.9/Changes in Study 
Conduct 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary by the Investigator will be made 
only after consultation with BioMarin, who will then issue a formal protocol amendment to implement the change. The only 
exception is when an Investigator considers that a subject’s safety is compromised without immediate action. In these 
circumstances, immediate approval of the chairman of the IRB/IEC/REB must be sought, and the Investigator should inform 
BioMarin and the full IRB/IEC/REB within 2 working days after the emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/IEC/REB must review and approve all protocol 
amendments. Protocol amendments that have an impact on subject risk or the study objectives, or require revision of the ICF, 
must receive approval from the IRB/IEC/REB prior to their implementation. 
9 

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When a protocol amendment substantially alters the study design or the potential risks or burden to subjects, the ICF will be 
amended and approved by BioMarin and the IRB/IEC/REB, and all active subjects must again provide informed consent. 
16/Costs, 
Compensation, and 
Injury 
BioMarin will pay the full costs of the study-related tests, procedures, and treatments set forth in this protocol. In addition, 
after IRB/IEC/REB approval, BioMarin may reimburse the reasonable cost of travel for study-related visits in accordance with 
BioMarin’s travel and reimbursement policy. 
9 
18/Study Monitoring
When in person site monitoring or source data verification cannot be conducted, remote site monitoring and/or source data 
verification will be conducted where allowed by country and local health authorities and IECs. 
9 
21/References 
George LA, Sullivan S, Teitel J, Cuker A et al.  Preliminary results of a phase 1/2 trial of SPK-9001, a hyperactive FIX variant 
delivered by a novel capsid, demonstrate consistent factor IX activity levels at the lowest dose cohort.  Haemophilia. 
2016;22(S4):151-152.
Heller CG & Clermont Y.  Kinetics of the germinal epithelium in man.  Recent Prog Horm Res.  1964;20:545-571.
Heller CG, Heller GV, Rowley MJ.  Human spermatogenesis: an estimate of the duration of each cell association and each cell 
type.  Excerpta Med Int Congr Ser.  1969;184:1012-1018.
Iorio A, Stonebraker JS, Chambost H, et al, for the Data and Demographics Committee of the World Federation of 
Hemophilia. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using 
National Registries. Ann Intern Med. 2019;171(8):540-546.
Monahan, P, Walsh CE, Powell JS, Konkle BA et al.  Update on a phase 1/2 open-label trial of BAX335, an adeno-associated 
virus 8 (AAV8) vector-based gene therapy program for hemophilia B.  J Thromb Haemostasis 13[Suppl 2], 1-997.  2015.
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin Haematol 5[2], 383-439. 1992.
National Hemophilia Foundation. MASAC recommendation for liver biopsies in gene therapy trials for hemophilia. Available 
at https://hemophilia.org/sites/default/files/ document/files/256.pdf. 2019. MASAC Recommendation #256. Last accessed 5 
June 202020 July 2021. 
Pasi KJ, Rangarajan S, Walsh LMitchell N, Lester W et al. Multiyear Follow-up of AAV5-Factor-hFVIII-SQ Gene Transfer in 
SevereTherapy for Hemophilia A. NEJM. 2017;377(26):2519-2530N Engl J Med. 2020;382(1):29-40. 
Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NSSantagostino E, Dougall A, Kitchen S et. al. WFH guidelines 
for the management of hemophilia., 3rd edition. Haemophilia 19[. 2020;26(Suppl 6):1], e1-47. 2013-158. 
9 

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Watkins, PB, Kaplowitz, N, Slattery, JT, Colonese, CR et al.  Aminotransferase Elevations in Healthy Adults Receiving 4 
Grams of Acetaminophen Daily: A Randomized Controlled Trial.  JAMA 296[1], 87-93.  2006. 
White, GC, Rosendaal, F, Aledort, FM, Lusher, JM et al.  Definitions in hemophilia.  Recommendation of the scientific 
subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International society on 
Thrombosis and Haemostasis.  Thromb Haemost. 85[3], 560.  2001. 
22.1/Conduct of Study 
In accordance with FDA Form 1572 and/or principles of ICH E6 R2 GCP, the Investigator will ensure that: 
He or she will inform any potential patients, or any persons used as controls, that the drugs are being used for 
investigational purposes and he or she will ensure that the requirements relating to obtaining informed consent in 21 
CFR Part 50 and/or ICH E6 R2 Sections 2.9 and 4.8 are met. As well, he or she will ensure that IRB/ IEC review and 
approval in 21 CFR Part 56 and/or ICH E6 R2 Section 2.6 are met. 
 
The IRB/IEC/REB complies with the requirements of 21 CFR Part 56, ICH E6 R2 Section 3.0, and other applicable 
regulations, and conducts initial and ongoing reviews and approvals of the study. He or she will also ensure that any 
change in research activity and all problems involving risks to human patients or others are reported to the 
IRB/IEC/REB. Additionally, he or she will not make any changes in the research without IRB/IEC/REB approval, 
except where necessary to eliminate apparent immediate hazards to human patients. 
9 
23/Signature Page 
Printed name: 
Nina Mitchell, MA MB BChir MSc,Tara Robinson, MD, PhD, Associate Medical Director, Clinical 
ScienceSciences
7 

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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
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Table 9.1.1: Schedule of Events – Screening and Infusion 
Assessment 
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BMN 270 
Infusion 
Visit (Day 1)k 
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) 
Assessment 
Follow-Up After BMN 270 Administration – Weeks* 
Week 1 
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4 
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6 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) 
Assessment
Follow-Up After BMN 270 Administration – Weeks* 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
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Assessment 
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Table 9.1.6:  Schedule of Events – Therapeutic Corticosteroids for LT Elevations 
 
Steroid Treatment Periodd 
Post-Steroid Periodc 
 
Week 
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2 
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3 
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4 
Week 
5 
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6 
Week 
7 
Week 
8 
Week 
9 
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10 
Week 
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4 
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Table 9.1.7:  Schedule of Events – Liver Biopsy Substudy 
 
Within 28 Days 
Before Biopsy Day 
Within 7 Days 
Before Biopsy Day 
1 Day Before Biopsy 
Day d 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
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Selection of Study Population 
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9.3.3 Liver Biopsy Substudy Inclusion and Exclusion Criteria 
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9.4.2 Identity of Investigational Product 
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Product Characteristics and Labeling 
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Glucocorticoid Treatment of Elevated Hepatic Transaminases 
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9.7.5 Pharmacodynamics 
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9.7.8 Liver Biopsy Substudy 
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9.7.9 Safety Variables 
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9.7.9.1 
Adverse Events 
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9.7.9.2 
Clinical Laboratory Assessments 
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Table 9.7.9.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
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Albumin 
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Calcium 
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including:
Chloride 
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Total cholesterol 
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CO2 
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Phosphorus 
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9.7.9.3 
Liver and Hepatitis Testing 
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Table 9.7.9.3.1:  Liver Tests 
Liver Tests (LTs) 
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9.7.9.4 
HIV Testing 
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9.7.9.5 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
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9.7.9.6 
Vector Shedding 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
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10.1.1.1 
Bleeding and Suspected Bleeding Events 
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10.2 
Serious Adverse Events 
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10.3 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.3.1 Adverse Event Reporting Period 
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Grade 
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10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on a eCRF 
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10.4.1.1 
Diagnosis versus Signs and Symptoms 
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10.4.1.2 
Adverse Events Occurring Secondary to Other Events 
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10.4.1.3 
Persistent or Recurrent Adverse Events 
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10.4.1.4 
Abnormal Laboratory Values 
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10.4.1.5 
Pre-existing Conditions 
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10.4.1.6 
General Physical Examination Findings 
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10.4.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
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10.4.1.8 
Deaths 
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10.4.1.9 
Pregnancy 
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10.5 
Reporting Requirements 
10.5.1 Expedited Reporting Requirements 
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10.7 
Post-Study Adverse Events 
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10.8 
Urgent Safety Measures 
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APPROPRIATENESS OF MEASUREMENTS 
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STUDY PROCEDURES 
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Prestudy 
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BMN 270 Infusion Follow-Up Visits 
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12.6 
Safety Follow-Up – Weeks 17-36 
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12.6.1 Once per week (Weeks 17 through 36) 
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12.6.3 Every 2 weeks (Weeks 21 through 36) 
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12.6.5 Every 8 Weeks  
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12.6.6 Week 26 
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12.7 
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12.7.1 Once per visit 
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12.7.2 Every 4 Weeks  
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12.7.4 Week 38 and 52 
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12.8 
Safety Follow-Up – Years 2-5 
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STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
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14.6 
Safety Analysis 
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Proprietary and Confidential
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene 
Transfer of Human Factor VIII in Patients with Severe Haemophilia A
Protocol Number:
270-201
Active Investigational Product:
AAV5-hFVIII-SQ
IND/European Union Drug 
Regulating Authorities Clinical 
Trials (EudraCT) Number:
2014-003880-38
Indication:
Haemophilia A
Sponsor:
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
Development Phase:
Phase 1/2
Sponsor's Responsible Medical 
Monitor:
, MA MB BChir MSc
BioMarin (UK) Ltd.
10 Bloomsbury Way
London, WC1A 2SL
Duration of Subject 
Participation:
Approximately 264 weeks
Dose:
Varied
Study Population:
Males aged 18 or older
Date of Original Protocol:
10 February 2015
Date of Amendment 1:
06 March 2015
Date of Amendment 2:
26 May 2015
Date of Amendment 3:
06 November 2015
Date of Amendment 4:
02 September 2016
Date of Amendment 5:
14 February 2017
Date of Amendment 6:
21 December 2017
Date of Amendment 7:
10 October 2018
Date of Amendment 8:
31 January 2019
Property of BioMarin
CONFIDENTIAL
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270-201 Amendment 8 
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31 January 2019
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 8
Date:  31 January 2019 
RATIONALE AND SUMMARY OF MAJOR CHANGES
A summary of major changes covered by Amendment 8 to the 270-201 protocol is provided 
below.   
1. An optional liver biopsy substudy has been added to the protocol. 
Rationale: BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of 
hFVIII under the control of a liver-selective promoter. It was designed to direct long term 
FVIII transgene expression within the liver as measured by an increase in circulating levels 
of hFVIII and produce less frequent episodes of bleeding and the need for exogenous FVIII 
infusions. Health of the liver after gene transduction has been monitored indirectly by 
periodic assessments of hepatic enzymes released into the blood stream. Inter-subject 
variability in post-therapy hFVIII levels has been observed. Neither the reasons for the 
variations in response to FVIII gene therapy nor the effects on hepatic tissue structure and 
function are known. The purpose of this exploratory substudy is to provide a better 
understanding of the variation in hFVIII levels observed after gene therapy by direct 
examination of liver tissue for any pathologic alterations within the liver or alterations in 
hepatocyte structure and to characterize the transduced gene form and distribution. 
2. Assessment of the Direct Thrombin Activity test has been removed from the Year 
2-5 follow-up visits. 
Rationale: Based on the lack of correlation observed between FVIII activity levels and 
Direct Thrombin Activity results in 270-201 to date, it has been determined that samples for 
this exploratory test will no longer be collected during long-term follow-up. 
3. Minor administrative changes have been made for consistency and clarity.
Specific changes included in this amendment, including the Synopsis, since 
Amendment 7 (approved 10 October 2018) are outlined in Section 24.
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2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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TITLE OF STUDY: 
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of BMN 270, an 
Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients 
with Severe Haemophilia A
PROTOCOL NUMBER:
270-201
STUDY SITES:
Approximately 6-10 sites worldwide.
PHASE OF DEVELOPMENT:
Phase 1/2
STUDY RATIONALE:
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an 
essential cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to 
a new mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 
1-5% of wild type activity and the mild form is 5-40% activity. The clinical manifestations of 
severe HA remain frequent spontaneous bleeding episodes, predominantly in joints and soft 
tissues, with a substantially increased risk of death from haemorrhage when the brain is involved.  
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life for 
FVIII (12 to 18 hours for most approved products) necessitates frequent infusions, and although a 
major advance in the treatment of HA, it remains common for severe HA patients to continue to 
have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up 
to 30 to 50 episodes/year for on demand treatment). The consequence of multiple bleeding events 
is the development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death. Chemical modification (eg, direct conjugation 
of polyethylene glycol (PEG) polymers) and bioengineering of FVIII (eg, FVIII-Fc fusion 
proteins) improve half-life by approximately 50%, and thus, show promise in reduced dosing and 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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maintaining activity levels above 1% trough. However, these longer acting FVIIIs remain 
dependent on multiple infusions to maintain critical levels of FVIII activity in severe HA patients. 
There is therefore a strong unmet need for a fully preventive treatment of HA to give patients a 
FVIII level compatible with a normal and haemorrhage-free life. 
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach because 
clinical manifestations are attributable to the lack of a single gene product (FVIII) that circulates in 
minute amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not 
essential, and modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml 
induces an increase in activity of 1%) can ameliorate the severe form of the disease.  Thus, 
relatively small changes in endogenous FVIII activity results in clinically relevant improvements 
in disease phenotype. Finally, the response to gene transduction can be assessed using validated 
quantitative rather than qualitative endpoints that are easily assayed using established laboratory 
techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific 
tissues such as the liver (for serotypes 2, 5 and 8 among others). Indeed, an on-going gene therapy 
clinical trial for a related disorder, haemophilia B, has established that stable (>36 months) 
expression of human factor IX at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
administration of AAV-8 vector. Several participants in this trial have been able to discontinue 
factor prophylaxis without suffering spontaneous haemorrhages, even when they undertook 
activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a liver-selective promoter (Figure 1).
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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Figure 1. hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from vector-transduced 
liver tissue. The clinical study 270-201 is a first-in-human study designed to assess the relationship 
of vector dose to the augmentation of residual FVIII activity, and whether these levels are 
sufficient to alter the clinical phenotype. The relationship of dose to safety will be correlated to the 
activity of hFVIII in patients with severe HA.
Liver Biopsy Substudy Rationale
The pattern of response in hFVIII activity observed so far after administration of BMN 270
demonstrates peak expression levels during the first 6-12 months post-treatment followed by a 
decline to a steady-state level of expression in the second year of follow-up, with mean hFVIII 
activity levels remaining above the lower limit of normal (50 IU/dL).  One of the explanations may 
lie in the kinetics of vector genome processing which involves a series of steps such as DNA 
degradation and repair, annealing, and circularization that can result in the formation of stable 
double-stranded circularized transgene DNA forms, and it is these circularized DNA species that 
are thought to be associated with long-term, persistent expression of the gene product in target 
cells.  Examination of transduced hepatocytes from subjects treated with BMN 270 in the 270-201
study will help to establish whether DNA circularization may occur and could account for the 
long-term hFVIII expression observed in humans.
Additionally, health of the liver after gene transduction has been monitored indirectly by periodic 
assessments of hepatic enzymes released into the blood stream.  Transient post-treatment 
elevations in ALT levels have been observed in some subjects, as well as inter-subject variability 
in post-therapy hFVIII levels. Neither the reasons for, nor the significance of, the ALT elevations 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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or variations in response to FVIII gene therapy are known. Moreover, the effects of BMN 270 on 
hepatic tissue structure and function are also currently unknown. 
The purpose of this exploratory substudy is to provide a better understanding of the long-term gene 
expression related to circularized genomes, health of the liver, and variation in hFVIII levels 
observed after gene therapy with BMN 270. Whilst consenting subjects may not derive any direct 
benefit themselves by participating in the substudy, the overall findings could aid future patients 
by helping to characterize the means by which long-term efficacy is achieved and the safety of 
liver-directed gene therapy. 
OBJECTIVES: 
The primary objectives of the study are:
x
To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. 
x
To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of 
normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose.
The secondary objectives of the study are:
x
To describe the immune response to the FVIII transgene and AAV capsid proteins 
following systemic administration of AAV5-hFVIII-SQ
x
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during 
the study
x
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study
The exploratory objectives of the liver biopsy substudy are:
x
To examine the histopathology of the liver following BMN 270 therapy, including 
assessing for possible safety findings (eg, fibrosis, fatty liver disease, lymphocytic 
invasion)
x
To quantify FVIII DNA, RNA, and protein expression within hepatocytes
x
To determine which forms of rAAV vector DNA are present at the time of biopsy.
x
To determine the transduction pattern of BMN 270 in humans (ie, peri-portal hepatocytes, 
central vein hepatocytes)
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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STUDY DESIGN AND PLAN: 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will be 
taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed 
for approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and 
do not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. 
Participants will be enrolled into one of up to four cohorts according to dose level: 
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv)
Cohort 2:  2E13 vg per kilogram, iv
Cohort 3:  6E13 vg per kilogram, iv
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies 
of mice and monkeys. The starting dose has a 10-fold safety margin from no observed adverse 
effect level (NOAEL) in non-human primates. 
Cohorts 1-3
The first 3 cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between 
cohorts. Dose escalation may occur after a single subject has been safely dosed if the resulting 
FVIII activity at the Week 3 visit is < 5 IU/dL in both the one-stage clotting and chromogenic 
substrate assays. Three weeks is expected to be the time the expression will be close to the 
maximum.  This escalation paradigm is intended to minimize the subject numbers exposed to 
subtherapeutic doses.
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study, the Data Review Board (DRB). 
If the FVIII activity reaches ≥ 5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.
Subject 1 will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram of 
body weight. If the FVIII activity level does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, 
then no further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with 
Subject 2 at the next dose (2E13 vg/kg). 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥ 5 IU/dL at the 
Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and enrollment into 
Cohort 3 (6E13) will initiate with the next subject. If the FVIII activity level in the first subject 
treated in Cohort 3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then the Data 
Review Board (DRB) will recommend whether to continue to add subjects to the cohort and/or 
whether to continue the study.
For the first subject treated in each of the first 3 cohorts, if the activity level reaches ≥5 IU/dL and 
no safety issue is found, then up to four subjects will be enrolled in the Cohort, though, the 
adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts based 
on activity levels of FVIII and safety signals. 
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg. If FVIII activity in these 3 subjects is 
≥5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in this 
cohort.
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB. The adaptive nature of this trial allows the DRB to recommend allocating 
subjects to the cohorts based on activity levels of FVIII and safety signals.
As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding consideration of 
FVIII activity levels by themselves or subjects in the reporting of bleeding episodes and FVIII 
usage.
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will 
discuss whether to resume prior FVIII prophylaxis. Subjects who do not respond to BMN 270 
treatment (ie, treatment failure, manifesting as either failure to achieve FVIII activity ≥ 5 IU/dL by 
Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due 
to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, 
as applicable and at the discretion of the Investigator. Because subjects develop neutralizing 
immunity upon exposure to the capsid, re-challenge of vector is not a likely treatment option and 
these subjects have effectively a single opportunity for therapy using this AAV capsid. Efficacy 
will be determined by FVIII activity at 16 weeks post dose. Safety will be evaluated for 
approximately 5 years after dosing.  Any safety signal may trigger a review of the data and 
possible additional immunogenicity studies that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMC).
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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Dossier:
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Liver Biopsy Substudy Design
All subjects enrolled in 270-201 and who are at least one year post-BMN 270 infusion are eligible 
for the optional liver biopsy substudy. Subjects who consent to participate in the substudy will 
have a liver biopsy via either the transjugular or percutaneous (ultrasound-guided) route, according 
to the standard procedures of the institution. To enhance safety, all subjects will have an ultrasound 
examination of the liver within 3 months prior to the procedure (to ensure there are no pathological 
findings such as bile duct obstruction that might interfere with the safe performance of the liver 
biopsy) and a FibroScan of the liver within one week before the liver biopsy (to correlate with any 
potential histopathologic findings of fibrosis on the biopsy). 
Subjects who consent should have their FVIII levels monitored/adjusted by the Investigator to 
enable the procedure to be performed safely.  This may require the administration of exogenous 
FVIII replacement products in order to achieve the desired FVIII activity.  The target FVIII 
activity level within 24 hours prior to the liver biopsy is at the discretion of the Investigator and/or 
according to local guidelines, but at a minimum should be at the lower limit of the normal range 
(ie, at least 50 IU/dL).
NUMBER OF SUBJECTS PLANNED:
Up to 15 subjects may enroll into the study; the actual number of subjects will depend on the FVIII 
activity levels seen in each Cohort.
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following criteria:
1.
Males that are 18 years or older with established severe haemophilia A as evidenced by 
their medical history.  Patients will be considered as severe if their base FVIII level is 
1 IU/dL or less
2.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs)
3.
Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis
4.
Able to sign informed consent and comply with requirements of the trial
5.
No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 
12 months
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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6.
Sexually active patients must be willing to use an acceptable method of contraception such 
as double barrier, including hormonal contraception for at least 6 months post-treatment.  
After 6 months, subjects may stop contraception use only if they have had 3 consecutive 
negative semen samples.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study:
1.
Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition or AAV5 total antibodies
2.
Any evidence of active infection or any immunosuppressive disorder.  
3.
HIV positive
4.
Significant liver dysfunction as defined by abnormal elevation of:
x
ALT (alanine transaminase) to 3 times the upper limit of normal;
x
Bilirubin above 3 times the upper limit of normal;
x
Alkaline phosphatase above 3 times the upper limit of normal; or
x
INR (international normalized ratio) ≥1.4
5.
Potential participants who have had a liver biopsy in the past 3 years are excluded if they 
had significant fibrosis of 3 or 4 as rated on a scale of 0-4
6.
Evidence of any bleeding disorder not related to Haemophilia A
7.
Platelet count of < 100 x 109/L
8.
Creatinine ≥1.5 mg/dL
9.
Liver cirrhosis of any etiology as assessed by liver ultrasound 
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive
12. Treatment with any IP within 30 days prior to the end of the screening period
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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13. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study including possible corticosteroid 
treatment outlined in the protocol.  The physician may exclude patients unwilling or 
unable to agree on not using alcohol for the 16-week period following the viral infusion.
14. Prior treatment with any vector or gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion
16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral 
infusion
Individuals eligible to participate in the liver biopsy substudy must meet all of the following 
criteria:
1.
Currently enrolled in 270-201
2.
Received BMN 270 infusion at least 1 year prior to enrollment in the substudy
3.
Able to sign informed consent and comply with requirements of the substudy
4.
FVIII activity at least >50 IU/dL (or higher, depending on local guidelines and/or 
Investigator discretion) within 24 hours prior to the liver biopsy being performed.  (FVIII 
levels should be assessed at the local laboratory.)  Subjects may be treated with additional 
exogenous FVIII replacement products in order to increase their FVIII levels to an 
appropriate level, under the supervision/instruction of the Investigator.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the liver biopsy substudy:
1.
Assessed by the investigator or a hepatologist as having a medical condition such that 
undergoing a liver biopsy would be contraindicated. These conditions could include (but 
are not limited to):
x
Significant thrombocytopenia (platelet count < 100 x 109/L)
x
Evidence of significant ascites
x
Abnormalities detected on liver ultrasound (performed within 90 days of procedure) 
that would preclude safe performance of the biopsy.
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
The study is open label with comparison of FVIII activity to baseline values. No reference therapy 
will be evaluated in this study.
DURATION OF TREATMENT:
BMN 270 is given as a single dose by intravenous infusion.
CRITERIA FOR EVALUATION:
Safety:
The following safety outcome measurements will be assessed:
x
Incidence of adverse events (AEs), including serious AEs (SAEs)
x
Change in clinical laboratory tests (serum chemistry and haematology)
x
Change in vital signs
x
Change in physical examination 
x
Vector shedding
x
Liver tests (LTs, including ALT, AST, GGT, LDH, bilirubin, alkaline phosphatase)
x
Immune response to FVIII transgene and AAV capsid proteins
No major toxicity is expected based on preclinical studies in mice and monkeys. Each subject will 
have comprehensive surveillance monitoring of LTs (at local labs, once per week for Weeks 1-36,
then once every 2 weeks from Week 37-52) during Year 1. LTs will be monitored every 4 weeks 
during Year 2, and then every 6 weeks for Years 3-5 post-dose in the safety extension; the 
frequency and duration of LT testing may be changed based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the 
study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration.
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Subjects will be 
asked to keep a subject diary to record the details in these areas.  
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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Pharmacodynamics:
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage 
clotting and/or chromogenic substrate assay (activity level), will be used for plasma profiles; FVIII 
activity will be used to determine PD parameters.  Traditional PK analysis is not applicable.
If supported by the FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss 
(time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  
Liver Biopsy Substudy:
The following exploratory assessments will be performed as part of the optional liver biopsy 
substudy:
x
Morphologic/pathogenic changes after FVIII gene transduction or any change that may be 
associated with sustained ALT rise 
x
Determine quantities of liver FVIII-SQ DNA/RNA
x
Determine forms of vector DNA in liver at the time of biopsy
x
Determine percentage of hepatocytes expressing FVIII protein 
x
Determine percentage of hepatocytes staining positive for vector DNA 
x
Determine hepatic liver transcriptome at single nuclei level if sufficient material is 
obtained
x
Identify the forms of vector DNA in the liver 
x
Examination of potential stress inducing cellular pathways
x
Other exploratory assessment to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer
STATISTICAL METHODS: 
The sample size is based upon clinical considerations and could detect a strong clinical efficacy 
signal. Up to 15 subjects may be dosed in the study.  The subjects will be followed in a 
longitudinal manner and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature but data collected in a longitudinal manner may be analyzed using 
longitudinal methods such as mixed effect model which takes into account the correlation among 
the observation taken at various time points within a participant. Efficacy is a secondary endpoint, 
defined as biologically active FVIII at ≥5 IU/dL by chromogenic substrate assay and/or one-stage 
clotting assay at 16 weeks following study treatment. FVIII activity will be assessed weekly during 
the study period.  We can only assess the true steady state of FVIII protein produced from 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
BMN 270 after a minimum of 72 hours has elapsed since the last infusion of FVIII protein 
concentrates.
Analysis of neutralizing antibody response and other immunological parameters as well as vector 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses.
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3
TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2 
2 SYNOPSIS...........................................................................................................................3 
3 TABLE OF CONTENTS...................................................................................................15 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................20 
5 ETHICS..............................................................................................................................22 
5.1 Institutional Review Board or Independent Ethics Committee ................................22 
5.2 Ethical Conduct of Study ..........................................................................................23 
5.3 Subject Information and Informed Consent ..............................................................23 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................24 
7 INTRODUCTION .............................................................................................................25 
7.1 Nonclinical Studies ...................................................................................................25 
7.2 Previous Clinical Studies ..........................................................................................27 
7.3 Study Rationale.........................................................................................................28 
7.3.1 
Liver Biopsy Substudy Rationale ................................................................30 
7.4 Summary of Overall Risks and Benefits...................................................................31 
7.4.1 
Liver Biopsy Substudy Risks and Benefits .................................................32 
8 STUDY OBJECTIVES......................................................................................................34 
9 INVESTIGATIONAL PLAN............................................................................................35 
9.1 Overall Study Design and Plan.................................................................................35 
9.2 Discussion of Study Design, Including Choice of Control Group ............................51 
9.3 Selection of Study Population ...................................................................................51 
9.3.1 
Inclusion Criteria.........................................................................................51 
9.3.2 
Exclusion Criteria........................................................................................52 
9.3.3 
Liver Biopsy Substudy Inclusion and Exclusion Criteria ...........................53 
9.3.4 
Removal of Subjects from Treatment or Assessment .................................53 
9.3.5 
Subject Identification and Replacement of Subjects...................................55 
9.3.6 
Duration of Subject Participation ................................................................55 
9.4 Treatments.................................................................................................................55 
9.4.1 
Treatments Administered ............................................................................55 
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9.4.2 
Identity of Investigational Product ..............................................................55 
9.4.3 
Storage.........................................................................................................56 
9.4.4 
Directions for Administration .....................................................................56 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................56 
9.4.6 
Selection of Doses Used in the Study .........................................................57 
9.4.7 
Blinding .......................................................................................................58 
9.4.8 
Prior and Concomitant Medications ............................................................58 
9.4.9 
Treatment Compliance ................................................................................60 
9.5 Investigational Product Accountability .....................................................................60 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................60 
9.6 Dietary or Other Protocol Restrictions......................................................................61 
9.7 Safety and Efficacy Variables...................................................................................61 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................61 
9.7.2 
Primary Efficacy Variables .........................................................................61 
9.7.3 
Secondary Efficacy Variables .....................................................................62 
9.7.4 
Immunogenicity...........................................................................................62 
9.7.5 
Pharmacodynamics......................................................................................63 
9.7.6 
Exploratory Assessments ............................................................................63 
9.7.7 
Haemo-QoL-A Quality of Life Assessment................................................64 
9.7.8 
Safety Variables ..........................................................................................65 
10 REPORTING ADVERSE EVENTS .................................................................................70 
10.1 Safety Parameters and Definitions............................................................................70 
10.1.1 Adverse Events............................................................................................70 
10.2 Serious Adverse Events ............................................................................................71 
10.2.1 Events of Special Interest (EOSI) ...............................................................71 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................71 
10.3.1 Adverse Event Reporting Period .................................................................71 
10.3.2 Eliciting Adverse Events.............................................................................72 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................72 
10.4 Procedures for Recording Adverse Events ...............................................................75 
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10.4.1 Recording Adverse Events on a eCRF ........................................................75 
10.5 Reporting Requirements ...........................................................................................78 
10.5.1 Expedited Reporting Requirements .............................................................78 
10.5.2 Ethics Committee Reporting Requirements ................................................79 
10.6 Follow-up of Subjects after Adverse Events .............................................................79 
10.7 Post-Study Adverse Events .......................................................................................79 
10.8 Urgent Safety Measures............................................................................................79 
10.9 BioMarin Pharmacovigilance Contact Information..................................................80 
11 APPROPRIATENESS OF MEASUREMENTS...............................................................81 
12 STUDY PROCEDURES ...................................................................................................82 
12.1 Prestudy.....................................................................................................................82 
12.2 Screening Visit..........................................................................................................82 
12.2.1 “Smart Rescreening” Visit ..........................................................................83 
12.3 Baseline Visit............................................................................................................84 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1)....................................................84 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................85 
12.5.1 Once per week (Weeks 1 through 16) .........................................................85 
12.5.2 Week 1 – Day 2 and Day 4 ..........................................................................86 
12.5.3 Week 1 – Day 8...........................................................................................87 
12.5.4 Every 2 Weeks.............................................................................................87 
12.5.5 Weeks 4, 8, 12, and 16 ................................................................................87 
12.5.6 Week 16.......................................................................................................87 
12.5.7 Weeks 8 and 16 ...........................................................................................88 
12.5.8 Weeks 2, 3, 4, and 16 ..................................................................................88 
12.5.9 Week 13.......................................................................................................88 
12.6 Safety Follow-Up – Weeks 17-36 .............................................................................88 
12.6.1 Once per week (Weeks 17 through 36) .......................................................88 
12.6.2 Once per week (Weeks 17 through 20) .......................................................89 
12.6.3 Every 2 weeks (Weeks 21 through 36) .......................................................89 
12.6.4 Every 4 Weeks.............................................................................................89 
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12.6.5 Every 8 Weeks.............................................................................................90 
12.6.6 Week 26.......................................................................................................90 
12.6.7 Week 28.......................................................................................................90 
12.7 Safety Follow-Up – Weeks 37-52 .............................................................................90 
12.7.1 Once per visit ...............................................................................................90 
12.7.2 Every 4 Weeks.............................................................................................91 
12.7.3 Every 8 Weeks.............................................................................................91 
12.7.4 Week 38 and 52 ...........................................................................................92 
12.7.5 Week 52.......................................................................................................92 
12.8 Safety Follow-Up – Years 2-5 ..................................................................................92 
12.8.1 Year 2 – Every 4 Weeks (not required for treatment failure) .....................92 
12.8.2 Years 3-5 – Every 6 Weeks (not required for treatment failure) .................93 
12.8.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)..................................................................................................95 
12.9 Liver Biopsy Substudy - Years 1-5 ...........................................................................96 
12.10 Early Termination Visit ............................................................................................98 
12.11 End of Study .............................................................................................................99 
13 DATA QUALITY ASSURANCE...................................................................................100 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................101 
14.1 Statistical and Analytical Plans...............................................................................101 
14.1.1 Interim Analyses........................................................................................101 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........101 
14.2 Primary and Secondary Efficacy Analysis..............................................................101 
14.3 Liver Biopsy Substudy Analysis .............................................................................101 
14.4 Immunogenicity ......................................................................................................101 
14.5 Pharmacodynamic Analyses ...................................................................................102 
14.6 Safety Analysis .......................................................................................................102 
14.7 Determination of Sample Size ................................................................................102 
14.8 Analysis Populations ...............................................................................................103 
14.9 Changes in the Conduct of the Study or Planned Analyses ....................................103 
15 DATA REVIEW BOARD...............................................................................................104 
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16 COMPENSATION, INSURANCE AND INDEMNITY................................................105 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS............................................106 
18 STUDY MONITORING AND AUDITING ...................................................................107 
19 RETENTION OF RECORDS .........................................................................................108 
20 USE OF INFORMATION AND PUBLICATION .........................................................109 
21 REFERENCES ................................................................................................................110 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................113 
22.1 Conduct of Study and Protection of Human Patients .............................................113 
23 SIGNATURE PAGE .......................................................................................................114 
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................115 
LIST OF TABLES
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................39 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) ............................41 
Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) .....................................43 
Table 9.1.4:  Schedule of Events – Safety Follow-Up (Week 33-52) .....................................45 
Table 9.1.5:  Schedule of Events – Safety Follow-Up (Years 2-5) .........................................47 
Table 9.1.6:  Schedule of Events – Therapeutic Corticosteroids for LT Elevations ...............49 
Table 9.1.7:  Schedule of Events – Liver Biopsy Substudy.....................................................50 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................66 
Table 9.7.8.3.1:  Liver Tests ....................................................................................................67 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale....................................................73 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................74 
LIST OF FIGURES
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic .............................................................30 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3...............................36 
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
AAV
adeno-associated virus
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
ALT
alanine transaminase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BPV
BioMarin Pharmacovigilance
BU
Bethesda Unit
CFR
Code of Federal Regulations
CRA
clinical research associate
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DRB
Data Review Board
eCRF
electronic case report form
ED
exposure days
EOSI
events of special interest
ETV
early termination visit
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FIH
first-in-human
FVIII
coagulation factor VIII
FXa
coagulation factor Xa
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
HA
Haemophilia A
hFVIII
human coagulation factor VIII
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6
IEC
independent ethics committee
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IND
Investigational New Drug (application)
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IV
intravenous
LT
liver test
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect level
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamics
PEG
polyethylene glycol
PK
Pharmacokinetics
PRO
patient-reported outcome
rhFVIII
recombinant human FVIII protein
REB
research ethics board
SAE
serious adverse event
SAP
statistical analysis plan
SDV
source data verification
ULN
upper limit of normal
vg
vector genomes
VWF:Ag
von Willebrand factor Antigen
Definition of Terms: 
Investigational Product (IP):
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]). 
The terms “IP” and “study drug” may be used interchangeably in the protocol.
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5
ETHICS
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards.
5.1
Institutional Review Board or Independent Ethics Committee
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries.
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin or its designee. The Investigator will provide the IRB/IEC/REB 
with all appropriate material, including the protocol, Investigator’s Brochure (IB), the 
Informed Consent Form (ICF) including compensation procedures, and any other written 
information provided to the subjects, including all ICFs translated to a language other than 
the native language of the clinical site. The study will not be initiated and Investigational 
Product (IP) supplies will not be shipped to the site until appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol, the ICF and all subject 
recruitment materials are obtained in writing by the Investigator and copies are received at 
BioMarin or its designee. The approval document should refer to the study by protocol title 
and BioMarin protocol number (if possible), identify the documents reviewed, and include 
the date of the review and approval. BioMarin will ensure that the appropriate reports on the 
progress of the study are made to the IRB/IEC/REB and BioMarin by the Investigator in 
accordance with applicable guidance documents and governmental regulations.
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5.2
Ethical Conduct of Study
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability.
This study will be conducted in accordance with the following:
x
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country
x
US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable
x
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6)
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the subjects will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF, and if applicable, a 
copy of the approved subject information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed.
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject.
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6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of subjects in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR.
Liver tests (LTs) will be performed at the local laboratories associated with the study sites.  
Local laboratory results of LTs will be used to trigger corticosteroid treatment as needed 
(refer to Section 9.4.8.2).  In case of discrepant results between local and central laboratories, 
the Investigator and Medical Monitor will decide further action.  Safety labs evaluations 
(including LTs) will be performed at the central lab, while bioanalytical samples will be 
performed at the appropriate specialty lab.  Refer to the Laboratory Manual for more details.
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INTRODUCTION
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.).
Chemical modification or bioengineering of FVIII may improve half-life to 18-19 hours 
(Kaufman, 2013, Blood). However, these long acting FVIII variants do not eliminate the 
need for lifelong FVIII protein administration (Hay, 2012, Blood).  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of human FVIII following a single administration of vector. Haemophilia A is 
well suited for this approach because its clinical manifestations are attributable to the lack of 
a single gene product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. 
Tightly regulated control of gene expression is not essential and a modest increase in the 
level of FVIII (a plasma level of 2 ng/ml protein leads to a 1% expression) can ameliorate the 
severe phenotype (Srivastava, 2013, Haemophilia.); thus the therapeutic goal for gene 
therapy is a modest increase in hFVIII. Finally, the consequences of gene transfer can be 
assessed using simple quantitative rather than qualitative endpoints that can be easily assayed 
in most clinical laboratories.
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study.
7.1
Nonclinical Studies
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 
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nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints.
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in FVIII KO x Rag2 mice given matched IU 
levels of Refacto®.
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.  
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed.
The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 
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the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence closely matching that of 
the protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Nathwani, 2006, Blood). Despite 
distribution to non-liver organs, no expression of Factor IX was detected in these tissues.  
Additionally, distribution to the testis was observed in another study in monkeys given an 
AAV5-codon-optimized human porphobilinogen deaminase; however, vector genomes in the 
semen were only transiently observed within one week but not thereafter (Paneda, 2013,
Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents 10-fold safety factor from the 
no observed adverse effect level (NOAEL) in the GLP enabling nonclinical toxicology study 
in mice. 
7.2
Previous Clinical Studies
This is the first clinical study for BMN 270.
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Engl.J.Med.), 
(Nathwani, 2014, N.Engl.J.Med.). The large size of the FVIII cDNA was shortened and a 
preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013,
Blood).
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AAV serotype 5 is being tested in other clinical trials and was reportedly well tolerated 
without treatment-related serious adverse events in a recent phase 1 study for treatment of 
Acute Intermittent Porphyria (D'Avola, 2014, J.Hepatol.). In addition, AAV using other 
serotypes have been used in 105 clinical studies to date and no safety issue specific to the 
vector was ever reported.  
7.3
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Mannucci, 2001, N.Engl.J.Med.). It is caused by deficiency in the activity
of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic coagulation cascade. 
This disorder can be either inherited, due to a new mutation or an acquired immunologic 
process, leading to insufficient quantities of FVIII or a dysfunctional FVIII, but all are 
characterized by a defective coagulation process. The clinical phenotype of HA patients is
largely governed by the level of residual expression. Severe HA is classified as FVIII activity
less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild type activity 
and the mild form is 5-40% activity. The clinical manifestations of severe HA remain
frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-4 times per 
week, and at the time of a bleed, to prevent or control bleeding episodes, respectively. The
half-life for FVIII (12-18 hours for most approved products) necessitates frequent infusions, 
and although a major advance in the treatment of HA, it remains common for severe HA 
patients to continue to have multiple bleeding events on treatment (mean of 
1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year for on demand 
treatment) (Nagel, 2011, Haemophilia.).  The consequence of multiple bleeding events is the 
development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death (Nagel, 2011, Haemophilia).  Chemical 
modification (eg, direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (eg, FVIII-Fc fusion proteins) improve half-life by approximately 
50%, and thus, show promise in reduced dosing and maintaining activity levels above 1% 
trough (Stonebraker, 2010, Haemophilia.), (Mahlangu, 2014, Blood). However, these longer 
acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive 
treatment of HA to give patients a FVIII level compatible with a normal and 
haemorrhage-free life. 
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Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Mannucci, 2001,
N.Engl.J.Med.). They have an excellent and well defined safety profile, and can direct long 
term transgene expression with tropism for specific tissues such as the liver (Nathwani, 2005,
Curr.Hematol.Rep.) for serotypes 2, 5 and 8 among others.  Indeed, an on-going gene therapy 
clinical trial for a related disorder, haemophilia B, has established that stable (>36 months) 
expression of human factor IX at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
administration of AAV-8 vector (Nathwani, 2014, N.Engl.J.Med.).  Several participants in 
this trial have been able to discontinue factor prophylaxis without suffering spontaneous 
haemorrhages, even when they undertook activities that previously resulted in bleeding. 
Thus, gene therapy treatment has resulted in a substantial improvement in their quality of life 
(Nathwani, 2011, Mol.Ther.), (Bainbridge, 2008, N.Engl.J.Med.), (Maguire, 2009, Lancet);
(Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a liver-selective promoter (Figure 7.3.1). 
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Figure 7.3.1: hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active FVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of FVIII in patients with severe 
HA.
7.3.1
Liver Biopsy Substudy Rationale
The pattern of response in hFVIII activity observed so far after administration of BMN 270
demonstrates peak expression levels during the first 6-12 months post-treatment followed by 
a decline to a steady-state level of expression in the second year of follow-up, with mean 
hFVIII activity levels remaining above the lower limit of normal (50 IU/dL).  One of the 
explanations may lie in the kinetics of vector genome processing which involves a series of 
steps such as DNA degradation and repair, annealing, and circularization that can result in 
the formation of stable double-stranded circularized transgene DNA forms. It is these 
circularized DNA species that are thought to be associated with long-term, persistent 
expression of the gene product in target cells.  Examination of transduced hepatocytes from 
subjects treated with BMN 270 in the 270-201 study will help to establish whether DNA 
circularization may occur and could account for the long-term hFVIII expression observed in 
humans.
Additionally, health of the liver after gene transduction has been monitored indirectly by 
periodic assessments of hepatic enzymes released into the blood stream.  Transient 
post-treatment elevations in ALT levels have been observed in some subjects, as well as 
inter-subject variability in post-therapy hFVIII levels. Neither the reasons for, nor the 
significance of, the ALT elevations or the variations in response to FVIII gene therapy are 
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known.  Moreover, the effects of BMN 270 on hepatic tissue structure and function are also 
currently unknown.  
The purpose of this exploratory substudy is to provide a better understanding of the 
long-term gene expression related to genome circularization, health of the liver, and variation 
in hFVIII levels observed after gene therapy with BMN 270.  Whilst consenting subjects may 
not derive any direct benefit themselves by participating in the substudy, the overall findings 
could aid future patients by helping to characterize the means by which long-term efficacy is 
achieved and the safety of liver-directed gene therapy. 
7.4
Summary of Overall Risks and Benefits 
The majority of subjects in the ongoing 270-201 clinical study who have received 4E13 or 
6E13 vg/kg doses of BMN 270 have had Grade 1 asymptomatic elevations in ALT. For most 
subjects, the elevations have reached only slightly above the upper limit of normal (ULN).  
Based on the effectiveness of transient oral corticosteroid used to suppress a presumed 
Class 1 (cytotoxic T-cell) response in prior studies with hepatic transduction with AAV 
vectors (Mingozzi, 2013), subjects were treated with 7-32 weeks of oral corticosteroids 
prophylactically or in response to the elevations in ALT to ensure preservation of the 
transduced hepatocytes. Using this approach, no sustained loss of FVIII activity has been 
observed in subjects with ALT elevations, consistent with maintaining a high level of 
hepatocyte function. Moreover, the rise in ALT levels were not accompanied by significant 
or lasting aberrations in other liver tests such as AST, bilirubin or albumin, indicating that 
extent of toxicity is limited. There has been one HIV-positive subject in the ongoing 270-302 
clinical study who experienced Grade 3 asymptomatic elevations in ALT and AST, which 
has been attributed to an interaction between one or more of his antiretroviral therapy 
medications and/or unsuspected underlying hepatic disease with BMN 270. In addition, there
has been one subject with Gilbert’s syndrome in the ongoing 270-301 clinical study who has 
experienced Grade 3 asymptomatic elevations in ALT and AST. These cases have led to the 
exclusion of subsequent HIV-positive subjects and requirement of liver tests at Screening 
that are <1.25 times the upper limit of the normal range in the ongoing 270-301 and 270-302 
clinical studies. Of note, two HIV-positive subjects in 270-301 and one presumed Gilbert’s 
syndrome subject in 270-201 have received BMN 270 without experiencing any elevations in 
ALT to date. Overall, the literature and clinical experience with BMN 270 suggests that 
transient elevations in liver enzymes are expected following AAV-based gene therapy for the 
treatment for hemophilia A or B without any long-term concerns of hepatic injury 
(Manno, 2006; Nathwani, 2011; George, 2016; Miesbach, 2016; Pasi, 2016). 
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The current data available for BMN 270 does not yet permit comprehensive assessment of 
the benefit:risk profile of this investigational drug. Given the monitoring measures in place in 
the clinical protocol(s) to minimize the risk to subjects participating in the existing studies, 
the identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-201 will have a comprehensive surveillance plan that monitors LTs 
during the study, and elevations in LT will be addressed according to the guidelines set forth 
in the protocol. Safety will be assessed by adverse event reporting and clinical laboratory 
assessments.
For additional information on safety findings in 270-201, refer to current version of the 
Investigator’s Brochure.
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose 
that maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the 
possibility of a sub-therapeutic effect. With this consideration in mind, the starting dose 
6E12 vg/kg was selected using overall data from the pre-clinical studies conducted in mice 
(normal and disease model, Rag2 -/- x FVIII -/-) and monkey. A detectable pharmacological 
response based on activity was observed at 6E12 vg/kg. A 10-fold safety margin based upon 
the NOAEL was observed in the GLP 13-week study in normal mouse at the highest dose 
administered. A 30-fold safety margin in an 8-week dose response study in disease model 
mice based on histology was observed at the highest dose administered. No BMN 270-related 
changes in clinical observations or chemistry was observed in the monkey at doses up to 
6E13 vg/kg, a 10-fold safety margin after 8-weeks. Overall, no BMN 270-related findings, 
except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model 
mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to subjects with the best chance of 
benefiting the subject therapeutically.
7.4.1
Liver Biopsy Substudy Risks and Benefits 
Liver biopsy is considered a safe procedure, with serious complications occurring less than 
once in every 10,000 procedures (Grant, 2004). Although the theoretical risks of significant 
complications are extremely small, the main complications would include bleeding and bile 
leakage. Another theoretical complication is infection at the needle insertion site; the sterile 
technique used makes this risk extremely small. 
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The most common problems include mild pain and a minor decrease in blood pressure. More 
serious complications, such as bleeding, infection, and injury to nearby organs, are very rare, 
but the subject will be monitored appropriately to ensure correct management should any of 
these occur. Any complications related to the liver biopsy should be reported as adverse 
events, as outlined in Section 10. The liver biopsy is a standard investigation, and will be 
explained more fully by the experienced clinician performing the biopsy.  
Each subject who participates in this optional substudy will have a comprehensive 
pre-/post-biopsy surveillance plan according to the standard procedures at the institution. 
Safety will be assessed by adverse event reporting and clinical laboratory assessments. Per 
the Investigator's discretion and/or according to local guidelines, the subject may be kept in 
overnight following the liver biopsy for additional safety monitoring; such an overnight stay 
would not be considered a hospitalization for serious adverse event (SAE) reporting purposes 
(refer to Section 10.4.1.7). 
There is no direct benefit from participating in this study other than contributing to 
understanding the mechanism of action of BMN 270. Consenting into this specific substudy
is optional and will not have any effect on the subject’s continued participation in 270-201.
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8
STUDY OBJECTIVES
The primary objectives of the study are:
x
To assess the safety of a single intravenous administration of a recombinant AAV5
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.
x
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals
with haemophilia A will be determined and correlated to an appropriate BMN 270
dose.
The secondary objectives of the study are:
x
To describe the immune response to the hFVIII transgene product and AAV capsid
proteins following systemic administration of AAV5-hFVIII-SQ
x
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy
during the study
x
To assess the impact of BMN 270 on the number of bleeding episodes requiring
treatment during the study
The exploratory objectives of the liver biopsy substudy are: 
x
To examine the histopathology of the liver following BMN 270 therapy, including
assessing for possible safety findings (eg, fibrosis, fatty liver disease, lymphocytic
invasion)
x
To quantify FVIII DNA, RNA, and protein expression within hepatocytes
x
To determine which forms of rAAV genomic DNA (eg, concatemers) are present at
the time of biopsy
x
To determine the transduction pattern in humans (ie, peri-portal hepatocytes, central
vein hepatocytes)
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled into one of up to four cohorts according to dose level: 
x
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv)
x
Cohort 2:  2E13 vg per kilogram, iv
x
Cohort 3:  6E13 vg per kilogram, iv
x
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys. The starting dose has a 10-fold safety margin from no 
observed adverse effect level (NOAEL) in mice. 
Cohorts 1-3
The first three cohorts will be enrolled sequentially, allowing a period of 3 weeks or more 
between cohorts. Dose escalation may occur after a single subject in a cohort has been safely 
dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both assays. 
Three weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic 
doses. The decision to escalate to the next dose level will be made based on the review of 
safety parameters and FVIII activity by the Sponsor and a panel of investigators participating 
in the study.   
If the FVIII activity reaches ≥5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3 
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg).
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.  
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in the Cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals. 
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.   
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There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the Data Review Board (DRB). The adaptive nature of this trial allows the DRB 
to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals.
As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not 
respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve 
FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic 
FVIII replacement therapy due to joint bleeding episodes, in the judgment of the 
Investigator) may, at the Investigator’s discretion and after discussion with the Medical 
Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the 
discretion of the Investigator.  
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity 
for therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dosing. Any safety signal 
may trigger a review of the data and possible additional immunogenicity studies that include 
an assessment of cellular immune responses using collected PBMC. Additionally, if any of 
the events listed in Section 9.3.4.1 occur, enrollment into the trial will be halted to complete 
an extensive safety analysis. Notification of the study enrollment halt will be sent by the 
Sponsor to the participating sites via telephone and email immediately after becoming aware 
of a safety concern. This will ensure no additional subjects are dosed until the signal has been 
completely evaluated. If, following safety review by the DRB and the Sponsor, it is deemed 
appropriate to restart dosing, a request to restart dosing with pertinent data will be submitted 
to the health authority. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3, Table 9.1.4, and Table 9.1.5 for Safety Follow-up.
Table 9.1.6, dealing with therapeutic corticosteroid use in the event of elevated LTs, is
discussed in Section 9.4.8.2.
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Liver Biopsy Substudy Design 
All subjects enrolled in 270-201 and who are at least one year post-BMN 270 infusion are 
eligible for the optional liver biopsy substudy. Subjects who consent to participate in the 
substudy will have a liver biopsy via either the transjugular or percutaneous 
(ultrasound-guided) route, according to the standard procedures of the institution. To enhance 
safety, all subjects will have an ultrasound examination of the liver within 3 months prior to 
the procedure (to ensure there are no pathological findings such as bile duct obstruction that 
might interfere with the safe performance of the liver biopsy) and a FibroScan of the liver 
within one week before the liver biopsy (to correlate with any potential histopathologic 
findings of fibrosis on the biopsy).  
Subjects who consent should have their FVIII levels monitored/adjusted by the Investigator 
to enable the procedure to be performed safely.  This may require the administration of 
exogenous FVIII replacement products in order to achieve the desired FVIII activity.  The 
target FVIII activity level within 24 hours prior to the liver biopsy is at the discretion of the 
Investigator and/or according to local guidelines, but at a minimum should be at the lower 
limit of the normal range (ie, at least 50 IU/dL). 
Table 9.1.7 presents the schedule of assessments for participation in the liver biopsy
substudy.
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Table 9.1.1: Schedule of Events – Screening and Infusion
Assessment
Prior to BMN 270 Infusion
BMN 270 
Infusion 
Visit (Day 1)k
Screeningi
(Day -28 to Day -1)
Smart Rescreeningi
(Day -28 to Day -1)
Baseline (Day -7
to Day -1)h
Informed consent
X
Medical History
X
Physical Examinationa
X
X
X
Height and Weighta
X
Vital Signs
X
X
X
Assessment of Adverse Events and Concomitant Medications
X
X
X
X
Documentation of bleeding episodes and FVIII usage (by either subject or 
clinical information)
X
X
X
Distribution of subject diaries and training in their use
X
Electrocardiogram
X
Chest X-ray
X
Liver Ultrasound
X
hFVIII Assaysb
X
Xj
AAV5 Assaysc
X
X
X
Screen for Hepatitis B, Hepatitis C, HIVd
X
Blood chemistry, haematology, coagulation screen, and CRPe
X
X
X
Urine Testse
X
X
X
Liver Testse
X
X
X
PBMC collection for CTL baseline
X
Von Willebrand Factor Antigen (VWF:Ag)
X
Direct Thrombin Test
X
PCR of vector DNA in blood, saliva, urine, semen, and stools
X
Biomarker testingf
X
Exploratory biomarker assessmentsg
X
Haemo-QoL-A Quality of Life (QoL) assessment
X
BMN 270 Infusion
X
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a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height will be recorded at 
Screening only.  Weight will be recorded at Screening and then every 6 months thereafter.
b Includes baseline hFVIII activity (chromogenic substrate assay and one-stage clotting assay), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay with 
Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).  
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction inhibition, in vitro 
transduction inhibition and AAV5 total antibody assays).  Sample collection on the day of the infusion visit must be performed before the BMN 270 infusion is given.
d Patients with documented negative results within the last 30 days do not need to be retested.
e Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.
f Includes HLA genotyping, FVIII genotyping, TNFD and IL10a single nucleotide polymorphisms.
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
h Should the screening visit occur within 7 days of the drug infusion, physical examination, blood chemistry, LTs, haematology, urine tests, coagulation screen, and CRP do not need to be 
repeated at Baseline.
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion prior to the closing 
of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion within 90 days of signing the original 
consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures. Subjects may not undergo smart rescreening more than 
once.
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening.
k Assessments on the day of infusion must be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, during the infusion 
every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes). 
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) 
Assessment
Follow-Up After BMN 270 Administration – Weeks*
Week 1
2 
3 
4 
5 
6 
7 
8 
9 
10
11
12
13
14
15
16
D2
D4
D8
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary 
for bleeding and FVIII use)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation 
screen, and CRPb
X 
X 
X 
X 
X 
X 
X 
Urine Testsb
X 
X 
X 
X 
Liver Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Tests (central)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII antibody titer
X
X
X
X
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolse
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
X 
X 
X 
X 
AAV5 antibody titer
X 
X 
Testing for reactivation of hepatitis B and 
hepatitis C
Xg
PBMC collection 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
X
Direct Thrombin test
X 
X 
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* Visit windows are ± 48 hours (and include the Day 4 visit)
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods
when a subject’s ALT is ≥ 3x ULN. Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional
blood tests, and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to 
above ULN; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the
Investigator based on a review of subject data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be 
adjusted based on discussion between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting assay and chromogenic substrate assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage clotting assay and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation 
activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after 
BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII
activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are 
above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection to occur on Day 2 and 4 following BMN 270 infusion, and then until at least 3 consecutive negative results are obtained.  Collection and testing of semen samples must continue 
through Week 12, even if 3 consecutive negative samples in that compartment have already been recorded.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
g Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of Hepatitis B or Hepatitis C prior to study entry, should be performed only in 
subjects who have not received therapeutic corticosteroids prior to Week 16; subjects who have received therapeutic corticosteroids will have hepatitis B and hepatitis C testing at the time 
points indicated in Table 9.1.6. 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) 
Assessment
Follow-Up After BMN 270 Administration – Weeks*
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight
X 
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary for 
bleeding and FVIII use)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, 
and CRPb
X 
X 
X 
X 
Urine Testsb
X 
X 
X 
X 
Liver Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Tests (central)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII antibody titer
X
X
PCR of vector DNA in blood, saliva, urine, semen, 
and stoolse
X 
X 
X 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
AAV5 antibody titer
X 
X 
X 
X 
PBMC collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
Direct Thrombin test
X 
* Visit windows are ± 48 hours
a Brief physical examination should be done at all weekly visits.  Refer to Section 9.7.8.5.
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b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods
when a subject’s ALT is ≥ 3x ULN.  Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional
blood tests, and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to 
above ULN; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the 
Investigator based on a review of subject data.  If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be
adjusted based on discussion between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay). If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection for each matrix to occur until at least 3 consecutive negative results are obtained.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
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Table 9.1.4:  Schedule of Events – Safety Follow-Up (Week 33-52) 
Assessment
Year 1 – Weeks*
33
34
35
36
38
40
42
44
46
48
50
52
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta
X 
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and FVIII use)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, haematology, coagulation screen, and CRPb
X 
X 
X 
X 
X 
Urine Testsb
X
X
X
X
X
Liver Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Tests (central)b
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
AAV5 antibody titer
X 
X 
X 
X 
X 
FVIII antibody titer
X
X
X
PBMC Collection (for determination of FVIII and Capsid specific CTL 
activity)
X 
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
X 
Direct Thrombin Test
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and stoolse
X 
X 
X 
X 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52.
a Complete physical examination should be performed at Week 52; brief physical examination may be performed at other study visits.  Refer to Section 9.7.8.5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods when a 
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subject’s ALT is ≥ 3x ULN. Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, 
and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to above ULN or 
increased by > 10 U/L from prior assessment; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the 
Medical Monitor and the Investigator based on a review of subject data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and 
ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay). If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism. 
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
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Table 9.1.5:  Schedule of Events – Safety Follow-Up (Years 2-5) 
Assessment
Years 2-5*
Year 2*
Years 3-5*
End of Year Visit
ETV
Q12W
Q4Wh
Q6Wh
Year 2
Year 3
Year 4
Year 5
W104
W156
W208
W260
Physical examinationa
Xa
Xa
X 
Weighta
Xa
Xa
X 
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and FVIII use)
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
Blood chemistry, haematology, coagulation screen, and CRPb
X 
X 
X 
Urine Testsb
X 
X 
X 
Liver Tests (local)b
X 
X 
X 
X 
X 
FVIII assays (local)c
X 
X 
X 
X 
X 
Liver Tests (central)b
X 
X 
X 
X 
X 
FVIII assays (central)d
X 
X 
X 
X 
X 
AAV5 antibody titer
X 
X 
X 
FVIII antibody titer
X 
X 
X 
PBMC Collection (for determination of FVIII and Capsid specific CTL 
activity)
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and stoolse
Xe
Xe
Xe
Xe
X 
Exploratory biomarker assessmentsg
X 
X 
X 
Haemo-QoL-A QoL assessment
Xf
Xf
X 
* Visit windows are ± 2 weeks for visits in Years 2-5. The Q6W visits during Years 3-5 should restart after each End of Year visit (eg, the first Q6W visit during Year 3 should be ~6 weeks
after the End of Year 2 visit).
a Complete physical examination should be performed at the End of Year visits; brief physical examination may be performed at other study visits. Weight should be recorded at the second 
Q12W visit each year and at every End of Year visit during Years 2-5.
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b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are ≥1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods
when a subject’s ALT is ≥ 3x ULN. Patients with ALT ≥ 1.5x ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional
blood tests, and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to
above ULN or increased by > 10 U/L from prior assessment; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion 
between the Medical Monitor and the Investigator based on a review of subject data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII
activity and ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator. During Years 2-5 of the Post-Infusion Follow-Up period, urine tests
and blood, chemistry, and coagulation tests should be performed at the second Q12W visit each year and at every End of Year visit.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen 
modification) during Years 3-5, a fresh sample should be collected within 4 weeks of the initial visit that had a positive result.  
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen modification) in years 3-5, a fresh sample 
should be collected within 4 weeks of the initial visit that had a positive result.
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.  Subjects who have not had 3 consecutive 
negative samples by Week 52 should continue to have PCR testing every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 3 consecutive negative samples are 
documented (or upon consultation between the Investigator and Medical Monitor).
f Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at the second Q12W visit each year and at every End of Year visit. 
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including any other exploratory assessments) will 
be performed only as deemed necessary by the Sponsor.
h Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 may omit the Q4W and Q6W visits during Years 2-5, and must attend only the Q12W and End of 
Year visits. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in all fluids must still provide samples Q4W (during Year 2) or Q6W (during 
Years 3-5) until vector shedding has been cleared (but do not need to do other scheduled assessments at those visit dates). 
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Table 9.1.6:  Schedule of Events – Therapeutic Corticosteroids for LT Elevations
Steroid Treatment Periodd
Post-Steroid Periodc
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11b
Week 
1
Week 
2
Week 
3
Week 
4
Week 
13
Therapeutic 
corticosteroids 
(dose in 
mg/day) a
60 mg
60 mg
40 mg
40 mg
30 mg
30 mg
20 mg
20 mg
15 mg
10 mg
5 mg
FVIII activity 
testing
X 
X 
X 
X 
Liver testing
X
X
X
X
Hepatitis B 
testinge
X 
X 
X 
HCV Viral 
Loade
X 
X 
X 
a Therapeutic corticosteroids may be initiated when a subject’s ALT value is ≥ 1.5x ULN or based on review of FVIII and liver enzyme data after consultation between the Investigator and 
the Medical Monitor.
b Following initiation or completion of steroid regimen, if ALT elevation  ≥ 1.5x ULN is reported, steroid management decisions will based on discussions between the Investigator and 
Medical Monitor.  Modification of the steroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression.
c After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values. If these assessments are already 
being done as part of normal study follow-up, they do not need to be duplicated.
d Regardless of the assessments listed in the Schedule of Assessments (Table 9.1.2, Table 9.1.3, or Table 9.1.4), subjects initiated on corticosteroids will only be required to have laboratory 
evaluations on a weekly basis.
e Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry.
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Table 9.1.7:  Schedule of Events – Liver Biopsy Substudy
Within 28 Days 
Before Biopsy Day
Within 7 Days 
Before Biopsy Day
1 Day Before Biopsy 
Day d
Biopsy Day (BD)
Informed Consent
X
Liver Ultrasounda
X 
Brief Physical Examination
X 
X 
X 
Hematology, Coagulation, Chemistry Assessmentsb
X 
X 
Liver Testsb
X 
X 
X 
FibroScan
X 
Local FVIII Activity Level Assessment
X 
X 
X 
Pre-Biopsy Consultationc
X 
Liver Biopsye
X 
a Liver ultrasound must be performed within 28 days prior to the scheduled biopsy, unless an ultrasound result from the prior 3 months is already available.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  
c Subjects will undergo a pre-biopsy consultation with the investigator (treating hematologist).
d  Subjects may need to repeat/extend this visit if their FVIII activity levels need adjustment before the biopsy, at the discretion of the investigator (treating hematologist).
e Biopsy will be a percutaneous or transjugular biopsy under ultrasound guidance, performed according to the standard procedure of the institution. If only a small amount of tissue (< 2 cm) 
is obtained at the time of the biopsy, the subject may be asked to consent for a second pass. In this case, the original < 2 cm sample should still be retained and handled according to the 
instructions for handling biopsy specimens in the Laboratory Manual. Following completion of the biopsy, the subject should remain in the hospital under observation for at least 4-6
hours. Overnight post-procedure observation may be done at the investigator’s discretion.
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9.2
Discussion of Study Design, Including Choice of Control Group
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Four doses of BMN 270 will be evaluated and the dose 
escalation decision tree for Cohorts 1-3 is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and the DRB. 
There will be no control group. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy). 
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3
Selection of Study Population 
Up to 15 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation. 
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2.
9.3.1
Inclusion Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
1. Males that are 18 years or older with established severe Haemophilia A as evidenced
by their medical history.  Patients will be considered as severe if their base FVIII
level is 1 IU/dL or less
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of
150 exposure days (EDs)
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the
previous 12 months.  Does not apply to patients on prophylaxis
4. Able to sign informed consent and comply with requirements of the trial
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less
than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within
the past 12 months
6. Sexually active patients must be willing to use an acceptable method of contraception
such as double barrier, including hormonal contraception for at least 6 months
post-treatment.  After 6 months, subjects may stop contraception use only if they have
had 3 consecutive negative semen samples.
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9.3.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study:
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition or AAV5 total antibodies
2. Any evidence of active infection or any immunosuppressive disorder.  
3. HIV positive
4. Significant liver dysfunction as defined by abnormal elevation of:
x
ALT (alanine transaminase) to 3 times the upper limit of normal;
x
Bilirubin above 3 times the upper limit of normal;
x
Alkaline phosphatase above 3 times the upper limit of normal; or
x
INR (international normalized ratio) ≥ 1.4. 
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if they 
had significant fibrosis of 3 or 4 as rated on a scale of 0-4
6. Evidence of any bleeding disorder not related to Haemophilia A
7. Platelet count of < 100 x 109/L
8. Creatinine ≥ 1.5 mg/dL
9. Liver cirrhosis of any etiology as assessed by liver ultrasound 
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive
12. Treatment with any IP within 30 days prior to the end of the screening period
13. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study including possible corticosteroid 
treatment outlined in the protocol.  The physician may exclude patients unwilling or 
unable to agree on not using alcohol for the 16-week period following the viral infusion.
14. Prior treatment with any gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion
16. Use of immunosuppressive agents or live vaccines within 30 days before the viral 
infusion
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9.3.3
Liver Biopsy Substudy Inclusion and Exclusion Criteria
Individuals eligible to participate in the liver biopsy substudy must meet all of the following 
criteria:
1. Currently enrolled in 270-201
2. Received BMN 270 infusion at least 1 year prior to enrollment in the substudy
3. Able to sign informed consent and comply with requirements of the substudy
4. FVIII activity at least >50 IU/dL (or higher, depending on local guidelines and/or 
Investigator discretion) within 24 hours prior to the liver biopsy being performed.  
(FVIII levels should be assessed at the local laboratory.)  Subjects may be treated 
with additional exogenous FVIII replacement products in order to increase their FVIII 
levels to an appropriate level, under the supervision/instruction of the Investigator.
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the liver biopsy substudy:
1. Assessed by the investigator or a hepatologist as having a medical condition such that 
undergoing a liver biopsy would be contraindicated. These conditions could include (but 
are not limited to):
x
Significant thrombocytopenia (platelet count < 100 x 109/L)
x
Evidence of significant ascites
x
Abnormalities detected on liver ultrasound (performed within 90 days of procedure)
that would preclude safe performance of the biopsy.
9.3.4
Removal of Subjects from Treatment or Assessment
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out.
BioMarin must be notified of all subject withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance.
Reasons for which the Investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following:
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x
Subject requires medication or medical procedure prohibited by the protocol 
x
Subject does not adhere to study requirements specified in the protocol 
x
Subject was erroneously admitted into the study or does not meet entry criteria 
x
Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study.
9.3.4.1
Study Safety Evaluation Criteria
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis 
per Section 9.1.
x
Any ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of 
BMN 270, in the absence of a definitive alternate etiology for the increase  
x
The occurrence of Grade 3 or higher adverse events (excluding ALT elevation) 
assessed as related to study drug, including liver failure and clinical hepatitis
x
The detection of neutralizing antibodies to hFVIII following BMN 270 infusion 
x
The detection of AAV vector DNA in the semen of a participant in 3 consecutive 
samples (which are at least 2 weeks apart) more than 52 weeks after BMN 270 
infusion, as discussed in Section 9.7.8.6
x
The occurrence of a malignancy excluding skin cancers at any point after BMN 270 
infusion 
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If the following event occurs in a subject in the study who has received BMN 270 infusion, a 
DRB review and analysis of safety data will be undertaken to determine whether the 
enrollment into the trial will be put on halt:
x
Grade 2 adverse event assessed as related to study drug that persists for at least 7 days 
9.3.5
Subject Identification and Replacement of Subjects
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used.
Subjects who withdraw from the study will not be replaced.
9.3.6
Duration of Subject Participation
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks.
9.4
Treatments
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites.
9.4.1
Treatments Administered
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study.
9.4.2
Identity of Investigational Product
9.4.2.1
Product Characteristics and Labeling
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer.
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements.
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9.4.3
Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 
stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4
Directions for Administration
After a physical examination performed by the PI or designee, participants will be admitted 
on the day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral 
vein (eg, the median cubital vein) and flushed with saline. FVIII replacement therapy will not 
be given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 ml/min while monitoring the vital signs (pulse, blood pressure, respiration 
rate and temperature) at 15 minute (± 5 minutes) intervals. The anticipated maximum interval 
from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, although the 
IP has been shown to be stable at room temperature for 6 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard protocol 
for infusing FVIII concentrates. Subjects will remain in the clinic for 24 hours to observe for 
any immediate toxicity of the procedure. After 24 hours, participants will be discharged from 
the clinic unless toxicity has been observed in which case the stay in the clinic may be 
extended or the subject may transfer to a separate facility based on the evaluation and 
judgment of the Principal Investigator after consultation with the Medical Monitor. 
9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study subject. Upon their enrollment into the study, subjects will be assigned a unique subject 
number and dose level by the Sponsor.
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Cohorts 1 to 3 are enrolled serially and their dose is defined in Section 9.4.6.2 below. 
Escalation is based on FVIII activity 3 weeks after injection. Cohorts may receive the next 
higher dose if subjects in the previous cohort does not meet the activity criteria, or the same 
dose if subjects in the previous cohort meets the activity criteria. Subjects in Cohort 4 will all 
be enrolled at a single dose.
9.4.6
Selection of Doses Used in the Study
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in mice. The dose escalation is half-logs based.    
9.4.6.1
Selection of Timing of Dose for Each Subject
A minimum of three weeks are required between subjects, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next subject will be made as described below. 
9.4.6.2
Selection of Dose for Each Subject
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus potentially decreasing the risk of immune response), and a new 
evaluation of the titer (PCR performed after hairpin removal). 
For Cohorts 1 to 3, approximately three weeks after an injection, the decision to escalate to 
the next dose level will be made based on the review of safety parameters and FVIII activity 
by the Sponsor and the DRB.  
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg).
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject. 
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
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For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in that cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB.  The adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals.
Refer to Figure 9.1.1 for a visual representation of the study design for Cohorts 1-3 
9.4.7
Blinding
This is an open-label study.
9.4.8
Prior and Concomitant Medications
All prescription and over-the-counter medications (including dietary and herbal supplements) 
taken by a subject for 30 days before Screening will be recorded on the designated CRF. The 
Investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF.
The following medications are prohibited starting 30 days before Screening: 
x
Live vaccines
x
Systemic immunosuppressive agents 
x
Emicizumab
x
Fitusiran
x
Concizumab 
x
Efavirenz
x
Lamivudine 
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Subjects who begin antiretroviral therapy following BMN 270 infusion and during their 
participation in 270-201 must have their antiretroviral medication regimen approved by the 
Investigator and Medical Monitor prior to starting antiretroviral treatment.
Medications which are predominately metabolized by the liver (eg, acetaminophen) and 
alcohol should, whenever possible, be avoided for the first 52 weeks of the study, and 
particularly within 48 hours prior to lab work.
9.4.8.1
Concomitant Haemophilia Treatments
Subjects on “on demand” therapy for FVIII will continue their treatment at will.  Subjects on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and
switch to an “on demand” schedule. FVIII can always be taken as needed by the subject, who 
will carefully record his treatment and bleeding episodes in his diary.  In addition, 
information on FVIII usage by medical history will be collected (if available) from subjects 
for the 6 month period immediately preceding study enrollment.
9.4.8.2
Glucocorticoid Treatment of Elevated Hepatic Transaminases
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject 
will have comprehensive surveillance plan monitoring of LTs (at local labs, once per week 
for Weeks 1-36, then once every 2 weeks from Week 37-52).  LTs may be monitored more 
or less frequently (and in particular when ALT values are >1.5x ULN) based on discussion 
between the Medical Monitor and the Investigator and review of subject data. 
9.4.8.2.1
Therapeutic Corticosteroids
In general, therapeutic corticosteroids may be initiated when a subject’s ALT value is 
≥1.5x ULN, or based on review of FVIII and liver enzyme data after consultation between 
the Medical Monitor and the Investigator.  
Reports of raised LTs (defined as ALT ≥ 1.5x ULN) should be made to the BioMarin 
medical monitor within 30 minutes of the lab value being available.  Local laboratory results 
of LTs will be used to trigger corticosteroid treatment as needed.  In case of discrepant 
results between local and central laboratories, the Investigator and Medical Monitor will 
decide further action. 
Following initiation or completion of therapeutic corticosteroids, if ALT elevation 
≥1.5x ULN is reported, steroid management decisions will based on discussions between the 
Investigator and Medical Monitor. Modification of the steroid regimen may take into 
consideration possible confounders for the ALT elevation and impact on FVIII expression.  
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Treatment with prednisolone will be initiated at a dose of 60 mg per day and then gradually 
tapered (60 mg daily for the first 2 weeks, then 40 mg the next 2 weeks, then 30 mg the next 
two weeks, then 20 mg the next two weeks, then 15 mg for the next week, then 10 mg for the 
next week, then 5 mg for the next week, then stop, for a total treatment of 11 weeks) (refer to 
Table 9.1.6). 
After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be
measured once a week for 4 weeks to ensure stability in values.
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This 
includes the contraindicated use of NSAIDs during corticosteroid treatment, and specific 
monitoring not already covered by the schedule of events. For the subjects with a past 
medical history of hepatitis B or hepatitis C prior to study entry, Hepatitis B status and HCV 
viral load will be rechecked 6 weeks after the start of corticosteroid treatment, and then 
1 week and 13 weeks after the completion of corticosteroid treatment. All adverse events 
should be reported as outlined in Section 10 of the protocol. 
9.4.9
Treatment Compliance
Study drug will be administered to subjects at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on a dispensing log.  Sites will 
be instructed to return or destroy all used and unused study drug containers. 
9.5
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data, if allowed by local SOPs.
9.5.1
Return and Disposition of Clinical Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials (or must be referenced in their institution 
SOPs).
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
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and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a study drug return form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6
Dietary or Other Protocol Restrictions
There are no dietary or other protocol restrictions for this study. 
Subjects should be advised to abstain from any blood or sperm donation after BMN 270 
infusion, until there is no further evidence of vector shedding from PCR analysis of samples. 
9.7
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.7.1.
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post 
BMN 270 administration. 
9.7.1
Safety and Efficacy Measurements Assessed
The Schedule of Events (Table 9.1.1 through Table 9.1.5) describes the timing of required 
evaluations.
9.7.2
Primary Efficacy Variables
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to expression of FVIII at 5 IU/dL or above, 
(ie, a mild severity). This is associated in natural history studies with clinically superior long 
term outcomes (Den Ujil, 2011, Haemophilia). 
The following assays (assessed by the central laboratory) will be used to measure the primary 
efficacy variable:
x
FVIII activity (chromogenic substrate assay)
x
FVIII activity by one-stage clotting assay
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made 
to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 
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The 72-hour wash-out period is only intended for subjects who have achieved FVIII 
≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care 
FVIII replacement therapy.
The FVIII activity level in both assays and the number of subjects with FVIII activity 
≥ 5 IU/dL in at least one of the two assays will be summarized.
FVIII activity assays will also be performed at the local laboratory at the time points 
indicated in Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5 but will be used in 
conjunction with local lab LT assessments to monitor subject safety and need for initiation of 
therapeutic corticosteroid dosing; local laboratory FVIII activity assessments will not be used 
to assess efficacy or to measure the primary efficacy outcome of the study.
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
either failure to achieve FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable 
and at the discretion of the Investigator.  
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, Table 9.1.4,
and Table 9.1.5.  Details on performing the assays are included in the Laboratory Manual. 
9.7.3
Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Subjects will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the subject’s diary or 
other subject records. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. 
9.7.4
Immunogenicity
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
5-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to a retrospective immunogenicity assessment to determine 
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anti-FVIII and capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be 
performed on collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.
9.7.5
Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage clotting and/or chromogenic substrate assay (activity).  Individual antigen and 
activity plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity 
measurements will be used to determine PD parameters.
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration),
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology. 
Sample collection times are indicated in Table 9.1.2, Table 9.1.3, Table 9.1.4, and 
Table 9.1.5.
9.7.6
Exploratory Assessments 
Blood samples will be collected at the time points indicated in Table 9.1.1, Table 9.1.2,
Table 9.1.3, Table 9.1.4, and Table 9.1.5 to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations.  Subjects may choose to opt out of the 
exploratory genetic/genomic research being done to study or try to discover genes that are 
not yet known to be associated with hemophilia A.  
Liver biopsy samples collected as part of the exploratory substudy may also be tested to 
evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer.  Subjects participating in the substudy 
may choose to opt out of the exploratory genetic/genomic research being done to study or try 
to discover genes that are not yet known to be associated with hemophilia A. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes may be used for exploratory use once the 
primary use has been completed.
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On an exploratory basis, samples may be fractionated prior to shedding analysis in order to 
better characterize the presence and location of vector DNA and/or vector capsid within each 
matrix. The fractionation may be performed with samples collected specifically for shedding 
analysis (saliva, blood, semen, urine, faeces), or by using exploratory samples, such as 
plasma, PBMCs, and red blood cells, collected under the study protocol.
9.7.7
Haemo-QoL-A Quality of Life Assessment
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to 
assess subject quality of life (QoL) during the study.  Assessments will occur at the time 
points listed in the Schedules of Assessments.
Details regarding the QoL assessment will be included in the Study Reference Manual.
9.7.7.1
Liver Biopsy Substudy
The objectives of the liver biopsy substudy are considered exploratory.
Subjects who consent to the procedure will have a liver biopsy via either the transjugular or 
percutaneous (ultrasound-guided) route, according to the standard procedures of the 
institution. To enhance safety, all subjects will have an ultrasound exam of the liver within 
28 days prior to the procedure (to ensure there is no obstruction to the liver that would 
interfere with the liver biopsy) and a FibroScan of the liver within one week before the liver 
biopsy (to correlate any histopathologic findings on the biopsy). Subjects will also undergo a 
pre-biopsy consultation with the investigator (treating hematologist).
Within 24 hours prior to the biopsy being performed, subjects must have a FVIII activity 
level of at least 50 IU/dL (or higher, depending on local guidelines and/or investigator 
discretion). FVIII activity levels for this purpose should be assessed at the local laboratory 
within 7 days before the biopsy, and again the day before the biopsy. As needed, subjects 
may be treated with additional exogenous FVIII replacement products in order to increase 
their FVIII activity levels to an appropriate level, under the supervision/instruction of the 
investigator, to ensure the safety of the subject during the procedure. This exogenous FVIII 
usage (if performed) should be recorded in the eCRF FVIII infusion pages under the category 
“Surgery/Procedure”.
The liver biopsy should be performed in the morning, and the biopsy procedure and 
follow-up care should be done according to the local standard of care. Additional details for 
handling the biopsy specimens are provided in the Laboratory Manual.
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Following completion of the biopsy, the subject should remain in the hospital under 
observation for at least 4-6 hours. Overnight post-procedure observation may be done at the 
investigator’s discretion and/or according to local guidelines. 
Safety findings arising from the histopathological analysis of the biopsy sample are subject to 
Adverse Event reporting (Section 10), and such findings should be further assessed and 
followed-up as clinically appropriate and in order to safeguard the subject’s ongoing medical 
care (this should be done in consultation with a hepatologist and/or other specialist clinicians 
if required).  In the event fibrotic changes being observed on the biopsy sample, additional 
follow-up Fibroscans may be considered (with the frequency of subsequent scans at the 
discretion of the Investigator and/or hepatologist). 
9.7.8
Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
9.7.8.1
Adverse Events
The occurrence of AEs will be assessed continuously from the time the subject signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1,
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5.
9.7.8.2
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5. The scheduled clinical 
laboratory tests are listed in Table 9.7.8.2.1. Refer to the Study Reference Manual for 
instructions on obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event.
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The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF.
Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry
Haematology
Urine Tests
Other
Albumin
Haemoglobin 
Appearance
CRP
BUN
Haematocrit 
Color
Calcium
WBC count
pH
Coagulation Screen
including:
Chloride
RBC count
Specific gravity
APTT
Total cholesterol
Platelet count
Ketones
PT/INR
CO2
Differential cell count 
Protein 
TT
CPK
ABO blood typing*
Glucose 
Creatinine
Bilirubin
Glucose 
Nitrite
Phosphorus
Urobilinogen
Potassium
Haemoglobin
Total protein
Sodium
Uric Acid
BUN, blood urea nitrogen; CO2, carbon dioxide; CRP, C-reactive protein; PT, prothrombin time; APTT, activated partial 
thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; INR, international normalized ratio.
* ABO blood typing assessment should be completed at the next regularly scheduled study visit (or at least prior
to the end of the subject’s participation in the study).
9.7.8.3
Liver and Hepatitis Testing
Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening. Subjects with documented results showing an absence of active hepatitis B or 
hepatitis C infection (as measured by positive surface antigen for hepatitis B or positive RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to be 
screened again.  
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with a 
history of hepatitis B or hepatitis C will be asked for information about the treatments 
received as part of their medical history assessment at Screening.
Subjects with a history of hepatitis B or hepatitis C infection prior to study entry will be 
tested for hepatitis B and hepatitis C reactivation at Week 16. Subjects who receive 
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therapeutic corticosteroids prior to Week 16 do not need to complete the Week 16 
reactivation assessment; instead, they will be tested for hepatitis B and hepatitis C 
reactivation at the time points listed in Table 9.1.6.
A liver ultrasound and LTs at Screening will identify any significant hepatic dysfunction, 
which is defined as: 
x
More than 3x the normal ALT level
x
More than 3x the normal bilirubin level
x
More than 3x the normal Alkaline phosphatase level.
x
INR > 1.4.
x
Thrombocytopenia under 100 x 109/L
x
Liver ultrasound results indicative of a liver cirrhosis
Liver tests will be monitored on a regular basis, at the time points indicated in Table 9.1.1,
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5.  At each time point, the following LTs 
should be assessed: 
Table 9.7.8.3.1:  Liver Tests
Liver Tests (LTs)
Alkaline Phosphatase
AST (SGOT)
Total Bilirubin
LDH
ALT (SGPT)
Direct Bilirubin
GGT
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, lactate 
dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase
Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, 
imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at 
the discretion of the investigator. 
9.7.8.4
HIV Testing
HIV testing will be performed at Screening. Subjects with documented negative results 
within the last 30 days prior to screening do not need to be retested.
9.7.8.5
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE.
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Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored prior to infusion, during the infusion every 
15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then 
every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).  
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 
and at the End of Years visits thereafter. A complete physical examination will include 
general appearance (head, eyes, ears, nose, and throat), cardiovascular, dermatologic, 
lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic 
systems.
At other visits, brief physical examinations may be performed at the discretion of the 
investigator based on the subject’s clinical condition. A brief physical examination will 
include general appearance, cardiovascular, respiratory, neurologic, dermatologic, 
musculoskeletal, and gastrointestinal assessments. Particular attention should be given to 
signs of bleeding, as well as assessing possible hemarthroses. 
Height will be recorded at Screening only. Weight will be recorded at Screening, at Weeks 
26 and 52 during Year 1, and then at the second Q12W visit each year and at every End of 
Years visit during Years 2-5. 
9.7.8.6
Vector Shedding
Vector shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 2007, J.Gene
Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the literature referenced above, including 
Haemophilia B clinical studies utilizing AAV2 and AAV8, vector was no longer detectable 
after 40 days in blood, saliva, urine or stool, but in one study was detected in the seminal 
fluid but not in motile sperm (Manno, 2006, Nat.Med.).  In these studies, the amount of 
vector present in these bodily fluids involved an extremely small fraction of the infused dose.  
More recent data from an ongoing AAV-FIX study demonstrates persistence of the vector in 
both the blood and the semen for at least 39 weeks (Miesbach, 2016, Haemophilia). 
During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily 
samples to look for evidence of vector shedding for possible viral transmission.  Bodily 
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fluids will be tested by PCR at the time points indicated in Table 9.1.2, Table 9.1.3,
Table 9.1.4, and Table 9.1.5.  Fluids tested will include:
x
Blood
x
Saliva
x
Semen
x
Urine
x
Stool
Vector shedding will also be extensively studied in the present clinical trial, every other week 
between Weeks 4-16, then every 4 weeks to Week 52 until at least 3 consecutive negative 
results are obtained. Testing of semen will continue through Week 12, even if 3 consecutive 
negative results have been recorded in that compartment prior to that timepoint.  Subjects 
who have not had 3 consecutive negative samples by Week 52 should continue to have PCR 
testing every 4 weeks until 3 consecutive negative samples are documented (or upon 
consultation between the Investigator and Medical Monitor). Subjects who meet the 
definition of treatment failure and wish to follow an abbreviated schedule (refer to 
Section 12.5.3 but who have not cleared vector shedding from all fluids must still provide 
samples for assessment until vector shedding has cleared: every 4 weeks (during Year 2), or 
every 6 weeks (during Years 3-5).
Contraception use may need to be extended beyond 26 weeks in individual subjects based on 
observed vector shedding in semen. After 6 months, subjects may stop contraception use 
only if they have had 3 consecutive negative semen samples (upon consultation between the 
Investigator and Medical Monitor). 
Details for sample collection and storage are provided in the Laboratory Manual. 
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10
REPORTING ADVERSE EVENTS
10.1
Safety Parameters and Definitions
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug.
10.1.1 Adverse Events
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(eg, sign, symptom, illness, disease or injury) in a subject administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
x
AEs not previously observed in the subject that emerge during the course of the
study.
x
Pre-existing medical conditions judged by the Investigator to have worsened in
severity or frequency or changed in character during the study.
x
Complications that occur as a result of non-drug protocol-imposed interventions
(eg, AEs related to screening procedures).
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis.
10.1.1.1
Bleeding and Suspected Bleeding Events
All bleeding events and suspected bleeding events, regardless of the need for exogenous 
FVIII therapy as treatment, should be captured in subject diaries and recorded on the 
designated bleeding eCRF.  Bleeding events and suspected bleeding events should not be 
reported as adverse events, with the following exception: 
x
All bleeding events and suspected bleeding events which meet one or more of the
criteria for being serious (refer to Section 10.2) should be reported as serious adverse
events (whether or not they are bleeding events that are normal sequelae of
hemophilia, and whether or not they required exogenous FVIII as treatment).
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10.2
Serious Adverse Events
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria:
x
Is fatal
x
Is life threatening
x
Note: Life-threatening refers to an event that places the subject at immediate risk of
death. This definition does not include a reaction that, had it occurred in a more
severe form, might have caused death.
x
Requires or prolongs inpatient hospitalization.
x
Results in persistent or significant disability or incapacity
x
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP
prior to conception or during pregnancy
x
Is an important medical event or reaction – that, based on medical judgment, may
jeopardize the subject or require intervention to prevent one of  the above
consequences (eg, anaphylaxis)
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs.
10.2.1 Events of Special Interest (EOSI) 
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality: 
x
Elevation of ALT ≥1.5x ULN, regardless of whether that triggers an initiation or
modification of  corticosteroid treatment
x
Thromboembolic event
10.3
Methods and Timing for Capturing and Assessing Safety Parameters
10.3.1 Adverse Event Reporting Period
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.1.1.1.
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10.3.2 Eliciting Adverse Events
Investigators will seek information on AEs, SAEs, and EOSI at each subject contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the subject’s medical record and on the AE Case Report 
Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.1.1.1
for SAE definitions).  These assessments must be made by a study clinician with the training 
and authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS).
10.3.3.1
Seriousness
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.1.1.  Seriousness serves as a guide for 
defining regulatory reporting obligations. 
10.3.3.2
Severity
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1.
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 
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Table 10.3.3.2.1: Adverse Event Grading (Severity) Scale
Grade
Description
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated
Grade 4 and 5 AEs 
should always be 
reported as SAEs
5
Death related to AE
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the telephone, 
managing money.
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, taking 
medications, not bedridden.
10.3.3.3
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1.
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Table 10.3.3.3.1: Causality Attribution Guidance
Relationship
Description
Not Related
x
Exposure to the IP has not occurred
x
OR
x
The administration of the IP and the occurrence of the AE are not
reasonably related in time
x
OR
x
The AE is considered likely to be related to an etiology other than the
use of the IP; that is, there are no facts, evidence, or arguments to
suggest a causal relationship to the IP.
Related
x
The administration of the IP and the occurrence of the AE are
reasonably related in time
AND
x
The AE could possibly be explained  by factors or causes other than
exposure to the IP
OR
x
The administration of IP and the occurrence of the AE are reasonably
related in time
AND
x
The AE is more likely explained by exposure to the IP than by other
factors or causes.
Factors suggestive of a causal relationship could include (but are not limited to): 
x
Plausible temporal relationship
x
Absence of alternative explanations
x
Rarity of event in a given patient or disease state
x
Absence of event prior to study drug exposure
x
Consistency with study product pharmacology
x
Known relationship to underlying mechanism of study drug action
x
Similarity to adverse reactions seen with related drug products
x
Abatement of AE with discontinuation of study drug, and/or recurrence of AE with
reintroduction of study drug
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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4
Procedures for Recording Adverse Events
10.4.1 Recording Adverse Events on a eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology.
10.4.1.1
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE (or SAE, as appropriate) eCRF, replacing the original 
entries where appropriate.
10.4.1.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3
Persistent or Recurrent Adverse Events
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF. 
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A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF.
10.4.1.4
Abnormal Laboratory Values
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable.
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF. Any laboratory result abnormality of CTCAE Grade 4
or 5 should be recorded as an SAE in the AE eCRF.
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met:
x
Accompanied by clinical symptoms
x
Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).
x
The abnormality suggests a disease and/or organ toxicity
x
The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.)
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported. 
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed.
10.4.1.5
Pre-existing Conditions
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF.
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A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches).
10.4.1.6
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF.
10.4.1.7
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.1.1).
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to:
x
Perform a protocol-mandated  procedure or assessment
x
Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
x
Insert an in-dwelling IV catheter (such as a Port-a-Cath or other brand) for 
administration of study drug or FVIII replacement therapy. 
x
Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8
Deaths
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
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10.4.1.9
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event. The Investigator must make every effort to 
follow the subject’s partner (with that partner’s consent) through resolution of the pregnancy 
(delivery or termination) and to report the resolution on the Pregnancy Follow-up eCRF. In 
the event of pregnancy in the partner of a study subject, the Investigator should make every 
reasonable attempt to obtain the woman’s consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5
Reporting Requirements
10.5.1 Expedited Reporting Requirements
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF and submitting to BPV within 24 hours of the site becoming 
aware of the event. Investigators should not wait to collect information that fully documents 
the event before notifying BPV of an SAE. BioMarin may be required to report certain SAEs 
to regulatory authorities within 7 calendar days of being notified about the event; therefore, it 
is important that Investigators submit any information requested by BioMarin as soon as it 
becomes available.
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations.
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF.
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10.5.2 Ethics Committee Reporting Requirements
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required.
10.6
Follow-up of Subjects after Adverse Events
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the subject is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the subject’s medical record to facilitate source data verification.
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report.
10.7
Post-Study Adverse Events
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment.
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study. 
10.8
Urgent Safety Measures
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
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protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.” 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
x
Immediate need to revise the IP administration (eg, modified dose amount or
frequency not defined in protocol)
x
Lack of study scientific value, or detrimental study conduct or management
x
Discovery that the quality or safety of the IP does not meet established safety
requirements
10.9
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows:
BioMarin Pharmaceutical Inc.
Address 
105 Digital Drive
Novato, CA 94949 
Phone: 
 
Fax: 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:
, MA MB BChir MSc
Address: 
Biomarin (UK) Ltd.
10 Bloomsbury Way 
London WC1A 2SL 
Phone
 (office)
 (mobile) 
E-mail:
 
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PI
PI
PI
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11
APPROPRIATENESS OF MEASUREMENTS
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic substrate assay and the one-stage clotting assay are both validated and 
utilize CE marked reagents.  The exploratory FVIII activity assay will be used for 
exploratory purposes only. 
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12
STUDY PROCEDURES
12.1
Prestudy
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed.
12.2
Screening Visit
Screening assessments will be performed within 28 days (+ 14 days) of BMN 270 infusion 
while baseline assessments will take place within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LTs, haematology, urine tests, coagulation screen, and CRP do 
not need to be repeated at Baseline. 
The following procedures will be performed during the Screening Period:
x
Full medical history, including haemophilia A history, hepatitis B, hepatitis C, and 
HIV. 
o
Subjects with a history of hepatitis B or hepatitis C will be asked for 
information about the treatments received. Any prior pharmacokinetics 
information obtained while the subject was receiving prophylactic or 
on-demand FVIII therapy prior to the study should also be collected. For 
subjects who have already enrolled in 270-201, this information should be 
collected at the next regularly scheduled study visit (or at least prior to the 
subject’s completion of study participation).
x
Complete Physical Examination 
x
Height and weight
x
Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature) 
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
x
Electrocardiogram
x
Chest X-ray
x
Liver Ultrasound
x
Samples for hFVIII Assays
o
Baseline hFVIII activity – chromogenic substrate (plasma)
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o
Baseline hFVIII activity level – one-stage clotting assay
o
hFVIII coagulation activity exploratory assay 
o
hFVIII inhibitor level (Bethesda assay with Nijmegen modification)
o
hFVIII total antibody assay
o
hFVIII antigen (ELISA) 
x
Blood sample for AAV5 Assays 
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay 
x
Screen for hepatitis B, hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested)
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
x
Urine Tests (refer to Table 9.7.8.2.1) 
x
Liver Tests (refer to Table 9.7.8.3.1) 
x
Von Willebrand Factor Antigen (VWF:Ag)  
x
Blood samples for Biomarker testing (including HLA genotyping, FVIII genotyping 
status, TNFD and IL10a single nucleotide polymorphisms) 
12.2.1 “Smart Rescreening” Visit
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study:
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification)
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x
Blood sample for AAV5 Assays 
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay 
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
x
Urine Tests (refer to Table 9.7.8.2.1) 
x
Liver Tests (refer to Table 9.7.8.3.1) 
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
Distribution of subject diaries and training in diary completion
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
x
Urine Tests (refer to Table 9.7.8.2.1) 
x
Liver Tests (refer to Table 9.7.8.3.1) 
x
PBMC collection for CTL baseline 
x
Direct Thrombin test
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
x
Exploratory biomarker assessments 
x
Haemo-QoL-A QoL assessment
12.4
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each subject.  Subjects will remain in the clinic for 
24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
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o
AAV5 antibody titer
o
AAV5 transduction inhibition assay
x
BMN 270 Infusion
x
Vital Signs
o
Vital signs will be recorded prior to BMN 270 infusion and then every
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion,
vital signs will be monitored every 1 hour (± 5 minutes) for the first
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at
4 hour (± 15 minutes) intervals for the remainder of the subject’s stay in
the clinic.
12.5
BMN 270 Infusion Follow-Up Visits
After BMN 270 has been infused, subjects will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Once per week (Weeks 1 through 16) 
The following procedures will be performed at one visit per week from Weeks 1 through 16: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
Samples for FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  The 72-hour wash-out period is only intended for 
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subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
o
Central assessment of FVIII activity level should be performed 1x/week
from Week 1 through Week 16
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
PBMC collection
12.5.2 Week 1 – Day 2 and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed: 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (Day 2 and Day 4)
x
Samples for FVIII Assays (Day 4 only) – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Liver Tests (refer to Table 9.7.8.3.1) (Day 4 only) – central laboratory assessment
x
Liver Tests (refer to Table 9.7.8.3.1) (Day 4 only) – local laboratory assessment
x
FVIII activity level (Day 4 only) – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
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12.5.3 Week 1 – Day 8 
On Day 8, the following procedures will be performed: 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
x
Direct Thrombin test
x
Haemo-QoL-A QoL assessment
12.5.4 Every 2 Weeks
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedures will be 
performed:
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
(not assessed at Week 14)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at
Week 2)
o
Collection to occur until at least 3 consecutive negative results are
obtained.  Semen samples should continue to be collected and tested
through Week 12, even if 3 consecutive negative results in that
compartment have been recorded prior to that timepoint.
12.5.5 Weeks 4, 8, 12, and 16 
At Weeks 4, 8, 12, and 16, the following procedures will be performed: 
x
Urine Tests (refer to Table 9.7.8.2.1)
x
VWF:Ag
x
FVIII antibody titer
x
Exploratory biomarker assessments
12.5.6 Week 16
At Week 16, the following procedures will be performed: 
x
Test for hepatitis B and hepatitis C reactivation (in subjects with a history of hepatitis
B or hepatitis C infection prior to study entry)
o
Subjects who receive therapeutic corticosteroids prior to Week 16 do not
need to complete the Week 16 reactivation assessment; instead, they will
be tested for hepatitis B and hepatitis C reactivation at the time points
listed in Table 9.1.6.
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12.5.7 Weeks 8 and 16 
At Weeks 8 and 16, the following procedures will be performed: 
x
AAV5 antibody titer
12.5.8 Weeks 2, 3, 4, and 16 
At Weeks 2, 3, 4, and 16, the following procedure will be performed: 
x
Haemo-QoL-A QoL assessment
12.5.9 Week 13
At Week 13, the following procedure will be performed: 
x
Direct Thrombin test
12.6
Safety Follow-Up – Weeks 17-36 
After the Post-Infusion Follow-Up visits are complete, subjects will return to the study site 
for Safety Follow-Up visits from Weeks 17 through Week 36 (± 48 hours), when the 
following procedures will be completed: 
12.6.1 Once per week (Weeks 17 through 36)
Once per week from Week 17 through Week 36, the following procedures will be performed: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
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Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
12.6.2 Once per week (Weeks 17 through 20)
Once per week from Week 17 through Week 20, the following procedures will be performed: 
x
PBMC collection
12.6.3 Every 2 weeks (Weeks 21 through 36) 
Every 2 weeks (Weeks 22, 24, 26, 28, 30, 32, 34, and 36), the following procedures will be 
performed:
x
PBMC collection
12.6.4 Every 4 Weeks 
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed: 
x
Exploratory biomarker assessments
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
VWF:Ag
x
AAV5 antibody titer
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Safety Follow-Up is not required if at least
3 consecutive samples are clear during the Post-Infusion Follow-Up period.
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12.6.5 Every 8 Weeks 
Every 8 weeks (Weeks 20, 28, and 36), the following procedure will be performed: 
x
FVIII antibody titer
12.6.6 Week 26
At Week 26, the following procedure will be performed: 
x
Direct Thrombin test
x
Weight
12.6.7 Week 28  
At Week 28, the following procedure will be performed: 
x
Haemo-QoL-A QoL assessment
12.7
 Safety Follow-Up – Weeks 37-52 
Subjects will return every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) from 
Week 37-52 (± 1 week), when the following procedures will be completed: 
12.7.1 Once per visit
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed:
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently based (and in particular when 
ALT values are >1.5x ULN) on discussion between the Medical Monitor and 
the Investigator and review of subject data.
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x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy.
12.7.2 Every 4 Weeks 
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed: 
x
Exploratory biomarker assessments
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
AAV5 antibody titer
x
VWF:Ag
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Safety Follow-Up is not required if at least
3 consecutive samples are clear during the Post-Infusion Follow-Up period.
Subjects who have not had 3 consecutive negative samples by Week 52
should continue to have PCR testing every 4 weeks until 3 consecutive
negative samples are documented (or upon consultation between the
Investigator and Medical Monitor).
12.7.3 Every 8 Weeks 
Every 8 weeks (Weeks 44 and 52), the following procedure will be performed: 
x
PBMC collection
x
FVIII antibody titer
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12.7.4 Week 38 and 52 
At Week 38 and Week 52, the following procedure will be performed: 
x
Direct Thrombin test
12.7.5 Week 52  
At Week 52, the following procedure will be performed: 
x
Haemo-QoL-A QoL assessment
x
Weight
12.8
Safety Follow-Up – Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
either failure to achieve FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by 
attending only the Q12W and End of Year visits during Years 2-5. 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
vector shedding has cleared (but do not have to perform other scheduled assessments at those 
study visits).
During Years 2-5 of Safety Follow-up, the following procedures will be completed: 
12.8.1 Year 2 – Every 4 Weeks (not required for treatment failure)
During Year 2, every 4 weeks (± 2 weeks), the following procedures will be performed: 
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
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x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Year 2 is not required if at least 3 consecutive samples
are negative during the Post-Infusion Follow-Up period in Weeks 1-52.
Subjects who have not had 3 consecutive negative semen samples by Week 52
should continue to have PCR testing of semen every 4 weeks during Year 2
until 3 consecutive negative samples are documented (or upon consultation
between the Investigator and Medical Monitor).
o
Subjects who meet the definition of treatment failure and wish to follow an
abbreviated schedule but who have not cleared vector shedding from all fluids
must still provide samples for assessment every 4 weeks during Year 2 until
vector shedding has cleared (in such a case, these subjects do not need to
perform other assessments except for PCR sample delivery scheduled at these
timepoints).
12.8.2 Years 3-5 – Every 6 Weeks (not required for treatment failure)
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
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o
LTs may be monitored more or less frequently (and in particular when ALT
values are >1.5x ULN) based on discussion between the Medical Monitor and
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Years 3-5 is not required if at least 3 consecutive
samples are negative during the Post-Infusion Follow-Up period in
Weeks 1-52 and/or Year 2.  Subjects who have not had 3 consecutive negative
semen samples by Week 52 should continue to have PCR testing of semen
every 6 weeks during Years 3-5 until 3 consecutive negative samples are
documented (or upon consultation between the Investigator and Medical
Monitor).
o
Subjects who meet the definition of treatment failure and wish to follow an
abbreviated schedule but who have not cleared vector shedding from all fluids
must still provide samples for assessment every 6 weeks during Years 3-5
until vector shedding has cleared (in such a case, these subjects do not need to
perform other assessments except for PCR sample delivery scheduled at these
timepoints).
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12.8.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects)
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks (±2 weeks):
x
Year 2 – Week 64, Week 76, Week 88, Week 104
x
Year 3 – Week 116, Week 128, Week 140, Week 156
x
Year 4 – Week 168, Week 180, Week 192, Week 208
x
Year 5 – Week 220, Week 232, Week 244, Week 260
For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and 
Week 260) will serve as an End of Year visit.
At the every 12 week and End of Year visits, the following procedures will be performed: 
x
Brief physical examination (at every 12 week visits) or complete physical
examination (at End of Year visits)
x
Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
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o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Vital Signs
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
o
ABO blood typing assessment should be performed at the next regularly 
scheduled study visit (or at least prior to the end of the subject’s participation 
in the study)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
AAV5 antibody titer
x
FVIII antibody titer
x
PBMC collection
x
VWF:Ag
x
Exploratory biomarker assessments
x
Haemo-QoL-A QOL assessment (at Week 76, Week 128, Week 180, Week 232, and
End of Year visits only)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Years 2-5 is not required if at least 3 consecutive
samples are negative during the Post-Infusion Follow-Up period in
Weeks 1-52.  Subjects who have not had 3 consecutive negative semen
samples by Week 52 should continue to have PCR testing of semen every
4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until
3 consecutive negative samples are documented (or upon consultation
between the Investigator and Medical Monitor).
12.9
Liver Biopsy Substudy - Years 1-5 
For the optional liver biopsy substudy (refer to Table 9.1.7), the following procedures will be 
performed at the following times:
x
Within 28 days before Biopsy Day
o
Informed consent
o
Liver ultrasound
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Liver ultrasound does not need to be performed if an ultrasound result
from the prior 3 months is already available
o
Brief physical examination
o
Hematology, Coagulation, and Chemistry Assessments (refer to
Table 9.7.8.2.1)
o
Liver Tests (refer to Table 9.7.8.3.1)
x
Within 7 Days before Biopsy Day
o
FibroScan
o
Local laboratory FVIII activity level assessment
o
Pre-biopsy consultation with investigator (treating hematologist).  This may
need to be repeated/extended if the subject’s FVIII activity levels need
adjustment before the biopsy, at the discretion of the investigator (treating
hematologist).
x
1 Day before Biopsy Day
o
Hematology, Coagulation, and Chemistry Assessments (refer to
Table 9.7.8.2.1)
o
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
Brief physical examination
o
Local laboratory FVIII activity level assessment

Subjects must have a FVIII activity level of at least 50 IU/dL (or
higher, depending on local guidelines and/or investigator discretion).
As needed, subjects may be treated with additional exogenous FVIII
replacement products in order to increase their FVIII activity levels to
an appropriate level, under the supervision/instruction of the
investigator, to ensure the safety of the subject during the procedure.
This exogenous FVIII usage (if performed) should be recorded in the
eCRF FVIII infusion pages under the category “Surgery/Procedure”.
x
Biopsy Day
o
Brief physical examination
o
Local laboratory FVIII activity level assessment (performed pre-biopsy)
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Subjects must have a FVIII activity level of at least 50 IU/dL (or
higher, depending on local guidelines and/or investigator discretion).
As needed, subjects may be treated with additional exogenous FVIII
replacement products in order to increase their FVIII activity levels to
an appropriate level, under the supervision/instruction of the
investigator, to ensure the safety of the subject during the procedure.
This exogenous FVIII usage (if performed) should be recorded in the
eCRF FVIII infusion pages under the category “Surgery/Procedure”.
o
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment (pre-
biopsy)
o
Liver Biopsy (refer to Laboratory Manual for guidelines for biopsy procedure
and handling of biopsy samples)

If only a small amount of tissue is obtained at the time of the biopsy,
the subject may be asked to consent for a second pass.
Following completion of the biopsy, the subject should remain in the hospital under 
observation for at least 4-6 hours. Overnight post-procedure observation may be done at the 
investigator’s discretion. 
12.10 Early Termination Visit
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit.
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
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o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
AAV5 antibody titer
x
FVIII antibody titer
x
PBMC collection
x
VWF:Ag
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing at the ETV is not required if at least 3 consecutive samples
are clear during the Post-Infusion Follow-Up period.
x
Exploratory biomarker assessment
x
Haemo-QoL-A QOL assessment
12.11 End of Study
The study will end after the last subject completes the last Safety Follow-Up visit 
(Week 260). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study subjects may be 
compromised. 
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13
DATA QUALITY ASSURANCE
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan.
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS.
14.1.1 Interim Analyses
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all subjects having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16). 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
Missing data will not be imputed. 
14.2
Primary and Secondary Efficacy Analysis 
The subjects will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of subjects, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined.
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic substrate assay and/or one-stage 
clotting assay as measured by the central laboratory at 16 weeks following study treatment.  
hFVIII activity will be assessed weekly during the study period.  We can only assess the true 
steady state of hFVIII protein produced from BMN 270 after a minimum of 72 hours has 
elapsed since the last infusion of FVIII protein concentrates.   
14.3
Liver Biopsy Substudy Analysis 
A separate report presenting and discussing analyses of the exploratory objectives for the 
optional liver biopsy substudy will be prepared. 
14.4
Immunogenicity
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons  
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14.5
Pharmacodynamic Analyses 
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by a 
one-stage clotting assay and/or chromogenic substrate assay (activity level), will be used for 
plasma profiles; FVIII activity will be used to determine PD parameters.  Traditional PK 
analysis is not applicable. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics. 
14.6
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF.
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of subjects who report hepatitis will be presented. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided.  
Detailed statistical methods will be provided in the SAP.
14.7
Determination of Sample Size
No formal sample size calculations based on statistical power were performed.
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 15 subjects may be dosed in the study; the actual number of 
subjects will depend on the criteria for dose escalation.  
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14.8
Analysis Populations
The Safety analysis population is defined as all enrolled subjects who receive any study drug. 
The analysis of safety data will be performed on Safety Set.
The Full Analysis Set (FAS) is defined as all enrolled subjects who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis.
14.9
Changes in the Conduct of the Study or Planned Analyses
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation.
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active subjects must again provide informed consent.
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail.
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15
DATA REVIEW BOARD
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established. 
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available subject safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene
for further assessment of subject safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites.
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COMPENSATION, INSURANCE AND INDEMNITY
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the subject’s health insurance company or other third party 
payer for the cost of this medical treatment. If the subject has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law.
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CASE REPORT FORMS AND SOURCE DOCUMENTS
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy.
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable. 
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to 
their medical records, and subjects will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
subject records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification.
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a subject’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 
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STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas AND to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files.
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RETENTION OF RECORDS
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained. 
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USE OF INFORMATION AND PUBLICATION
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  
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REFERENCES
Bainbridge, JW, Smith, AJ, Barker, SS, Robbie, S et. al. Effect of gene therapy on visual 
function in Leber's congenital amaurosis. N Engl J Med 358[21], 2231-2239. 2008. 
Berntorp, E, Peake, I, Budde, U, Laffan, M et. al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia 18 Suppl 6, 1-13. 2012. 
Croteau, GA, Martin, DB, Camp, J, Yost, M et. al. Evaluation of exposure and health care 
worker response to nebulized administration of tgAAVCF to patients with cystic fibrosis. 
Ann Occup Hyg 48[8], 673-681. 2004. 
D'Avola, D. Phase 1 Clinical Trial of Liver Directed Gene Therapy with rAAV5-PBGD in 
Acute Intermittent Porphyria: Preliminary Safety Data. J Hepatol 60[S58]. 2014. 
Den Ujil, Mauser Bunschoten, Roosendaal, Schutgens et. al. Clinical Severity of haemophilia 
A: does the classification of the 1950s still stand? Haemophilia 17, 849-853. 2011. 
George, LA, Sullivan, S, Teitel, J, Cuker, A et al.  Preliminary results of a phase 1/2 trial of 
SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent 
factor IX activity levels at the lowest dose cohort.  Haemophilia 22[Suppl. 4], 151-152.  
2016.
Grant A, Neuberger J, Day C, Saxseena S. British Society of Gastroenterology Guidelines on 
the use of Liver Biopsy in Clinical Practice. 2004. Available at: 
https://www.bsg.org.uk/resource/bsg-guidelines-on-the-use-of-liver-biopsy-in-clinical-
practice.html (last visited 1 December 2018).
Hay, CR, DiMichele, DM. The principal results of the International Immune Tolerance 
Study: a randomized dose comparison. Blood 119[6], 1335-1344. 2012. 
Heller CG & Clermont Y.  Kinetics of the germinal epithelium in man.  Recent Prog Horm 
Res.  1964;20:545-571. 
Heller CG, Heller GV, Rowley MJ.  Human spermatogenesis: an estimate of the duration of 
each cell association and each cell type.  Excerpta Med Int Congr Ser.  1969;184:1012-1018. 
Kaufman, RJ, Powell, JS. Molecular approaches for improved clotting factors for hemophilia 
1. Blood 122[22], 3568-3574. 2013.
Maguire, AM, High, KA, Auricchio, A, Wright, JF et. al. Age-dependent effects of RPE65 
gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 
374[9701], 1597-1605. 2009. 
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Mahlangu, J, Powell, JS, Ragni, MV, Chowdary, P et. al. Phase 3 study of recombinant factor 
VIII Fc fusion protein in severe hemophilia A
8. Blood 123[3], 317-325. 2014.
Manno, CS, Chew, AJ, Hutchison, S, Larson, PJ et. al. AAV-mediated factor IX gene 
transfer to skeletal muscle in patients with severe hemophilia B
1. Blood 101[8], 2963-2972. 2003.
Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006.
Mannucci, PM, Tuddenham, EG. The hemophilias--from royal genes to gene therapy
1. N Engl J Med 344[23], 1773-1779. 2001.
McIntosh, J, Lenting, PJ, Rosales, C, Lee, D et. al. Therapeutic levels of FVIII following a 
single peripheral vein administration of rAAV vector encoding a novel human factor VIII 
variant. Blood 121[17], 3335-3344. 2013.
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016.
Mingozzi, F and High, KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013.
Monahan, P, Walsh CE, Powell JS, Konkle BA et al.  Update on a phase 1/2 open-label trial 
of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for 
hemophilia B.  J Thromb Haemostasis 13[Suppl 2], 1-997.  2015.
Nagel, K, Walker, I, Decker, K, Chan, AK et. al. Comparing bleed frequency and factor 
concentrate use between haemophilia A and B patients. Haemophilia 17[6], 872-874. 2011.
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992.
Nathwani, AC, McIntosh, J, Davidoff, AM. An update on gene therapy for hemophilia. Curr 
Hematol Rep 4[4], 287-293. 2005.
Nathwani, AC, Gray, JT, Ng, CY, Zhou, J et. al. Self-complementary adeno-associated virus 
vectors containing a novel liver-specific human factor IX expression cassette enable highly 
efficient transduction of murine and nonhuman primate liver. Blood 107[7], 2653-2661.
2006.
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Nathwani, AC, Rosales, C, McIntosh, J, Rastegarlari, G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011. 
Nathwani, AC, Tuddenham, EG, Rangarajan, S, Rosales, C et. al. Adenovirus-associated 
virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365[25], 2357-2365. 
2011.
Nathwani, AC, Reiss, UM, Tuddenham, EG, Rosales, C et. al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014. 
Paneda, A, Lopez-Franco, E, Kaeppel, C, Unzu, C et. al. Safety and liver transduction 
efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute 
intermittent porphyria. Hum Gene Ther 24[12], 1007-1017. 2013. 
Pasi, J, Wong, W, Rangarajan, S, Wilde, J et al.  Interim results of an open-label, phase 1/2 
study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A.  Haemophilia 
22[Suppl. 4], 151-152.  2016. 
Rangarajan S, Walsh L, Lester W et al. AAV5-Factor Gene Transfer in Severe Hemophilia 
A. NEJM. 2017;377(26):2519-2530. 
Schenk-Braat, EA, van Mierlo, MM, Wagemaker, G, Bangma, CH et. al. An inventory of 
shedding data from clinical gene therapy trials. J Gene Med 9[10], 910-921. 2007. 
Simonelli, F, Maguire, AM, Testa, F, Pierce, EA et. al. Gene therapy for Leber's congenital 
amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18[3], 
643-650. 2010. 
Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS et. al. Guidelines for the 
management of hemophilia. Haemophilia 19[1], e1-47. 2013. 
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010.
Watkins, PB, Kaplowitz, N, Slattery, JT, Colonese, CR et al.  Aminotransferase Elevations in 
Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized Controlled 
Trial.  JAMA 296[1], 87-93.  2006. 
White, GC, Rosendaal, F, Aledort, FM, Lusher, JM et al.  Definitions in hemophilia.  
Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific 
and standardization committee of the International society on Thrombosis and Haemostasis.  
Thromb Haemost. 85[3], 560.  2001. 
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INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Patients 
In accordance with FDA Form 1572 and/or principles of ICH E6 R2 GCP, the Investigator 
will ensure that:
x
He or she will conduct the study in accordance with the relevant, current protocol and
will only make changes in a protocol after notifying the sponsor, except when
necessary to protect the safety, rights, or welfare of patients.
x
He or she will personally conduct or supervise the study.
x
He or she will inform any potential patients, or any persons used as controls, that the
drugs are being used for investigational purposes and he or she will ensure that the
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or ICH E6
R2 Sections 2.9 and 4.8 are met. As well, he or she will ensure that IRB/ IEC review
and approval in 21 CFR Part 56 and/or ICH E6 R2 Section 2.6 are met.
x
He or she will report to the sponsor adverse experiences that occur in the course of
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 R2 Section 4.11.
x
He or she has read and understands the information in the Investigator’s Brochure,
including potential risks and side effects of the drug.
x
His or her staff and all persons who assist in the conduct of the study are informed
about their obligations in meeting the above commitments.
x
Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 R2
Section 4.9 are kept, and those records are available for inspection in accordance with
21 CFR 312.68 and/or ICH E6 R2 Section 4.9.7.
x
The IRB/IEC/REB complies with the requirements of 21 CFR Part 56, ICH E6 R2
Section 3.0, and other applicable regulations, and conducts initial and ongoing
reviews and approvals of the study. He or she will also ensure that any change in
research activity and all problems involving risks to human patients or others are
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in
the research without IRB/IEC/REB approval, except where necessary to eliminate
apparent immediate hazards to human patients.
x
He or she agrees to comply with all other requirements regarding the obligations of
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or
ICH E6 R2.
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SIGNATURE PAGE
Protocol Title: A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII in Patients with Severe Haemophilia A
Protocol Number: 270-201 Amendment 8
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including  
ICH E6 R2, as stated in the protocol, and other information supplied to me.
Investigator Signature
Date
Printed name _______________________________________________________________
Accepted for the Sponsor:
Medical Monitor Signature
Date
Printed name:
, MA MB BChir MSc, 
, Clinical Science
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PI
PI
PI

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PROTOCOL AMENDMENT TEXT REVISIONS
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See page 2).  Text that 
has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font.
Section No./Title
Revision
Rationale
Synopsis (Study 
Rationale)
Liver Biopsy Substudy Rationale
The pattern of response in hFVIII activity observed so far after administration of BMN 270 demonstrates peak expression 
levels during the first 6-12 months post-treatment followed by a decline to a steady-state level of expression in the second year 
of follow-up, with mean hFVIII activity levels remaining above the lower limit of normal (50 IU/dL).  One of the explanations 
may lie in the kinetics of vector genome processing which involves a series of steps such as DNA degradation and repair, 
annealing, and circularization that can result in the formation of stable double-stranded circularized transgene DNA forms, and 
it is these circularized DNA species that are thought to be associated with long-term, persistent expression of the gene product 
in target cells.  Examination of transduced hepatocytes from subjects treated with BMN 270 in the 270-201 study will help to 
establish whether DNA circularization may occur and could account for the long-term hFVIII expression observed in humans.
Additionally, health of the liver after gene transduction has been monitored indirectly by periodic assessments of hepatic 
enzymes released into the blood stream.  Transient post-treatment elevations in ALT levels have been observed in some 
subjects, as well as inter-subject variability in post-therapy hFVIII levels. Neither the reasons for, nor the significance of, the 
ALT elevations or variations in response to FVIII gene therapy are known.  Moreover, the effects of BMN 270 on hepatic 
tissue structure and function are also currently unknown. 
The purpose of this exploratory substudy is to provide a better understanding of the  long-term gene expression related to 
circularized genomes, health of the liver, and variation in hFVIII levels observed after gene therapy with BMN 270.  Whilst 
consenting subjects may not derive any direct benefit themselves by participating in the substudy, the overall findings could
aid future patients by helping to characterize the means by which long-term efficacy is achieved and the safety of liver-
directed gene therapy.
1
Synopsis (Objectives)
The exploratory objectives of the liver biopsy substudy are:
x
To examine the histopathology of the liver following BMN 270 therapy, including assessing for possible safety 
findings (eg, fibrosis, fatty liver disease, lymphocytic invasion)
x
To quantify FVIII DNA, RNA, and protein expression within hepatocytes
x
To determine which forms of rAAV vector DNA are present at the time of biopsy.
x
To determine the transduction pattern of BMN 270 in humans (ie, peri-portal hepatocytes, central vein hepatocytes)
1
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Section No./Title
Revision
Rationale
Synopsis (Study Design 
and Plan)
Liver Biopsy Substudy Design
All subjects enrolled in 270-201 and who are at least one year post-BMN 270 infusion are eligible for the optional liver biopsy 
substudy. Subjects who consent to participate in the substudy will have a liver biopsy via either the transjugular or 
percutaneous (ultrasound-guided) route, according to the standard procedures of the institution. To enhance safety, all subjects 
will have an ultrasound examination of the liver within 3 months prior to the procedure (to ensure there are no pathological 
findings such as bile duct obstruction that might interfere with the safe performance of the liver biopsy) and a FibroScan of the 
liver within one week before the liver biopsy (to correlate with any potential histopathologic findings of fibrosis on the 
biopsy). 
Subjects who consent should have their FVIII levels monitored/adjusted by the Investigator to enable the procedure to be 
performed safely.  This may require the administration of exogenous FVIII replacement products in order to achieve the 
desired FVIII activity.  The target FVIII activity level within 24 hours prior to the liver biopsy is at the discretion of the 
Investigator and/or according to local guidelines, but at a minimum should be at the lower limit of the normal range (ie, at 
least 50 IU/dL).
1
Synopsis (Inclusion and 
Exclusion Criteria)
Individuals eligible to participate in the liver biopsy substudy must meet all of the following criteria:
5.
Currently enrolled in 270-201
6.
Received BMN 270 infusion at least 1 year prior to enrollment in the substudy
7.
Able to sign informed consent and comply with requirements of the substudy
8.
FVIII activity at least >50 IU/dL (or higher, depending on local guidelines and/or Investigator discretion) within 24 
hours prior to the liver biopsy being performed.  (FVIII levels should be assessed at the local laboratory.)  Subjects 
may be treated with additional exogenous FVIII replacement products in order to increase their FVIII levels to an 
appropriate level, under the supervision/instruction of the Investigator.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the liver biopsy substudy:
9.
Assessed by the investigator or a hepatologist as having a medical condition such that undergoing a liver biopsy 
would be contraindicated. These conditions could include (but are not limited to):
x
Significant thrombocytopenia (platelet count < 100 x 109/L)
x
Evidence of significant ascites
1
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Section No./Title
Revision
Rationale
x
Abnormalities detected on liver ultrasound (performed within 90 days of procedure) that would preclude safe 
performance of the biopsy.
Synopsis (Criteria for 
Evaluation)
Liver Biopsy Substudy:
The following exploratory assessments will be performed as part of the optional liver biopsy substudy:
x
Morphologic/pathogenic changes after FVIII gene transduction or any change that may be associated with sustained 
ALT rise 
x
Determine quantities of liver FVIII-SQ DNA/RNA
x
Determine forms of vector DNA in liver at the time of biopsy
x
Determine percentage of hepatocytes expressing FVIII protein 
x
Determine percentage of hepatocytes staining positive for vector DNA 
x
Determine hepatic liver transcriptome at single nuclei level if sufficient material is obtained
x
Identify the forms of vector DNA in the liver 
x
Examination of potential stress inducing cellular pathways
x
Other exploratory assessment to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer
1
7.3.1/Liver Biopsy 
Substudy Rationale
The pattern of response in hFVIII activity observed so far after administration of BMN 270 demonstrates peak expression 
levels during the first 6-12 months post-treatment followed by a decline to a steady-state level of expression in the second year 
of follow-up, with mean hFVIII activity levels remaining above the lower limit of normal (50 IU/dL).  One of the explanations 
may lie in the kinetics of vector genome processing which involves a series of steps such as DNA degradation and repair, 
annealing, and circularization that can result in the formation of stable double-stranded circularized transgene DNA forms. It 
is these circularized DNA species that are thought to be associated with long-term, persistent expression of the gene product in 
target cells.  Examination of transduced hepatocytes from subjects treated with BMN 270 in the 270-201 study will help to 
establish whether DNA circularization may occur and could account for the long-term hFVIII expression observed in humans.
Additionally, health of the liver after gene transduction has been monitored indirectly by periodic assessments of hepatic 
enzymes released into the blood stream.  Transient post-treatment elevations in ALT levels have been observed in some 
subjects, as well as inter-subject variability in post-therapy hFVIII levels. Neither the reasons for, nor the significance of, the 
ALT elevations or the variations in response to FVIII gene therapy are known.  Moreover, the effects of BMN 270 on hepatic 
tissue structure and function are also currently unknown. 
1
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Section No./Title
Revision
Rationale
The purpose of this exploratory substudy is to provide a better understanding of the long-term gene expression related to 
genome circularization, health of the liver, and variation in hFVIII levels observed after gene therapy with BMN 270.  Whilst 
consenting subjects may not derive any direct benefit themselves by participating in the substudy, the overall findings could
aid future patients by helping to characterize the means by which long-term efficacy is achieved and the safety of liver-
directed gene therapy. 
7.4.1.1/Liver Biopsy 
Substudy Risks and 
Benefits
Liver biopsy is considered a safe procedure, with serious complications occurring less than once in every 10,000 procedures 
(Grant, 2004). Although the theoretical risks of significant complications are extremely small, the main complications would 
include bleeding and bile leakage. Another theoretical complication is infection at the needle insertion site; the sterile 
technique used makes this risk extremely small. 
The most common problems include mild pain and a minor decrease in blood pressure. More serious complications, such as 
bleeding, infection, and injury to nearby organs, are very rare, but the subject will be monitored appropriately to ensure correct 
management should any of these occur. Any complications related to the liver biopsy should be reported as adverse events, as 
outlined in Section 10. The liver biopsy is a standard investigation, and will be explained more fully by the experienced 
clinician performing the biopsy. 
Each subject who participates in this optional substudy will have a comprehensive pre-/post-biopsy surveillance plan 
according to the standard procedures at the institution. Safety will be assessed by adverse event reporting and clinical
laboratory assessments. Per the Investigator's discretion and/or according to local guidelines, the subject may be kept in 
overnight following the liver biopsy for additional safety monitoring; such an overnight stay would not be considered a 
hospitalization for serious adverse event (SAE) reporting purposes (refer to Section 10.4.1.7). 
There is no direct benefit from participating in this study other than contributing to understanding the mechanism of action of 
BMN 270. Consenting into this specific substudy is optional and will not have any effect on the subject’s continued 
participation in 270-201.
1 
8/Study Objectives
The exploratory objectives of the liver biopsy substudy are:
x
To examine the histopathology of the liver following BMN 270 therapy, including assessing for possible safety
findings (eg, fibrosis, fatty liver disease, lymphocytic invasion)
1 
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Section No./Title
Revision
Rationale
x
To quantify FVIII DNA, RNA, and protein expression within hepatocytes
x
To determine which forms of rAAV genomic DNA (eg, concatemers) are present at the time of biopsy
x
To determine the transduction pattern in humans (ie, peri-portal hepatocytes, central vein hepatocytes)
9.1/Overall Study 
Design and Plan
Liver Biopsy Substudy Design
All subjects enrolled in 270-201 and who are at least one year post-BMN 270 infusion are eligible for the optional liver biopsy 
substudy. Subjects who consent to participate in the substudy will have a liver biopsy via either the transjugular or 
percutaneous (ultrasound-guided) route, according to the standard procedures of the institution. To enhance safety, all subjects 
will have an ultrasound examination of the liver within 3 months prior to the procedure (to ensure there are no pathological 
findings such as bile duct obstruction that might interfere with the safe performance of the liver biopsy) and a FibroScan of the 
liver within one week before the liver biopsy (to correlate with any potential histopathologic findings of fibrosis on the 
biopsy). 
Subjects who consent should have their FVIII levels monitored/adjusted by the Investigator to enable the procedure to be 
performed safely.  This may require the administration of exogenous FVIII replacement products in order to achieve the 
desired FVIII activity.  The target FVIII activity level within 24 hours prior to the liver biopsy is at the discretion of the 
Investigator and/or according to local guidelines, but at a minimum should be at the lower limit of the normal range (ie, at 
least 50 IU/dL).
Table 9.1.7 presents the schedule of assessments for participation in the liver biopsy substudy.
1
Table 9.1.5/Safety 
Follow-Up
The Direct Thrombin Test has been removed from this schedule of events and footnote g.
2
Table 9.1.7/Liver 
Biopsy Substudy
Table 9.1.7 has been added as part of this amendment.
1
9.3.3/Liver Biopsy 
Substudy Inclusion and 
Exclusion Criteria
Individuals eligible to participate in the liver biopsy substudy must meet all of the following criteria:
2.
Currently enrolled in 270-201
10. Received BMN 270 infusion at least 1 year prior to enrollment in the substudy
11. Able to sign informed consent and comply with requirements of the substudy
1
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Section No./Title
Revision
Rationale
12. FVIII activity at least >50 IU/dL (or higher, depending on local guidelines and/or Investigator discretion) within 24 
hours prior to the liver biopsy being performed.  (FVIII levels should be assessed at the local laboratory.)  Subjects 
may be treated with additional exogenous FVIII replacement products in order to increase their FVIII levels to an 
appropriate level, under the supervision/instruction of the Investigator.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the liver biopsy substudy:
3.
Assessed by the investigator or a hepatologist as having a medical condition such that undergoing a liver biopsy would be 
contraindicated. These conditions could include (but are not limited to):
x
Significant thrombocytopenia (platelet count < 100 x 109/L)
x
Evidence of significant ascites
x
Abnormalities detected on liver ultrasound (performed within 90 days of procedure) that would preclude safe 
performance of the biopsy.
9.7.6/Exploratory 
Assessments
Liver biopsy samples collected as part of the exploratory substudy may also be tested to evaluate biochemical, molecular, 
cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer. Subjects participating 
in the substudy may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes
that are not yet known to be associated with hemophilia A.
1
9.7.7.1/Liver Biopsy 
Substudy
The objectives of the liver biopsy substudy are considered exploratory.
Subjects who consent to the procedure will have a liver biopsy via either the transjugular or percutaneous (ultrasound-guided) 
route, according to the standard procedures of the institution. To enhance safety, all subjects will have an ultrasound exam of 
the liver within 28 days prior to the procedure (to ensure there is no obstruction to the liver that would interfere with the liver 
biopsy) and a FibroScan of the liver within one week before the liver biopsy (to correlate any histopathologic findings on the 
biopsy). Subjects will also undergo a pre-biopsy consultation with the investigator (treating hematologist).
Within 24 hours prior to the biopsy being performed, subjects must have a FVIII activity level of at least 50 IU/dL (or higher, 
depending on local guidelines and/or investigator discretion). FVIII activity levels for this purpose should be assessed at the 
local laboratory within 7 days before the biopsy, and again the day before the biopsy. As needed, subjects may be treated with 
additional exogenous FVIII replacement products in order to increase their FVIII activity levels to an appropriate level, under 
1
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Section No./Title
Revision
Rationale
the supervision/instruction of the investigator, to ensure the safety of the subject during the procedure. This exogenous FVIII 
usage (if performed) should be recorded in the eCRF FVIII infusion pages under the category “Surgery/Procedure”.
The liver biopsy should be performed in the morning, and the biopsy procedure and follow-up care should be done according 
to the local standard of care. Additional details for handling the biopsy specimens are provided in the Laboratory Manual.
Following completion of the biopsy, the subject should remain in the hospital under observation for at least 4-6 hours. 
Overnight post-procedure observation may be done at the investigator’s discretion and/or according to local guidelines.
Safety findings arising from the histopathological analysis of the biopsy sample are subject to Adverse Event reporting 
(Section 10), and such findings should be further assessed and followed-up as clinically appropriate and in order to safeguard 
the subject’s ongoing medical care (this should be done in consultation with a hepatologist and/or other specialist clinicians if 
required).  In the event fibrotic changes being observed on the biopsy sample, additional follow-up Fibroscans may be 
considered (with the frequency of subsequent scans at the discretion of the Investigator and/or hepatologist).
10.4.1.7/Hospitalization, 
Prolonged 
Hospitalization, or 
Surgery
There are some hospitalization scenarios that do not require reporting as an SAE when there is no occurrence of an AE.  These
scenarios include planned hospitalizations or prolonged hospitalizations to:
x
Perform a protocol-mandated efficacy measurement procedure or assessment
1
12.8.3/Years 2-5 –
Every 12 Weeks and 
End of Year Visits
At the every 12 week and End of Year visits, the following procedures will be performed:
x
Direct Thrombin test
2
12.9/Liver Biopsy 
Substudy – Years 1-5
For the optional liver biopsy substudy (refer to Table 9.1.7), the following procedures will be performed at the following 
times:
x
Within 28 days before Biopsy Day
o
Informed consent
o
Liver ultrasound

Liver ultrasound does not need to be performed if an ultrasound result from the prior 3 months is 
already available
1
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Section No./Title
Revision
Rationale
o
Brief physical examination
o
Hematology, Coagulation, and Chemistry Assessments (refer to Table 9.7.8.2.1)
o
Liver Tests (refer to Table 9.7.8.3.1)
x
Within 7 Days before Biopsy Day
o
FibroScan
o
Local laboratory FVIII activity level assessment
o
Pre-biopsy consultation with investigator (treating hematologist).  This may need to be repeated/extended if 
the subject’s FVIII activity levels need adjustment before the biopsy, at the discretion of the investigator 
(treating hematologist).
x
1 Day before Biopsy Day
o
Hematology, Coagulation, and Chemistry Assessments (refer to Table 9.7.8.2.1)
o
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
Brief physical examination
o
Local laboratory FVIII activity level assessment

Subjects must have a FVIII activity level of at least 50 IU/dL (or higher, depending on local 
guidelines and/or investigator discretion). As needed, subjects may be treated with additional 
exogenous FVIII replacement products in order to increase their FVIII activity levels to an 
appropriate level, under the supervision/instruction of the investigator, to ensure the safety of the 
subject during the procedure. This exogenous FVIII usage (if performed) should be recorded in the 
eCRF FVIII infusion pages under the category “Surgery/Procedure”.
x
Biopsy Day
o
Brief physical examination
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Section No./Title
Revision
Rationale
o
Local laboratory FVIII activity level assessment (performed pre-biopsy)

Subjects must have a FVIII activity level of at least 50 IU/dL (or higher, depending on local
guidelines and/or investigator discretion). As needed, subjects may be treated with additional
exogenous FVIII replacement products in order to increase their FVIII activity levels to an
appropriate level, under the supervision/instruction of the investigator, to ensure the safety of the
subject during the procedure. This exogenous FVIII usage (if performed) should be recorded in the
eCRF FVIII infusion pages under the category “Surgery/Procedure”.
o
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment (pre-biopsy)
o
Liver Biopsy (refer to Laboratory Manual for guidelines for biopsy procedure and handling of biopsy
samples)

If only a small amount of tissue is obtained at the time of the biopsy, the subject may be asked to
consent for a second pass.
Following completion of the biopsy, the subject should remain in the hospital under observation for at least 4-6 hours. 
Overnight post-procedure observation may be done at the investigator’s discretion.
12.10/Early Termination 
Visit
At the Early Termination visit, as many of the following assessments as possible should be done:
x
Direct Thrombin test
2 
14.3/Liver Biopsy 
Substudy Analysis
A separate report presenting and discussing analyses of the exploratory objectives for the optional liver biopsy substudy will 
be prepared.
1
21/References
Grant A, Neuberger J, Day C, Saxseena S. British Society of Gastroenterology Guidelines on the use of Liver Biopsy in 
Clinical Practice. 2004. Available at: https://www.bsg.org.uk/resource/bsg-guidelines-on-the-use-of-liver-biopsy-in-clinical-
practice.html (last visited 1 December 2018).
1
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Proprietary and Confidential
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene 
Transfer of Human Factor VIII in Patients with Severe Haemophilia A
Protocol Number:
270-201
Active Investigational Product:
AAV5-hFVIII-SQ
IND/European Union Drug 
Regulating Authorities Clinical 
Trials (EudraCT) Number:
2014-003880-38
Indication:
Haemophilia A
Sponsor:
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
Development Phase:
Phase 1/2
Sponsor's Responsible Medical 
Monitor:
, MA MB BChir MSc
BioMarin (UK) Ltd.
10 Bloomsbury Way
London, WC1A 2SL
Duration of Subject 
Participation:
Approximately 264 weeks
Dose:
Varied
Study Population:
Males aged 18 or older
Date of Original Protocol:
10 February 2015
Date of Amendment 1:
06 March 2015
Date of Amendment 2:
26 May 2015
Date of Amendment 3:
06 November 2015
Date of Amendment 4:
02 September 2016
Date of Amendment 5:
14 February 2017
Date of Amendment 6:
21 December 2017
Date of Amendment 7:
10 October 2018
Property of BioMarin
CONFIDENTIAL
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin.
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code 
of Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving 
of essential documents
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PI

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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY
Amendment: 7
Date: 10 October 2018
RATIONALE AND SUMMARY OF MAJOR CHANGES
A summary of major changes covered by Amendment 7 to the BMN 270-201 protocol is 
provided below.  
1. Efavirenz, lamivudine, and experimental hemophilia treatments (emicizumab, 
fitusiran, and concizumab) have been added to the list of prohibited concomitant 
medications.
Rationale: An HIV-positive subject in Study 270-302 developed markedly elevated 
transaminase levels after receiving 4E13 vg/kg of BMN 270. The subject was receiving 
HAART treatment that included efavirenz and lamivudine for his HIV infection, and it is 
hypothesized that the combination of BMN 270, one or more of his HAART medications, 
and/or unsuspected underlying hepatic disease may have contributed to the subject’s elevated 
transaminase levels. Experimental hemophilia treatments are prohibited during the study as 
they could affect the assessment of FVIII levels in 270-201 subjects.
2. The timing of assessment visits during Years 2-5 has been modified.
Rationale: The original timing (which required visits on every 4 week, every 6 week, and 
every 3 month schedules) created burdens on sites in trying to align visits within allowed 
visit windows to minimize subject burden. The revised timing (which has substituted visits 
every 12 weeks and at specified end of year timepoints for the every 3 month visits) has 
simplified the calendar of visits and should ease site burden.
3. An abbreviated visit schedule has been made available during Years 2-5 for subjects 
who are considered to have not responded to BMN 270 therapy.
Rationale: Treatment failure—manifesting as either failure to achieve FVIII 
activity ≥5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII 
replacement therapy due to joint bleeding episodes, in the judgment of the Investigator—
may, at the Investigator’s discretion and after discussion with the Medical Monitor, enable 
subjects to follow an abbreviated visit schedule after Week 52 of the study by attending only 
the Q12W and End of Year visits during Years 2-5.
Subjects who meet the “treatment failure” definition and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
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vector shedding has cleared (but do not need to perform other assessments at those study 
visits).
4. Additional details have been included concerning information to be collected as part 
of the medical history.
Rationale: In subjects with a history of hepatitis B or hepatitis C infection, information on 
the specific treatments received for that infection should be collected. In addition, any 
previous pharmacokinetic data collected at the time the subject was receiving on-demand or 
prophylactic FVIII treatment should be collected. This additional history data could help 
explain a subject’s FVIII response (or lack of FVIII response) to BMN 270. As all subjects 
have already gone through Screening and reported medical history during 270-201, this 
additional history should be collected at the next regularly scheduled study visit (or at least 
prior to the end of the subject’s participation in the study).
5. Language concerning when to consider restarting FVIII prophylaxis following 
BMN 270 infusion has been modified.
Rationale: The decision for reinstitution of FVIII prophylaxis should be based on clinical 
grounds (eg, the advent of bleeding episodes), in consultation with the Medical Monitor. The 
need to reinstitute FVIII prophylaxis if the FVIII activity is below a certain level 
post-BMN 270 has not yet been clinically established but will be informed by results from 
this study.
6. Language was added to include ABO testing.
Rationale: ABO blood type results will be obtained to potentially correlate with FVIII 
activity level results in an exploratory manner. This assessment should be completed at the 
next regularly scheduled study visit (or at least prior to the end of the subject's participation 
in the study).
7. Clarified that vector shedding assessments, if required, can be performed at the every 
6 week visits during Years 3-5.
Rationale: Previously, the protocol called for vector shedding assessments, if required, to be 
done every 4 weeks after Week 52 until clearance. During Years 3-5, when subjects are 
being assessed for FVIII and liver function every 6 weeks, an every 4-week schedule for 
vector shedding would add to subject burden. Obtaining results every 6 weeks is sufficient to 
monitor vector shedding for subject safety and also aligns these assessments with the FVIII 
and liver test assessment visits.
8. Assessment of dermatologic and musculoskeletal systems has been added to the brief 
physical examination.
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Rationale: Both organ systems are routinely assessed as part of comprehensive hemophilia 
care visits.
9. Testing of the exploratory samples for the Direct Thrombin Activity Test has been 
clarified as optional.
Rationale:  While exploratory samples for Direct Thrombin Activity Test will be collected at 
the time points indicated in the protocol, analysis of these samples will be optional.
10. Subjects will be advised to abstain from blood or sperm donation after BMN 270 
infusion until there is no further evidence of vector shedding.
Rationale: Vector shedding in the blood and semen following BMN 270 infusion has been 
observed, which could serve for vector transmission if subjects were to donate blood or 
semen following the BMN 270 infusion. 
11. In the event of a positive Bethesda assay result during Years 3-5, an additional 
sample has been added to be collected within 4 weeks of the visit where the positive 
result was obtained.
Rationale: During Years 3-5, samples are being regularly collected every 6 weeks. However, 
to align with EMA guidance (which suggests that a confirmatory test on a second sample 
should be done within a month after a positive Bethesda assay result), language has been 
added to require the site to conduct an unscheduled visit within 4 weeks after the date when 
the positive Bethesda result was obtained.
12. Twice weekly evaluation of liver function tests (LFTs) has been added during times 
when a subject’s ALT is ≥ 3x ULN.
Rationale: The decision is based on clinical experience with subject LFT elevations and use 
of oral corticosteroids in 270-201.  More frequent LFT monitoring may be undertaken 
following review of a subject’s data and upon discussion between the investigator and the 
medical monitor.  However, in order to enhance subject safety, the protocol has been 
modified to mandate twice weekly LFT monitoring when a subject’s ALT is ≥ 3x ULN. 
13. The identity of the medical monitor has been updated.
14. Minor administrative changes have been made for consistency and clarity.
Specific changes included in this amendment, including the Synopsis, since Amendment 6
(approved 21 December 2017) are outlined in Section 24.
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2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
TITLE OF STUDY: 
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of BMN 270, an 
Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients 
with Severe Haemophilia A
PROTOCOL NUMBER:
270-201
STUDY SITES:
Approximately 6-10 sites worldwide.
PHASE OF DEVELOPMENT:
Phase 1/2
STUDY RATIONALE:
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an 
essential cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to 
a new mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 
1-5% of wild type activity and the mild form is 5-40% activity. The clinical manifestations of 
severe HA remain frequent spontaneous bleeding episodes, predominantly in joints and soft 
tissues, with a substantially increased risk of death from haemorrhage when the brain is involved.  
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life for 
FVIII (12 to 18 hours for most approved products) necessitates frequent infusions, and although a 
major advance in the treatment of HA, it remains common for severe HA patients to continue to 
have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up 
to 30 to 50 episodes/year for on demand treatment). The consequence of multiple bleeding events 
is the development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death. Chemical modification (eg, direct conjugation 
of polyethylene glycol (PEG) polymers) and bioengineering of FVIII (eg, FVIII-Fc fusion 
proteins) improve half-life by approximately 50%, and thus, show promise in reduced dosing and 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
maintaining activity levels above 1% trough. However, these longer acting FVIIIs remain 
dependent on multiple infusions to maintain critical levels of FVIII activity in severe HA patients. 
There is therefore a strong unmet need for a fully preventive treatment of HA to give patients a 
FVIII level compatible with a normal and haemorrhage-free life. 
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach because 
clinical manifestations are attributable to the lack of a single gene product (FVIII) that circulates in 
minute amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not 
essential, and modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml 
induces an increase in activity of 1%) can ameliorate the severe form of the disease.  Thus, 
relatively small changes in endogenous FVIII activity results in clinically relevant improvements 
in disease phenotype. Finally, the response to gene transduction can be assessed using validated 
quantitative rather than qualitative endpoints that are easily assayed using established laboratory 
techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific 
tissues such as the liver (for serotypes 2, 5 and 8 among others). Indeed, an on-going gene therapy 
clinical trial for a related disorder, haemophilia B, has established that stable (>36 months) 
expression of human factor IX at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
administration of AAV-8 vector. Several participants in this trial have been able to discontinue 
factor prophylaxis without suffering spontaneous haemorrhages, even when they undertook 
activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a liver-selective promoter (Figure 1).
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Figure 1. hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from vector-transduced 
liver tissue. The clinical study 270-201 is a first-in-human study designed to assess the relationship 
of vector dose to the augmentation of residual FVIII activity, and whether these levels are 
sufficient to alter the clinical phenotype. The relationship of dose to safety will be correlated to the 
activity of hFVIII in patients with severe HA.
OBJECTIVES: 
The primary objectives of the study are:
x
To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. 
x
To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of 
normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose.
The secondary objectives of the study are:
x
To describe the immune response to the FVIII transgene and AAV capsid proteins 
following systemic administration of AAV5-hFVIII-SQ
x
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during 
the study
x
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
STUDY DESIGN AND PLAN: 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will be 
taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed 
for approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and 
do not have transduction inhibition activity to AAV5 will be eligible to enroll in the study.
Participants will be enrolled into one of up to four cohorts according to dose level: 
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv)
Cohort 2:  2E13 vg per kilogram, iv
Cohort 3:  6E13 vg per kilogram, iv
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies 
of mice and monkeys. The starting dose has a 10-fold safety margin from no observed adverse 
effect level (NOAEL) in non-human primates. 
Cohorts 1-3
The first 3 cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between 
cohorts. Dose escalation may occur after a single subject has been safely dosed if the resulting 
FVIII activity at the Week 3 visit is < 5 IU/dL in both the one-stage clotting and chromogenic 
substrate assays. Three weeks is expected to be the time the expression will be close to the 
maximum.  This escalation paradigm is intended to minimize the subject numbers exposed to 
subtherapeutic doses.
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study, the Data Review Board (DRB). 
If the FVIII activity reaches ≥ 5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.
Subject 1 will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram of 
body weight. If the FVIII activity level does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, 
then no further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with 
Subject 2 at the next dose (2E13 vg/kg). 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥ 5 IU/dL at the 
Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and enrollment into 
Cohort 3 (6E13) will initiate with the next subject. If the FVIII activity level in the first subject 
treated in Cohort 3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then the Data 
Review Board (DRB) will recommend whether to continue to add subjects to the cohort and/or 
whether to continue the study.
For the first subject treated in each of the first 3 cohorts, if the activity level reaches ≥5 IU/dL and 
no safety issue is found, then up to four subjects will be enrolled in the Cohort, though, the 
adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts based 
on activity levels of FVIII and safety signals. 
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg. If FVIII activity in these 3 subjects is 
≥5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in this 
cohort.
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB. The adaptive nature of this trial allows the DRB to recommend allocating 
subjects to the cohorts based on activity levels of FVIII and safety signals.
As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding consideration of 
FVIII activity levels by themselves or subjects in the reporting of bleeding episodes and FVIII 
usage.
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will 
discuss whether to resume prior FVIII prophylaxis. Subjects who do not respond to BMN 270 
treatment (ie, treatment failure, manifesting as either failure to achieve FVIII activity ≥ 5 IU/dL by 
Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due 
to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion 
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, 
as applicable and at the discretion of the Investigator. Because subjects develop neutralizing 
immunity upon exposure to the capsid, re-challenge of vector is not a likely treatment option and 
these subjects have effectively a single opportunity for therapy using this AAV capsid. Efficacy 
will be determined by FVIII activity at 16 weeks post dose. Safety will be evaluated for 
approximately 5 years after dosing.  Any safety signal may trigger a review of the data and 
possible additional immunogenicity studies that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMC).
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
NUMBER OF SUBJECTS PLANNED:
Up to 15 subjects may enroll into the study; the actual number of subjects will depend on the FVIII 
activity levels seen in each Cohort.
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following criteria:
1.
Males that are 18 years or older with established severe haemophilia A as evidenced by 
their medical history.  Patients will be considered as severe if their base FVIII level is 
1 IU/dL or less
2.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs)
3.
Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis
4.
Able to sign informed consent and comply with requirements of the trial
5.
No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 
12 months
6.
Sexually active patients must be willing to use an acceptable method of contraception such 
as double barrier, including hormonal contraception for at least 6 months post-treatment.  
After 6 months, subjects may stop contraception use only if they have had 3 consecutive 
negative semen samples.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study:
1.
Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition or AAV5 total antibodies
2.
Any evidence of active infection or any immunosuppressive disorder.  
3.
HIV positive
4.
Significant liver dysfunction as defined by abnormal elevation of:
x
ALT (alanine transaminase) to 3 times the upper limit of normal;
x
Bilirubin above 3 times the upper limit of normal;
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
x
Alkaline phosphatase above 3 times the upper limit of normal; or
x
INR (international normalized ratio) ≥1.4
5.
Potential participants who have had a liver biopsy in the past 3 years are excluded if they 
had significant fibrosis of 3 or 4 as rated on a scale of 0-4
6.
Evidence of any bleeding disorder not related to Haemophilia A
7.
Platelet count of < 100 x 109/L
8.
Creatinine ≥1.5 mg/dL
9.
Liver cirrhosis of any etiology as assessed by liver ultrasound 
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive
12. Treatment with any IP within 30 days prior to the end of the screening period
13. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study including possible corticosteroid 
treatment outlined in the protocol.  The physician may exclude patients unwilling or 
unable to agree on not using alcohol for the 16-week period following the viral infusion.
14. Prior treatment with any vector or gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion
16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral 
infusion
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level.
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
The study is open label with comparison of FVIII activity to baseline values. No reference therapy 
will be evaluated in this study.
DURATION OF TREATMENT:
BMN 270 is given as a single dose by intravenous infusion.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
CRITERIA FOR EVALUATION:
Safety:
The following safety outcome measurements will be assessed:
x
Incidence of adverse events (AEs), including serious AEs (SAEs) 
x
Change in clinical laboratory tests (serum chemistry and haematology)
x
Change in vital signs
x
Change in physical examination 
x
Vector shedding
x
Liver tests (LTs, including ALT, AST, GGT, LDH, bilirubin, alkaline phosphatase)
x
Immune response to FVIII transgene and AAV capsid proteins
No major toxicity is expected based on preclinical studies in mice and monkeys. Each subject will 
have comprehensive surveillance monitoring of LTs (at local labs, once per week for Weeks 1-36,
then once every 2 weeks from Week 37-52) during Year 1. LTs will be monitored every 4 weeks 
during Year 2, and then every 6 weeks for Years 3-5 post-dose in the safety extension; the 
frequency and duration of LT testing may be changed based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the 
study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration.
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Subjects will be 
asked to keep a subject diary to record the details in these areas.  
Pharmacodynamics:
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage 
clotting and/or chromogenic substrate assay (activity level), will be used for plasma profiles; FVIII 
activity will be used to determine PD parameters.  Traditional PK analysis is not applicable.
If supported by the FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss 
(time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
STATISTICAL METHODS:
The sample size is based upon clinical considerations and could detect a strong clinical efficacy 
signal. Up to 15 subjects may be dosed in the study.  The subjects will be followed in a 
longitudinal manner and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature but data collected in a longitudinal manner may be analyzed using 
longitudinal methods such as mixed effect model which takes into account the correlation among 
the observation taken at various time points within a participant. Efficacy is a secondary endpoint, 
defined as biologically active FVIII at ≥5 IU/dL by chromogenic substrate assay and/or one-stage 
clotting assay at 16 weeks following study treatment. FVIII activity will be assessed weekly during 
the study period.  We can only assess the true steady state of FVIII protein produced from 
BMN 270 after a minimum of 72 hours has elapsed since the last infusion of FVIII protein 
concentrates.
Analysis of neutralizing antibody response and other immunological parameters as well as vector 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses.
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3
TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY............................................2 
2 SYNOPSIS...........................................................................................................................5 
3 TABLE OF CONTENTS...................................................................................................14 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................19 
5 ETHICS..............................................................................................................................21 
5.1 Institutional Review Board or Independent Ethics Committee ................................21 
5.2 Ethical Conduct of Study..........................................................................................22 
5.3 Subject Information and Informed Consent..............................................................22 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................23 
7 INTRODUCTION .............................................................................................................24 
7.1 Nonclinical Studies ...................................................................................................24 
7.2 Previous Clinical Studies ..........................................................................................26 
7.3 Study Rationale.........................................................................................................27 
7.4 Summary of Overall Risks and Benefits...................................................................29 
8 STUDY OBJECTIVES......................................................................................................31 
9 INVESTIGATIONAL PLAN............................................................................................32 
9.1 Overall Study Design and Plan.................................................................................32 
9.2 Discussion of Study Design, Including Choice of Control Group............................47 
9.3 Selection of Study Population...................................................................................47 
9.3.1 
Inclusion Criteria.........................................................................................47 
9.3.2 
Exclusion Criteria........................................................................................48 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................49 
9.3.4 
Subject Identification and Replacement of Subjects...................................50 
9.3.5 
Duration of Subject Participation................................................................50 
9.4 Treatments.................................................................................................................50 
9.4.1 
Treatments Administered ............................................................................50 
9.4.2 
Identity of Investigational Product..............................................................51 
9.4.3 
Storage.........................................................................................................51 
9.4.4 
Directions for Administration .....................................................................51 
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9.4.5 
Method of Assigning Subjects to Treatment Groups..................................52 
9.4.6 
Selection of Doses Used in the Study .........................................................52 
9.4.7 
Blinding.......................................................................................................53 
9.4.8 
Prior and Concomitant Medications............................................................53 
9.4.9 
Treatment Compliance ................................................................................55 
9.5 Investigational Product Accountability.....................................................................55 
9.5.1 
Return and Disposition of Clinical Supplies...............................................56 
9.6 Dietary or Other Protocol Restrictions......................................................................56 
9.7 Safety and Efficacy Variables...................................................................................56 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................56 
9.7.2 
Primary Efficacy Variables .........................................................................56 
9.7.3 
Secondary Efficacy Variables .....................................................................57 
9.7.4 
Immunogenicity...........................................................................................58 
9.7.5 
Pharmacodynamics......................................................................................58 
9.7.6 
Exploratory Assessments ............................................................................58 
9.7.7 
Haemo-QoL-A Quality of Life Assessment................................................59 
9.7.8 
Safety Variables ..........................................................................................59 
10 REPORTING ADVERSE EVENTS .................................................................................65 
10.1 Safety Parameters and Definitions............................................................................65 
10.1.1 Adverse Events............................................................................................65 
10.2 Serious Adverse Events ............................................................................................66 
10.2.1 Events of Special Interest (EOSI) ...............................................................66 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters.....................66 
10.3.1 Adverse Event Reporting Period.................................................................66 
10.3.2 Eliciting Adverse Events.............................................................................67 
10.3.3 Assessment of Seriousness, Severity, and Causality...................................67 
10.4 Procedures for Recording Adverse Events ...............................................................70 
10.4.1 Recording Adverse Events on a eCRF........................................................70 
10.5 Reporting Requirements ...........................................................................................73 
10.5.1 Expedited Reporting Requirements.............................................................73 
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10.5.2 Ethics Committee Reporting Requirements................................................74 
10.6 Follow-up of Subjects after Adverse Events.............................................................74 
10.7 Post-Study Adverse Events.......................................................................................74 
10.8 Urgent Safety Measures............................................................................................74 
10.9 BioMarin Pharmacovigilance Contact Information..................................................76 
11 APPROPRIATENESS OF MEASUREMENTS...............................................................77 
12 STUDY PROCEDURES ...................................................................................................78 
12.1 Prestudy.....................................................................................................................78 
12.2 Screening Visit..........................................................................................................78 
12.2.1 “Smart Rescreening” Visit ..........................................................................79 
12.3 Baseline Visit............................................................................................................80 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1)....................................................80 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................81 
12.5.1 Once per week (Weeks 1 through 16).........................................................81 
12.5.2 Week 1 – Day 2 and Day 4..........................................................................82 
12.5.3 Week 1 – Day 8...........................................................................................82 
12.5.4 Every 2 Weeks.............................................................................................83 
12.5.5 Weeks 4, 8, 12, and 16 ................................................................................83 
12.5.6 Week 16.......................................................................................................83 
12.5.7 Weeks 8 and 16 ...........................................................................................83 
12.5.8 Weeks 2, 3, 4, and 16 ..................................................................................84 
12.5.9 Week 13.......................................................................................................84 
12.6 Safety Follow-Up – Weeks 17-36.............................................................................84 
12.6.1 Once per week (Weeks 17 through 36).......................................................84 
12.6.2 Once per week (Weeks 17 through 20).......................................................85 
12.6.3 Every 2 weeks (Weeks 21 through 36) .......................................................85 
12.6.4 Every 4 Weeks.............................................................................................85 
12.6.5 Every 8 Weeks.............................................................................................85 
12.6.6 Week 26.......................................................................................................85 
12.6.7 Week 28.......................................................................................................86 
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12.7 Safety Follow-Up – Weeks 37-52 .............................................................................86 
12.7.1 Once per visit ...............................................................................................86 
12.7.2 Every 4 Weeks .............................................................................................87 
12.7.3 Every 8 Weeks .............................................................................................87 
12.7.4 Week 38 and 52 ...........................................................................................87 
12.7.5 Week 52 .......................................................................................................87 
12.8 Safety Follow-Up – Years 2-5 ..................................................................................88 
12.8.1 Year 2 – Every 4 Weeks (not required for treatment failure) .....................88 
12.8.2 Years 3-5 – Every 6 Weeks (not required for treatment failure) .................89 
12.8.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)..................................................................................................90 
12.9 Early Termination Visit ............................................................................................92 
12.10  End of Study ............................................................................................................93 
13 DATA QUALITY ASSURANCE .....................................................................................95 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................96 
14.1 Statistical and Analytical Plans .................................................................................96 
14.1.1 Interim Analyses ..........................................................................................96 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........96 
14.2 Missing data will not be imputed. .............................................................................96 
14.3 Primary and Secondary Efficacy Analysis................................................................96 
14.4 Immunogenicity ........................................................................................................96 
14.5 Pharmacodynamic Analyses .....................................................................................96 
14.6 Safety Analysis .........................................................................................................97 
14.7 Determination of Sample Size ..................................................................................97 
14.8 Analysis Populations .................................................................................................97 
14.9 Changes in the Conduct of the Study or Planned Analyses ......................................98 
15 DATA REVIEW BOARD .................................................................................................99 
16 COMPENSATION, INSURANCE AND INDEMNITY ................................................100 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................101 
18 STUDY MONITORING AND AUDITING ...................................................................103 
19 RETENTION OF RECORDS .........................................................................................104 
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20 USE OF INFORMATION AND PUBLICATION .........................................................105 
21 REFERENCES ................................................................................................................106 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................109 
22.1 Conduct of Study and Protection of Human Patients .............................................109 
23 SIGNATURE PAGE .......................................................................................................110 
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................111 
LIST OF TABLES
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................35 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16)............................37 
Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) .....................................39 
Table 9.1.4:  Schedule of Events – Safety Follow-Up (Week 33-52) .....................................41 
Table 9.1.5:  Schedule of Events – Safety Follow-Up (Years 2-5) .........................................43 
Table 9.1.6:  Schedule of Events – Therapeutic Corticosteroids for LT Elevations ...............46 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................61 
Table 9.7.8.3.1:  Liver Tests ....................................................................................................62 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale....................................................68 
Table 10.3.3.3.1:  Causality Attribution Guidance..................................................................69 
LIST OF FIGURES
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic .............................................................29 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3...............................33 
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
AAV
adeno-associated virus
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
ALT
alanine transaminase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BPV
BioMarin Pharmacovigilance
BU
Bethesda Unit
CFR
Code of Federal Regulations
CRA
clinical research associate
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DRB
Data Review Board
eCRF
electronic case report form
ED
exposure days
EOSI
events of special interest
ETV
early termination visit
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FIH
first-in-human
FVIII
coagulation factor VIII
FXa
coagulation factor Xa
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
HA
Haemophilia A
hFVIII
human coagulation factor VIII
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6
IEC
independent ethics committee
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IND
Investigational New Drug (application)
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IV
intravenous
LT
liver test
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect level
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamics
PEG
polyethylene glycol
PK
Pharmacokinetics
PRO
patient-reported outcome
rhFVIII
recombinant human FVIII protein
REB
research ethics board
SAE
serious adverse event
SAP
statistical analysis plan
SDV
source data verification
ULN
upper limit of normal
vg
vector genomes
VWF:Ag
von Willebrand factor Antigen
Definition of Terms: 
Investigational Product (IP):
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]). 
The terms “IP” and “study drug” may be used interchangeably in the protocol.
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5
ETHICS
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards.
5.1
Institutional Review Board or Independent Ethics Committee
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries.
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin or its designee. The Investigator will provide the IRB/IEC/REB 
with all appropriate material, including the protocol, Investigator’s Brochure (IB), the 
Informed Consent Form (ICF) including compensation procedures, and any other written 
information provided to the subjects, including all ICFs translated to a language other than 
the native language of the clinical site. The study will not be initiated and Investigational 
Product (IP) supplies will not be shipped to the site until appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol, the ICF and all subject 
recruitment materials are obtained in writing by the Investigator and copies are received at 
BioMarin or its designee. The approval document should refer to the study by protocol title 
and BioMarin protocol number (if possible), identify the documents reviewed, and include 
the date of the review and approval. BioMarin will ensure that the appropriate reports on the 
progress of the study are made to the IRB/IEC/REB and BioMarin by the Investigator in 
accordance with applicable guidance documents and governmental regulations.
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5.2
Ethical Conduct of Study
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability.
This study will be conducted in accordance with the following:
x
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country
x
US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable
x
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6)
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the subjects will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF, and if applicable, a 
copy of the approved subject information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed.
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject.
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INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate.
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of subjects in this study.
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required.
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR.
Liver tests (LTs) will be performed at the local laboratories associated with the study sites.  
Local laboratory results of LTs will be used to trigger corticosteroid treatment as needed 
(refer to Section 9.4.8.2).  In case of discrepant results between local and central laboratories, 
the Investigator and Medical Monitor will decide further action.  Safety labs evaluations 
(including LTs) will be performed at the central lab, while bioanalytical samples will be 
performed at the appropriate specialty lab.  Refer to the Laboratory Manual for more details.
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7
INTRODUCTION
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.).
Chemical modification or bioengineering of FVIII may improve half-life to 18-19 hours 
(Kaufman, 2013, Blood). However, these long acting FVIII variants do not eliminate the 
need for lifelong FVIII protein administration (Hay, 2012, Blood).
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of human FVIII following a single administration of vector. Haemophilia A is 
well suited for this approach because its clinical manifestations are attributable to the lack of 
a single gene product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. 
Tightly regulated control of gene expression is not essential and a modest increase in the 
level of FVIII (a plasma level of 2 ng/ml protein leads to a 1% expression) can ameliorate the 
severe phenotype (Srivastava, 2013, Haemophilia.); thus the therapeutic goal for gene 
therapy is a modest increase in hFVIII. Finally, the consequences of gene transfer can be 
assessed using simple quantitative rather than qualitative endpoints that can be easily assayed 
in most clinical laboratories.
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study.
7.1
Nonclinical Studies
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 
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nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints.
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in FVIII KO x Rag2 mice given matched IU 
levels of Refacto®.
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.  
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed.
The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 
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the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence closely matching that of 
the protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Nathwani, 2006, Blood). Despite 
distribution to non-liver organs, no expression of Factor IX was detected in these tissues.  
Additionally, distribution to the testis was observed in another study in monkeys given an 
AAV5-codon-optimized human porphobilinogen deaminase; however, vector genomes in the 
semen were only transiently observed within one week but not thereafter (Paneda, 2013, 
Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents 10-fold safety factor from the 
no observed adverse effect level (NOAEL) in the GLP enabling nonclinical toxicology study 
in mice. 
7.2
Previous Clinical Studies
This is the first clinical study for BMN 270.
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Engl.J.Med.), 
(Nathwani, 2014, N.Engl.J.Med.). The large size of the FVIII cDNA was shortened and a 
preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013, 
Blood).
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AAV serotype 5 is being tested in other clinical trials and was reportedly well tolerated 
without treatment-related serious adverse events in a recent phase 1 study for treatment of 
Acute Intermittent Porphyria (D'Avola, 2014, J.Hepatol.). In addition, AAV using other 
serotypes have been used in 105 clinical studies to date and no safety issue specific to the 
vector was ever reported.  
7.3
Study Rationale
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Mannucci, 2001, N.Engl.J.Med.).  It is caused by deficiency in the activity 
of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic coagulation cascade. 
This disorder can be either inherited, due to a new mutation or an acquired immunologic 
process, leading to insufficient quantities of FVIII or a dysfunctional FVIII, but all are 
characterized by a defective coagulation process. The clinical phenotype of HA patients is 
largely governed by the level of residual expression. Severe HA is classified as FVIII activity 
less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild type activity 
and the mild form is 5-40% activity. The clinical manifestations of severe HA remain 
frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.  
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-4 times per 
week, and at the time of a bleed, to prevent or control bleeding episodes, respectively. The 
half-life for FVIII (12-18 hours for most approved products) necessitates frequent infusions, 
and although a major advance in the treatment of HA, it remains common for severe HA 
patients to continue to have multiple bleeding events on treatment (mean of 
1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year for on demand 
treatment) (Nagel, 2011, Haemophilia.). The consequence of multiple bleeding events is the 
development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death (Nagel, 2011, Haemophilia).  Chemical 
modification (eg, direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (eg, FVIII-Fc fusion proteins) improve half-life by approximately 
50%, and thus, show promise in reduced dosing and maintaining activity levels above 1% 
trough (Stonebraker, 2010, Haemophilia.), (Mahlangu, 2014, Blood). However, these longer 
acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive 
treatment of HA to give patients a FVIII level compatible with a normal and 
haemorrhage-free life. 
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Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Mannucci, 2001, 
N.Engl.J.Med.). They have an excellent and well defined safety profile, and can direct long 
term transgene expression with tropism for specific tissues such as the liver (Nathwani, 2005, 
Curr.Hematol.Rep.) for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene 
therapy clinical trial for a related disorder, haemophilia B, has established that stable 
(>36 months) expression of human factor IX at levels that are sufficient for conversion of 
their bleeding phenotype from severe to moderate or mild is achievable following a single 
peripheral vein administration of AAV-8 vector (Nathwani, 2014, N.Engl.J.Med.).  Several 
participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in 
bleeding. Thus, gene therapy treatment has resulted in a substantial improvement in their 
quality of life (Nathwani, 2011, Mol.Ther.), (Bainbridge, 2008, N.Engl.J.Med.), (Maguire, 
2009, Lancet); (Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a liver-selective promoter (Figure 7.3.1). 
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Figure 7.3.1: hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active FVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of FVIII in patients with severe 
HA.
7.4
Summary of Overall Risks and Benefits
The majority of subjects in the ongoing 270-201 clinical study who have received 4E13 or 
6E13 vg/kg doses of BMN 270 have had Grade 1 asymptomatic elevations in ALT. For most 
subjects, the elevations have reached only slightly above the upper limit of normal (ULN).  
Based on the effectiveness of transient oral corticosteroid used to suppress a presumed 
Class 1 (cytotoxic T-cell) response in prior studies with hepatic transduction with AAV 
vectors (Mingozzi, 2013), subjects were treated with 7-32 weeks of oral corticosteroids 
prophylactically or in response to the elevations in ALT to ensure preservation of the 
transduced hepatocytes. Using this approach, no sustained loss of FVIII activity has been 
observed in subjects with ALT elevations, consistent with maintaining a high level of 
hepatocyte function. Moreover, the rise in ALT levels were not accompanied by significant 
or lasting aberrations in other liver tests such as AST, bilirubin or albumin, indicating that 
extent of toxicity is limited. There has been one HIV-positive subject in the ongoing 270-302
clinical study who experienced Grade 3 asymptomatic elevations in ALT and AST, which 
has been attributed to an interaction between one or more of his antiretroviral therapy 
medications and/or unsuspected underlying hepatic disease with BMN 270. In addition, there 
has been one subject with Gilbert’s syndrome in the ongoing 270-301 clinical study who has 
experienced Grade 3 asymptomatic elevations in ALT and AST. These cases have led to the 
exclusion of subsequent HIV-positive subjects and requirement of liver tests at Screening 
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that are <1.25 times the upper limit of the normal range in the ongoing 270-301 and 270-302 
clinical studies. Of note, two HIV-positive subjects in 270-301 and one presumed Gilbert’s
syndrome subject in 270-201 have received BMN 270 without experiencing any elevations in
ALT to date. Overall, the literature and clinical experience with BMN 270 suggests that 
transient elevations in liver enzymes are expected following AAV-based gene therapy for the
treatment for hemophilia A or B without any long-term concerns of hepatic injury (Manno,
2006; Nathwani, 2011; George, 2016; Miesbach, 2016; Pasi, 2016).
The current data available for BMN 270 does not yet permit comprehensive assessment of 
the benefit:risk profile of this investigational drug. Given the monitoring measures in place in 
the clinical protocol(s) to minimize the risk to subjects participating in the existing studies, 
the identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-201 will have a comprehensive surveillance plan that monitors LTs 
during the study, and elevations in LT will be addressed according to the guidelines set forth 
in the protocol. Safety will be assessed by adverse event reporting and clinical laboratory 
assessments.
For additional information on safety findings in 270-201, refer to current version of the 
Investigator’s Brochure.
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose 
that maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the 
possibility of a sub-therapeutic effect. With this consideration in mind, the starting dose 
6E12 vg/kg was selected using overall data from the pre-clinical studies conducted in mice 
(normal and disease model, Rag2 -/- x FVIII -/-) and monkey. A detectable pharmacological 
response based on activity was observed at 6E12 vg/kg. A 10-fold safety margin based upon 
the NOAEL was observed in the GLP 13-week study in normal mouse at the highest dose 
administered. A 30-fold safety margin in an 8-week dose response study in disease model 
mice based on histology was observed at the highest dose administered. No BMN 270-related 
changes in clinical observations or chemistry was observed in the monkey at doses up to 
6E13 vg/kg, a 10-fold safety margin after 8-weeks. Overall, no BMN 270-related findings, 
except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model 
mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to subjects with the best chance of 
benefiting the subject therapeutically.
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8
STUDY OBJECTIVES
The primary objectives of the study are:
x
To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. 
x
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII 
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270
dose.
The secondary objectives of the study are:
x
To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of AAV5-hFVIII-SQ
x
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study
x
To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled into one of up to four cohorts according to dose level: 
x
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv)
x
Cohort 2:  2E13 vg per kilogram, iv
x
Cohort 3:  6E13 vg per kilogram, iv
x
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys. The starting dose has a 10-fold safety margin from no 
observed adverse effect level (NOAEL) in mice. 
Cohorts 1-3
The first three cohorts will be enrolled sequentially, allowing a period of 3 weeks or more 
between cohorts. Dose escalation may occur after a single subject in a cohort has been safely 
dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both assays. 
Three weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic 
doses. The decision to escalate to the next dose level will be made based on the review of 
safety parameters and FVIII activity by the Sponsor and a panel of investigators participating 
in the study.   
If the FVIII activity reaches ≥5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg).
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject. 
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study. 
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in the Cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg. If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.
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There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the Data Review Board (DRB). The adaptive nature of this trial allows the DRB 
to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals.
As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage.
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not 
respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve 
FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic 
FVIII replacement therapy due to joint bleeding episodes, in the judgment of the 
Investigator) may, at the Investigator’s discretion and after discussion with the Medical 
Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the 
discretion of the Investigator. 
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity 
for therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dosing. Any safety signal 
may trigger a review of the data and possible additional immunogenicity studies that include 
an assessment of cellular immune responses using collected PBMC. Additionally, if any of 
the events listed in Section 9.3.3.1 occur, enrollment into the trial will be halted to complete 
an extensive safety analysis. Notification of the study enrollment halt will be sent by the 
Sponsor to the participating sites via telephone and email immediately after becoming aware 
of a safety concern. This will ensure no additional subjects are dosed until the signal has been 
completely evaluated. If, following safety review by the DRB and the Sponsor, it is deemed 
appropriate to restart dosing, a request to restart dosing with pertinent data will be submitted 
to the health authority.
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 and Table 9.1.4 for Safety Follow-up.
Table 9.1.6, dealing with therapeutic corticosteroid use in the event of elevated LTs, is 
discussed in Section 9.4.8.2.
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Table 9.1.1: Schedule of Events – Screening and Infusion
Assessment
Prior to BMN 270 Infusion
BMN 270 
Infusion 
Visit (Day 1)k
Screeningi
(Day -28 to Day -1)
Smart Rescreeningi
(Day -28 to Day -1)
Baseline (Day -7
to Day -1)h
Informed consent
X
Medical History
X
Physical Examinationa
X
X
X
Height and Weighta
X
Vital Signs
X
X
X
Assessment of Adverse Events and Concomitant Medications
X
X
X
X
Documentation of bleeding episodes and FVIII usage (by either subject or 
clinical information)
X
X
X
Distribution of subject diaries and training in their use
X
Electrocardiogram
X
Chest X-ray
X
Liver Ultrasound
X
hFVIII Assaysb
X
Xj
AAV5 Assaysc
X
X
X
Screen for Hepatitis B, Hepatitis C, HIVd
X
Blood chemistry, haematology, coagulation screen, and CRPe
X
X
X
Urine Testse
X
X
X
Liver Testse
X
X
X
PBMC collection for CTL baseline
X
Von Willebrand Factor Antigen (VWF:Ag)
X
Direct Thrombin Test
X
PCR of vector DNA in blood, saliva, urine, semen, and stools
X
Biomarker testingf
X
Exploratory biomarker assessmentsg
X
Haemo-QoL-A Quality of Life (QoL) assessment
X
BMN 270 Infusion
X
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a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height will be recorded at 
Screening only.  Weight will be recorded at Screening and then every 6 months thereafter.
b Includes baseline hFVIII activity (chromogenic substrate assay and one-stage clotting assay), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay with 
Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).  
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction inhibition, in vitro 
transduction inhibition and AAV5 total antibody assays).  Sample collection on the day of the infusion visit must be performed before the BMN 270 infusion is given.
d Patients with documented negative results within the last 30 days do not need to be retested.
e Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.
f Includes HLA genotyping, FVIII genotyping, TNFD and IL10a single nucleotide polymorphisms.
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
h Should the screening visit occur within 7 days of the drug infusion, physical examination, blood chemistry, LTs, haematology, urine tests, coagulation screen, and CRP do not need to be 
repeated at Baseline.
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion prior to the closing 
of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion within 90 days of signing the original 
consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures. Subjects may not undergo smart rescreening more than 
once.
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening.
k Assessments on the day of infusion must be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, during the infusion 
every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16)
Assessment
Follow-Up After BMN 270 Administration – Weeks*
Week 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
D2
D4
D8
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary 
for bleeding and FVIII use)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, haematology, coagulation 
screen, and CRPb
X
X
X
X
X
X
X
Urine Testsb
X
X
X
X
Liver Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Tests (central)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII antibody titer
X
X
X
X
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolse
X
X
X
X
X
X
X
X
X
X
Exploratory biomarker assessmentsf
X
X
X
X
Haemo-QoL-A QoL assessment
X
X
X
X
X
AAV5 antibody titer
X
X
Testing for reactivation of hepatitis B and 
hepatitis C
Xg
PBMC collection 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
X
Direct Thrombin test
X
X
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* Visit windows are ± 48 hours (and include the Day 4 visit)
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods when a 
subject’s ALT is ≥ 3x ULN. Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, 
and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to above ULN; (2) 
Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the Investigator based on a 
review of subject data.  If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion 
between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting assay and chromogenic substrate assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage clotting assay and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation 
activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after 
BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII 
activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are 
above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection to occur on Day 2 and 4 following BMN 270 infusion, and then until at least 3 consecutive negative results are obtained.  Collection and testing of semen samples must continue 
through Week 12, even if 3 consecutive negative samples in that compartment have already been recorded.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
g Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of Hepatitis B or Hepatitis C prior to study entry, should be performed only in 
subjects who have not received therapeutic corticosteroids prior to Week 16; subjects who have received therapeutic corticosteroids will have hepatitis B and hepatitis C testing at the time 
points indicated in Table 9.1.6.
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Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32)
Assessment
Follow-Up After BMN 270 Administration – Weeks*
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary for 
bleeding and FVIII use)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, haematology, coagulation screen, 
and CRPb
X
X
X
X
Urine Testsb
X
X
X
X
Liver Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Tests (central)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII antibody titer
X
X
PCR of vector DNA in blood, saliva, urine, semen, 
and stoolse
X
X
X
X
Exploratory biomarker assessmentsf
X
X
X
X
Haemo-QoL-A QoL assessment
X
AAV5 antibody titer
X
X
X
X
PBMC collection 
X
X
X
X
X
X
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
X
Direct Thrombin test
X
* Visit windows are ± 48 hours
a Brief physical examination should be done at all weekly visits.  Refer to Section 9.7.8.5.
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b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods when a 
subject’s ALT is ≥ 3x ULN.  Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, 
and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to above ULN; (2) 
Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the Investigator based on a 
review of subject data.  If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion 
between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay). If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection for each matrix to occur until at least 3 consecutive negative results are obtained.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
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Table 9.1.4:  Schedule of Events – Safety Follow-Up (Week 33-52)
Assessment
Year 1 – Weeks*
33
34
35
36
38
40
42
44
46
48
50
52
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
Weighta
X
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and FVIII use)
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, haematology, coagulation screen, and CRPb
X
X
X
X
X
Urine Testsb
X
X
X
X
X
Liver Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
Liver Tests (central)b
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
AAV5 antibody titer
X
X
X
X
X
FVIII antibody titer
X
X
X
PBMC Collection (for determination of FVIII and Capsid specific CTL 
activity)
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
X
X
Direct Thrombin Test
X
X
PCR of vector DNA in blood, saliva, urine, semen, and stoolse
X
X
X
X
X
Exploratory biomarker assessmentsf
X
X
X
X
X
Haemo-QoL-A QoL assessment
X
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52.
a Complete physical examination should be performed at Week 52; brief physical examination may be performed at other study visits.  Refer to Section 9.7.8.5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods when a 
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subject’s ALT is ≥ 3x ULN. Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, 
and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to above ULN or 
increased by > 10 U/L from prior assessment; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the 
Medical Monitor and the Investigator based on a review of subject data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and 
ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay). If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism. 
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
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Table 9.1.5:  Schedule of Events – Safety Follow-Up (Years 2-5)
Assessment
Years 2-5*
Year 2*
Years 3-5*
End of Year Visit
ETV
Q12W
Q4Wh
Q6Wh
Year 2
Year 3
Year 4
Year 5
W104
W156
W208
W260
Physical examinationa
Xa
Xa
X
Weighta
Xa
Xa
X
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and FVIII use)
X
X
X
X
X
Vital Signs
X
X
X
Blood chemistry, haematology, coagulation screen, and CRPb
X
X
X
Urine Testsb
X
X
X
Liver Tests (local)b
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
Liver Tests (central)b
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
AAV5 antibody titer
X
X
X
FVIII antibody titer
X
X
X
PBMC Collection (for determination of FVIII and Capsid specific CTL 
activity)
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
Direct Thrombin Test
X
X
X
PCR of vector DNA in blood, saliva, urine, semen, and stoolse
Xe
Xe
Xe
Xe
X
Exploratory biomarker assessmentsg
X
X
X
Haemo-QoL-A QoL assessment
Xf
Xf
X
* Visit windows are ± 2 weeks for visits in Years 2-5. The Q6W visits during Years 3-5 should restart after each End of Year visit (eg, the first Q6W visit during Year 3 should be ~6 weeks 
after the End of Year 2 visit).
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a Complete physical examination should be performed at the End of Year visits; brief physical examination may be performed at other study visits. Weight should be recorded at the second 
Q12W visit each year and at every End of Year visit during Years 2-5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests.  LTs may be monitored more or less frequently (and in particular when ALT values 
are ≥1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during periods when a 
subject’s ALT is ≥ 3x ULN. Patients with ALT ≥1.5x ULN during the study may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, 
and/or liver biopsy) at the discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT has increased to above ULN or 
increased by > 10 U/L from prior assessment; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the 
Medical Monitor and the Investigator based on a review of subject data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and
ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator. During Years 2-5 of the Post-Infusion Follow-Up period, urine tests and blood, 
chemistry, and coagulation tests should be performed at the second Q12W visit each year and at every End of Year visit.
c Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 
16 weeks after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen 
modification) during Years 3-5, a fresh sample should be collected within 4 weeks of the initial visit that had a positive result.
d Includes hFVIII activity level (one-stage clotting and chromogenic substrate assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen modification) in years 3-5, a fresh sample 
should be collected within 4 weeks of the initial visit that had a positive result.
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.  Subjects who have not had 3 consecutive 
negative samples by Week 52 should continue to have PCR testing every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 3 consecutive negative samples are 
documented (or upon consultation between the Investigator and Medical Monitor).
f Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at the second Q12W visit each year and at every End of Year visit.
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for Direct Thrombin Activity test 
and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
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h Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 may omit the Q4W and Q6W visits during Years 2-5, and must attend only the Q12W and End of 
Year visits. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in all fluids must still provide samples Q4W (during Year 2) or Q6W (during 
Years 3-5) until vector shedding has been cleared (but do not need to do other scheduled assessments at those visit dates).
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Table 9.1.6:  Schedule of Events – Therapeutic Corticosteroids for LT Elevations
Steroid Treatment Periodd
Post-Steroid Periodc
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11b
Week 
1
Week 
2
Week 
3
Week 
4
Week 
13
Therapeutic 
corticosteroids 
(dose in 
mg/day) a 
60 mg
60 mg
40 mg
40 mg
30 mg
30 mg
20 mg
20 mg
15 mg
10 mg
5 mg
FVIII activity 
testing
X
X
X
X
Liver testing
X
X
X
X
Hepatitis B 
testinge
X
X
X
HCV Viral 
Loade
X
X
X
a Therapeutic corticosteroids may be initiated when a subject’s ALT value is ≥ 1.5x ULN or based on review of FVIII and liver enzyme data after consultation between the Investigator and 
the Medical Monitor.
b Following initiation or completion of steroid regimen, if ALT elevation  ≥ 1.5x ULN is reported, steroid management decisions will based on discussions between the Investigator and 
Medical Monitor.  Modification of the steroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression.
c After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values. If these assessments are already 
being done as part of normal study follow-up, they do not need to be duplicated.
d Regardless of the assessments listed in the Schedule of Assessments (Table 9.1.2, Table 9.1.3, or Table 9.1.4), subjects initiated on corticosteroids will only be required to have laboratory 
evaluations on a weekly basis.
e Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry.
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9.2
Discussion of Study Design, Including Choice of Control Group
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Four doses of BMN 270 will be evaluated and the dose 
escalation decision tree for Cohorts 1-3 is summarized in Figure 9.1.1.
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and the DRB.
There will be no control group. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy). 
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible. 
9.3
Selection of Study Population
Up to 15 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation. 
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2.
9.3.1
Inclusion Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
1. Males that are 18 years or older with established severe Haemophilia A as evidenced 
by their medical history.  Patients will be considered as severe if their base FVIII 
level is 1 IU/dL or less
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs)
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis
4. Able to sign informed consent and comply with requirements of the trial
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less 
than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within 
the past 12 months
6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment.  After 6 months, subjects may stop contraception use only if they have 
had 3 consecutive negative semen samples.
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9.3.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study:
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition or AAV5 total antibodies
2. Any evidence of active infection or any immunosuppressive disorder.  
3. HIV positive
4. Significant liver dysfunction as defined by abnormal elevation of:
5. ALT (alanine transaminase) to 3 times the upper limit of normal;
6. Bilirubin above 3 times the upper limit of normal;
7. Alkaline phosphatase above 3 times the upper limit of normal; or
8. INR (international normalized ratio) ≥ 1.4. 
9. Potential participants who have had a liver biopsy in the past 3 years are excluded if 
they had significant fibrosis of 3 or 4 as rated on a scale of 0-4
10. Evidence of any bleeding disorder not related to Haemophilia A
11. Platelet count of < 100 x 109/L
12. Creatinine ≥ 1.5 mg/dL
13. Liver cirrhosis of any etiology as assessed by liver ultrasound 
14. Hepatitis B if surface antigen is positive
15. Hepatitis C if RNA is positive
16. Treatment with any IP within 30 days prior to the end of the screening period
17. Any disease or condition at the physician’s discretion that would prevent the patient 
from fully complying with the requirements of the study including possible 
corticosteroid treatment outlined in the protocol.  The physician may exclude patients 
unwilling or unable to agree on not using alcohol for the 16-week period following 
the viral infusion.
18. Prior treatment with any gene transfer agent
19. Major surgery planned in the 16-week period following the viral infusion
20. Use of immunosuppressive agents or live vaccines within 30 days before the viral 
infusion
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9.3.3
Removal of Subjects from Treatment or Assessment
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out.
BioMarin must be notified of all subject withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance.
Reasons for which the Investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following:
x
Subject requires medication or medical procedure prohibited by the protocol
x
Subject does not adhere to study requirements specified in the protocol
x
Subject was erroneously admitted into the study or does not meet entry criteria
x
Subject is lost to follow-up
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records. 
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study.
9.3.3.1
Study Safety Evaluation Criteria
If any of the following events occur in a subject in the study who has received BMN 270
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis 
per Section 9.1.
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x
Any ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of 
BMN 270, in the absence of a definitive alternate etiology for the increase  
x
The occurrence of Grade 3 or higher adverse events (excluding ALT elevation) 
assessed as related to study drug, including liver failure and clinical hepatitis
x
The detection of neutralizing antibodies to hFVIII following BMN 270 infusion
x
The detection of AAV vector DNA in the semen of a participant in 3 consecutive 
samples (which are at least 2 weeks apart) more than 52 weeks after BMN 270
infusion, as discussed in Section 9.7.8.6
x
The occurrence of a malignancy excluding skin cancers at any point after BMN 270
infusion
If the following event occurs in a subject in the study who has received BMN 270 infusion, a 
DRB review and analysis of safety data will be undertaken to determine whether the 
enrollment into the trial will be put on halt:
x
Grade 2 adverse event assessed as related to study drug that persists for at least 7 days 
9.3.4
Subject Identification and Replacement of Subjects
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used.
Subjects who withdraw from the study will not be replaced.
9.3.5
Duration of Subject Participation
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks.
9.4
Treatments
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites.
9.4.1
Treatments Administered
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study.
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9.4.2
Identity of Investigational Product
9.4.2.1
Product Characteristics and Labeling
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer.
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements.
9.4.3
Storage
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 
stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures.
9.4.4
Directions for Administration
After a physical examination performed by the PI or designee, participants will be admitted 
on the day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral 
vein (eg, the median cubital vein) and flushed with saline. FVIII replacement therapy will not 
be given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions.
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 ml/min while monitoring the vital signs (pulse, blood pressure, respiration 
rate and temperature) at 15 minute (± 5 minutes) intervals. The anticipated maximum interval 
from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, although the 
IP has been shown to be stable at room temperature for 6 hours.
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard protocol 
for infusing FVIII concentrates. Subjects will remain in the clinic for 24 hours to observe for 
any immediate toxicity of the procedure. After 24 hours, participants will be discharged from 
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the clinic unless toxicity has been observed in which case the stay in the clinic may be 
extended or the subject may transfer to a separate facility based on the evaluation and 
judgment of the Principal Investigator after consultation with the Medical Monitor.
9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study subject. Upon their enrollment into the study, subjects will be assigned a unique subject 
number and dose level by the Sponsor.
Cohorts 1 to 3 are enrolled serially and their dose is defined in Section 9.4.6.2 below. 
Escalation is based on FVIII activity 3 weeks after injection. Cohorts may receive the next 
higher dose if subjects in the previous cohort does not meet the activity criteria, or the same 
dose if subjects in the previous cohort meets the activity criteria. Subjects in Cohort 4 will all 
be enrolled at a single dose.
9.4.6
Selection of Doses Used in the Study
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in mice. The dose escalation is half-logs based.   
9.4.6.1
Selection of Timing of Dose for Each Subject
A minimum of three weeks are required between subjects, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next subject will be made as described below. 
9.4.6.2
Selection of Dose for Each Subject
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus potentially decreasing the risk of immune response), and a new 
evaluation of the titer (PCR performed after hairpin removal).
For Cohorts 1 to 3, approximately three weeks after an injection, the decision to escalate to 
the next dose level will be made based on the review of safety parameters and FVIII activity 
by the Sponsor and the DRB. 
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)
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at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg).
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject. 
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study. 
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in that cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.  
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg. If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB. The adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals.
Refer to Figure 9.1.1 for a visual representation of the study design for Cohorts 1-3
9.4.7
Blinding
This is an open-label study.
9.4.8
Prior and Concomitant Medications
All prescription and over-the-counter medications (including dietary and herbal supplements) 
taken by a subject for 30 days before Screening will be recorded on the designated CRF. The 
Investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF.
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The following medications are prohibited starting 30 days before Screening:
x
Live vaccines
x
Systemic immunosuppressive agents
x
Emicizumab
x
Fitusiran
x
Concizumab
x
Efavirenz
x
Lamivudine
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their 
participation in 270-201 must have their antiretroviral medication regimen approved by the 
Investigator and Medical Monitor prior to starting antiretroviral treatment.
Medications which are predominately metabolized by the liver (eg, acetaminophen) and 
alcohol should, whenever possible, be avoided for the first 52 weeks of the study, and 
particularly within 48 hours prior to lab work.
9.4.8.1
Concomitant Haemophilia Treatments
Subjects on “on demand” therapy for FVIII will continue their treatment at will.  Subjects on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and 
switch to an “on demand” schedule. FVIII can always be taken as needed by the subject, who 
will carefully record his treatment and bleeding episodes in his diary.  In addition, 
information on FVIII usage by medical history will be collected (if available) from subjects 
for the 6 month period immediately preceding study enrollment.
9.4.8.2
Glucocorticoid Treatment of Elevated Hepatic Transaminases
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject 
will have comprehensive surveillance plan monitoring of LTs (at local labs, once per week 
for Weeks 1-36, then once every 2 weeks from Week 37-52).  LTs may be monitored more 
or less frequently (and in particular when ALT values are >1.5x ULN) based on discussion 
between the Medical Monitor and the Investigator and review of subject data. 
9.4.8.2.1
Therapeutic Corticosteroids
In general, therapeutic corticosteroids may be initiated when a subject’s ALT value is 
≥1.5x ULN, or based on review of FVIII and liver enzyme data after consultation between 
the Medical Monitor and the Investigator.  
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Reports of raised LTs (defined as ALT ≥ 1.5x ULN) should be made to the BioMarin 
medical monitor within 30 minutes of the lab value being available.  Local laboratory results 
of LTs will be used to trigger corticosteroid treatment as needed.  In case of discrepant 
results between local and central laboratories, the Investigator and Medical Monitor will 
decide further action. 
Following initiation or completion of therapeutic corticosteroids, if ALT elevation 
≥1.5x ULN is reported, steroid management decisions will based on discussions between the 
Investigator and Medical Monitor. Modification of the steroid regimen may take into 
consideration possible confounders for the ALT elevation and impact on FVIII expression.  
Treatment with prednisolone will be initiated at a dose of 60 mg per day and then gradually 
tapered (60 mg daily for the first 2 weeks, then 40 mg the next 2 weeks, then 30 mg the next 
two weeks, then 20 mg the next two weeks, then 15 mg for the next week, then 10 mg for the 
next week, then 5 mg for the next week, then stop, for a total treatment of 11 weeks) (refer to 
Table 9.1.6). 
After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be 
measured once a week for 4 weeks to ensure stability in values.
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This 
includes the contraindicated use of NSAIDs during corticosteroid treatment, and specific 
monitoring not already covered by the schedule of events. For the subjects with a past 
medical history of hepatitis B or hepatitis C prior to study entry, Hepatitis B status and HCV 
viral load will be rechecked 6 weeks after the start of corticosteroid treatment, and then 
1 week and 13 weeks after the completion of corticosteroid treatment. All adverse events 
should be reported as outlined in Section 10 of the protocol.
9.4.9
Treatment Compliance
Study drug will be administered to subjects at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on a dispensing log.  Sites will 
be instructed to return or destroy all used and unused study drug containers.
9.5
Investigational Product Accountability
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data, if allowed by local SOPs.
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9.5.1
Return and Disposition of Clinical Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials (or must be referenced in their institution 
SOPs).
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a study drug return form 
provided by BioMarin.
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures.
9.6
Dietary or Other Protocol Restrictions
There are no dietary or other protocol restrictions for this study.
Subjects should be advised to abstain from any blood or sperm donation after BMN 270
infusion, until there is no further evidence of vector shedding from PCR analysis of samples.
9.7
Safety and Efficacy Variables
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8.
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥5 IU/dL at 16 weeks post 
BMN 270 administration. 
9.7.1
Safety and Efficacy Measurements Assessed
The Schedule of Events (Table 9.1.1 through Table 9.1.5) describes the timing of required 
evaluations.
9.7.2
Primary Efficacy Variables
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
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BMN 270 required to convert severe HA patients to expression of FVIII at 5 IU/dL or above, 
(ie, a mild severity). This is associated in natural history studies with clinically superior long 
term outcomes (Den Ujil, 2011, Haemophilia).
The following assays (assessed by the central laboratory) will be used to measure the primary 
efficacy variable:
x
FVIII activity (chromogenic substrate assay)
x
FVIII activity by one-stage clotting assay
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made 
to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 
The 72-hour wash-out period is only intended for subjects who have achieved FVIII 
≥5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care 
FVIII replacement therapy.
The FVIII activity level in both assays and the number of subjects with FVIII activity 
≥5 IU/dL in at least one of the two assays will be summarized.
FVIII activity assays will also be performed at the local laboratory at the time points 
indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4, but will be used in conjunction with 
local lab LT assessments to monitor subject safety and need for initiation of therapeutic 
corticosteroid dosing; local laboratory FVIII activity assessments will not be used to assess 
efficacy or to measure the primary efficacy outcome of the study.
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
either failure to achieve FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable 
and at the discretion of the Investigator. 
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.  Details on performing the assays are included in the Laboratory Manual.
9.7.3
Secondary Efficacy Variables
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Subjects will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the subject’s diary or 
other subject records.
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In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis.
9.7.4
Immunogenicity
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
5-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to a retrospective immunogenicity assessment to determine 
anti-FVIII and capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be 
performed on collected PBMCs.
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.
9.7.5
Pharmacodynamics
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage clotting and/or chromogenic substrate assay (activity).  Individual antigen and 
activity plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity 
measurements will be used to determine PD parameters.
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration),
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose
will be used to assess clinical pharmacology.
Sample collection times are indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4.
9.7.6
Exploratory Assessments
Blood samples will be collected at the time points indicated in Table 9.1.1, Table 9.1.2,
Table 9.1.3, and Table 9.1.4 to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations. Subjects may choose to opt out of the 
exploratory genetic/genomic research being done to study or try to discover genes that are 
not yet known to be associated with hemophilia A. 
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All biomarker samples collected in this study may be used for exploratory biomarker 
research including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes may be used for exploratory use once the 
primary use has been completed.
On an exploratory basis, samples may be fractionated prior to shedding analysis in order to 
better characterize the presence and location of vector DNA and/or vector capsid within each 
matrix. The fractionation may be performed with samples collected specifically for shedding 
analysis (saliva, blood, semen, urine, faeces), or by using exploratory samples, such as 
plasma, PBMCs, and red blood cells, collected under the study protocol.  
9.7.7
Haemo-QoL-A Quality of Life Assessment
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to 
assess subject quality of life (QoL) during the study.  Assessments will occur at the time 
points listed in the Schedules of Assessments.
Details regarding the QoL assessment will be included in the Study Reference Manual.
9.7.8
Safety Variables
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity.
9.7.8.1
Adverse Events
The occurrence of AEs will be assessed continuously from the time the subject signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1,
Table 9.1.2, Table 9.1.3, and Table 9.1.4.
9.7.8.2
Clinical Laboratory Assessments
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5. The scheduled clinical 
laboratory tests are listed in Table 9.7.8.2.1. Refer to the Study Reference Manual for 
instructions on obtaining and shipping samples.
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant.
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All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event.
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF.
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Table 9.7.8.2.1:  Clinical Laboratory Tests
Blood Chemistry
Haematology
Urine Tests
Other
Albumin
Haemoglobin 
Appearance
CRP
BUN
Haematocrit 
Color
Calcium
WBC count
pH
Coagulation Screen
including:
Chloride
RBC count
Specific gravity
APTT
Total cholesterol
Platelet count
Ketones
PT/INR
CO2
Differential cell count 
Protein 
TT
CPK
ABO blood typing*
Glucose 
Creatinine
Bilirubin
Glucose
Nitrite
Phosphorus
Urobilinogen
Potassium
Haemoglobin
Total protein
Sodium
Uric Acid
BUN, blood urea nitrogen; CO2, carbon dioxide; CRP, C-reactive protein; PT, prothrombin time; APTT, activated partial 
thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; INR, international normalized ratio.
* ABO blood typing assessment should be completed at the next regularly scheduled study visit (or at least prior 
to the end of the subject’s participation in the study).
9.7.8.3
Liver and Hepatitis Testing
Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening. Subjects with documented results showing an absence of active hepatitis B or 
hepatitis C infection (as measured by positive surface antigen for hepatitis B or positive RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to be 
screened again.  
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with a 
history of hepatitis B or hepatitis C will be asked for information about the treatments 
received as part of their medical history assessment at Screening.
Subjects with a history of hepatitis B or hepatitis C infection prior to study entry will be 
tested for hepatitis B and hepatitis C reactivation at Week 16. Subjects who receive 
therapeutic corticosteroids prior to Week 16 do not need to complete the Week 16
reactivation assessment; instead, they will be tested for hepatitis B and hepatitis C 
reactivation at the time points listed in Table 9.1.6.
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A liver ultrasound and LTs at Screening will identify any significant hepatic dysfunction, 
which is defined as:
x
More than 3x the normal ALT level
x
More than 3x the normal bilirubin level
x
More than 3x the normal Alkaline phosphatase level.
x
INR > 1.4.
x
Thrombocytopoenia under 100 x 109/L
x
Liver ultrasound results indicative of a liver cirrhosis 
Liver tests will be monitored on a regular basis, at the time points indicated in Table 9.1.1,
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5.  At each time point, the following LTs 
should be assessed:
Table 9.7.8.3.1:  Liver Tests
Liver Tests (LTs)
Alkaline Phosphatase
AST (SGOT)
Total Bilirubin
LDH
ALT (SGPT)
Direct Bilirubin
GGT
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, lactate 
dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase
Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (eg, 
imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at 
the discretion of the investigator.
9.7.8.4
HIV Testing
HIV testing will be performed at Screening. Subjects with documented negative results 
within the last 30 days prior to screening do not need to be retested.
9.7.8.5
Vital Signs, Physical Examinations and Other Observations Related to Safety
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE.
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270
Infusion, vital signs will be monitored prior to infusion, during the infusion every 
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15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then
every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 
and at the End of Years visits thereafter. A complete physical examination will include 
general appearance (head, eyes, ears, nose, and throat), cardiovascular, dermatologic, 
lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic 
systems.
At other visits, brief physical examinations may be performed at the discretion of the 
investigator based on the subject’s clinical condition. A brief physical examination will 
include general appearance, cardiovascular, respiratory, neurologic, dermatologic, 
musculoskeletal, and gastrointestinal assessments. Particular attention should be given to 
signs of bleeding, as well as assessing possible hemarthroses.
Height will be recorded at Screening only. Weight will be recorded at Screening, at Weeks 
26 and 52 during Year 1, and then at the second Q12W visit each year and at every End of 
Years visit during Years 2-5.
9.7.8.6
Vector Shedding
Vector shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 2007, J.Gene 
Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the literature referenced above, including 
Haemophilia B clinical studies utilizing AAV2 and AAV8, vector was no longer detectable 
after 40 days in blood, saliva, urine or stool, but in one study was detected in the seminal 
fluid but not in motile sperm (Manno, 2006, Nat.Med.). In these studies, the amount of 
vector present in these bodily fluids involved an extremely small fraction of the infused dose.  
More recent data from an ongoing AAV-FIX study demonstrates persistence of the vector in 
both the blood and the semen for at least 39 weeks (Miesbach, 2016, Haemophilia).
During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily 
samples to look for evidence of vector shedding for possible viral transmission.  Bodily 
fluids will be tested by PCR at the time points indicated in Table 9.1.2, Table 9.1.3,
Table 9.1.4, and Table 9.1.5. Fluids tested will include:
x
Blood
x
Saliva
x
Semen
x
Urine
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x
Stool
Vector shedding will also be extensively studied in the present clinical trial, every other week 
between Weeks 4-16, then every 4 weeks to Week 52 until at least 3 consecutive negative 
results are obtained. Testing of semen will continue through Week 12, even if 3 consecutive 
negative results have been recorded in that compartment prior to that timepoint.  Subjects 
who have not had 3 consecutive negative samples by Week 52 should continue to have PCR
testing every 4 weeks until 3 consecutive negative samples are documented (or upon 
consultation between the Investigator and Medical Monitor). Subjects who meet the 
definition of treatment failure and wish to follow an abbreviated schedule (refer to 
Section 12.5.3 but who have not cleared vector shedding from all fluids must still provide 
samples for assessment until vector shedding has cleared: every 4 weeks (during Year 2), or 
every 6 weeks (during Years 3-5).
Contraception use may need to be extended beyond 26 weeks in individual subjects based on 
observed vector shedding in semen. After 6 months, subjects may stop contraception use 
only if they have had 3 consecutive negative semen samples (upon consultation between the 
Investigator and Medical Monitor).
Details for sample collection and storage are provided in the Laboratory Manual.
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10
REPORTING ADVERSE EVENTS
10.1
Safety Parameters and Definitions
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug.
10.1.1 Adverse Events
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(eg, sign, symptom, illness, disease or injury) in a subject administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following:
x
AEs not previously observed in the subject that emerge during the course of the 
study.
x
Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study.
x
Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures).
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE.
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis.
10.1.1.1
Bleeding and Suspected Bleeding Events
All bleeding events and suspected bleeding events, regardless of the need for exogenous 
FVIII therapy as treatment, should be captured in subject diaries and recorded on the 
designated bleeding eCRF.  Bleeding events and suspected bleeding events should not be 
reported as adverse events, with the following exception:
x
All bleeding events and suspected bleeding events which meet one or more of the 
criteria for being serious (refer to Section 10.2) should be reported as serious adverse 
events (whether or not they are bleeding events that are normal sequelae of 
hemophilia, and whether or not they required exogenous FVIII as treatment).
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10.2
Serious Adverse Events
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria:
x
Is fatal
x
Is life threatening 
x
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death.
x
Requires or prolongs inpatient hospitalization.  
x
Results in persistent or significant disability or incapacity
x
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy
x
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of  the above 
consequences (eg, anaphylaxis)
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs.
10.2.1 Events of Special Interest (EOSI) 
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality: 
x
Elevation of ALT ≥1.5x ULN, regardless of whether that triggers an initiation or 
modification of  corticosteroid treatment
x
Thromboembolic event
10.3
Methods and Timing for Capturing and Assessing Safety Parameters
10.3.1 Adverse Event Reporting Period
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported. After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.1.1.1.
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10.3.2 Eliciting Adverse Events
Investigators will seek information on AEs, SAEs, and EOSI at each subject contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the subject’s medical record and on the AE Case Report 
Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.1.1.1
for SAE definitions).  These assessments must be made by a study clinician with the training 
and authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS).
10.3.3.1
Seriousness
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.1.1.  Seriousness serves as a guide for 
defining regulatory reporting obligations.
10.3.3.2
Severity
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1.
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below.
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Table 10.3.3.2.1: Adverse Event Grading (Severity) Scale
Grade
Description
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated
2
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a
3
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb
4
Life threatening or debilitating: consequences; urgent intervention 
indicated
Grade 4 and 5 AEs 
should always be 
reported as SAEs
5
Death related to AE
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the telephone, 
managing money.
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, taking 
medications, not bedridden.
10.3.3.3
Causality
The Investigator will determine the relationship of an AE to the study drug and will record it
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1.
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Table 10.3.3.3.1: Causality Attribution Guidance
Relationship
Description
Not Related
x
Exposure to the IP has not occurred
x
OR
x
The administration of the IP and the occurrence of the AE are not 
reasonably related in time 
x
OR
x
The AE is considered likely to be related to an etiology other than the 
use of the IP; that is, there are no facts, evidence, or arguments to 
suggest a causal relationship to the IP.
Related
x
The administration of the IP and the occurrence of the AE are 
reasonably related in time
AND
x
The AE could possibly be explained  by factors or causes other than 
exposure to the IP
OR
x
The administration of IP and the occurrence of the AE are reasonably 
related in time 
AND
x
The AE is more likely explained by exposure to the IP than by other 
factors or causes.
Factors suggestive of a causal relationship could include (but are not limited to):
x
Plausible temporal relationship
x
Absence of alternative explanations
x
Rarity of event in a given patient or disease state
x
Absence of event prior to study drug exposure
x
Consistency with study product pharmacology
x
Known relationship to underlying mechanism of study drug action
x
Similarity to adverse reactions seen with related drug products
x
Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug
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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities.
10.4
Procedures for Recording Adverse Events
10.4.1 Recording Adverse Events on a eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations.
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries).
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology.
10.4.1.1
Diagnosis versus Signs and Symptoms
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE (or SAE, as appropriate) eCRF, replacing the original 
entries where appropriate.
10.4.1.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF.
10.4.1.3
Persistent or Recurrent Adverse Events
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF.
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A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF.
10.4.1.4
Abnormal Laboratory Values
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable.
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF. Any laboratory result abnormality of CTCAE Grade 4
or 5 should be recorded as an SAE in the AE eCRF.
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met:
x
Accompanied by clinical symptoms
x
Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).
x
The abnormality suggests a disease and/or organ toxicity
x
The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.)
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed.
10.4.1.5
Pre-existing Conditions
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF.
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A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches).
10.4.1.6
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF.
10.4.1.7
Hospitalization, Prolonged Hospitalization, or Surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.1.1).
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to:
x
Perform a protocol-mandated efficacy measurement
x
Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed
x
Insert an in-dwelling IV catheter (such as a Port-a-Cath or other brand) for 
administration of study drug or FVIII replacement therapy.
x
Receive scheduled therapy (study drug or otherwise) for the study indication
10.4.1.8
Deaths
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF.
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10.4.1.9
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion.
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event. The Investigator must make every effort to 
follow the subject’s partner (with that partner’s consent) through resolution of the pregnancy 
(delivery or termination) and to report the resolution on the Pregnancy Follow-up eCRF. In 
the event of pregnancy in the partner of a study subject, the Investigator should make every 
reasonable attempt to obtain the woman’s consent for release of protected health information.
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE.
10.5
Reporting Requirements
10.5.1 Expedited Reporting Requirements
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF and submitting to BPV within 24 hours of the site becoming 
aware of the event. Investigators should not wait to collect information that fully documents 
the event before notifying BPV of an SAE. BioMarin may be required to report certain SAEs 
to regulatory authorities within 7 calendar days of being notified about the event; therefore, it 
is important that Investigators submit any information requested by BioMarin as soon as it 
becomes available.
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations.
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF.
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10.5.2 Ethics Committee Reporting Requirements
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required.
10.6
Follow-up of Subjects after Adverse Events
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the subject is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the subject’s medical record to facilitate source data verification.
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report.
10.7
Post-Study Adverse Events
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment.
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study. 
10.8
Urgent Safety Measures
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
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protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.” 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours.
Examples of situations that may require urgent safety measures include discovery of the 
following:
x
Immediate need to revise the IP administration (eg, modified dose amount or 
frequency not defined in protocol)
x
Lack of study scientific value, or detrimental study conduct or management
x
Discovery that the quality or safety of the IP does not meet established safety 
requirements
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10.9
BioMarin Pharmacovigilance Contact Information
Contact information for BioMarin Pharmacovigilance is as follows:
BioMarin Pharmaceutical Inc.
Address
105 Digital Drive
Novato, CA 94949
Phone:
Fax:
E-mail:
drugsafety@bmrn.com
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows:
Name:
, MA MB BChir MSc
Address:
Biomarin (UK) Ltd.
10 Bloomsbury Way
London WC1A 2SL
Phone
 (office)
 (mobile)
E-mail:
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PI
PI
PI
PI
PI
PI

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11
APPROPRIATENESS OF MEASUREMENTS
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures.
The chromogenic substrate assay and the one-stage clotting assay are both validated and 
utilize CE marked reagents.  The exploratory FVIII activity assay will be used for 
exploratory purposes only.
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12
STUDY PROCEDURES
12.1
Prestudy
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed.
12.2
Screening Visit
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LTs, haematology, urine tests, coagulation screen, and CRP do 
not need to be repeated at Baseline. 
The following procedures will be performed during the Screening Period:
x
Full medical history, including haemophilia A history, hepatitis B, hepatitis C, and 
HIV. Subjects with a history of hepatitis B or hepatitis C will be asked for 
information about the treatments received. Any prior pharmacokinetics information 
obtained while the subject was receiving prophylactic or on-demand FVIII therapy 
prior to the study should also be collected. For subjects who have already enrolled in 
270-201, this information should be collected at the next regularly scheduled study 
visit (or at least prior to the subject’s completion of study participation).
x
Complete Physical Examination 
x
Height and weight
x
Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature) 
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
x
Electrocardiogram
x
Chest X-ray
x
Liver Ultrasound
x
Samples for hFVIII Assays
o
Baseline hFVIII activity – chromogenic substrate (plasma)
o
Baseline hFVIII activity level – one-stage clotting assay
o
hFVIII coagulation activity exploratory assay
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o
hFVIII inhibitor level (Bethesda assay with Nijmegen modification)
o
hFVIII total antibody assay
o
hFVIII antigen (ELISA)
x
Blood sample for AAV5 Assays
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay
x
Screen for hepatitis B, hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested)
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Tests (refer to Table 9.7.8.3.1)
x
Von Willebrand Factor Antigen (VWF:Ag) 
x
Blood samples for Biomarker testing (including HLA genotyping, FVIII genotyping 
status, TNFD and IL10a single nucleotide polymorphisms)
12.2.1 “Smart Rescreening” Visit
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once.
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study:
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
x
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification)
x
Blood sample for AAV5 Assays
o
AAV5 antibody titer
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AAV5 transduction inhibition assay
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Tests (refer to Table 9.7.8.3.1)
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period:
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
x
Distribution of subject diaries and training in diary completion
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Tests (refer to Table 9.7.8.3.1)
x
PBMC collection for CTL baseline
x
Direct Thrombin test
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
x
Exploratory biomarker assessments
x
Haemo-QoL-A QoL assessment
12.4
Treatment Visit/BMN 270 Infusion Visit (Day 1)
There will be one treatment visit for each subject.  Subjects will remain in the clinic for 
24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit:
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion)
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay
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BMN 270 Infusion
x
Vital Signs
o
Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the subject’s stay in 
the clinic.
12.5
BMN 270 Infusion Follow-Up Visits
After BMN 270 has been infused, subjects will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed:
12.5.1 Once per week (Weeks 1 through 16) 
The following procedures will be performed at one visit per week from Weeks 1 through 16:
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
Samples for FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
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Central assessment of FVIII activity level should be performed 1x/week 
from Week 1 through Week 16
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
PBMC collection
12.5.2 Week 1 – Day 2 and Day 4
On Day 2 and Day 4 of Week 1, the following procedures will be performed:
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (Day 2 and Day 4)
x
Samples for FVIII Assays (Day 4 only) – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Liver Tests (refer to Table 9.7.8.3.1) (Day 4 only) – central laboratory assessment
x
Liver Tests (refer to Table 9.7.8.3.1) (Day 4 only) – local laboratory assessment
x
FVIII activity level (Day 4 only) – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
12.5.3 Week 1 – Day 8
On Day 8, the following procedures will be performed:
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PCR of vector DNA in blood, saliva, urine, semen, and stools
x
Direct Thrombin test
x
Haemo-QoL-A QoL assessment
12.5.4 Every 2 Weeks
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedures will be 
performed:
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
(not assessed at Week 14)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at 
Week 2)
o
Collection to occur until at least 3 consecutive negative results are 
obtained.  Semen samples should continue to be collected and tested 
through Week 12, even if 3 consecutive negative results in that 
compartment have been recorded prior to that timepoint.
12.5.5 Weeks 4, 8, 12, and 16
At Weeks 4, 8, 12, and 16, the following procedures will be performed:
x
Urine Tests (refer to Table 9.7.8.2.1)
x
VWF:Ag
x
FVIII antibody titer
x
Exploratory biomarker assessments
12.5.6 Week 16
At Week 16, the following procedures will be performed:
x
Test for hepatitis B and hepatitis C reactivation (in subjects with a history of hepatitis 
B or hepatitis C infection prior to study entry)
o
Subjects who receive therapeutic corticosteroids prior to Week 16 do not 
need to complete the Week 16 reactivation assessment; instead, they will 
be tested for hepatitis B and hepatitis C reactivation at the time points 
listed in Table 9.1.6.
12.5.7 Weeks 8 and 16
At Weeks 8 and 16, the following procedures will be performed:
x
AAV5 antibody titer
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12.5.8 Weeks 2, 3, 4, and 16
At Weeks 2, 3, 4, and 16, the following procedure will be performed:
x
Haemo-QoL-A QoL assessment
12.5.9 Week 13
At Week 13, the following procedure will be performed:
x
Direct Thrombin test
12.6
Safety Follow-Up – Weeks 17-36
After the Post-Infusion Follow-Up visits are complete, subjects will return to the study site 
for Safety Follow-Up visits from Weeks 17 through Week 36 (± 48 hours), when the 
following procedures will be completed:
12.6.1 Once per week (Weeks 17 through 36)
Once per week from Week 17 through Week 36, the following procedures will be performed:
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
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Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
12.6.2 Once per week (Weeks 17 through 20)
Once per week from Week 17 through Week 20, the following procedures will be performed:
x
PBMC collection
12.6.3 Every 2 weeks (Weeks 21 through 36)
Every 2 weeks (Weeks 22, 24, 26, 28, 30, 32, 34, and 36), the following procedures will be 
performed:
x
PBMC collection
12.6.4 Every 4 Weeks 
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed:
x
Exploratory biomarker assessments
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
VWF:Ag
x
AAV5 antibody titer
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period.
12.6.5 Every 8 Weeks 
Every 8 weeks (Weeks 20, 28, and 36), the following procedure will be performed:
x
FVIII antibody titer
12.6.6 Week 26
At Week 26, the following procedure will be performed:
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Direct Thrombin test
x
Weight
12.6.7 Week 28 
At Week 28, the following procedure will be performed:
x
Haemo-QoL-A QoL assessment
12.7
Safety Follow-Up – Weeks 37-52
Subjects will return every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) from 
Week 37-52 (± 1 week), when the following procedures will be completed:
12.7.1 Once per visit
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed:
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently based (and in particular when 
ALT values are >1.5x ULN) on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
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FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all 
efforts should be made to obtain FVIII activity measurements when a 72-hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥5 IU/dL at 16 weeks after 
BMN 270 infusion and who have not resumed standard of care FVIII 
replacement therapy.
12.7.2 Every 4 Weeks 
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed:
x
Exploratory biomarker assessments
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
AAV5 antibody titer
x
VWF:Ag
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period.  
Subjects who have not had 3 consecutive negative samples by Week 52
should continue to have PCR testing every 4 weeks until 3 consecutive 
negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor).
12.7.3 Every 8 Weeks 
Every 8 weeks (Weeks 44 and 52), the following procedure will be performed:
x
PBMC collection
x
FVIII antibody titer
12.7.4 Week 38 and 52
At Week 38 and Week 52, the following procedure will be performed:
x
Direct Thrombin test
12.7.5 Week 52 
At Week 52, the following procedure will be performed:
x
Haemo-QoL-A QoL assessment
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Weight
12.8
Safety Follow-Up – Years 2-5
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
either failure to achieve FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by 
attending only the Q12W and End of Year visits during Years 2-5.
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
vector shedding has cleared (but do not have to perform other scheduled assessments at those 
study visits).
During Years 2-5 of Safety Follow-up, the following procedures will be completed:
12.8.1 Year 2 – Every 4 Weeks (not required for treatment failure)
During Year 2, every 4 weeks (± 2 weeks), the following procedures will be performed:
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
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o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Year 2 is not required if at least 3 consecutive samples 
are negative during the Post-Infusion Follow-Up period in Weeks 1-52.
Subjects who have not had 3 consecutive negative semen samples by Week 52
should continue to have PCR testing of semen every 4 weeks during Year 2
until 3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor).
o
Subjects who meet the definition of treatment failure and wish to follow an 
abbreviated schedule but who have not cleared vector shedding from all fluids 
must still provide samples for assessment every 4 weeks during Year 2 until 
vector shedding has cleared (in such a case, these subjects do not need to 
perform other assessments except for PCR sample delivery scheduled at these 
timepoints).
12.8.2 Years 3-5 – Every 6 Weeks (not required for treatment failure)
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
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o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Years 3-5 is not required if at least 3 consecutive
samples are negative during the Post-Infusion Follow-Up period in 
Weeks 1-52 and/or Year 2.  Subjects who have not had 3 consecutive negative 
semen samples by Week 52 should continue to have PCR testing of semen 
every 6 weeks during Years 3-5 until 3 consecutive negative samples are 
documented (or upon consultation between the Investigator and Medical 
Monitor).
o
Subjects who meet the definition of treatment failure and wish to follow an 
abbreviated schedule but who have not cleared vector shedding from all fluids 
must still provide samples for assessment every 6 weeks during Years 3-5
until vector shedding has cleared (in such a case, these subjects do not need to 
perform other assessments except for PCR sample delivery scheduled at these 
timepoints).
12.8.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects)
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks (±2 weeks):
x
Year 2 – Week 64, Week 76, Week 88, Week 104
x
Year 3 – Week 116, Week 128, Week 140, Week 156
x
Year 4 – Week 168, Week 180, Week 192, Week 208
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Year 5 – Week 220, Week 232, Week 244, Week 260
For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and 
Week 260) will serve as an End of Year visit.
At the every 12 week and End of Year visits, the following procedures will be performed:
x
Brief physical examination (at every 12 week visits) or complete physical 
examination (at End of Year visits)
x
Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Vital Signs
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Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
o
ABO blood typing assessment should be performed at the next regularly 
scheduled study visit (or at least prior to the end of the subject’s participation 
in the study)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
AAV5 antibody titer
x
FVIII antibody titer
x
PBMC collection
x
VWF:Ag
x
Direct Thrombin test
x
Exploratory biomarker assessments
x
Haemo-QoL-A QOL assessment (at Week 76, Week 128, Week 180, Week 232, and 
End of Year visits only)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are negative during the Post-Infusion Follow-Up period in 
Weeks 1-52.  Subjects who have not had 3 consecutive negative semen 
samples by Week 52 should continue to have PCR testing of semen every 
4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor).
12.9
Early Termination Visit
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit.
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done:
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
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Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
AAV5 antibody titer
x
FVIII antibody titer
x
PBMC collection
x
VWF:Ag
x
Direct Thrombin test
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing at the ETV is not required if at least 3 consecutive samples 
are clear during the Post-Infusion Follow-Up period.
x
Exploratory biomarker assessment
x
Haemo-QoL-A QOL assessment
12.10 End of Study
The study will end after the last subject completes the last Safety Follow-Up visit 
(Week 260). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
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noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study subjects may be 
compromised.
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13
DATA QUALITY ASSURANCE
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan.
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS.
14.1.1 Interim Analyses
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all subjects having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16).
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
14.2
Missing data will not be imputed. 
14.3
Primary and Secondary Efficacy Analysis
The subjects will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of subjects, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined.
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic substrate assay and/or one-stage 
clotting assay as measured by the central laboratory at 16 weeks following study treatment.  
hFVIII activity will be assessed weekly during the study period.  We can only assess the true 
steady state of hFVIII protein produced from BMN 270 after a minimum of 72 hours has 
elapsed since the last infusion of FVIII protein concentrates.  
14.4
Immunogenicity
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons  
14.5
Pharmacodynamic Analyses
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage clotting assay and/or chromogenic substrate assay (activity level), will be used for 
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plasma profiles; FVIII activity will be used to determine PD parameters.  Traditional PK 
analysis is not applicable.
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics. 
14.6
Safety Analysis
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF.
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of subjects who report hepatitis will be presented.
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided. 
Detailed statistical methods will be provided in the SAP.
14.7
Determination of Sample Size
No formal sample size calculations based on statistical power were performed.
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 15 subjects may be dosed in the study; the actual number of 
subjects will depend on the criteria for dose escalation. 
14.8
Analysis Populations
The Safety analysis population is defined as all enrolled subjects who receive any study drug. 
The analysis of safety data will be performed on Safety Set.
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The Full Analysis Set (FAS) is defined as all enrolled subjects who receive study drug and
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis.
14.9
Changes in the Conduct of the Study or Planned Analyses
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation.
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active subjects must again provide informed consent.
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail.
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15
DATA REVIEW BOARD
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established.
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available subject safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene 
for further assessment of subject safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites.
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16
COMPENSATION, INSURANCE AND INDEMNITY
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected.
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the subject’s health insurance company or other third party 
payer for the cost of this medical treatment. If the subject has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law.
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17
CASE REPORT FORMS AND SOURCE DOCUMENTS
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy.
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable. 
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator.
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to 
their medical records, and subjects will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
subject records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification.
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed. 
Before a subject’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
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completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents.
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18
STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files.
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RETENTION OF RECORDS
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained.
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USE OF INFORMATION AND PUBLICATION
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP). 
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21
REFERENCES
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Berntorp, E, Peake, I, Budde, U, Laffan, M et. al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia 18 Suppl 6, 1-13. 2012.
Croteau, GA, Martin, DB, Camp, J, Yost, M et. al. Evaluation of exposure and health care 
worker response to nebulized administration of tgAAVCF to patients with cystic fibrosis. 
Ann Occup Hyg 48[8], 673-681. 2004.
D'Avola, D. Phase 1 Clinical Trial of Liver Directed Gene Therapy with rAAV5-PBGD in 
Acute Intermittent Porphyria: Preliminary Safety Data. J Hepatol 60[S58]. 2014.
Den Ujil, Mauser Bunschoten, Roosendaal, Schutgens et. al. Clinical Severity of haemophilia 
A: does the classification of the 1950s still stand? Haemophilia 17, 849-853. 2011.
George, LA, Sullivan, S, Teitel, J, Cuker, A et al.  Preliminary results of a phase 1/2 trial of 
SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent 
factor IX activity levels at the lowest dose cohort.  Haemophilia 22[Suppl. 4], 151-152.
2016.
Hay, CR, DiMichele, DM. The principal results of the International Immune Tolerance 
Study: a randomized dose comparison. Blood 119[6], 1335-1344. 2012.
Heller CG & Clermont Y.  Kinetics of the germinal epithelium in man.  Recent Prog Horm 
Res.  1964;20:545-571.
Heller CG, Heller GV, Rowley MJ.  Human spermatogenesis: an estimate of the duration of 
each cell association and each cell type.  Excerpta Med Int Congr Ser.  1969;184:1012-1018.
Kaufman, RJ, Powell, JS. Molecular approaches for improved clotting factors for hemophilia
1. Blood 122[22], 3568-3574. 2013.
Maguire, AM, High, KA, Auricchio, A, Wright, JF et. al. Age-dependent effects of RPE65 
gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 
374[9701], 1597-1605. 2009.
Mahlangu, J, Powell, JS, Ragni, MV, Chowdary, P et. al. Phase 3 study of recombinant factor 
VIII Fc fusion protein in severe hemophilia A
8. Blood 123[3], 317-325. 2014.
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Manno, CS, Chew, AJ, Hutchison, S, Larson, PJ et. al. AAV-mediated factor IX gene
transfer to skeletal muscle in patients with severe hemophilia B
1. Blood 101[8], 2963-2972. 2003.
Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006.
Mannucci, PM, Tuddenham, EG. The hemophilias--from royal genes to gene therapy
1. N Engl J Med 344[23], 1773-1779. 2001.
McIntosh, J, Lenting, PJ, Rosales, C, Lee, D et. al. Therapeutic levels of FVIII following a
single peripheral vein administration of rAAV vector encoding a novel human factor VIII 
variant. Blood 121[17], 3335-3344. 2013.
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016.
Mingozzi, F and High, KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013.
Monahan, P, Walsh CE, Powell JS, Konkle BA et al.  Update on a phase 1/2 open-label trial 
of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for 
hemophilia B.  J Thromb Haemostasis 13[Suppl 2], 1-997.  2015.
Nagel, K, Walker, I, Decker, K, Chan, AK et. al. Comparing bleed frequency and factor 
concentrate use between haemophilia A and B patients. Haemophilia 17[6], 872-874. 2011.
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992.
Nathwani, AC, McIntosh, J, Davidoff, AM. An update on gene therapy for hemophilia. Curr 
Hematol Rep 4[4], 287-293. 2005.
Nathwani, AC, Gray, JT, Ng, CY, Zhou, J et. al. Self-complementary adeno-associated virus 
vectors containing a novel liver-specific human factor IX expression cassette enable highly 
efficient transduction of murine and nonhuman primate liver. Blood 107[7], 2653-2661.
2006.
Nathwani, AC, Rosales, C, McIntosh, J, Rastegarlari, G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011.
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Nathwani, AC, Tuddenham, EG, Rangarajan, S, Rosales, C et. al. Adenovirus-associated 
virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365[25], 2357-2365.
2011.
Nathwani, AC, Reiss, UM, Tuddenham, EG, Rosales, C et. al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014.
Paneda, A, Lopez-Franco, E, Kaeppel, C, Unzu, C et. al. Safety and liver transduction 
efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute 
intermittent porphyria. Hum Gene Ther 24[12], 1007-1017. 2013.
Pasi, J, Wong, W, Rangarajan, S, Wilde, J et al.  Interim results of an open-label, phase 1/2 
study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A.  Haemophilia 
22[Suppl. 4], 151-152.  2016.
Schenk-Braat, EA, van Mierlo, MM, Wagemaker, G, Bangma, CH et. al. An inventory of 
shedding data from clinical gene therapy trials. J Gene Med 9[10], 910-921. 2007.
Simonelli, F, Maguire, AM, Testa, F, Pierce, EA et. al. Gene therapy for Leber's congenital 
amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18[3], 
643-650. 2010.
Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS et. al. Guidelines for the 
management of hemophilia. Haemophilia 19[1], e1-47. 2013.
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010.
Watkins, PB, Kaplowitz, N, Slattery, JT, Colonese, CR et al.  Aminotransferase Elevations in 
Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized Controlled 
Trial.  JAMA 296[1], 87-93.  2006.
White, GC, Rosendaal, F, Aledort, FM, Lusher, JM et al.  Definitions in hemophilia.  
Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific 
and standardization committee of the International society on Thrombosis and Haemostasis.  
Thromb Haemost. 85[3], 560.  2001.
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INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Patients 
In accordance with FDA Form 1572 and/or principles of ICH E6 R2 GCP, the Investigator 
will ensure that:
x
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients.
x
He or she will personally conduct or supervise the study.
x
He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or ICH E6 
R2 Sections 2.9 and 4.8 are met. As well, he or she will ensure that IRB/ IEC review 
and approval in 21 CFR Part 56 and/or ICH E6 R2 Section 2.6 are met. 
x
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 R2 Section 4.11.
x
He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug.
x
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments.
x
Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 R2 
Section 4.9 are kept, and those records are available for inspection in accordance with 
21 CFR 312.68 and/or ICH E6 R2 Section 4.9.7.
x
The IRB/IEC/REB complies with the requirements of 21 CFR Part 56, ICH E6 R2 
Section 3.0, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients.
x
He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6 R2.
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SIGNATURE PAGE
Protocol Title: A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII in Patients with Severe Haemophilia A
Protocol Number: 270-201, Amendment 7
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including  
ICH E6 R2, as stated in the protocol, and other information supplied to me.
Investigator Signature
Date
Printed name _______________________________________________________________
Accepted for the Sponsor:
Medical Monitor Signature
Date
Printed name:
, MA MB BChir MSc,
, Clinical Science
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PROTOCOL AMENDMENT TEXT REVISIONS
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See pages 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font.
Section No./Title
Revision
Rationale
Synopsis (Study Design 
and Plan)
As the relationship between activity assay results of the BMN 270 gene product and bleeding remains to be established, 
Investigators should strive to minimize bias by avoiding consideration of FVIII activity levels by themselves or subjects in the 
reporting of bleeding episodes and FVIII usage.
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume 
prior FVIII prophylaxis. Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either 
failure to achieve FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII 
replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion 
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the 
discretion of the Investigator. Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity for therapy using this AAV 
capsid. Efficacy will be determined by FVIII activity at 16 weeks post dose. Safety will be evaluated for approximately 
5 years after dosing.  Any safety signal may trigger a review of the data and possible additional immunogenicity studies that 
include an assessment of cellular immune responses using collected peripheral blood mononuclear cells (PBMC).
5, 14
7.4/Summary of Overall 
Risks and Benefits
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based on prior human studies with 
peripheral injections of AAV vectors, there is no known safety risk of AAV gene therapy. However, a mild asymptomatic 
transaminitis was observed at week 7-12 after administration in humans with an AAV8-FIX, providing the rationale for the 
following surveillance plan . Each subject will have a comprehensive surveillance plan that monitors LFTs during the study.
The majority of subjects in the ongoing 270-201 clinical study who have received 4E13 or 6E13 vg/kg doses of BMN 270
have had Grade 1 asymptomatic elevations in ALT. For most subjects, the elevations have reached only slightly above the 
upper limit of normal (ULN).  Based on the effectiveness of transient oral corticosteroid used to suppress a presumed Class 1
(cytotoxic T-cell) response in prior studies with hepatic transduction with AAV vectors (Mingozzi, 2013), subjects were 
treated with 7-32 weeks of oral corticosteroids prophylactically or in response to the elevations in ALT to ensure preservation 
of the transduced hepatocytes. Using this approach, no sustained loss of FVIII activity has been observed in subjects with ALT 
elevations, consistent with maintaining a high level of hepatocyte function. Moreover, the rise in ALT levels were not 
accompanied by significant or lasting aberrations in other liver tests such as AST, bilirubin or albumin, indicating that extent 
14
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of toxicity is limited. There has been one HIV-positive subject in the ongoing 270-302 clinical study who experienced Grade 3
asymptomatic elevations in ALT and AST, which has been attributed to an interaction between one or more of his 
antiretroviral therapy medications and/or unsuspected underlying hepatic disease with BMN 270. In addition, there has been 
one subject with Gilbert’s syndrome in the ongoing 270-301 clinical study who has experienced Grade 3 asymptomatic 
elevations in ALT and AST. These cases have led to the exclusion of subsequent HIV-positive subjects and requirement of 
liver tests at Screening that are <1.25 times the upper limit of the normal range in the ongoing 270-301 and 270-302 clinical 
studies. Of note, two HIV-positive subjects in 270-301 and one presumed Gilbert’s syndrome subject in 270-201 have 
received BMN 270 without experiencing any elevations in ALT to date. Overall, the literature and clinical experience with 
BMN 270 suggests that transient elevations in liver enzymes are expected following AAV-based gene therapy for the
treatment for hemophilia A or B without any long-term concerns of hepatic injury (Manno, 2006; Nathwani, 2011; George, 
2016; Miesbach, 2016; Pasi, 2017). 
The current data available for BMN 270 does not yet permit comprehensive assessment of the benefit:risk profile of this 
investigational drug. Given the monitoring measures in place in the clinical protocol(s) to minimize the risk to subjects 
participating in the existing studies, the identified risks are justified by the anticipated benefits that may be afforded to 
subjects.  Each subject in 270-201 will have a comprehensive surveillance plan that monitors LTs during the study, and 
elevations in LT will be addressed according to the guidelines set forth in the protocol. Safety will be assessed by adverse 
event reporting and clinical laboratory assessments.
9.1/Overall Study 
Design and Plan
As the relationship between activity assay results of the BMN 270 gene product and bleeding remains to be established, 
Investigators should strive to minimize bias by avoiding consideration of FVIII activity levels by themselves or subjects in the 
reporting of bleeding episodes and FVIII usage.
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume 
prior FVIII prophylaxis. Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either 
failure to achieve FVIII activity ≥ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII 
replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the 
discretion of the Investigator. 
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Table 9.1.1, Table 9.1.2, 
Table 9.1.3
Table 9.1.1, Table 9.1.2, and Table 9.1.3 have been updated to reflect the changes made elsewhere in the protocol.
4, 6, 9, 12, 
14
Table 9.1.1 (Footnotes)
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may 
choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet 
known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, 
testing of these samples (including those for Direct Thrombin Activity test and any other exploratory assessments) will be 
performed only as deemed necessary by the Sponsor.
9
Table 9.1.2 (Footnotes)
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTsLTs
may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based on discussion between 
the Medical Monitor and the Investigator and review of subject data. , but LTs will be monitored at least twice weekly during 
periods when a subject’s ALT is ≥ 3x ULN. Patients with ALT > 1.5 ULN during the study may undergo additional 
evaluations (e.g.,eg, imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the 
discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT 
has increased to above ULN; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII 
activity level; or after a discussion between the Medical Monitor and the Investigator based on a review of subject data.  If 
FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels 
may be adjusted based on discussion between the Medical Monitor and the Investigator.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may 
choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet 
known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, 
testing of these samples (including those for Direct Thrombin Activity test and any other exploratory assessments) will be 
performed only as deemed necessary by the Sponsor.
9, 12, 14
Table 9.1.3 (Footnotes)
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTsLTs
may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based on discussion between 
the Medical Monitor and the Investigator and review of subject data., but LTs will be monitored at least twice weekly during 
periods when a subject’s ALT is ≥ 3x ULN. Patients with ALT > 1.5 ULN during the study may undergo additional 
9, 12, 14
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evaluations (e.g.,eg, imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the 
discretion of the investigator. Additional testing of FVIII and LTs during any study week may be performed if: (1) the ALT 
has increased to above ULN; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII 
activity level; or after a discussion between the Medical Monitor and the Investigator based on a review of subject data.  If 
FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels 
may be adjusted based on discussion between the Medical Monitor and the Investigator.
e Collection for each matrix to occur until at least 3 consecutive negative results are obtained.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may 
choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet 
known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, 
testing of these samples (including those for Direct Thrombin Activity test and any other exploratory assessments) will be 
performed only as deemed necessary by the Sponsor.
Table 9.1.4 and Table 
9.1.5
Table 9.1.4 and Table 9.1.5 and their associated footnotes have been modified/added to reflect changes made elsewhere in the 
protocol.
2, 3, 6, 9, 
11, 12, 14
9.4.8/Prior and 
Concomitant 
Medications
The following medications are prohibited starting 30 days before Screening:
x
Emicizumab
x
Fitusiran
x
Concizumab
x
Efavirenz
x
Lamivudine
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their participation in 270-201 must have 
their antiretroviral medication regimen approved by the Investigator and Medical Monitor prior to starting antiretroviral 
treatment.
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9.4.9/Treatment 
Compliance
Study drug will be administered to subjects at the study site by a qualified professional.  The quantity dispensed, returned, 
used, lost, etc. must be recorded on thea dispensing log provided for the study.  Sites will be instructed to return or destroy all 
used and unused study drug containers.
14
9.5/IP Accountability
The Investigator or designee is responsible for maintaining accurate records (including dates and quantities) of IP(s) received 
and IP lost or accidentally or deliberately destroyed. The Investigator or designee must retain all unused or expired study 
supplies until the study monitor (on-site CRA) has confirmed the accountability data, if allowed by local SOPs.
14
9.5.1/Return and 
Disposition of Clinical 
Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by the study monitor. The 
Investigator or designee must provide an explanation for any destroyed or missing study drug or study materials. (or must be 
referenced in their institution SOPs).
14
9.6/Dietary or Other 
Protocol Restrictions
Subjects should be advised to abstain from any blood or sperm donation after BMN 270 infusion, until there is no further 
evidence of vector shedding from PCR analysis of samples.
10
9.7.2/Primary Efficacy 
Variables
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
activity ≥ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due to joint 
bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the discretion of the Investigator.
3
9.7.3/Secondary 
Efficacy Variables
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume 
prior FVIII prophylaxis.
5
Table 9.7.8.2.1
Table 9.7.8.2.1 (and its footnotes) have been updated to reflect changes made elsewhere in the protocol.
6
9.7.8.3/Liver and 
Hepatitis Testing
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects who have clearedwith a history of hepatitis 
B infection or are seronegative do not need to receive the hepatitis B vaccination. C will be asked for information about the 
treatments received as part of their medical history assessment at Screening.
4
9.7.8.5/Vital Signs, 
Physical Examinations 
and Other Safety 
Observations
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 and every 52 weeks thereafter; at 
other visits, brief physical examinations may be performed at the discretion of the investigator based on the subject’s clinical 
condition. Particular attention should be given to signs of bleeding, as well as assessing possible hemarthroses. at the End of 
2, 8, 14
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Years visits thereafter. A complete physical examination will include general appearance (head, eyes, ears, nose, and throat), 
cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems.
At other visits, brief physical examinations may be performed at the discretion of the investigator based on the subject’s 
clinical condition. A brief physical examination will include general appearance, cardiovascular, respiratory, neurologic, 
dermatologic, musculoskeletal, and gastrointestinal assessments. Particular attention should be given to signs of bleeding, as 
well as assessing possible hemarthroses.
Height will be recorded at Screening only. Weight will be recorded at Screening, at Weeks 26 and 52 during Year 1, and then 
at the second Q12W visit each year and at every 6 months thereafterEnd of Years visit during Years 2-5.
9.7.8.6/Vector Shedding
Vector shedding will also be extensively studied in the present clinical trial, every other week between Weeks 4-16, then every 
4 weeks to Week 52 until at least 3 consecutive negative results are obtained. Testing of semen will continue through Week 
12, even if 3 consecutive negative results have been recorded in that compartment prior to that timepoint.  Subjects who have
not had 3 consecutive negative samples by Week 52 should continue to have PCR testing every 4 weeks until 3 consecutive 
negative samples are documented (or upon consultation between the Investigator and Medical Monitor). Subjects who meet 
the definition of treatment failure and wish to follow an abbreviated schedule (refer to Section 12.5.3) but who have not
cleared vector shedding from all fluids must still provide samples for assessment until vector shedding has cleared: every 
4 weeks (during Year 2), or every 6 weeks (during Years 3-5).
Contraception use may need to be extended beyond 26 weeks in individual subjects based on observed vector shedding in 
semen. After 6 months, subjects may stop contraception use only if they have had 3 consecutive negative semen samples.
(upon consultation between the Investigator and Medical Monitor).
3, 7, 14
10.1.1/Adverse Events
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only because the subject is a 
haemophiliac) should not be recorded as AEs but will instead be captured in subject diaries.  Bleeding events that occur where 
a normal (ie, non-haemophiliac) patient would bleed, such as bleeding as a result of major trauma, should be recorded as 
adverse events.  All bleeding events which meet criteria for being serious should be reported as serious adverse events (SAEs)
whether or not they are bleeding events that are normal sequelae of haemophilia.
14
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10.1.1.1/Bleeding and 
Suspected Bleeding 
Events
All bleeding events and suspected bleeding events, regardless of the need for exogenous FVIII therapy as treatment, should be 
captured in subject diaries and recorded on the designated bleeding eCRF.  Bleeding events and suspected bleeding events 
should not be reported as adverse events, with the following exception:
x
All bleeding events and suspected bleeding events which meet one or more of the criteria for being serious (refer to 
Section 10.2) should be reported as serious adverse events (whether or not they are bleeding events that are normal 
sequelae of hemophilia, and whether or not they required exogenous FVIII as treatment).
14
10.2.1/Events of Special 
Interest
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, irrespective of seriousness, severity 
or causality: 
x
Elevation of liver enzymes (ALT) ≥1.5x ULN, regardless of whether that triggers an initiation or modification of  
corticosteroid treatment
x
Thromboembolic event
14
10.4.1.4/Abnormal 
Laboratory Values
A clinical laboratory abnormality is considered clinically significant and should be documented as an AE if not refuted by a
repeat test to confirm the abnormality and any one or more of the following conditions is met:
x
Leading to a change in study medication (e.g. dose modification, interruption or permanent discontinuation) 
14
10.4.1.7/Hospitalization, 
Prolonged 
Hospitalization, or 
Surgery
There are some hospitalization scenarios that do not require reporting as an SAE when there is no occurrence of an AE.  These
scenarios include planned hospitalizations or prolonged hospitalizations to:
x
Hospitalization solely for the purpose of insertion ofInsert an in-dwelling IV catheter (such as a Port-a-Cath or other 
brand) for administration of study drug will not be considered an SAEor FVIII replacement therapy.
14
10.4.1.9/Pregnancy
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the pregnancy by entering the 
information on the Pregnancy eCRF and submitting to BPV within 24 hours of the site becoming aware of the event. 
The Investigator must make every effort to follow the subject’s partner (with that partner’s consent) through resolution of the 
pregnancy (delivery or termination) and to report the resolution on the Pregnancy Follow-up Form in the study reference 
materials.eCRF.
14
10.9/BioMarin Contact 
Information
Contact information for the medical monitor is as follows:
13
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Name:
Mitra Tavakkoli, MD, PharmD 
Address:105 Digital Drive
Novato, CA 94949 USA
Phone:
+1 (415) 257-5974
E-mail:
fatemeh.tavakkoli@bmrn.com
Name: Nina Mitchell, MA MB BChir MSc
Address: Biomarin (UK) Ltd.
10 Bloomsbury Way
London WC1A 2SL
Phone: +44 (0) 207 420 3414 (office)
+44 (0) 7761 659 535 (mobile)
E-mail: nina.mitchell@bmrn.com
12.2/Screening Visit
The following procedures will be performed during the Screening Period:
x
Full medical history, including haemophilia A history, hepatitis B, hepatitis C, and HIV. Subjects with a history of 
hepatitis B or hepatitis C will be asked for information about the treatments received. Any prior pharmacokinetics 
information obtained while the subject was receiving prophylactic or on-demand FVIII therapy prior to the study 
should also be collected. For subjects who have already enrolled in 270-201, this information should be collected at 
the next regularly scheduled study visit (or at least prior to the subject’s completion of study participation).
4
12.8/Safety Follow-Up 
(Years 2-5)
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
activity ≥ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due to joint 
bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of 
Year visits during Years 2-5.
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule but who have not cleared 
vector shedding from all fluids must still provide samples for assessment every 4 weeks (during Year 2) or every 6 weeks 
(during Years 3-5) until vector shedding has cleared (but do not have to perform other scheduled assessments at those study 
visits).
3, 7
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12.8.1/Year 2 – Every 4 
Weeks
During Year 2, every 4 weeks (+(± 2 weeks), the following procedures will be performed:
x
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief Physical Examinations may 
be performed at other visits.
x
Vital Signs
x
Exploratory biomarker assessments
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Year 2 is not required if at least 3 consecutive samples are negative during the Post-
Infusion Follow-Up period in Weeks 1-52.  Subjects who have not had 3 consecutive negative semen 
samples by Week 52 should continue to have PCR testing of semen every 4 weeks during Year 2 until 
3 consecutive negative samples are documented (or upon consultation between the Investigator and Medical 
Monitor).
o
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule but who 
have not cleared vector shedding from all fluids must still provide samples for assessment every 4 weeks 
during Year 2 until vector shedding has cleared (in such a case, these subjects do not need to perform other 
assessments except for PCR sample delivery scheduled at these timepoints).
2, 14
12.8.2/Years 3-5 –
Every 6 Weeks
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
x
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief Physical Examinations may 
be performed at other visits.
x
Vital Signs
x
Exploratory biomarker assessments
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
2, 7, 14
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o
Sample testing during Years 3-5 is not required if at least 3 consecutive samples are negative during the 
Post-Infusion Follow-Up period in Weeks 1-52 and/or Year 2.  Subjects who have not had 3 consecutive 
negative semen samples by Week 52 should continue to have PCR testing of semen every 6 weeks during 
Years 3-5 until 3 consecutive negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor).
o
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule but who 
have not cleared vector shedding from all fluids must still provide samples for assessment every 6 weeks 
during Years 3-5 until vector shedding has cleared (in such a case, these subjects do not need to perform 
other assessments except for PCR sample delivery scheduled at these timepoints).
12.8.3/Years 2-5 –
Every 3 Months Every 
12 Weeks and End of 
Year Visits
During Years 2-5, every 3 months (± 2 weeks), the following procedures will be performed:
During Years 2-5, subjects will be asked to return to the study site for visits at the following study weeks ( ± 2 weeks):
x
Year 2 – Week 64, Week 76, Week 88, Week 104
x
Year 3 – Week 116, Week 128, Week 140, Week 156
x
Year 4 – Week 168, Week 180, Week 192, Week 208
x
Year 5 – Week 220, Week 232, Week 244, Week 260
For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and Week 260) will serve as an End of 
Year visit.
At the every 12 week and End of Year visits, the following procedures will be performed:
x
Brief physical examination (at every 12 week visits) or complete physical examination (at End of Year visits)
x
Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and 
FVIII use)
x
Liver Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
2, 3, 7, 11, 
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x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
x
Liver Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage clotting assay)
o
FVIII activity level (chromogenic substrate assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed standard of care FVIII replacement therapy.
x
Vital Signs
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
o
ABO blood typing assessment should be performed at the next regularly scheduled study visit (or at least 
prior to the end of the subject’s participation in the study)
x
Exploratory biomarker assessments
x
Haemo-QoL-A QOL assessment (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
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o
Sample testing during Years 2-5 is not required if at least 3 consecutive samples are negative during the 
Post-Infusion Follow-Up period in Weeks 1-52.  Subjects who have not had 3 consecutive negative semen 
samples by Week 52 should continue to have PCR testing of semen every 4 weeks (during Year 2) or every 
6 weeks (during Years 3-5) until 3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor).
12.8.4/Years 2-5 –
Every 6 Months
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the end of Year 1 of the Safety Follow-
up period), the following procedures will be performed:
x
Haemo-QoL-A QOL assessment
x
Weight
2
12.8.5/Years 2-5 –
Every 4 Weeks
Every four weeks during Years 2-5, the following procedure may be performed:
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Years 2-5 is not required if at least 3 consecutive samples are clear during the Post-
Infusion Follow-Up period.  Subjects who have not had 3 consecutive negative samples by Week 52 should 
continue to have PCR testing every 4 weeks during Years 2-5 until 3 consecutive negative samples are 
documented (or upon consultation between the Investigator and Medical Monitor).
2
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CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene 
Transfer of Human Factor VIII in Patients with Severe Haemophilia A
Protocol Number:
270-201
Active Investigational Product:
AAV5-hFVIII-SQ
IND/European Union Drug 
Regulating Authorities Clinical 
Trials (EudraCT) Number:
2014-003880-38
Indication:
Haemophilia A
Sponsor:
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
Development Phase:
Phase 1/2
Sponsor's Responsible Medical 
Monitor:
, MD, PharmD
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
Duration of Subject 
Participation:
Approximately 264 weeks
Dose:
Varied
Study Population:
Males aged 18 or older
Date of Original Protocol:
10 February 2015
Date of Amendment 1:
06 March 2015
Date of Amendment 2:
26 May 2015
Date of Amendment 3:
06 November 2015
Date of Amendment 4:
02 September 2016
Date of Amendment 5:
14 February 2017
Date of Amendment 6:
21 December 2017
Property of BioMarin
CONFIDENTIAL
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin.
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code 
of Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving 
of essential documents
DocuSign Envelope ID: 6255452C-C7A9-4900-BDB5-7FECA2D22426
PI
PI

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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY
Amendment: 6
Date: 21 December 2017
RATIONALE AND SUMMARY OF MAJOR CHANGES
A summary of major changes covered by Amendment 6 to the BMN 270-201 protocol is 
provided below.  
1. The frequency of liver function and FVIII testing has been increased during the 
Years 2-5 follow-up period. Testing will be performed every 4 weeks (+ 2 weeks) 
during year 2, and every 6 weeks (± 2 weeks) during years 3-5.
Rationale:  To maintain adequate surveillance of potential hepatocyte injury and trending of 
FVIII activity beyond Week 52 post-BMN 270 infusion, the frequency of liver function and 
FVIII testing has been increased during the Years 2-5 follow-up period from every 3 months 
beyond Week 52. A brief physical examination, assessment of vital signs, and review of 
adverse events, concomitant medications, and diaries of FVII usage and bleeding events will 
also occur at these visits.
2. Exploratory biomarker sampling has been extended beyond Week 24.  Samples will 
now be collected every 4 weeks through the end of Year 2, and then every 6 weeks 
during Years 3-5.
Rationale:  Additional biomarker sampling will permit further analysis of exploratory 
endpoints during the study.
3. Clarified that the 72-hour washout period prior to assessment of FVIII levels is 
necessary only for subjects who have achieved FVIII levels ≥5 IU/dL by Week 16
after BMN 270 infusion and have not resumed standard of care FVIII replacement 
therapy.
Rationale:  The current language in the protocol states: If a subject has used FVIII within 
72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved.” The proposed 
language is to make it more clear that the 72 hour wash-out period prior to FVIII assessment 
is not intended for the subjects who have resumed standard of care FVIII replacement 
therapy.
4. Clarified that testing for reactivation of hepatitis B and hepatitis C at Week 16 is 
necessary only in subjects who have a past medical history of hepatitis B or hepatitis 
C prior to study entry.
5. Minor administrative changes have been made for consistency and clarity.
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6. The identity of the medical monitor has been updated.
Specific changes included in this amendment, including the Synopsis, since Amendment 5
(approved 14 February 2017) are outlined in Section 24.
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2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
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Page: 
Reference: 
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AUTHORITY USE 
ONLY:
TITLE OF STUDY: 
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of BMN 270, an 
Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients 
with Severe Haemophilia A
PROTOCOL NUMBER:
270-201
STUDY SITES:
Approximately 6-10 sites worldwide.
PHASE OF DEVELOPMENT:
Phase 1/2
STUDY RATIONALE:
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an 
essential cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to 
a new mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 
1-5% of wild type activity and the mild form is 5-40% activity. The clinical manifestations of 
severe HA remain frequent spontaneous bleeding episodes, predominantly in joints and soft 
tissues, with a substantially increased risk of death from haemorrhage when the brain is involved.  
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life for 
FVIII (12 to 18 hours for most approved products) necessitates frequent infusions, and although a 
major advance in the treatment of HA, it remains common for severe HA patients to continue to 
have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up 
to 30 to 50 episodes/year for on demand treatment). The consequence of multiple bleeding events 
is the development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death. Chemical modification (e.g. direct 
conjugation of polyethylene glycol (PEG) polymers) and bioengineering of FVIII (e.g. FVIII-Fc 
fusion proteins) improve half-life by approximately 50%, and thus, show promise in reduced 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
dosing and maintaining activity levels above 1% trough. However, these longer acting FVIIIs 
remain dependent on multiple infusions to maintain critical levels of FVIII activity in severe HA 
patients. There is therefore a strong unmet need for a fully preventive treatment of HA to give 
patients a FVIII level compatible with a normal and haemorrhage-free life. 
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach because 
clinical manifestations are attributable to the lack of a single gene product (FVIII) that circulates in 
minute amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not 
essential, and modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml 
induces an increase in activity of 1%) can ameliorate the severe form of the disease.  Thus, 
relatively small changes in endogenous FVIII activity results in clinically relevant improvements 
in disease phenotype. Finally, the response to gene transduction can be assessed using validated 
quantitative rather than qualitative endpoints that are easily assayed using established laboratory 
techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific 
tissues such as the liver (for serotypes 2, 5 and 8 among others). Indeed, an on-going gene therapy 
clinical trial for a related disorder, haemophilia B, has established that stable (>36 months) 
expression of human factor IX at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
administration of AAV-8 vector. Several participants in this trial have been able to discontinue 
factor prophylaxis without suffering spontaneous haemorrhages, even when they undertook 
activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a liver-selective promoter (Figure 1).
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Figure 1. hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from vector-transduced 
liver tissue. The clinical study 270-201 is a first-in-human study designed to assess the relationship 
of vector dose to the augmentation of residual FVIII activity, and whether these levels are 
sufficient to alter the clinical phenotype. The relationship of dose to safety will be correlated to the 
activity of hFVIII in patients with severe HA.
OBJECTIVES: 
The primary objectives of the study are:
x
To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. 
x
To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of 
normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose.
The secondary objectives of the study are:
x
To describe the immune response to the FVIII transgene and AAV capsid proteins 
following systemic administration of AAV5-hFVIII-SQ
x
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during 
the study
x
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
STUDY DESIGN AND PLAN: 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will be 
taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed 
for approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and 
do not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. 
Participants will be enrolled into one of up to four cohorts according to dose level: 
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv)
Cohort 2:  2E13 vg per kilogram, iv
Cohort 3:  6E13 vg per kilogram, iv
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies 
of mice and monkeys. The starting dose has a 10-fold safety margin from no observed adverse 
effect level (NOAEL) in non-human primates. 
Cohorts 1-3
The first 3 cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between 
cohorts. Dose escalation may occur after a single subject has been safely dosed if the resulting 
FVIII activity at the Week 3 visit is < 5 IU/dL in both the one-stage aPTT and chromogenic assays. 
Three weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic doses.
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study, the Data Review Board (DRB). 
If the FVIII activity reaches ≥ 5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.
Subject 1 will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram of 
body weight. If the FVIII activity level does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, 
then no further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with 
Subject 2 at the next dose (2E13 vg/kg). 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥ 5 IU/dL at the 
Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and enrollment into 
Cohort 3 (6E13) will initiate with the next subject. If the FVIII activity level in the first subject 
treated in Cohort 3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then the Data 
Review Board (DRB) will recommend whether to continue to add subjects to the cohort and/or 
whether to continue the study.
For the first subject treated in each of the first 3 cohorts, if the activity level reaches ≥5 IU/dL and 
no safety issue is found, then up to four subjects will be enrolled in the Cohort, though, the 
adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts based 
on activity levels of FVIII and safety signals. 
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg. If FVIII activity in these 3 subjects is 
≥5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in this 
cohort.
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB. The adaptive nature of this trial allows the DRB to recommend allocating 
subjects to the cohorts based on activity levels of FVIII and safety signals.
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity for 
therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post 
dose. Safety will be evaluated for approximately 5 years after dosing.  Any safety signal may 
trigger a review of the data and possible additional immunogenicity studies that include an 
assessment of cellular immune responses using collected peripheral blood mononuclear cells 
(PBMC).
NUMBER OF SUBJECTS PLANNED:
Up to 15 subjects may enroll into the study; the actual number of subjects will depend on the FVIII 
activity levels seen in each Cohort.
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following criteria:
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
1.
Males that are 18 years or older with established severe haemophilia A as evidenced by 
their medical history.  Patients will be considered as severe if their base FVIII level is 
1 IU/dL or less
2.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs)
3.
Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis
4.
Able to sign informed consent and comply with requirements of the trial
5.
No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 
12 months
6.
Sexually active patients must be willing to use an acceptable method of contraception such 
as double barrier, including hormonal contraception for at least 6 months post-treatment.  
After 6 months, subjects may stop contraception use only if they have had 3 consecutive 
negative semen samples.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study:
1.
Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition or AAV5 total antibodies
2.
Any evidence of active infection or any immunosuppressive disorder.  
3.
HIV positive
4.
Significant liver dysfunction as defined by abnormal elevation of:
x
ALT (alanine transaminase) to 3 times the upper limit of normal;
x
Bilirubin above 3 times the upper limit of normal;
x
Alkaline phosphatase above 3 times the upper limit of normal; or
x
INR (international normalized ratio) ≥1.4
5.
Potential participants who have had a liver biopsy in the past 3 years are excluded if they 
had significant fibrosis of 3 or 4 as rated on a scale of 0-4
6.
Evidence of any bleeding disorder not related to Haemophilia A
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
7.
Platelet count of < 100 x 109/L
8.
Creatinine ≥1.5 mg/dL
9.
Liver cirrhosis of any etiology as assessed by liver ultrasound 
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive
12. Treatment with any IP within 30 days prior to the end of the screening period
13. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study including possible corticosteroid 
treatment outlined in the protocol.  The physician may exclude patients unwilling or 
unable to agree on not using alcohol for the 16-week period following the viral infusion.
14. Prior treatment with any vector or gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion
16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral 
infusion
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level.
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
The study is open label with comparison of FVIII activity to baseline values. No reference therapy 
will be evaluated in this study.
DURATION OF TREATMENT:
BMN 270 is given as a single dose by intravenous infusion.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
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AUTHORITY USE 
ONLY:
CRITERIA FOR EVALUATION:
Safety:
The following safety outcome measurements will be assessed:
x
Incidence of adverse events (AEs), including serious AEs (SAEs) 
x
Change in clinical laboratory tests (serum chemistry and haematology)
x
Change in vital signs
x
Change in physical examination 
x
Vector shedding
x
Liver function tests (LFTs, including ALT, AST, GGT, LDH, bilirubin, alkaline 
phosphatase)
x
Immune response to FVIII transgene and AAV capsid proteins
No major toxicity is expected based on preclinical studies in mice and monkeys. Each subject will 
have comprehensive surveillance monitoring of LFTs (at local labs, once per week for Weeks 
1-36, then once every 2 weeks from Week 37-52) during Year 1. LFTs will be monitored every 
4 weeks during Year 2, and then every 6 weeks for Years 3-5 post-dose in the safety extension; the 
frequency and duration of LFT testing may be changed based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the 
study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration.
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Subjects will be 
asked to keep a subject diary to record the details in these areas.  
Pharmacodynamics:
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage 
APTT and/or chromogenic FXa assay (activity level), will be used for plasma profiles; FVIII 
activity will be used to determine PD parameters.  Traditional PK analysis is not applicable.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
If supported by the FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss 
(time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  
STATISTICAL METHODS: 
The sample size is based upon clinical considerations and could detect a strong clinical efficacy 
signal. Up to 15 subjects may be dosed in the study.  The subjects will be followed in a 
longitudinal manner and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature but data collected in a longitudinal manner may be analyzed using 
longitudinal methods such as mixed effect model which takes into account the correlation among 
the observation taken at various time points within a participant. Efficacy is a secondary endpoint, 
defined as biologically active FVIII at ≥5 IU/dL by chromogenic FXa assay and/or one-stage 
APTT assay at 16 weeks following study treatment. FVIII activity will be assessed weekly during
the study period.  We can only assess the true steady state of FVIII protein produced from 
BMN 270 after a minimum of 72 hours has elapsed since the last infusion of FVIII protein 
concentrates.
Analysis of neutralizing antibody response and other immunological parameters as well as vector 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses.
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3
TABLE OF CONTENTS
2 SYNOPSIS...........................................................................................................................4 
3 TABLE OF CONTENTS...................................................................................................13 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................18 
5 ETHICS..............................................................................................................................20 
5.1 Institutional Review Board or Independent Ethics Committee ................................20 
5.2 Ethical Conduct of Study..........................................................................................21 
5.3 Subject Information and Informed Consent..............................................................21 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................22 
7 INTRODUCTION .............................................................................................................23 
7.1 Nonclinical Studies ...................................................................................................23 
7.2 Previous Clinical Studies ..........................................................................................25 
7.3 Study Rationale.........................................................................................................26 
7.4 Summary of Overall Risks and Benefits...................................................................28 
8 STUDY OBJECTIVES......................................................................................................30 
9 INVESTIGATIONAL PLAN............................................................................................31 
9.1 Overall Study Design and Plan.................................................................................31 
9.2 Discussion of Study Design, Including Choice of Control Group............................43 
9.3 Selection of Study Population...................................................................................43 
9.3.1 
Inclusion Criteria.........................................................................................43 
9.3.2 
Exclusion Criteria........................................................................................44 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................45 
9.3.4 
Subject Identification and Replacement of Subjects...................................46 
9.3.5 
Duration of Subject Participation................................................................46 
9.4 Treatments.................................................................................................................46 
9.4.1 
Treatments Administered ............................................................................46 
9.4.2 
Identity of Investigational Product..............................................................47 
9.4.3 
Storage.........................................................................................................47 
9.4.4 
Directions for Administration .....................................................................47 
9.4.5 
Method of Assigning Subjects to Treatment Groups..................................48 
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9.4.6 
Selection of Doses Used in the Study .........................................................48 
9.4.7 
Blinding.......................................................................................................49 
9.4.8 
Prior and Concomitant Medications............................................................49 
9.4.9 
Treatment Compliance ................................................................................51 
9.5 Investigational Product Accountability.....................................................................51 
9.5.1 
Return and Disposition of Clinical Supplies...............................................51 
9.6 Dietary or Other Protocol Restrictions......................................................................52 
9.7 Safety and Efficacy Variables...................................................................................52 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................52 
9.7.2 
Primary Efficacy Variables .........................................................................52 
9.7.3 
Secondary Efficacy Variables .....................................................................53 
9.7.4 
Immunogenicity...........................................................................................53 
9.7.5 
Pharmacodynamics......................................................................................53 
9.7.6 
Exploratory Assessments ............................................................................54 
9.7.7 
Haemo-QoL-A Quality of Life Assessment................................................54 
9.7.8 
Safety Variables ..........................................................................................54 
10 REPORTING ADVERSE EVENTS .................................................................................60 
10.1 Safety Parameters and Definitions............................................................................60 
10.1.1 Adverse Events............................................................................................60 
10.2 Serious Adverse Events ............................................................................................61 
10.2.1 Events of Special Interest (EOSI) ...............................................................61 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters.....................61 
10.3.1 Adverse Event Reporting Period.................................................................61 
10.3.2 Eliciting Adverse Events.............................................................................62 
10.3.3 Assessment of Seriousness, Severity, and Causality...................................62 
10.4 Procedures for Recording Adverse Events ...............................................................65 
10.4.1 Recording Adverse Events on a eCRF........................................................65 
10.5 Reporting Requirements ...........................................................................................68 
10.5.1 Expedited Reporting Requirements.............................................................68 
10.5.2 Ethics Committee Reporting Requirements................................................69 
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10.6 Follow-up of Subjects after Adverse Events.............................................................69 
10.7 Post-Study Adverse Events.......................................................................................69 
10.8 Urgent Safety Measures............................................................................................69 
10.9 BioMarin Pharmacovigilance Contact Information..................................................71 
11 APPROPRIATENESS OF MEASUREMENTS...............................................................72 
12 STUDY PROCEDURES ...................................................................................................73 
12.1 Prestudy.....................................................................................................................73 
12.2 Screening Visit..........................................................................................................73 
12.2.1 “Smart Rescreening” Visit ..........................................................................74 
12.3 Baseline Visit............................................................................................................75 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1)....................................................75 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................76 
12.5.1 Once per week (Weeks 1 through 16).........................................................76 
12.5.2 Week 1 – Day 2 and Day 4..........................................................................77 
12.5.3 Week 1 – Day 8...........................................................................................77 
12.5.4 Every 2 Weeks.............................................................................................78 
12.5.5 Weeks 4, 8, 12, and 16 ................................................................................78 
12.5.6 Week 16.......................................................................................................78 
12.5.7 Weeks 8 and 16 ...........................................................................................78 
12.5.8 Weeks 2, 3, 4, and 16 ..................................................................................78 
12.5.9 Week 13.......................................................................................................79 
12.6 Safety Follow-Up – Weeks 17-36.............................................................................79 
12.6.1 Once per week (Weeks 17 through 36).......................................................79 
12.6.2 Once per week (Weeks 17 through 20).......................................................80 
12.6.3 Every 2 weeks (Weeks 21 through 36) .......................................................80 
12.6.4 Every 4 Weeks.............................................................................................80 
12.6.5 Every 8 Weeks.............................................................................................80 
12.6.6 Week 26.......................................................................................................80 
12.6.7 Week 28.......................................................................................................81 
12.7 Safety Follow-Up – Weeks 37-52.............................................................................81 
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12.7.1 Once per visit...............................................................................................81 
12.7.2 Every 4 Weeks.............................................................................................82 
12.7.3 Every 8 Weeks.............................................................................................82 
12.7.4 Week 38 and 52...........................................................................................82 
12.7.5 Week 52.......................................................................................................82 
12.8 Safety Follow-Up – Years 2-5 ..................................................................................83 
12.8.1 Year 2 – Every 4 Weeks..............................................................................83 
12.8.2 Years 3-5 – Every 6 Weeks.........................................................................84 
12.8.3 Years 2-5 – Every 3 Months........................................................................85 
12.8.4 Years 2-5 – Every 6 Months........................................................................85 
12.8.5 Years 2-5 – Every 4 Weeks.........................................................................85 
12.9 Early Termination Visit ............................................................................................85 
12.10 End of Study .............................................................................................................87 
13 DATA QUALITY ASSURANCE.....................................................................................88 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE..................89 
14.1 Statistical and Analytical Plans.................................................................................89 
14.1.1 Interim Analyses..........................................................................................89 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data..........89 
14.2 Missing data will not be imputed..............................................................................89 
14.3 Primary and Secondary Efficacy Analysis................................................................89 
14.4 Immunogenicity ........................................................................................................89 
14.5 Pharmacodynamic Analyses .....................................................................................89 
14.6 Safety Analysis .........................................................................................................90 
14.7 Determination of Sample Size ..................................................................................90 
14.8 Analysis Populations.................................................................................................90 
14.9 Changes in the Conduct of the Study or Planned Analyses......................................91 
15 DATA REVIEW BOARD.................................................................................................92 
16 COMPENSATION, INSURANCE AND INDEMNITY..................................................93 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS..............................................94 
18 STUDY MONITORING AND AUDITING .....................................................................96 
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19 RETENTION OF RECORDS ...........................................................................................97 
20 USE OF INFORMATION AND PUBLICATION ...........................................................98 
21 REFERENCES ..................................................................................................................99 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................102 
22.1 Conduct of Study and Protection of Human Patients .............................................102 
23 SIGNATURE PAGE .......................................................................................................103 
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................104 
LIST OF TABLES
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................34 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16)............................36 
Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) .....................................38 
Table 9.1.4:  Schedule of Events – Safety Follow-Up.............................................................40 
Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids.............................................42 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................56 
Table 9.7.8.3.1:  Liver Function Tests.....................................................................................57 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale....................................................63 
Table 10.3.3.3.1:  Causality Attribution Guidance..................................................................64 
LIST OF FIGURES
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic .............................................................28 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3...............................32 
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
AAV
adeno-associated virus
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
ALT
alanine transaminase
APTT
activated partial thromboplastin time
BPV
BioMarin Pharmacovigilance
BU
Bethesda Unit
CFR
Code of Federal Regulations
CRA
clinical research associate
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DRB
Data Review Board
eCRF
electronic case report form
ED
exposure days
EOSI
events of special interest
ETV
early termination visit
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
first-in-human
FVIII
coagulation factor VIII
FXa
coagulation factor Xa
GCP
Good Clinical Practice
HA
Haemophilia A
hFVIII
human coagulation factor VIII
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6
IEC
independent ethics committee
IND
Investigational New Drug (application)
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INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect level
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamics
PEG
polyethylene glycol
PK
Pharmacokinetics
PRO
patient-reported outcome
rhFVIII
recombinant human FVIII protein
REB
research ethics board
SAE
serious adverse event
SAP
statistical analysis plan
SDV
source data verification
ULN
upper limit of normal
vg
vector genomes
VWF:Ag
von Willebrand factor Antigen
Definition of Terms: 
Investigational Product (IP):
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]). 
The terms “IP” and “study drug” may be used interchangeably in the protocol.
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5
ETHICS
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards.
5.1
Institutional Review Board or Independent Ethics Committee
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries.
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin or its designee. The Investigator will provide the IRB/IEC/REB 
with all appropriate material, including the protocol, Investigator’s Brochure (IB), the 
Informed Consent Form (ICF) including compensation procedures, and any other written 
information provided to the subjects, including all ICFs translated to a language other than 
the native language of the clinical site. The study will not be initiated and Investigational 
Product (IP) supplies will not be shipped to the site until appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol, the ICF and all subject 
recruitment materials are obtained in writing by the Investigator and copies are received at 
BioMarin or its designee. The approval document should refer to the study by protocol title 
and BioMarin protocol number (if possible), identify the documents reviewed, and include 
the date of the review and approval. BioMarin will ensure that the appropriate reports on the 
progress of the study are made to the IRB/IEC/REB and BioMarin by the Investigator in 
accordance with applicable guidance documents and governmental regulations.
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5.2
Ethical Conduct of Study
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability.
This study will be conducted in accordance with the following:
x
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country
x
US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable
x
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6)
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the subjects will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF, and if applicable, a 
copy of the approved subject information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed.
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject.
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6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate.
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of subjects in this study.
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required.
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR.
Liver function tests (LFTs) will be performed at the local laboratories associated with the 
study sites.  Local laboratory results of LFTs will be used to trigger corticosteroid treatment 
as needed (refer to Section 9.4.8.2).  In case of discrepant results between local and central 
laboratories, the Investigator and Medical Monitor will decide further action.  Safety labs 
evaluations (including LFTs) will be performed at the central lab, while bioanalytical 
samples will be performed at the appropriate specialty lab.  Refer to the Laboratory Manual 
for more details.
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7
INTRODUCTION
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.).
Chemical modification or bioengineering of FVIII may improve half-life to 18-19 hours 
(Kaufman, 2013, Blood). However, these long acting FVIII variants do not eliminate the
need for lifelong FVIII protein administration (Hay, 2012, Blood).  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of human FVIII following a single administration of vector. Haemophilia A is
well suited for this approach because its clinical manifestations are attributable to the lack of
a single gene product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. 
Tightly regulated control of gene expression is not essential and a modest increase in the 
level of FVIII (a plasma level of 2 ng/ml protein leads to a 1% expression) can ameliorate the 
severe phenotype (Srivastava, 2013, Haemophilia.); thus the therapeutic goal for gene
therapy is a modest increase in hFVIII. Finally, the consequences of gene transfer can be
assessed using simple quantitative rather than qualitative endpoints that can be easily assayed 
in most clinical laboratories.
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study.
7.1
Nonclinical Studies
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 
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nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints. 
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in FVIII KO x Rag2 mice given matched IU 
levels of Refacto®.   
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.   
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed. 
The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 
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the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence closely matching that of 
the protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Nathwani, 2006, Blood). Despite 
distribution to non-liver organs, no expression of Factor IX was detected in these tissues.  
Additionally, distribution to the testis was observed in another study in monkeys given an 
AAV5-codon-optimized human porphobilinogen deaminase; however, vector genomes in the 
semen were only transiently observed within one week but not thereafter (Paneda, 2013, 
Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents 10-fold safety factor from the 
no observed adverse effect level (NOAEL) in the GLP enabling nonclinical toxicology study 
in mice. 
7.2
Previous Clinical Studies
This is the first clinical study for BMN 270.
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Engl.J.Med.),
(Nathwani, 2014, N.Engl.J.Med.). The large size of the FVIII cDNA was shortened and a
preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013, 
Blood).
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AAV serotype 5 is being tested in other clinical trials and was reportedly well tolerated 
without treatment-related serious adverse events in a recent phase 1 study for treatment of 
Acute Intermittent Porphyria (D'Avola, 2014, J.Hepatol.). In addition, AAV using other 
serotypes have been used in 105 clinical studies to date and no safety issue specific to the 
vector was ever reported.  
7.3
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Mannucci, 2001, N.Engl.J.Med.).  It is caused by deficiency in the activity 
of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic coagulation cascade. 
This disorder can be either inherited, due to a new mutation or an acquired immunologic 
process, leading to insufficient quantities of FVIII or a dysfunctional FVIII, but all are 
characterized by a defective coagulation process. The clinical phenotype of HA patients is 
largely governed by the level of residual expression. Severe HA is classified as FVIII activity 
less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild type activity 
and the mild form is 5-40% activity. The clinical manifestations of severe HA remain 
frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-4 times per
week, and at the time of a bleed, to prevent or control bleeding episodes, respectively. The 
half-life for FVIII (12-18 hours for most approved products) necessitates frequent infusions, 
and although a major advance in the treatment of HA, it remains common for severe HA
patients to continue to have multiple bleeding events on treatment (mean of 
1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year for on demand 
treatment) (Nagel, 2011, Haemophilia.).  The consequence of multiple bleeding events is the
development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death (Nagel, 2011, Haemophilia).  Chemical 
modification (e.g. direct conjugation of polyethylene glycol (PEG) polymers) and
bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by approximately
50%, and thus, show promise in reduced dosing and maintaining activity levels above 1%
trough (Stonebraker, 2010, Haemophilia.), (Mahlangu, 2014, Blood). However, these longer
acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive 
treatment of HA to give patients a FVIII level compatible with a normal and
haemorrhage-free life.
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Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but
adeno-associated viral (AAV) vectors show the greatest promise (Mannucci, 2001, 
N.Engl.J.Med.). They have an excellent and well defined safety profile, and can direct long
term transgene expression with tropism for specific tissues such as the liver (Nathwani, 2005, 
Curr.Hematol.Rep.) for serotypes 2, 5 and 8 among others). Indeed, an on-going gene
therapy clinical trial for a related disorder, haemophilia B, has established that stable
(>36 months) expression of human factor IX at levels that are sufficient for conversion of 
their bleeding phenotype from severe to moderate or mild is achievable following a single 
peripheral vein administration of AAV-8 vector (Nathwani, 2014, N.Engl.J.Med.).  Several
participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in 
bleeding. Thus, gene therapy treatment has resulted in a substantial improvement in their
quality of life (Nathwani, 2011, Mol.Ther.), (Bainbridge, 2008, N.Engl.J.Med.), (Maguire, 
2009, Lancet); (Simonelli, 2010, Mol.Ther.).
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a liver-selective promoter (Figure 7.3.1). 
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Figure 7.3.1: hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active FVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of FVIII in patients with severe 
HA.
7.4
Summary of Overall Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based 
on prior human studies with peripheral injections of AAV vectors, there is no known safety 
risk of AAV gene therapy. However, a mild asymptomatic transaminitis was observed at 
week 7-12 after administration in humans with an AAV8-FIX, providing the rationale for the 
following surveillance plan (Nathwani, 2011, Mol.Ther.). Each subject will have a 
comprehensive surveillance plan that monitors LFTs during the study. 
For additional information on safety findings in 270-201, refer to current version of the 
Investigator’s Brochure.
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose 
that maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the 
possibility of a sub-therapeutic effect. With this consideration in mind, the starting dose 
6E12 vg/kg was selected using overall data from the pre-clinical studies conducted in mice 
(normal and disease model, Rag2 -/- x FVIII -/-) and monkey. A detectable pharmacological 
response based on activity was observed at 6E12 vg/kg. A 10-fold safety margin based upon 
the NOAEL was observed in the GLP 13-week study in normal mouse at the highest dose 
administered. A 30-fold safety margin in an 8-week dose response study in disease model 
mice based on histology was observed at the highest dose administered. No BMN 270-related 
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changes in clinical observations or chemistry was observed in the monkey at doses up to 
6E13 vg/kg, a 10-fold safety margin after 8-weeks. Overall, no BMN 270-related findings, 
except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model 
mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to subjects with the best chance of 
benefiting the subject therapeutically.
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8
STUDY OBJECTIVES
The primary objectives of the study are:
x
To assess the safety of a single intravenous administration of a recombinant AAV5
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.
x
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals
with haemophilia A will be determined and correlated to an appropriate BMN 270
dose.
The secondary objectives of the study are:
x
To describe the immune response to the hFVIII transgene product and AAV capsid
proteins following systemic administration of AAV5-hFVIII-SQ
x
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy
during the study
x
To assess the impact of BMN 270 on the number of bleeding episodes requiring
treatment during the study
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled into one of up to four cohorts according to dose level:  
x
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single
intravenous dose (iv)
x
Cohort 2:  2E13 vg per kilogram, iv
x
Cohort 3:  6E13 vg per kilogram, iv
x
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys.  The starting dose has a 10-fold safety margin from no 
observed adverse effect level (NOAEL) in mice. 
Cohorts 1-3
The first three cohorts will be enrolled sequentially, allowing a period of 3 weeks or more 
between cohorts. Dose escalation may occur after a single subject in a cohort has been safely 
dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both assays. 
Three weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic 
doses.  The decision to escalate to the next dose level will be made based on the review of 
safety parameters and FVIII activity by the Sponsor and a panel of investigators participating 
in the study.    
If the FVIII activity reaches ≥5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3 
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg).
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject. 
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in the Cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the Data Review Board (DRB). The adaptive nature of this trial allows the DRB 
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to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals.
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity 
for therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dosing. Any safety signal 
may trigger a review of the data and possible additional immunogenicity studies that include 
an assessment of cellular immune responses using collected PBMC. Additionally, if any of 
the events listed in Section 9.3.3.1 occur, enrollment into the trial will be halted to complete 
an extensive safety analysis. Notification of the study enrollment halt will be sent by the 
Sponsor to the participating sites via telephone and email immediately after becoming aware 
of a safety concern. This will ensure no additional subjects are dosed until the signal has been 
completely evaluated. If, following safety review by the DRB and the Sponsor, it is deemed 
appropriate to restart dosing, a request to restart dosing with pertinent data will be submitted 
to the health authority. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 and Table 9.1.4 for Safety Follow-up. 
Table 9.1.5, dealing with therapeutic corticosteroid use in the event of elevated LFTs, is 
discussed in Section 9.4.8.2.
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Table 9.1.1: Schedule of Events – Screening and Infusion
Assessment
Prior to BMN 270 Infusion
BMN 270 
Infusion 
Visit (Day 1)k
Screeningi
(Day -28 to Day -1)
Smart Rescreeningi
(Day -28 to Day -1)
Baseline (Day -7
to Day -1)h
Informed consent
X
Medical History
X
Physical Examinationa
X
X
X
Height and Weighta
X
Vital Signs
X
X
X
Assessment of Adverse Events and Concomitant Medications
X
X
X
X
Documentation of bleeding episodes and FVIII usage (by either subject or 
clinical information)
X
X
X
Distribution of subject diaries and training in their use
X
Electrocardiogram
X
Chest X-ray
X
Liver Ultrasound
X
hFVIII Assaysb
X
Xj
AAV5 Assaysc
X
X
X
Screen for Hepatitis B, Hepatitis C, HIVd
X
Blood chemistry, haematology, coagulation screen, and CRPe
X
X
X
Urine Testse
X
X
X
Liver Function Testse
X
X
X
PBMC collection for CTL baseline
X
Von Willebrand Factor Antigen (VWF:Ag)
X
Direct Thrombin Test
X
PCR of vector DNA in blood, saliva, urine, semen, and stools
X
Biomarker testingf
X
Exploratory biomarker assessmentsg
X
Haemo-QoL-A Quality of Life (QoL) assessment
X
BMN 270 Infusion
X
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a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height will be recorded at 
Screening only.  Weight will be recorded at Screening and then every 6 months thereafter.
b Includes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).  
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction inhibition, in vitro 
transduction inhibition and AAV5 total antibody assays).  Sample collection on the day of the infusion visit must be performed before the BMN 270 infusion is given.
d Patients with documented negative results within the last 30 days do not need to be retested.
e Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.
f Includes HLA genotyping, FVIII genotyping, TNFD and IL10a single nucleotide polymorphisms.
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the 
Sponsor.
h Should the screening visit occur within 7 days of the drug infusion, physical examination, blood chemistry, LFTs, haematology, urine tests, coagulation screen, and CRP do not need to be 
repeated at Baseline.
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion prior to the closing 
of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion within 90 days of signing the original 
consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures.  Subjects may not undergo smart rescreening more than 
once.
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening.
k Assessments on the day of infusion must be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, during the infusion 
every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) 
Assessment
Follow-Up After BMN 270 Administration – Weeks*
Week 1
2 
3 
4 
5 
6 
7 
8 
9 
10
11
12
13
14
15
16
D2
D4
D8
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary 
for bleeding and FVIII use)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation 
screen, and CRPb
X
X
X
X
X
X
X
Urine Testsb
X 
X 
X 
X 
Liver Function Tests (local)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests (central)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer
X 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolse
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
X 
X 
X 
X 
AAV5 antibody titer
X
X
Testing for reactivation of hepatitis B and 
hepatitis C
Xg
PBMC collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
Direct Thrombin test
X 
X 
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* Visit windows are ± 48 hours (and include the Day 4 visit)
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data.  Patients with ALT > 1.5 ULN during the study may 
undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator.
c Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks 
after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII 
activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are 
above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection to occur on Day 2 and 4 following BMN 270 infusion, and then until at least 3 consecutive negative results are obtained.  Collection and testing of semen samples must continue 
through Week 12, even if 3 consecutive negative samples in that compartment have already been recorded.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the 
Sponsor. 
g Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of Hepatitis B or Hepatitis C prior to study entry, should be performed only in 
subjects who have not received therapeutic corticosteroids prior to Week 16; subjects who have received therapeutic corticosteroids will have hepatitis B and hepatitis C testing at the time 
points indicated in Table 9.1.5. 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) 
Assessment
Follow-Up After BMN 270 Administration – Weeks*
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary for 
bleeding and FVIII use)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, 
and CRPb
X
X
X
X
Urine Testsb
X 
X 
X 
X 
Liver Function Tests (local)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests (central)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, 
and stoolse
X 
X 
X 
X 
Exploratory biomarker assessmentsf
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
AAV5 antibody titer
X
X
X
X
PBMC collection 
X
X
X
X
X
X
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
Direct Thrombin test
X
* Visit windows are ± 48 hours
a Brief physical examination should be done at all weekly visits.  Refer to Section 9.7.8.5.
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b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data. Patients with ALT > 1.5 ULN during the study may 
undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator.
c Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks 
after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII
activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are 
above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection to occur until at least 3 consecutive negative results are obtained.
f Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the 
Sponsor. 
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Table 9.1.4:  Schedule of Events – Safety Follow-Up
Assessment
Year 1 – Weeks*
Years
2-5*
Year 
2*
Years 
3-5*
ETV
33
34
35
36
38
40
42
44
46
48
50
52
Q3M
Q4W
Q6W
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weighta
X
Xa
Assessment of Adverse Events and Concomitant 
Medications (including review of subject diary for 
bleeding and FVIII use)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, and 
CRPb
X 
X 
X 
X 
X 
X 
X 
Urine Testsb
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests (local)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests (central)b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AAV5 antibody titer
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer
X 
X 
X 
X 
X 
PBMC Collection (for determination of FVIII and 
Capsid specific CTL activity)
X 
X 
X 
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag)
X 
X 
X 
X 
X 
X 
X 
Direct Thrombin Test
X
X
X
X
PCR of vector DNA in blood, saliva, urine, semen, and 
stoolse
X 
X 
X 
X 
X 
Xe
X 
Exploratory biomarker assessmentsg
X 
X 
X 
X 
X 
X 
X 
X 
Haemo-QoL-A QoL assessment
X 
Xf
X 
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* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52 and ± 2 weeks for visits in Years 2-5. For LFT, FVIII, and exploratory biomarker testing during Years 2-5, the
visit windows are every 4 weeks (+ 2 weeks) during Year 2, and every 6 weeks (±2 weeks) during Years 3-5.
a Complete physical examination should be performed at Week 52 and every 52 weeks thereafter; brief physical examination may be performed at other study visits.  Refer to Section
9.7.8.5.  During Years 2-5, weight should be performed every 6 months.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data. Patients with ALT > 1.5 ULN during the study may 
undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator.
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks 
after BMN 270 infusion and who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII 
activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are 
above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when 
a 72 hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen modification) in years 3-5, a fresh sample 
should be collected within 4 weeks of the initial visit that had a positive result.
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.  Subjects who have not had 3 consecutive 
negative samples by Week 52 should continue to have PCR testing every 4 weeks until 3 consecutive negative samples are documented (or upon consultation between the Investigator and 
Medical Monitor).
f Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 6 months) starting with the Week 78 visit (ie, 26 weeks after the 
Week 52 visit at the end of Year 1 of the Safety Follow-up period).
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the 
Sponsor. 
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Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids
Steroid Treatment Periodd
Post-Steroid Periodc
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11b
Week 
1
Week 
2
Week 
3
Week 
4
Week 
13
Therapeutic 
corticosteroids 
(dose in 
mg/day) a
60 mg
60 mg
40 mg
40 mg
30 mg
30 mg
20 mg
20 mg
15 mg
10 mg
5 mg
FVIII activity 
testing
X 
X 
X 
X 
Liver function 
testing
X 
X 
X 
X 
Hepatitis B 
testinge
X
X
X
HCV Viral 
Loade
X 
X 
X 
a Therapeutic corticosteroids may be initiated when a subject’s ALT value is ≥ 1.5x ULN or based on review of FVIII and liver enzyme data after consultation between the Investigator and 
the Medical Monitor.
b Following initiation or completion of steroid regimen, if ALT elevation  ≥ 1.5x ULN is reported, steroid management decisions will based on discussions between the Investigator and 
Medical Monitor.  Modification of the steroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression.
c After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values. If these assessments are already 
being done as part of normal study follow-up, they do not need to be duplicated.
d Regardless of the assessments listed in the Schedule of Assessments (Table 9.1.2, Table 9.1.3, or Table 9.1.4), subjects initiated on corticosteroids will only be required to have laboratory 
evaluations on a weekly basis.
e Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry.
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9.2
Discussion of Study Design, Including Choice of Control Group
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Four doses of BMN 270 will be evaluated and the dose 
escalation decision tree for Cohorts 1-3 is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and the DRB. 
There will be no control group. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy). 
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3
Selection of Study Population 
Up to 15 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation.  
Additional criteria for participation in the study are provided in Section 9.3.1
and Section 9.3.2.
9.3.1
Inclusion Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
1. Males that are 18 years or older with established severe Haemophilia A as evidenced
by their medical history.  Patients will be considered as severe if their base FVIII
level is 1 IU/dL or less
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of
150 exposure days (EDs)
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the
previous 12 months.  Does not apply to patients on prophylaxis
4. Able to sign informed consent and comply with requirements of the trial
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less
than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within
the past 12 months
6. Sexually active patients must be willing to use an acceptable method of contraception
such as double barrier, including hormonal contraception for at least 6 months
post-treatment.  After 6 months, subjects may stop contraception use only if they have
had 3 consecutive negative semen samples.
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9.3.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5
transduction inhibition or AAV5 total antibodies
2. Any evidence of active infection or any immunosuppressive disorder.
3. HIV positive
4. Significant liver dysfunction as defined by abnormal elevation of:
x
ALT (alanine transaminase) to 3 times the upper limit of normal;
x
Bilirubin above 3 times the upper limit of normal;
x
Alkaline phosphatase above 3 times the upper limit of normal; or
x
INR (international normalized ratio) ≥ 1.4.
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if
they had significant fibrosis of 3 or 4 as rated on a scale of 0-4
6. Evidence of any bleeding disorder not related to Haemophilia A
7. Platelet count of < 100 x 109/L
8. Creatinine ≥ 1.5 mg/dL
9. Liver cirrhosis of any etiology as assessed by liver ultrasound
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive
12. Treatment with any IP within 30 days prior to the end of the screening period
13. Any disease or condition at the physician’s discretion that would prevent the patient
from fully complying with the requirements of the study including possible
corticosteroid treatment outlined in the protocol.  The physician may exclude patients
unwilling or unable to agree on not using alcohol for the 16-week period following
the viral infusion.
14. Prior treatment with any gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion
16. Use of immunosuppressive agents or live vaccines within 30 days before the viral
infusion
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9.3.3
Removal of Subjects from Treatment or Assessment
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 
BioMarin must be notified of all subject withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following: 
x
Subject requires medication or medical procedure prohibited by the protocol
x
Subject does not adhere to study requirements specified in the protocol
x
Subject was erroneously admitted into the study or does not meet entry criteria
x
Subject is lost to follow-up
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study.
9.3.3.1
Study Safety Evaluation Criteria
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis 
per Section 9.1.
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x
Any ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of
BMN 270, in the absence of a definitive alternate etiology for the increase
x
The occurrence of Grade 3 or higher adverse events (excluding ALT elevation)
assessed as related to study drug, including liver failure and clinical hepatitis
x
The detection of neutralizing antibodies to hFVIII following BMN 270 infusion
x
The detection of AAV vector DNA in the semen of a participant in 3 consecutive
samples (which are at least 2 weeks apart) more than 52 weeks after BMN 270
infusion, as discussed in Section 9.7.8.6
x
The occurrence of a malignancy excluding skin cancers at any point after BMN 270
infusion
If the following event occurs in a subject in the study who has received BMN 270 infusion, a 
DRB review and analysis of safety data will be undertaken to determine whether the 
enrollment into the trial will be put on halt:
x
Grade 2 adverse event assessed as related to study drug that persists for at least 7 days
9.3.4
Subject Identification and Replacement of Subjects
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Subjects who withdraw from the study will not be replaced. 
9.3.5
Duration of Subject Participation
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks.
9.4
Treatments
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1
Treatments Administered
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
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9.4.2
Identity of Investigational Product 
9.4.2.1
Product Characteristics and Labeling
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
9.4.3
Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 
stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4
Directions for Administration
After a physical examination performed by the PI or designee, participants will be admitted 
on the day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral 
vein (e.g. the median cubital vein) and flushed with saline. FVIII replacement therapy will 
not be given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 ml/min while monitoring the vital signs (pulse, blood pressure, respiration 
rate and temperature) at 15 minute (± 5 minutes) intervals. The anticipated maximum 
interval from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, 
although the IP has been shown to be stable at room temperature for 6 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis
at the puncture site will be established by applying pressure according to standard
protocol for infusing FVIII concentrates. Subjects will remain in the clinic for 24 hours to
observe for any immediate toxicity of the procedure. After 24 hours, participants will be 
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discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical
Monitor. 
9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study subject. Upon their enrollment into the study, subjects will be assigned a unique subject 
number and dose level by the Sponsor.
Cohorts 1 to 3 are enrolled serially and their dose is defined in Section 9.4.6.2 below. 
Escalation is based on FVIII activity 3 weeks after injection. Cohorts may receive the next 
higher dose if subjects in the previous cohort does not meet the activity criteria, or the same 
dose if subjects in the previous cohort meets the activity criteria. Subjects in Cohort 4 will all 
be enrolled at a single dose.
9.4.6
Selection of Doses Used in the Study
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in mice. The dose escalation is half-logs based.    
9.4.6.1
Selection of Timing of Dose for Each Subject
A minimum of three weeks are required between subjects, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next subject will be made as described below.  
9.4.6.2
Selection of Dose for Each Subject
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus potentially decreasing the risk of immune response), and a new 
evaluation of the titer (PCR performed after hairpin removal). 
For Cohorts 1 to 3, approximately three weeks after an injection, the decision to escalate to 
the next dose level will be made based on the review of safety parameters and FVIII activity 
by the Sponsor and the DRB.  
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)
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at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject. 
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in that cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB.  The adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals.
Refer to Figure 9.1.1 for a visual representation of the study design for Cohorts 1-3 
9.4.7
Blinding
This is an open-label study.
9.4.8
Prior and Concomitant Medications
All prescription and over-the-counter medications (including dietary and herbal supplements) 
taken by a subject for 30 days before Screening will be recorded on the designated CRF. The 
Investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF.
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The following medications are prohibited starting 30 days before Screening: 
x
Live vaccines
x
Systemic immunosuppressive agents
Medications which are predominately metabolized by the liver (e.g., acetaminophen) and 
alcohol should, whenever possible, be avoided for the first 52 weeks of the study, and 
particularly within 48 hours prior to lab work. 
9.4.8.1
Concomitant Haemophilia Treatments 
Subjects on “on demand” therapy for FVIII will continue their treatment at will.  Subjects on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and 
switch to an “on demand” schedule. FVIII can always be taken as needed by the subject, who 
will carefully record his treatment and bleeding episodes in his diary.  In addition, 
information on FVIII usage by medical history will be collected (if available) from subjects 
for the 6 month period immediately preceding study enrollment. 
9.4.8.2
Glucocorticoid Treatment of Elevated Hepatic Transaminases
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject 
will have comprehensive surveillance plan monitoring of LFTs (at local labs, once per week 
for Weeks 1-36, then once every 2 weeks from Week 37-52).  LFTs may be monitored more 
or less frequently (and in particular when ALT values are >1.5x ULN) based on discussion 
between the Medical Monitor and the Investigator and review of subject data. 
9.4.8.2.1
Therapeutic Corticosteroids
In general, therapeutic corticosteroids may be initiated when a subject’s ALT value is 
≥ 1.5x ULN, or based on review of FVIII and liver enzyme data after consultation between 
the Medical Monitor and the Investigator.   
Reports of raised LFTs (defined as ALT ≥ 1.5x ULN) should be made to the BioMarin 
medical monitor within 30 minutes of the lab value being available.  Local laboratory results 
of LFTs will be used to trigger corticosteroid treatment as needed.  In case of discrepant 
results between local and central laboratories, the Investigator and Medical Monitor will 
decide further action.
Following initiation or completion of therapeutic corticosteroids, if ALT elevation 
≥ 1.5x ULN is reported, steroid management decisions will based on discussions between the 
Investigator and Medical Monitor. Modification of the steroid regimen may take into 
consideration possible confounders for the ALT elevation and impact on FVIII expression.   
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Treatment with prednisolone will be initiated at a dose of 60 mg per day and then gradually 
tapered (60 mg daily for the first 2 weeks, then 40 mg the next 2 weeks, then 30 mg the next 
two weeks, then 20 mg the next two weeks, then 15 mg for the next week, then 10 mg for the 
next week, then 5 mg for the next week, then stop, for a total treatment of 11 weeks) (refer to 
Table 9.1.5). 
After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be 
measured once a week for 4 weeks to ensure stability in values.
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This 
includes the contraindicated use of NSAIDs during corticosteroid treatment, and specific 
monitoring not already covered by the schedule of events. For the subjects with a past 
medical history of hepatitis B or hepatitis C prior to study entry, Hepatitis B status and HCV 
viral load will be rechecked 6 weeks after the start of corticosteroid treatment, and then 
1 week and 13 weeks after the completion of corticosteroid treatment. All adverse events 
should be reported as outlined in Section 10 of the protocol. 
9.4.9
Treatment Compliance
Study drug will be administered to subjects at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided 
for the study.  Sites will be instructed to return or destroy all used and unused study drug 
containers.
9.5
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data.
9.5.1
Return and Disposition of Clinical Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials.
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
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and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a study drug return form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6
Dietary or Other Protocol Restrictions
There are no dietary or other protocol restrictions for this study. 
9.7
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8.
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post
BMN 270 administration. 
9.7.1
Safety and Efficacy Measurements Assessed
The Schedule of Events (Table 9.1.1 through Table 9.1.4) describes the timing of required 
evaluations.
9.7.2
Primary Efficacy Variables
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to expression of FVIII at 5 IU/dL or above, 
i.e., a mild severity. This is associated in natural history studies with clinically superior long
term outcomes (Den Ujil, 2011, Haemophilia). 
The following assays (assessed by the central laboratory) will be used to measure the primary 
efficacy variable:
x
FVIII activity (chromogenic FXa assay)
x
FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time)
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made 
to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 
The 72-hour wash-out period is only intended for subjects who have achieved FVIII 
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≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care 
FVIII replacement therapy.
The FVIII activity level in both assays and the number of subjects with FVIII activity 
≥ 5 IU/dL in at least one of the two assays will be summarized.
FVIII activity assays will also be performed at the local laboratory at the time points 
indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4, but will be used in conjunction with 
local lab LFT assessments to monitor subject safety and need for initiation of therapeutic 
corticosteroid dosing; local laboratory FVIII activity assessments will not be used to assess 
efficacy or to measure the primary efficacy outcome of the study.
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.  Details on performing the assays are included in the Laboratory Manual. 
9.7.3
Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Subjects will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the subject’s diary or 
other subject records. 
9.7.4
Immunogenicity
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
5-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to a retrospective immunogenicity assessment to determine 
anti-FVIII and capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be 
performed on collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.
9.7.5
Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage APTT and/or chromogenic FXa assay (activity).  Individual antigen and activity 
plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity measurements 
will be used to determine PD parameters.
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If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration),
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology.
Sample collection times are indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4.
9.7.6
Exploratory Assessments 
Blood samples will be collected at the time points indicated in Table 9.1.1, Table 9.1.2,
Table 9.1.3, and Table 9.1.4 to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations.  Subjects may choose to opt out of the 
exploratory genetic/genomic research being done to study or try to discover genes that are 
not yet known to be associated with hemophilia A.  
All biomarker samples collected in this study may be used for exploratory biomarker 
research including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes may be used for exploratory use once the 
primary use has been completed.
On an exploratory basis, samples may be fractionated prior to shedding analysis in order to 
better characterize the presence and location of vector DNA and/or vector capsid within each 
matrix. The fractionation may be performed with samples collected specifically for shedding 
analysis (saliva, blood, semen, urine, faeces), or by using exploratory samples, such as 
plasma, PBMCs, and red blood cells, collected under the study protocol.  
9.7.7
Haemo-QoL-A Quality of Life Assessment
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to 
assess subject quality of life (QoL) during the study.  Assessments will occur at the time 
points listed in the Schedules of Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual.
9.7.8
Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
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9.7.8.1
Adverse Events
The occurrence of AEs will be assessed continuously from the time the subject signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1,
Table 9.1.2, Table 9.1.3, and Table 9.1.4. 
9.7.8.2
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, and Table 9.1.4. The scheduled clinical laboratory tests 
are listed in Table 9.7.8.2.1. Refer to the Study Reference Manual for instructions on 
obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant.
All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF.
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Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry
Haematology
Urine Tests
Other
Albumin
Haemoglobin 
Appearance
CRP
BUN
Haematocrit 
Color
Calcium
WBC count
pH
Coagulation Screen
including:
Chloride
RBC count
Specific gravity
APTT
Total cholesterol
Platelet count
Ketones
PT/INR
CO2
Differential cell count 
Protein 
TT
CPK
Glucose 
Creatinine
Bilirubin
Glucose 
Nitrite
Phosphorus
Urobilinogen
Potassium
Haemoglobin
Total protein
Sodium
Uric Acid
BUN, blood urea nitrogen; CO2, carbon dioxide; CRP, C-reactive protein; PT, prothrombin time; APTT, activated partial 
thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; INR, international normalized ratio.
9.7.8.3
Liver Function and Hepatitis Testing
Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening.   Subjects with documented results showing an absence of active hepatitis B or 
hepatitis C infection (as measured by positive surface antigen for hepatitis B or positive RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to be 
screened again.  
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects who have 
cleared a hepatitis B infection or are seronegative do not need to receive the hepatitis B 
vaccination.  
Subjects with a history of hepatitis B or hepatitis C infection prior to study entry will be 
tested for hepatitis B and hepatitis C reactivation at Week 16. Subjects who receive 
therapeutic corticosteroids prior to Week 16 do not need to complete the Week 16 
reactivation assessment; instead, they will be tested for hepatitis B and hepatitis C 
reactivation at the time points listed in Table 9.1.5.
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A liver ultrasound and liver function testing at Screening will identify any significant hepatic 
dysfunction, which is defined as: 
x
More than 3x the normal ALT level
x
More than 3x the normal bilirubin level
x
More than 3x the normal Alkaline phosphatase level.
x
INR > 1.4.
x
Thrombocytopoenia under 100 x 109/L
x
Liver ultrasound results indicative of a liver cirrhosis
Liver function tests will be monitored on a regular basis, at the time points indicated in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, and Table 9.1.4.  At each time point, the following 
LFTs should be assessed: 
Table 9.7.8.3.1:  Liver Function Tests
Liver Function Tests
Alkaline Phosphatase
AST (SGOT)
Total Bilirubin
LDH
ALT (SGPT)
Direct Bilirubin
GGT
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, lactate 
dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase
Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (e.g., 
imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at 
the discretion of the investigator. 
9.7.8.4
HIV Testing
HIV testing will be performed at Screening.  Subjects with documented negative results 
within the last 30 days prior to screening do not need to be retested. 
9.7.8.5
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE.
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored prior to infusion, during the infusion every 
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15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then 
every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).  
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 
and every 52 weeks thereafter; at other visits, brief physical examinations may be performed 
at the discretion of the investigator based on the subject’s clinical condition. Particular 
attention should be given to signs of bleeding, as well as assessing possible hemarthroses.
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems. 
A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 
Height will be recorded at Screening only.  Weight will be recorded at Screening and then 
every 6 months thereafter. 
9.7.8.6
Vector Shedding
Vector shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 2007, J.Gene 
Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the literature referenced above, including 
Haemophilia B clinical studies utilizing AAV2 and AAV8, vector was no longer detectable 
after 40 days in blood, saliva, urine or stool, but in one study was detected in the seminal 
fluid but not in motile sperm (Manno, 2006, Nat.Med.).  In these studies, the amount of 
vector present in these bodily fluids involved an extremely small fraction of the infused dose.  
More recent data from an ongoing AAV-FIX study demonstrates persistence of the vector in 
both the blood and the semen for at least 39 weeks (Miesbach, 2016, Haemophilia).
During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily 
samples to look for evidence of vector shedding for possible viral transmission.  Bodily 
fluids will be tested by PCR at the time points indicated in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.  Fluids tested will include:
x
Blood
x
Saliva
x
Semen
x
Urine
x
Stool
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Vector shedding will also be extensively studied in the present clinical trial, every other week 
between Weeks 4-16, then every 4 weeks to Week 52 until at least 3 consecutive negative 
results are obtained.  Testing of semen will continue through Week 12, even if 3 consecutive 
negative results have been recorded in that compartment prior to that timepoint.  Subjects 
who have not had 3 consecutive negative samples by Week 52 should continue to have PCR 
testing every 4 weeks until 3 consecutive negative samples are documented (or upon 
consultation between the Investigator and Medical Monitor). 
Contraception use may need to be extended beyond 26 weeks in individual subjects based on 
observed vector shedding in semen.  After 6 months, subjects may stop contraception use 
only if they have had 3 consecutive negative semen samples. 
Details for sample collection and storage are provided in the Laboratory Manual. 
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10
REPORTING ADVERSE EVENTS
10.1
Safety Parameters and Definitions
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug.
10.1.1 Adverse Events
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a subject administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
x
AEs not previously observed in the subject that emerge during the course of the
study.
x
Pre-existing medical conditions judged by the Investigator to have worsened in
severity or frequency or changed in character during the study.
x
Complications that occur as a result of non-drug protocol-imposed interventions
(eg, AEs related to screening procedures).
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only 
because the subject is a haemophiliac) should not be recorded as AEs but will instead be 
captured in subject diaries.  Bleeding events that occur where a normal 
(ie, non-haemophiliac) patient would bleed, such as bleeding as a result of major trauma, 
should be recorded as adverse events.  All bleeding events which meet criteria for being 
serious should be reported as serious adverse events (SAEs) whether or not they are bleeding 
events that are normal sequelae of haemophilia.
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis.
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10.2
Serious Adverse Events
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria:
x
Is fatal
x
Is life threatening
Note: Life-threatening refers to an event that places the subject at immediate risk of
death. This definition does not include a reaction that, had it occurred in a more
severe form, might have caused death.
x
Requires or prolongs inpatient hospitalization.
x
Results in persistent or significant disability or incapacity
x
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP
prior to conception or during pregnancy
x
Is an important medical event or reaction – that, based on medical judgment, may
jeopardize the subject or require intervention to prevent one of  the above
consequences (e.g. anaphylaxis)
All adverse events that do not meet any of the criteria for SAEs should be regarded as non-
serious AEs.
10.2.1 Events of Special Interest (EOSI) 
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality: 
x
Elevation of liver enzymes (ALT) that triggers an initiation or modification of
corticosteroid treatment
10.3
Methods and Timing for Capturing and Assessing Safety Parameters
10.3.1 Adverse Event Reporting Period
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.2.
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10.3.2 Eliciting Adverse Events
Investigators will seek information on AEs, SAEs, and EOSI at each subject contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the subject’s medical record and on the AE Case Report 
Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.2 for 
SAE definitions).  These assessments must be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS).
10.3.3.1
Seriousness
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.3.3.2
Severity
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1.
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 
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Table 10.3.3.2.1: Adverse Event Grading (Severity) Scale
Grade
Description
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated
Grade 4 and 5 AEs 
should always be 
reported as SAEs
5
Death related to AE
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the telephone, 
managing money.
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, taking 
medications, not bedridden.
10.3.3.3
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1.
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Table 10.3.3.3.1: Causality Attribution Guidance
Relationship
Description
Not Related
x
Exposure to the IP has not occurred
x
OR
x
The administration of the IP and the occurrence of the AE are not
reasonably related in time
x
OR
x
The AE is considered likely to be related to an etiology other than the
use of the IP; that is, there are no facts, evidence, or arguments to
suggest a causal relationship to the IP.
Related
x
The administration of the IP and the occurrence of the AE are
reasonably related in time
AND
x
The AE could possibly be explained  by factors or causes other than
exposure to the IP
OR
x
The administration of IP and the occurrence of the AE are reasonably
related in time
AND
x
The AE is more likely explained by exposure to the IP than by other
factors or causes.
Factors suggestive of a causal relationship could include (but are not limited to):
x
Plausible temporal relationship
x
Absence of alternative explanations
x
Rarity of event in a given patient or disease state
x
Absence of event prior to study drug exposure
x
Consistency with study product pharmacology
x
Known relationship to underlying mechanism of study drug action
x
Similarity to adverse reactions seen with related drug products
x
Abatement of AE with discontinuation of study drug, and/or recurrence of AE with
reintroduction of study drug
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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4
Procedures for Recording Adverse Events
10.4.1 Recording Adverse Events on a eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology.
10.4.1.1
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE (or SAE, as appropriate) eCRF, replacing the original 
entries where appropriate.
10.4.1.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3
Persistent or Recurrent Adverse Events
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF. 
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A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.4.1.4
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF. Any laboratory result abnormality of CTCAE Grade 4 
or 5 should be recorded as an SAE in the AE eCRF. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met:
x
Accompanied by clinical symptoms
x
Leading to a change in study medication (e.g. dose modification, interruption or
permanent discontinuation)
x
Requiring a change in concomitant therapy (e.g. addition of, interruption of,
discontinuation of, or any other change in a concomitant medication, therapy or
treatment).
x
The abnormality suggests a disease and/or organ toxicity
x
The abnormality is of a degree that requires active management (eg, change of dose,
discontinuation of study drug, more frequent follow-up assessments, further
diagnostic investigation, etc.)
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed. 
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10.4.1.5
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF.
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches).
10.4.1.6
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.4.1.7
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2).
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to:
x
Perform a protocol-mandated efficacy measurement
x
Undergo a diagnostic or elective surgical procedure for a pre-existing medical
condition that has not changed
x
Hospitalization solely for the purpose of insertion of an in-dwelling IV catheter (such
as a Port-a-Cath or other brand) for administration of study drug will not be
considered an SAE.
x
Receive scheduled therapy (study drug or otherwise) for the study indication
10.4.1.8
Deaths
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
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is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event.  The Investigator must make every effort to 
follow the subject’s partner (with that partner’s consent) through resolution of the pregnancy 
(delivery or termination) and to report the resolution on the Pregnancy Follow-up Form in the 
study reference materials. In the event of pregnancy in the partner of a study subject, the 
Investigator should make every reasonable attempt to obtain the woman’s consent for release 
of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5
Reporting Requirements
10.5.1 Expedited Reporting Requirements
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF  and submitting  to BPV within 24 hours of the site 
becoming aware of the event.  Investigators should not wait to collect information that fully 
documents the event before notifying BPV of an SAE.  BioMarin may be required to report 
certain SAEs to regulatory authorities within 7 calendar days of being notified about the 
event; therefore, it is important that Investigators submit any information requested by 
BioMarin as soon as it becomes available.
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations.
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
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becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF.
10.5.2 Ethics Committee Reporting Requirements
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required. 
10.6
Follow-up of Subjects after Adverse Events
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the subject is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the subject’s medical record to facilitate source data verification.
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report.
10.7
Post-Study Adverse Events
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment.
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study.  
10.8
Urgent Safety Measures
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
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investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.” 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
x
Immediate need to revise the IP administration (eg, modified dose amount or
frequency not defined in protocol)
x
Lack of study scientific value, or detrimental study conduct or management
x
Discovery that the quality or safety of the IP does not meet established safety
requirements
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10.9
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc.
Address 
105 Digital Drive
Novato, CA 94949 
Phone: 
Fax: 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name: 
, MD, PharmD 
Address: 
105 Digital Drive
Novato, CA 94949 USA 
Phone: 
E-mail:
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11
APPROPRIATENESS OF MEASUREMENTS
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic FXa assay and the one-stage APTT assay are both validated and utilize CE 
marked reagents.  The exploratory FVIII activity assay will be used for exploratory purposes 
only. 
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12
STUDY PROCEDURES
12.1
Prestudy
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed.
12.2
Screening Visit
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LFTs, haematology, urine tests, coagulation screen, and CRP do 
not need to be repeated at Baseline. 
The following procedures will be performed during the Screening Period: 
x
Full medical history, including haemophilia A history, hepatitis B, hepatitis C, and
HIV.
x
Complete Physical Examination
x
Height and weight
x
Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and
temperature)
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical
information)
x
Electrocardiogram
x
Chest X-ray
x
Liver Ultrasound
x
Samples for hFVIII Assays
o
Baseline hFVIII activity – chromogenic FXa (plasma)
o
Baseline hFVIII activity level – one-stage APTT assay
o
hFVIII coagulation activity exploratory assay
o
hFVIII inhibitor level (Bethesda assay with Nijmegen modification)
o
hFVIII total antibody assay
o
hFVIII antigen (ELISA)
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x
Blood sample for AAV5 Assays
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay
x
Screen for hepatitis B, hepatitis C, and HIV if required (subjects with documented
negative results 30 days prior to informed consent being obtained do not need to be
retested)
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Function Tests (refer to Table 9.7.8.3.1)
x
Von Willebrand Factor Antigen (VWF:Ag)
x
Blood samples for Biomarker testing (including HLA genotyping, FVIII genotyping
status, TNFD and IL10a single nucleotide polymorphisms)
12.2.1 “Smart Rescreening” Visit
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study:
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical
information)
x
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen
modification)
x
Blood sample for AAV5 Assays

AAV5 antibody titer

AAV5 transduction inhibition assay
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to
Table 9.7.8.2.1)
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x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Function Tests (refer to Table 9.7.8.3.1)
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical
information)
x
Distribution of subject diaries and training in diary completion
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Function Tests (refer to Table 9.7.8.3.1)
x
PBMC collection for CTL baseline
x
Direct Thrombin test
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
x
Exploratory biomarker assessments
x
Haemo-QoL-A QoL assessment
12.4
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each subject.  Subjects will remain in the clinic for 
24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion)
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay
x
BMN 270 Infusion
x
Vital Signs
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o
Vital signs will be recorded prior to BMN 270 infusion and then every
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion,
vital signs will be monitored every 1 hour (± 5 minutes) for the first
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at
4 hour (± 15 minutes) intervals for the remainder of the subject’s stay in
the clinic.
12.5
BMN 270 Infusion Follow-Up Visits
After BMN 270 has been infused, subjects will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Once per week (Weeks 1 through 16) 
The following procedures will be performed at one visit per week from Weeks 1 through 16: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when
ALT values are >1.5x ULN) based on discussion between the Medical
Monitor and the Investigator and review of subject data.
x
Samples for FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
o
Central assessment of FVIII activity level should be performed 1x/week
from Week 1 through Week 16
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x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when
ALT values are >1.5x ULN) based on discussion between the Medical
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
x
PBMC collection
12.5.2 Week 1 – Day 2 and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed: 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (Day 2 and Day 4)
x
Samples for FVIII Assays (Day 4 only) – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – central laboratory
assessment
x
Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – local laboratory
assessment
x
FVIII activity level (Day 4 only) – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
12.5.3 Week 1 – Day 8 
On Day 8, the following procedures will be performed: 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
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x
Direct Thrombin test
x
Haemo-QoL-A QoL assessment
12.5.4 Every 2 Weeks
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedures will be 
performed:
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
(not assessed at Week 14)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at
Week 2)
o
Collection to occur until at least 3 consecutive negative results are
obtained.  Semen samples should continue to be collected and tested
through Week 12, even if 3 consecutive negative results in that
compartment have been recorded prior to that timepoint.
12.5.5 Weeks 4, 8, 12, and 16 
At Weeks 4, 8, 12, and 16, the following procedures will be performed: 
x
Urine Tests (refer to Table 9.7.8.2.1)
x
VWF:Ag
x
FVIII antibody titer
x
Exploratory biomarker assessments
12.5.6 Week 16
At Week 16, the following procedures will be performed: 
x
Test for hepatitis B and hepatitis C reactivation (in subjects with a history of hepatitis
B or hepatitis C infection prior to study entry)
o
Subjects who receive therapeutic corticosteroids prior to Week 16 do not
need to complete the Week 16 reactivation assessment; instead, they will
be tested for hepatitis B and hepatitis C reactivation at the time points
listed in Table 9.1.5.
12.5.7 Weeks 8 and 16 
At Weeks 8 and 16, the following procedures will be performed: 
x
AAV5 antibody titer
12.5.8 Weeks 2, 3, 4, and 16 
At Weeks 2, 3, 4, and 16, the following procedure will be performed: 
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x
Haemo-QoL-A QoL assessment
12.5.9 Week 13
At Week 13, the following procedure will be performed: 
x
Direct Thrombin test
12.6
Safety Follow-Up – Weeks 17-36 
After the Post-Infusion Follow-Up visits are complete, subjects will return to the study site 
for Safety Follow-Up visits from Weeks 17 through Week 36 (± 48 hours), when the 
following procedures will be completed: 
12.6.1 Once per week (Weeks 17 through 36)
Once per week from Week 17 through Week 36, the following procedures will be performed: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT
values are >1.5x ULN) based on discussion between the Medical Monitor and
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
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o
LFTs may be monitored more or less frequently (and in particular when
ALT values are >1.5x ULN) based on discussion between the Medical
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
12.6.2 Once per week (Weeks 17 through 20)
Once per week from Week 17 through Week 20, the following procedures will be performed: 
x
PBMC collection
12.6.3 Every 2 weeks (Weeks 21 through 36) 
Every 2 weeks (Weeks 22, 24, 26, 28, 30, 32, 34, and 36), the following procedures will be 
performed:
x
PBMC collection
12.6.4 Every 4 Weeks 
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed: 
x
Exploratory biomarker assessments
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
VWF:Ag
x
AAV5 antibody titer
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Safety Follow-Up is not required if at least
3 consecutive samples are clear during the Post-Infusion Follow-Up period.
12.6.5 Every 8 Weeks 
Every 8 weeks (Weeks 20, 28, and 36), the following procedure will be performed: 
x
FVIII antibody titer
12.6.6 Week 26
At Week 26, the following procedure will be performed: 
x
Direct Thrombin test
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x
Weight
12.6.7 Week 28  
At Week 28, the following procedure will be performed: 
x
Haemo-QoL-A QoL assessment
12.7
 Safety Follow-Up – Weeks 37-52 
Subjects will return every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) from 
Week 37-52 (± 1 week), when the following procedures will be completed: 
12.7.1 Once per visit
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed: 
x
Physical examination
x
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when
ALT values are >1.5x ULN) based on discussion between the Medical
Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently based (and in particular when
ALT values are >1.5x ULN) on discussion between the Medical Monitor and
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
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Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
12.7.2 Every 4 Weeks 
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed:
x
Exploratory biomarker assessments
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
AAV5 antibody titer
x
VWF:Ag
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period.  
Subjects who have not had 3 consecutive negative samples by Week 52
should continue to have PCR testing every 4 weeks until 3 consecutive
negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor).
12.7.3 Every 8 Weeks 
Every 8 weeks (Weeks 44 and 52), the following procedure will be performed:
x
PBMC collection
x
FVIII antibody titer
12.7.4 Week 38 and 52
At Week 38 and Week 52, the following procedure will be performed:
x
Direct Thrombin test
12.7.5 Week 52 
At Week 52, the following procedure will be performed:
x
Haemo-QoL-A QoL assessment
x
Weight
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12.8
Safety Follow-Up – Years 2-5
During Years 2-5 of Safety Follow-up, the following procedures will be completed:
12.8.1 Year 2 – Every 4 Weeks
During Year 2, every 4 weeks (+ 2 weeks), the following procedures will be performed:
x
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief 
Physical Examinations may be performed at other visits.
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (FXa chromogenic assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
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x
Exploratory biomarker assessments
12.8.2 Years 3-5 – Every 6 Weeks
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
x
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief 
Physical Examinations may be performed at other visits.
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (FXa chromogenic assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
Exploratory biomarker assessments
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12.8.3 Years 2-5 – Every 3 Months
During Years 2-5, every 3 months (± 2 weeks), the following procedures will be performed:
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
AAV5 antibody titer
x
FVIII antibody titer
x
PBMC collection
x
VWF:Ag
x
Direct Thrombin test
12.8.4 Years 2-5 – Every 6 Months
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the 
end of Year 1 of the Safety Follow-up period), the following procedures will be performed:
x
Haemo-QoL-A QOL assessment
x
Weight
12.8.5 Years 2-5 – Every 4 Weeks
Every four weeks during Years 2-5, the following procedure may be performed:
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are clear during the Post-Infusion Follow-Up period.  Subjects who 
have not had 3 consecutive negative samples by Week 52 should continue to 
have PCR testing every 4 weeks during Years 2-5 until 3 consecutive negative 
samples are documented (or upon consultation between the Investigator and 
Medical Monitor).
12.9
Early Termination Visit
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit.
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done:
x
Physical examination
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x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Vital Signs
x
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
x
Urine Tests (refer to Table 9.7.8.2.1)
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed standard of care FVIII replacement therapy.
x
AAV5 antibody titer
x
FVIII antibody titer
x
PBMC collection
x
VWF:Ag
x
Direct Thrombin test
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing at the ETV is not required if at least 3 consecutive samples 
are clear during the Post-Infusion Follow-Up period.
x
Exploratory biomarker assessment
x
Haemo-QoL-A QOL assessment
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12.10 End of Study
The study will end after the last subject completes the last Safety Follow-Up visit 
(Week 260). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study subjects may be 
compromised.
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13
DATA QUALITY ASSURANCE
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan.
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS.
14.1.1 Interim Analyses
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all subjects having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16).
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
14.2
Missing data will not be imputed. 
14.3
Primary and Secondary Efficacy Analysis
The subjects will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of subjects, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined.
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay as 
measured by the central laboratory at 16 weeks following study treatment.  hFVIII activity 
will be assessed weekly during the study period.  We can only assess the true steady state of 
hFVIII protein produced from BMN 270 after a minimum of 72 hours has elapsed since the 
last infusion of FVIII protein concentrates.  
14.4
Immunogenicity
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons 
14.5
Pharmacodynamic Analyses
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage APTT and/or chromogenic FXa assay (activity level), will be used for plasma 
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profiles; FVIII activity will be used to determine PD parameters.  Traditional PK analysis is 
not applicable.
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics. 
14.6
Safety Analysis
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF.
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of subjects who report hepatitis will be presented.
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided. 
Detailed statistical methods will be provided in the SAP.
14.7
Determination of Sample Size
No formal sample size calculations based on statistical power were performed.
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 15 subjects may be dosed in the study; the actual number of
subjects will depend on the criteria for dose escalation. 
14.8
Analysis Populations
The Safety analysis population is defined as all enrolled subjects who receive any study drug. 
The analysis of safety data will be performed on Safety Set.
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The Full Analysis Set (FAS) is defined as all enrolled subjects who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis.
14.9
Changes in the Conduct of the Study or Planned Analyses
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation.
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the
IRB/IEC/REB, and all active subjects must again provide informed consent.
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail.
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15
DATA REVIEW BOARD
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established.
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available subject safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene 
for further assessment of subject safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites.
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COMPENSATION, INSURANCE AND INDEMNITY
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected.
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the subject’s health insurance company or other third party 
payer for the cost of this medical treatment. If the subject has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law.
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CASE REPORT FORMS AND SOURCE DOCUMENTS
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy.
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable. 
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator.
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to 
their medical records, and subjects will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
subject records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification.
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed. 
Before a subject’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
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completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents.
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STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees.
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files.
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RETENTION OF RECORDS
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained.
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USE OF INFORMATION AND PUBLICATION
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP). 
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INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Patients 
In accordance with FDA Form 1572 and/or principles of ICH E6 R2 GCP, the Investigator 
will ensure that:
x
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients.
x
He or she will personally conduct or supervise the study.
x
He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and/or ICH E6 
R2 Sections 2.9 and 4.8 are met. As well, he or she will ensure that IRB/ IEC review 
and approval in 21 CFR Part 56 and/or ICH E6 R2 Section 2.6 are met. 
x
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 R2 Section 4.11.
x
He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug.
x
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments.
x
Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 R2 
Section 4.9 are kept, and those records are available for inspection in accordance with 
21 CFR 312.68 and/or ICH E6 R2 Section 4.9.7.
x
The IRB/IEC/REB complies with the requirements of 21 CFR Part 56, ICH E6 R2
Section 3.0, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients.
x
He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6 R2.
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23
SIGNATURE PAGE
Protocol Title: A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII in Patients with Severe Haemophilia A
Protocol Number: 270-201, Amendment 6
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including  
ICH E6 R2, as stated in the protocol, and other information supplied to me.
Investigator Signature
Date
Printed name:
Accepted for the Sponsor:
Medical Monitor Signature
Date
Printed name:
, MD, PharmD, 
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PI
PI
PI

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24
PROTOCOL AMENDMENT TEXT REVISIONS
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See pages 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font.
Section No./Title
Text Revisions
Rationale
Synopsis/Study 
Design and Plan
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of mice and monkeys.  The 
starting dose has a significant10-fold safety margin (10-fold) from no observed adverse effect level (NOAEL) in non-human 
primates. 
5
Synopsis/Criteria for 
Evaluation
LFTs will be monitored every three months4 weeks during Year 2, and then every 6 weeks for up to Years 3-5 years post-dose 
in the safety extension; the frequency and duration of LFT testing may be changed based on discussion between the Medical 
Monitor and the Investigator and review of subject data.
1
9.1/Overall Study 
Design and Plan
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of mice and monkeys.  The 
starting dose has a significant10-fold safety margin (10-fold) from no observed adverse effect level (NOAEL) in non-human 
primates. 
5
Table 9.1.1 
(Footnotes)
g Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
Haemophilia hemophilia A disease. , coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects 
may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing on of these samples is 
optional will be performed only as deemed necessary by the Sponsor.
5
Table 9.1.2 
(Footnotes)
c Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay).  If a subject has used FVIII within 72 hours of a measurement 
day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour 
wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not
resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of 
FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII 
inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a 
measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved;
the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who 
3, 4, 5
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have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be 
considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a 
venous thromboembolism.  
f Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
Haemophilia hemophilia A disease. , coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects 
may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing on of these samples is 
optional will be performed only as deemed necessary by the Sponsor.
g Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of Hepatitis B or Hepatitis C prior 
to study entry, should be performed only in subjects who have not received therapeutic corticosteroids prior to Week 16; subjects who have 
received therapeutic corticosteroids will have hepatitis B and hepatitis C testing at the time points indicated in Table 9.1.5.
Table 9.1.3
Table 9.1.3 has been updated to be consistent with changes made elsewhere in the protocol.
2
Table 9.1.3 
(Footnotes)
c Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay).  If a subject has used FVIII within 72 hours of a measurement 
day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour 
wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not
resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of 
FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII 
inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a 
measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved;
the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who 
have not resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be 
considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a 
venous thromboembolism.  
f Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
Haemophilia hemophilia A disease. , coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects 
may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
2, 3, 5
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associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing on of these samples is 
optional will be performed only as deemed necessary by the Sponsor.
Table 9.1.4
Table 9.1.4 has been updated to be consistent with changes made elsewhere in the protocol.
1, 2, 3
Table 9.1.4 
(Footnotes)
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52 and ± 2 weeks for visits in Years 2-5. For LFT, FVIII, and 
exploratory biomarker testing during Years 2-5, the visit windows are every 4 weeks (+ 2 weeks) during Year 2, and every 6 weeks (±2 
weeks) during Years 3-5.
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay). If a subject has used FVIII within 72 hours of a measurement 
day, all efforts should be made to obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved; the 72-hour 
wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed standard of care FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of 
FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), Bethesda assay (with Nijmegen modification) for hFVIII 
inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a 
measurement day, all efforts should be made to obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved.;
the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who 
have not resumed standard of care FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be 
considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a 
venous thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen modification) in years 3-5, a fresh sample should 
be collected within 4 weeks of the initial visit that had a positive result.
g Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, 
coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory 
genetic/genomic research being done to study or try to discover genes that are not yet known to be associated with hemophilia A. While 
exploratory samples will be collected at the time points indicated above, testing of these samples will be performed only as deemed 
necessary by the Sponsor.
1, 2, 3, 5
Table 9.1.5 
(Footnotes)
e Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry.
4
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9.4.8.2.1/Therapeutic 
Corticosteroids
For subjects with a past medical history of hepatitis B or hepatitis C prior to study entry, Hepatitis B status and HCV viral load 
will be rechecked 6 weeks after the start of corticosteroid treatment, and then 1 week and 13 weeks after the completion of 
corticosteroid treatment.
4
9.7.2/Primary Efficacy 
Variable
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved. The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of care 
FVIII replacement therapy.
3
9.7.6/Exploratory 
Assessments
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1, Table 9.1.2, Table 9.1.3, and 
Table 9.1.4 to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease. The 
exploratory genetic/genomic testing is optional. hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays 
used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or 
try to discover genes that are not yet known to be associated with hemophilia A. 
5
9.7.8.3/Liver Function 
and Hepatitis Testing
Subjects with a history of hepatitis B or hepatitis C infection prior to study entry will be tested for hepatitis B and hepatitis C 
reactivation at Week 16.
4
10.4.1.4/Abnormal 
Laboratory Values
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported as such, and recorded in addition 
to being the AE eCRF. Any laboratory result abnormality of CTCAE Grade 4 or 5 should be recorded as an AESAE in the AE 
eCRF.
5
10.9/BioMarin 
Contact Information
Contact information for the medical monitor is as follows:
Name:
Liron WalshMitra Tavakkoli, MD, PharmD
Address:105 Digital Drive
Novato, CA 94949 USA
Phone:
+1 (415) 455-7870257-5974
E-mail:
liron.walshfatemeh.tavakkoli@bmrn.com
5
12.5.1/Once per Week 
(Weeks 1-16)
The following procedures will be performed at one visit per week from Weeks 1 through 16:
x
Samples for FVIII Assays – central laboratory assessment
6
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Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved. The 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed standard of care FVIII replacement therapy.
12.5.1/Week 1 – Day 
2 and Day 4
On Day 2 and Day 4 of Week 1, the following procedures will be performed:
x
Samples for FVIII Assays (Day 4 only) – central laboratory assessment
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved. The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of 
care FVIII replacement therapy.
3
12.5.6/Week 16
At Week 16, the following procedures will be performed:
x
Test for hepatitis B and hepatitis C reactivation (in subjects with a history of hepatitis B or hepatitis C infection prior 
to study entry)
o
Subjects will be tested for hepatitis B and hepatitis C reactivation at Week 16.  Subjects who receive 
therapeutic corticosteroids prior to Week 16 do not need to complete the Week 16 reactivation 
assessment; instead, they will be tested for hepatitis B and hepatitis C reactivation at the time points listed 
in Table 9.1.5.
4, 5
12.6.1/Once per Week 
(Weeks 17 through 
36)
Once per week from Week 17 through Week 36, the following procedures will be performed:
x
FVIII Assays – central laboratory assessment
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved. The 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed standard of care FVIII replacement therapy.
3
12.6.4/Every 4 Weeks
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed:
x
Exploratory biomarker assessments (Weeks 20 and 24 only)
2
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12.7.1/Once per visit
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed:
x
FVIII Assays – central laboratory assessment
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved. The 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed standard of 
care FVIII replacement therapy.
3
12.7.2/Every 4 Weeks
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed:
x
Exploratory biomarker assessments
2
12.8/Safety Follow-
Up
During Years 2-5 of Safety Follow-up, subjects will be assessed every 3 months (± 2 weeks). At these times, the following 
procedures will be completed:
5
12.8.1/Year 2 – Every 
4 Weeks
During Year 2, every 4 weeks (+ 2 weeks), the following procedures will be performed:
x
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief Physical Examinations may be 
performed at other visits.
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and 
FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
1, 2, 3, 5
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x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (FXa chromogenic assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed standard of care FVIII replacement therapy.
x
Exploratory biomarker assessments
12.8.2/Years 3-5 –
Every 6 Weeks
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
x
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief Physical Examinations may be 
performed at other visits.
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and 
FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
1, 2, 3, 5
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o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (FXa chromogenic assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed standard of care FVIII replacement therapy.
x
Exploratory biomarker assessments
12.8.3/Every Visit
Years 2-5 – Every 3 
Months
Every During Years 2-5, every 3 months (± 2 weeks), the following procedures will be performed:
x
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief Physical Examinations may be 
performed at other visits.
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and 
FVIII use)
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
1, 3, 5
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o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
x
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
x
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
x
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (FXa chromogenic assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved.
12.8.4/Every Other 
Visit Years 2-5 –
Every 6 Months
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the end of Year 1 of the Safety Follow-up 
period), the following procedure procedures will be performed:
5
12.8.5/Years 2-5 –
Every 4 Weeks
Every four weeks during Years 2-5, the following procedure may be performed:
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing during Years 2-5 is not required if at least 3 consecutive samples are clear during the Post-
Infusion Follow-Up period.  Subjects who have not had 3 consecutive negative samples by Week 52 should 
continue to have PCR testing every 4 weeks during Years 2-5 until 3 consecutive negative samples are 
documented (or upon consultation between the Investigator and Medical Monitor).
5
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12.9/Early 
Termination Visit
At the Early Termination visit, as many of the following assessments as possible should be done:
x
FVIII Assays – central laboratory assessment
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only 
intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed standard of care FVIII replacement therapy.
x
Exploratory biomarker assessment
2, 3
22.1/Conduct of Study 
and Protection of 
Human Patients
In accordance with FDA Form 1572 and/or principles of ICH E6 R2 GCP, the Investigator will ensure that:
x
He or she will inform any potential patients, or any persons used as controls, that the drugs are being used for 
investigational purposes and he or she will ensure that the requirements relating to obtaining informed consent in 21 
CFR Part 50 and/or ICH E6 R2 Sections 2.9 and 4.8 are met. As well, he or she will ensure that IRB/ IEC review and 
approval in 21 CFR Part 56 and/or ICH E6 R2 Section 2.6 are met. 
x
He or she will report to the sponsor adverse experiences that occur in the course of the investigation in accordance with 
21 CFR 312.64 and/or ICH E6 R2 Section 4.11.
x
He or she will ensure that Adequate and accurate records in accordance with 21 CFR 312.62 and to make/or ICH E6 
R2 Section 4.9 are kept, and those records are available for inspection in accordance with 21 CFR 312.68.
x
He and/or she will ensure that ICH E6 R2 Section 4.9.7.
x
The IRB/IEC/REB complies with the requirements of 21 CFR Part 56, ICH E6 R2 Section 3.0, and other applicable 
regulations, and conducts initial and ongoing reviews and approvals of the study. He or she will also ensure that any 
change in research activity and all problems involving risks to human patients or others are reported to the 
IRB/IEC/REB. Additionally, he or she will not make any changes in the research without IRB/IEC/REB approval, 
except where necessary to eliminate apparent immediate hazards to human patients.
x
He or she agrees to comply with all other requirements regarding the obligations of clinical Investigators and all other 
pertinent requirements in 21 CFR Part 312 and/or ICH E6 R2.
5
DocuSign Envelope ID: 6255452C-C7A9-4900-BDB5-7FECA2D22426

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer 
of Human Factor VIII in Patients with Severe Haemophilia A
Protocol Number:
270-201
Active Investigational 
Product:
AAV5-hFVIII-SQ
IND/European Union Drug 
Regulating Authorities 
Clinical Trials (EudraCT) 
Number:
2014-003880-38
Indication:
Haemophilia A
Sponsor:
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
Development Phase:
Phase 1/2
Sponsor's Responsible 
Medical Monitor:
, MD
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
Duration of Subject
Participation:
Approximately 264 weeks
Dose:
Varied
Study Population:
Males aged 18 or older
Date of Original Protocol:
10 February 2015
Date of Amendment 1:
06 March 2015
Date of Amendment 2:
26 May 2015
Date of Amendment 3:
06 November 2015
Date of Amendment 4:
02 September 2016
Date of Amendment 5:
14 February 2017
Property of BioMarin
CONFIDENTIAL
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin.
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code 
of Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving 
of essential documents
PI
PI

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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY
Amendment: 5 
Date: 14 February 2017 
RATIONALE AND SUMMARY OF MAJOR CHANGES
A summary of major changes covered by Amendment 5 to the BMN 270-201 protocol is 
provided below.   
1. Twice weekly testing (at the local laboratories) of FVIII and ALT levels during 
Weeks 1-20 has been reduced to once weekly testing. 
Rationale: Current data from subjects enrolled in the study support a reduced frequency of 
local ALT and FVIII assessments in order to maintain adequate surveillance of hepatocyte 
injury and FVIII activity.  The accumulated data suggest that week-to-week increases in ALT 
(if observed) are mild, and as such timely administration of corticosteroids will not be 
impacted by a reduction to once weekly testing.  As already stipulated in the protocol, an 
observed increase in ALT, or decline in FVIII activity, may require an adjustment to the 
monitoring schedule as needed based on individual subject data (ie, increased monitoring in 
case of increases in ALT) and upon discussion between the Investigator and the Medical 
Monitor. 
2. The frequency of PBMC collection has been increased to weekly through Week 20, 
then every other week through Week 36. 
Rationale:  Previous FIX gene-therapy clinical studies have demonstrated an association 
between increases in ALT and declines in FIX expression, which are thought to be due to a 
cell-mediated immune response to transduced hepatocytes (Manno, 2006, Nat.Med.)
(Mingozzi, 2013, Blood); (Nathwani, 2014, N.Engl.J.Med.); (Nathwani, 2011, Mol.Ther.).
An analysis of this immune response requires the collection of peripheral blood mononuclear 
cells (PBMC), which is part of the current schedule of assessments.  The transient nature of 
the reported data indicates we may need to sample more frequently to identify a potential 
cell-mediated immune response to transduced hepatocytes. The frequency of PBMC 
collection has been increased from every 4 weeks to weekly through Week 20, then to every 
2 weeks through Week 36.   

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3. Subjects will be required to continue to provide semen samples for PCR analysis 
through Week 12, even if they have already had 3 consecutive negative results in 
semen prior to that timepoint.
Rationale: A monitoring period of at least 12 weeks is required for semen to conform with 
regulatory guidances for shedding analysis, which recommend monitoring for at least one 
complete cycle of spermatogenesis (mean: 74 days, 95% CI interval: 70-78 days) (Heller and 
Clermont, 1964; Heller, 1969). Collection and testing of semen for vector DNA will 
therefore be continued through Week 12, regardless of whether the semen fluid compartment 
is considered to have cleared (i.e., the subject has had 3 consecutive negative sample tests). 
This new minimal monitoring period should account for the potentially delayed appearance 
of vector DNA in semen if a sperm progenitor cell had been transduced.   
4.
Language has been added to allow exploratory fractionation of collected samples 
(such as plasma, PBMCs, and red blood cells).
Rationale:  On an exploratory basis, samples may be fractionated prior to shedding analysis 
in order to better characterize the presence and location of vector DNA and/or vector capsid 
within each matrix. The fractionation may be performed with a portion of samples designated 
for shedding analysis (saliva, blood, semen, urine, faeces), or by using exploratory samples, 
such as plasma, PBMCs, and red blood cells, collected under the study protocol. 
5. Minor administrative changes have been made for consistency and clarity. 
Specific changes included in this amendment, including the Synopsis, since Amendment 4 
(approved 2 September 2016) are outlined in Section 24.

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2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
TITLE OF STUDY: 
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of BMN 270, an 
Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients 
with Severe Haemophilia A
PROTOCOL NUMBER:
270-201
STUDY SITES:
Approximately 6-10 sites worldwide.
PHASE OF DEVELOPMENT:
Phase 1/2
STUDY RATIONALE:
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an 
essential cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to 
a new mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 
1-5% of wild type activity and the mild form is 5-40% activity. The clinical manifestations of 
severe HA remain frequent spontaneous bleeding episodes, predominantly in joints and soft 
tissues, with a substantially increased risk of death from haemorrhage when the brain is involved.  
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life for 
FVIII (12 to 18 hours for most approved products) necessitates frequent infusions, and although a 
major advance in the treatment of HA, it remains common for severe HA patients to continue to 
have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up 
to 30 to 50 episodes/year for on demand treatment). The consequence of multiple bleeding events 
is the development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death. Chemical modification (e.g.direct 
conjugation of polyethylene glycol (PEG) polymers) and bioengineering of FVIII (e.g. FVIII-Fc 
fusion proteins) improve half-life by approximately 50%, and thus, show promise in reduced 

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
dosing and maintaining activity levels above 1% trough. However, these longer acting FVIIIs 
remain dependent on multiple infusions to maintain critical levels of FVIII activity in severe HA 
patients. There is therefore a strong unmet need for a fully preventive treatment of HA to give 
patients a FVIII level compatible with a normal and haemorrhage-free life. 
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach because 
clinical manifestations are attributable to the lack of a single gene product (FVIII) that circulates in 
minute amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not 
essential, and modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml 
induces an increase in activity of 1%) can ameliorate the severe form of the disease.  Thus, 
relatively small changes in endogenous FVIII activity results in clinically relevant improvements 
in disease phenotype. Finally, the response to gene transduction can be assessed using validated 
quantitative rather than qualitative endpoints that are easily assayed using established laboratory 
techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific 
tissues such as the liver (for serotypes 2, 5 and 8 among others). Indeed, an on-going gene therapy 
clinical trial for a related disorder, haemophilia B, has established that stable (>36 months) 
expression of human factor IX at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
administration of AAV-8 vector. Several participants in this trial have been able to discontinue 
factor prophylaxis without suffering spontaneous haemorrhages, even when they undertook 
activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a liver-selective promoter (Figure 1).

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
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ONLY:
Figure 1. hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from vector-transduced 
liver tissue. The clinical study 270-201 is a first-in-human study designed to assess the relationship 
of vector dose to the augmentation of residual FVIII activity, and whether these levels are 
sufficient to alter the clinical phenotype. The relationship of dose to safety will be correlated to the 
activity of hFVIII in patients with severe HA.
OBJECTIVES: 
The primary objectives of the study are:
To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. 
To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of 
normal activity (>5 IU/dL) at 16 weeks after infusion. The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose.
The secondary objectives of the study are:
To describe the immune response to the FVIII transgene and AAV capsid proteins 
following systemic administration of AAV5-hFVIII-SQ
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during 
the study

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
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Reference: 
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To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study
STUDY DESIGN AND PLAN: 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 16-
week Post-Infusion Follow-Up period during which safety and efficacy assessments will be taken. 
After the primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed for 
approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and 
do not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. 
Participants will be enrolled into one of up to four cohorts according to dose level: 
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv)
Cohort 2:  2E13 vg per kilogram, iv
Cohort 3:  6E13 vg per kilogram, iv
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies 
of mice and monkeys. The starting dose has a significant safety margin (10-fold) from no observed 
adverse effect level (NOAEL) in non-human primates. 
Cohorts 1-3
The first 3 cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between 
cohorts. Dose escalation may occur after a single subject has been safely dosed if the resulting 
FVIII activity at the Week 3 visit is < 5 IU/dL in both the one-stage aPTT and chromogenic assays. 
Three weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic doses.
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study, the Data Review Board (DRB). 
5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Subject 1 will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram of 
body weight. If the FVIII 
IU/dL at the Week 3 visit in both assays, 
then no further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with 
Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in Cohort 2 
IU/dL at the 
Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and enrollment into 
Cohort 3 (6E13) will initiate with the next subject. If the FVIII activity level in the first subject
treated in Cohort 3 
Review Board (DRB) will recommend whether to continue to add subjects to the cohort and/or 
whether to continue the study.
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 5 IU/dL and 
no safety issue is found, then up to four subjects will be enrolled in the Cohort, though, the 
adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts based 
on activity levels of FVIII and safety signals. 
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.
5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in this 
cohort.
There will be an ongoing review of individual patient safety and efficacy data by the 
medical monitor and the DRB. The adaptive nature of this trial allows the DRB to 
recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals.
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity for 
therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post 
dose. Safety will be evaluated for approximately 5 years after dosing.  Any safety signal may 
trigger a review of the data and possible additional immunogenicity studies that include an 
assessment of cellular immune responses using collected peripheral blood mononuclear cells 
(PBMC).
NUMBER OF SUBJECTS PLANNED:
Up to 15 subjects may enroll into the study; the actual number of subjects will depend on the FVIII 
activity levels seen in each Cohort.

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
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AUTHORITY USE 
ONLY:
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following criteria:
1.
Males that are 18 years or older with established severe haemophilia A as evidenced by 
their medical history.  Patients will be considered as severe if their base FVIII level is 1 
IU/dL or less
2.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs)
3.
Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis
4.
Able to sign informed consent and comply with requirements of the trial
5.
No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 
12 months
6.
Sexually active patients must be willing to use an acceptable method of contraception such 
as double barrier, including hormonal contraception for at least 6 months post-treatment.
After 6 months, subjects may stop contraception use only if they have had 3 consecutive 
negative semen samples.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study:
1.
Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition or AAV5 total antibodies
2.
Any evidence of active infection or any immunosuppressive disorder.  
3.
HIV positive
4.
Significant liver dysfunction as defined by abnormal elevation of:
ALT (alanine transaminase) to 3 times the upper limit of normal;
Bilirubin above 3 times the upper limit of normal;
Alkaline phosphatase above 3 times the upper limit of normal; or

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
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Reference: 
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5.
Potential participants who have had a liver biopsy in the past 3 years are excluded if they 
had significant fibrosis of 3 or 4 as rated on a scale of 0-4
6.
Evidence of any bleeding disorder not related to Haemophilia A
7.
Platelet count of < 100 x 109/L
8.
Creatinine 1.5 mg/dL
9.
Liver cirrhosis of any etiology as assessed by liver ultrasound 
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive
12. Treatment with any IP within 30 days prior to the end of the screening period
13. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study including possible corticosteroid 
treatment outlined in the protocol. The physician may exclude patients unwilling or 
unable to agree on not using alcohol for the 16-week period following the viral infusion.
14. Prior treatment with any vector or gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion
16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral 
infusion
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level.
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
The study is open label with comparison of FVIII activity to baseline values. No reference therapy 
will be evaluated in this study.
DURATION OF TREATMENT:
BMN 270 is given as a single dose by intravenous infusion.

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
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AUTHORITY USE 
ONLY:
CRITERIA FOR EVALUATION:
Safety:
The following safety outcome measurements will be assessed:
Incidence of adverse events (AEs), including serious AEs (SAEs) 
Change in clinical laboratory tests (serum chemistry and haematology)
Change in vital signs
Change in physical examination 
Vector shedding
Liver function tests (LFTs, including ALT, AST, GGT, LDH, bilirubin, alkaline 
phosphatase)
Immune response to FVIII transgene and AAV capsid proteins
No major toxicity is expected based on preclinical studies in mice and monkeys. Each subject will 
have comprehensive surveillance monitoring of LFTs (at local labs, once per week for Weeks 
1-36,  then once every 2 weeks from Week 37-52) during Year 1. LFTs will be monitored every 
three months for up to 5 years post-dose in the safety extension; the frequency and duration of LFT 
testing may be changed based on discussion between the Medical Monitor and the Investigator and 
review of subject data.
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the 
study is to establish
BMN 270 
administration.
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Subjects will be 
asked to keep a subject diary to record the details in these areas.  
Pharmacodynamics:
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage 
APTT and/or chromogenic FXa assay (activity level), will be used for plasma profiles; FVIII 
activity will be used to determine PD parameters.  Traditional PK analysis is not applicable.

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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
If supported by the FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss 
(time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  
STATISTICAL METHODS: 
The sample size is based upon clinical considerations and could detect a strong clinical efficacy 
signal. Up to 15 subjects may be dosed in the study.  The subjects will be followed in a 
longitudinal manner and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature but data collected in a longitudinal manner may be analyzed using 
longitudinal methods such as mixed effect model which takes into account the correlation among 
the observation taken at various time points within a participant. Efficacy is a secondary endpoint, 
5 IU/dL by chromogenic FXa assay and/or one-stage 
APTT assay at 16 weeks following study treatment. FVIII activity will be assessed weekly during 
the study period.  We can only assess the true steady state of FVIII protein produced from BMN 
270 after a minimum of 72 hours has elapsed since the last infusion of FVIII protein concentrates.
Analysis of neutralizing antibody response and other immunological parameters as well as vector 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses.

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3
TABLE OF CONTENTS
2
SYNOPSIS ...........................................................................................................................4
3
TABLE OF CONTENTS ...................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................19
5
ETHICS..............................................................................................................................21
5.1
Institutional Review Board or Independent Ethics Committee ................................21
5.2
Ethical Conduct of Study ..........................................................................................22
5.3
Subject Information and Informed Consent ..............................................................22
6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................23
7
INTRODUCTION .............................................................................................................24
7.1
Nonclinical Studies ...................................................................................................24
7.2
Previous Clinical Studies ..........................................................................................26
7.3
Study Rationale .........................................................................................................27
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic ..............................................29
7.4
Summary of Overall Risks and Benefits ...................................................................29
8
STUDY OBJECTIVES ......................................................................................................31
9
INVESTIGATIONAL PLAN ............................................................................................32
9.1
Overall Study Design and Plan .................................................................................32
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3 ...............33
Table 9.1.1: Schedule of Events – Screening and Infusion ......................................35
Table 9.1.4:  Schedule of Events – Safety Follow-Up .............................................41
Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids .............................43
9.2
Discussion of Study Design, Including Choice of Control Group ............................44
9.3
Selection of Study Population ...................................................................................44
9.3.1
Inclusion Criteria .........................................................................................44
9.3.2
Exclusion Criteria ........................................................................................45
9.3.3
Removal of Subjects from Treatment or Assessment .................................46
9.3.4
Subject Identification and Replacement of Subjects ...................................47
9.3.5
Duration of Subject Participation ................................................................47
9.4
Treatments .................................................................................................................47

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9.4.1
Treatments Administered ............................................................................47
9.4.2
Identity of Investigational Product ..............................................................48
9.4.3
Storage .........................................................................................................48
9.4.4
Directions for Administration .....................................................................48
9.4.5
Method of Assigning Subjects to Treatment Groups ..................................49
9.4.6
Selection of Doses Used in the Study .........................................................49
9.4.7
Blinding .......................................................................................................50
9.4.8
Prior and Concomitant Medications ............................................................50
9.4.9
Treatment Compliance ................................................................................52
9.5
Investigational Product Accountability .....................................................................52
9.5.1
Return and Disposition of Clinical Supplies ...............................................52
9.6
Dietary or Other Protocol Restrictions......................................................................53
9.7
Safety and Efficacy Variables ...................................................................................53
9.7.1
Safety and Efficacy Measurements Assessed .............................................53
9.7.2
Primary Efficacy Variables .........................................................................53
9.7.3
Secondary Efficacy Variables .....................................................................54
9.7.4
Immunogenicity ...........................................................................................54
9.7.5
Pharmacodynamics ......................................................................................54
9.7.6
Exploratory Assessments ............................................................................55
9.7.7
Haemo-QoL-A Quality of Life Assessment ................................................55
9.7.8
Safety Variables ..........................................................................................55
10 REPORTING ADVERSE EVENTS .................................................................................60
10.1 Safety Parameters and Definitions ............................................................................60
10.1.1 Adverse Events ............................................................................................60
10.2 Serious Adverse Events ............................................................................................61
10.2.1 Events of Special Interest (EOSI) ...............................................................61
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................61
10.3.1 Adverse Event Reporting Period .................................................................61
10.3.2 Eliciting Adverse Events .............................................................................62
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................62

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10.4 Procedures for Recording Adverse Events ...............................................................65
10.4.1 Recording Adverse Events on a eCRF ........................................................65
10.5 Reporting Requirements ...........................................................................................68
10.5.1 Expedited Reporting Requirements .............................................................68
10.5.2 Ethics Committee Reporting Requirements ................................................69
10.6 Follow-up of Subjects after Adverse Events .............................................................69
10.7 Post-Study Adverse Events .......................................................................................69
10.8 Urgent Safety Measures ............................................................................................69
10.9 BioMarin Pharmacovigilance Contact Information ..................................................70
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................71
12 STUDY PROCEDURES ...................................................................................................72
12.1 Prestudy .....................................................................................................................72
12.2 Screening Visit ..........................................................................................................72
12.2.1 “Smart Rescreening” Visit ..........................................................................73
12.3 Baseline Visit ............................................................................................................74
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................74
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................75
12.5.1 Once per week (Weeks 1 through 16) .........................................................75
12.5.2 Week 1 – Day 2 and Day 4 ..........................................................................76
12.5.3 Week 1 – Day 8 ...........................................................................................76
12.5.4 Every 2 Weeks .............................................................................................77
12.5.5 Weeks 4, 8, 12, and 16 ................................................................................77
12.5.6 Week 16 .......................................................................................................77
12.5.7 Weeks 8 and 16 ...........................................................................................77
12.5.8 Weeks 2, 3, 4, and 16 ..................................................................................77
12.5.9 Week 13 .......................................................................................................78
12.6 Safety Follow-Up – Weeks 17-36 .............................................................................78
12.6.1 Once per week (Weeks 17 through 36) .......................................................78
12.6.2 Once per week (Weeks 17 through 20) .......................................................79
12.6.3 Every 2 weeks (Weeks 21 through 36) .......................................................79

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12.6.4 Every 4 Weeks .............................................................................................79
12.6.5 Every 8 Weeks .............................................................................................79
12.6.6 Week 26 .......................................................................................................79
12.6.7 Week 28 .......................................................................................................79
12.7 Safety Follow-Up – Weeks 37-52 .............................................................................80
12.7.1 Once per visit ...............................................................................................80
12.7.2 Every 4 Weeks .............................................................................................80
12.7.3 Every 8 Weeks .............................................................................................81
12.7.4 Week 38 and 52 ...........................................................................................81
12.7.5 Week 52 .......................................................................................................81
12.8 Safety Follow-Up – Years 2-5 ..................................................................................81
12.8.1 Every Visit ...................................................................................................81
12.8.2 Every Other Visit (Every 6 Months) ...........................................................83
12.9 Early Termination Visit ............................................................................................83
12.10End of Study .............................................................................................................84
13 DATA QUALITY ASSURANCE .....................................................................................85
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................86
14.1 Statistical and Analytical Plans .................................................................................86
14.1.1 Interim Analyses ..........................................................................................86
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........86
14.2 Primary and Secondary Efficacy Analysis................................................................86
14.3 Immunogenicity ........................................................................................................86
14.4 Pharmacodynamic Analyses .....................................................................................86
14.5 Safety Analysis .........................................................................................................87
14.6 Determination of Sample Size ..................................................................................87
14.7 Analysis Populations .................................................................................................87
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................88
15 DATA REVIEW BOARD .................................................................................................89
16 COMPENSATION, INSURANCE AND INDEMNITY ..................................................90
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................91

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18 STUDY MONITORING AND AUDITING .....................................................................93
19 RETENTION OF RECORDS ...........................................................................................94
20 USE OF INFORMATION AND PUBLICATION ...........................................................95
21 REFERENCES ..................................................................................................................96
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................99
22.1 Conduct of Study and Protection of Human Patients ...............................................99
23 SIGNATURE PAGE .......................................................................................................100
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................101

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LIST OF TABLES
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................35
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) ............................37
Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) .....................................39
Table 9.1.4:  Schedule of Events – Safety Follow-Up .............................................................41
Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids .............................................43
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................56
Table 9.7.8.3.1:  Liver Function Tests .....................................................................................57
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................63
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................64
LIST OF FIGURES
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic .............................................................29
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3...............................33

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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
AAV
adeno-associated virus
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
ALT
alanine transaminase
APTT
activated partial thromboplastin time
BPV
BioMarin Pharmacovigilance
BU
Bethesda Unit
CFR
Code of Federal Regulations
CRA
clinical research associate
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DRB
Data Review Board
eCRF
electronic case report form
ED
exposure days
EOSI
events of special interest
ETV
early termination visit
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
first-in-human
FVIII
coagulation factor VIII
FXa
coagulation factor Xa
GCP
Good Clinical Practice
HA
Haemophilia A
hFVIII
human coagulation factor VIII
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6
IEC
independent ethics committee
IND
Investigational New Drug (application)

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INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect level
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamics
PEG
polyethylene glycol
PK
Pharmacokinetics
PRO
patient-reported outcome
rhFVIII
recombinant human FVIII protein
REB
research ethics board
SAE
serious adverse event
SAP
statistical analysis plan
SDV
source data verification
ULN
upper limit of normal
vg
vector genomes
VWF:Ag
von Willebrand factor Antigen
Definition of Terms: 
Investigational Product (IP):
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]). 
The terms “IP” and “study drug” may be used interchangeably in the protocol.

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5
ETHICS
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards.
5.1
Institutional Review Board or Independent Ethics Committee
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries.
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin or its designee. The Investigator will provide the IRB/IEC/REB 
with all appropriate material, including the protocol, Investigator’s Brochure (IB), the 
Informed Consent Form (ICF) including compensation procedures, and any other written 
information provided to the subjects, including all ICFs translated to a language other than 
the native language of the clinical site. The study will not be initiated and Investigational 
Product (IP) supplies will not be shipped to the site until appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol, the ICF and all subject
recruitment materials are obtained in writing by the Investigator and copies are received at 
BioMarin or its designee. The approval document should refer to the study by protocol title 
and BioMarin protocol number (if possible), identify the documents reviewed, and include 
the date of the review and approval. BioMarin will ensure that the appropriate reports on the 
progress of the study are made to the IRB/IEC/REB and BioMarin by the Investigator in 
accordance with applicable guidance documents and governmental regulations.

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5.2
Ethical Conduct of Study
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible subjects for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability.
This study will be conducted in accordance with the following:
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country
US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6)
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the subjects will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF, and if applicable, a 
copy of the approved subject information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed.
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject.

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6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of subjects in this study.
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR.
Liver function tests (LFTs) will be performed at the local laboratories associated with the 
study sites.  Local laboratory results of LFTs will be used to trigger corticosteroid treatment 
as needed (refer to Section 9.4.8.2).  In case of discrepant results between local and central 
laboratories, the Investigator and Medical Monitor will decide further action.  Safety labs 
evaluations (including LFTs) will be performed at the central lab, while bioanalytical 
samples will be performed at the appropriate specialty lab.  Refer to the Laboratory Manual 
for more details.

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7
INTRODUCTION
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia ) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia ).
Chemical modification or bioengineering of FVIII may improve half-life to 18-19 hours
(Kaufman, 2013, Blood). However, these long acting FVIII variants do not eliminate the 
need for lifelong FVIII protein administration (Hay, 2012, Blood).  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of human FVIII following a single administration of vector. Haemophilia A is 
well suited for this approach because its clinical manifestations are attributable to the lack of 
a single gene product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. 
Tightly regulated control of gene expression is not essential and a modest increase in the 
level of FVIII (a plasma level of 2 ng/ml protein leads to a 1% expression) can ameliorate the 
severe phenotype (Srivastava, 2013, Haemophilia.); thus the therapeutic goal for gene 
therapy is a modest increase in hFVIII. Finally, the consequences of gene transfer can be 
assessed using simple quantitative rather than qualitative endpoints that can be easily assayed 
in most clinical laboratories.
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study.
7.1
Nonclinical Studies
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 

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nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints.
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in FVIII KO x Rag2 mice given matched IU 
levels of Refacto®.
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.  
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed.
The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 

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the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence closely matching that of 
the protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Nathwani, 2006, Blood). Despite 
distribution to non-liver organs, no expression of Factor IX was detected in these tissues.  
Additionally, distribution to the testis was observed in another study in monkeys given an 
AAV5-codon-optimized human porphobilinogen deaminase; however, vector genomes in the 
semen were only transiently observed within one week but not thereafter (Paneda, 2013,
Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents 10-fold safety factor from the 
no observed adverse effect level (NOAEL) in the GLP enabling nonclinical toxicology study 
in mice.
7.2
Previous Clinical Studies
This is the first clinical study for BMN 270.
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Engl.J.Med.), 
(Nathwani, 2014, N.Engl.J.Med.). The large size of the FVIII cDNA was shortened and a 
preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013,
Blood).

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AAV serotype 5 is being tested in other clinical trials and was reportedly well tolerated 
without treatment-related serious adverse events in a recent phase 1 study for treatment of 
Acute Intermittent Porphyria (D'Avola, 2014, J.Hepatol.). In addition, AAV using other 
serotypes have been used in 105 clinical studies to date and no safety issue specific to the 
vector was ever reported.  
7.3
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Mannucci, 2001, N.Engl.J.Med.).  It is caused by deficiency in the activity 
of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic coagulation cascade. 
This disorder can be either inherited, due to a new mutation or an acquired immunologic 
process, leading to insufficient quantities of FVIII or a dysfunctional FVIII, but all are 
characterized by a defective coagulation process. . The clinical phenotype of HA patients is 
largely governed by the level of residual expression. Severe HA is classified as FVIII activity 
less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild type activity 
and the mild form is 5-40% activity. The clinical manifestations of severe HA remain 
frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-4 times per 
week, and at the time of a bleed, to prevent or control bleeding episodes, respectively. The 
half-life for FVIII (12-18 hours for most approved products) necessitates frequent infusions, 
and although a major advance in the treatment of HA, it remains common for severe HA 
patients to continue to have multiple bleeding events on treatment (mean of 
1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year for on demand 
treatment) (Nagel, 2011, Haemophilia.).  The consequence of multiple bleeding events is the 
development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death (Nagel, 2011, Haemophilia).  Chemical 
modification (e.g. direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by approximately 
50%, and thus, show promise in reduced dosing and maintaining activity levels above 1% 
trough (Stonebraker, 2010, Haemophilia.), (Mahlangu, 2014, Blood). However, these longer 
acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive 
treatment of HA to give patients a FVIII level compatible with a normal and 
haemorrhage-free life. 

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Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, but
adeno-associated viral (AAV) vectors show the greatest promise (Mannucci, 2001,
N.Engl.J.Med.). They have an excellent and well defined safety profile, and can direct long 
term transgene expression with tropism for specific tissues such as the liver (Nathwani, 2005,
Curr.Hematol.Rep.) for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene 
therapy clinical trial for a related disorder, haemophilia B, has established that stable 
(>36 months) expression of human factor IX at levels that are sufficient for conversion of 
their bleeding phenotype from severe to moderate or mild is achievable following a single 
peripheral vein administration of AAV-8 vector (Nathwani, 2014, N.Engl.J.Med.). Several 
participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in 
bleeding. Thus, gene therapy treatment has resulted in a substantial improvement in their 
quality of life (Nathwani, 2011, Mol.Ther.), (Bainbridge, 2008, N.Engl.J.Med.), (Maguire,
2009, Lancet); (Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a liver-selective promoter (Figure 7.3.1). 

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Figure 7.3.1: hFVIII-SQ Vector Genome Schematic
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active FVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of FVIII in patients with severe 
HA.
7.4
Summary of Overall Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based 
on prior human studies with peripheral injections of AAV vectors, there is no known safety 
risk of AAV gene therapy. However, a mild asymptomatic transaminitis was observed at 
week 7-12 after administration in humans with an AAV8-FIX, providing the rationale for the 
following surveillance plan (Nathwani, 2011, Mol.Ther.). Each subject will have a 
comprehensive surveillance plan that monitors LFTs during the study. 
For additional information on safety findings in 270-201, refer to current version of the 
Investigator’s Brochure.
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose 
that maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the 
possibility of a sub-therapeutic effect. With this consideration in mind, the starting dose 
6E12 vg/kg was selected using overall data from the pre-clinical studies conducted in mice 
(normal and disease model, Rag2 -/- x FVIII -/-) and monkey. A detectable pharmacological 
response based on activity was observed at 6E12 vg/kg. A 10-fold safety margin based upon 
the NOAEL was observed in the GLP 13-week study in normal mouse at the highest dose 
administered. A 30-fold safety margin in an 8-week dose response study in disease model 
mice based on histology was observed at the highest dose administered. No BMN 270-related 

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changes in clinical observations or chemistry was observed in the monkey at doses up to 
6E13 vg/kg, a 10-fold safety margin after 8-weeks. Overall, no BMN 270-related findings, 
except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model 
mouse and monkey, respectively.
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to subjects with the best chance of 
benefiting the subject therapeutically.

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8
STUDY OBJECTIVES
The primary objectives of the study are:
To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. 
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII 
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270
dose.
The secondary objectives of the study are:
To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of AAV5-hFVIII-SQ
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study
To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study

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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years.
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled into one of up to four cohorts according to dose level: 
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single
intravenous dose (iv)
Cohort 2:  2E13 vg per kilogram, iv
Cohort 3:  6E13 vg per kilogram, iv
Cohort 4:  4E13 vg per kilogram, iv
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys. The starting dose has a significant safety margin (10-fold) 
from no observed adverse effect level (NOAEL) in mice.
Cohorts 1-3
The first three cohorts will be enrolled sequentially, allowing a period of 3 weeks or more 
between cohorts. Dose escalation may occur after a single subject in a cohort has been safely 
dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both assays. 
Three weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic 
doses. The decision to escalate to the next dose level will be made based on the review of 
safety parameters and FVIII activity by the Sponsor and a panel of investigators participating
in the study.   
IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects.

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Figure 9.1.1: Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3 
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in Cohort 2 
IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.
If the FVIII activity level in the first subject treated in Cohort 3 
IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in the Cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals. 
Cohort 4   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the Data Review Board (DRB).  The adaptive nature of this trial allows the DRB 

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to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals.
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity 
for therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dosing. Any safety signal
may trigger a review of the data and possible additional immunogenicity studies that include 
an assessment of cellular immune responses using collected PBMC. Additionally, if any of 
the events listed in Section 9.3.3.1 occur, enrollment into the trial will be halted to complete 
an extensive safety analysis. Notification of the study enrollment halt will be sent by the 
Sponsor to the participating sites via telephone and email immediately after becoming aware 
of a safety concern. This will ensure no additional subjects are dosed until the signal has been 
completely evaluated. If, following safety review by the DRB and the Sponsor, it is deemed 
appropriate to restart dosing, a request to restart dosing with pertinent data will be submitted 
to the health authority. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 and Table 9.1.4 for Safety Follow-up. 
Table 9.1.5, dealing with therapeutic corticosteroid use in the event of elevated LFTs, is 
discussed in Section 9.4.8.2.

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Table 9.1.1: Schedule of Events – Screening and Infusion
Assessment
Prior to BMN 270 Infusion
BMN 270 
Infusion 
Visit (Day 1)k
Screeningi
(Day -28 to Day -1)
Smart Rescreeningi
(Day -28 to Day -1)
Baseline (Day -7
to Day -1)h
Informed consent
X
Medical History
X
Physical Examinationa
X
X
X
Height and Weighta
X
Vital Signs
X
X
X
Assessment of Adverse Events and Concomitant Medications
X
X
X
X
Documentation of bleeding episodes and FVIII usage (by either subject or 
clinical information)
X
X
X
Distribution of subject diaries and training in their use
X
Electrocardiogram
X
Chest X-ray
X
Liver Ultrasound
X
hFVIII Assaysb
X
Xj
AAV5 Assaysc
X
X
X
Screen for Hepatitis B, Hepatitis C, HIVd
X
Blood chemistry, haematology, coagulation screen, and CRPe
X
X
X
Urine Testse
X
X
X
Liver Function Testse
X
X
X
PBMC collection for CTL baseline
X
Von Willebrand Factor Antigen (VWF:Ag)
X
Direct Thrombin Test
X
PCR of vector DNA in blood, saliva, urine, semen, and stools
X
Biomarker testingf
X
Exploratory biomarker assessmentsg
X
Haemo-QoL-A Quality of Life (QoL) assessment
X
BMN 270 Infusion
X

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a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height will be 
recorded at Screening only. Weight will be recorded at Screening and then every 6 months thereafter.
b Includes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay 
with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).  
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction 
inhibition, in vitro transduction inhibition and AAV5 total antibody assays).  Sample collection on the day of the infusion visit must be performed before the BMN 270 
infusion is given.
d Patients with documented negative results within the last 30 days do not need to be retested.
e Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.
f Includes HLA genotyping, FVIII genotyping, TNF
and IL10a single nucleotide polymorphisms.
g Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease. The 
exploratory genetic/genomic testing on these samples is optional.
h Should the screening visit occur within 7 days of the drug infusion, physical examination, blood chemistry, LFTs, haematology, urine tests, coagulation screen, and CRP 
do not need to be repeated at Baseline.
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion 
prior to the closing of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion
within 90 days of signing the original consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures.
Subjects may not undergo smart rescreening more than once.
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening.
k Assessments on the day of infusion must be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, 
during the infusion every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at
4 hour intervals (± 15 minutes). 

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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16)
Assessment
Follow-Up After BMN 270 Administration – Weeks*
Week 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
D2
D4
D8
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary 
for bleeding and FVIII use)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, haematology, coagulation 
screen, and CRPb
X
X
X
X
X
X
X
Urine Testsb
X
X
X
X
Liver Function Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Function Tests (central)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII antibody titer
X
X
X
X
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolse
X
X
X
X
X
X
X
X
X
X
Exploratory biomarker assessmentsf
X
X
X
X
Haemo-QoL-A QoL assessment
X
X
X
X
X
AAV5 antibody titer
X
X
Testing for reactivation of hepatitis B and 
hepatitis C
Xg
PBMC collection 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
X
Direct Thrombin test
X
X

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* Visit windows are ± 48 hours (and include the Day 4 visit)
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests. LFTs may be monitored more or less frequently (and in 
particular when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data. Patients with ALT > 1.5 
ULN during the study may undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the 
discretion of the investigator.
c Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay). If a subject has used FVIII within 72 hours of a measurement day, all efforts should be 
made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved. If FVIII levels are elevated or stable over the course of several 
weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A d-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII 
coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances 
in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection to occur on Day 2 and 4 following BMN 270 infusion, and then until at least 3 consecutive negative results are obtained. Collection and testing of semen 
samples must continue through Week 12, even if 3 consecutive negative samples in that compartment have already been recorded.
f Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease. The 
exploratory genetic/genomic testing on these samples is optional.
g Testing for reactivation of hepatitis B and hepatitis C at Week 16 should be performed only in subjects who have not received therapeutic corticosteroids prior to 
Week 16; subjects who have received therapeutic corticosteroids will have hepatitis B and hepatitis C testing at the time points indicated in Table 9.1.5. 

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Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) 
Assessment
Follow-Up After BMN 270 Administration – Weeks*
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary for 
bleeding and FVIII use)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, haematology, coagulation screen, 
and CRPb
X
X
X
X
Urine Testsb
X
X
X
X
Liver Function Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Function Tests (central)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII antibody titer
X
X
PCR of vector DNA in blood, saliva, urine, semen, 
and stoolse
X
X
X
X
Exploratory biomarker assessmentsf
X
X
Haemo-QoL-A QoL assessment
X
AAV5 antibody titer
X
X
X
X
PBMC collection 
X
X
X
X
X
X
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
X
Direct Thrombin test
X
* Visit windows are ± 48 hours
a Brief physical examination should be done at all weekly visits.  Refer to Section 9.7.8.5.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests. LFTs may be monitored more or less frequently (and in 
particular when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data.  Patients with ALT > 1.5 
ULN during the study may undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the 
discretion of the investigator.

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c Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be 
made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several 
weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII 
coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances 
in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
e Collection to occur until at least 3 consecutive negative results are obtained.
f Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease. The 
exploratory genetic/genomic testing on these samples is optional.

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Table 9.1.4:  Schedule of Events – Safety Follow-Up
Assessment
Year 1 – Weeks*
Years 2-5
ETV
33
34
35
36
38
40
42
44
46
48
50
52
Q3M
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weighta
X
Xa
Assessment of Adverse Events and Concomitant 
Medications (including review of subject diary for 
bleeding and FVIII use)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, haematology, coagulation screen, and 
CRPb
X
X
X
X
X
X
X
Urine Testsb
X
X
X
X
X
X
X
Liver Function Tests (local)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (local)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Function Tests (central)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FVIII assays (central)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AAV5 antibody titer
X
X
X
X
X
X
X
FVIII antibody titer
X
X
X
X
X
PBMC Collection (for determination of FVIII and 
Capsid specific CTL activity)
X
X
X
X
X
X
Von Willebrand Factor Antigen (VWF:Ag)
X
X
X
X
X
X
X
Direct Thrombin Test
X
X
X
X
PCR of vector DNA in blood, saliva, urine, semen, and 
stoolse
X
X
X
X
X
X
Haemo-QoL-A QoL assessment
X
Xf
X

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* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52 and ± 2 weeks for visits in Years 2-5.
a Complete physical examination should be performed at Week 52 and every 52 weeks thereafter; brief physical examination may be performed at other study visits.  
Refer to Section 9.7.8.5. During Years 2-5, weight should be performed every 6 months.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests. LFTs may be monitored more or less frequently (and in 
particular when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data. Patients with ALT > 1.5 
ULN during the study may undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the 
discretion of the investigator.
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be 
made to obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved. If FVIII levels are elevated or stable over the course of several 
weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII 
coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances 
in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period. Subjects who have not 
had 3 consecutive negative samples by Week 52 should continue to have PCR testing every 4 weeks until 3 consecutive negative samples are documented (or upon 
consultation between the Investigator and Medical Monitor).
f Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 6 months) starting with the Week 78 visit (ie, 
26 weeks after the Week 52 visit at the end of Year 1 of the Safety Follow-up period).

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Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids
Steroid Treatment Periodd
Post-Steroid Periodc
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11b
Week 
1
Week 
2
Week 
3
Week 
4
Week 
13
Therapeutic
corticosteroids 
(dose in 
mg/day) a 
60 mg
60 mg
40 mg
40 mg
30 mg
30 mg
20 mg
20 mg
15 mg
10 mg
5 mg
FVIII activity 
testing
X 
X 
X 
X 
Liver function 
testing
X 
X 
X 
X 
Hepatitis B 
testing
X
X
X
HCV Viral 
Load
X 
X 
X 
a Therapeutic corticosteroids 
review of FVIII and liver enzyme data after consultation between 
the Investigator and the Medical Monitor.
b Following initiation or completion of steroid regimen, if ALT elevation  
1.5x ULN is reported, steroid management decisions will based on discussions between the 
Investigator and Medical Monitor. Modification of the steroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII
expression.
c After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values. If these 
assessments are already being done as part of normal study follow-up, they do not need to be duplicated.
d Regardless of the assessments listed in the Schedule of Assessments (Table 9.1.2, Table 9.1.3, or Table 9.1.4), subjects initiated on corticosteroids will only be required 
to have laboratory evaluations on a weekly basis.

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9.2
Discussion of Study Design, Including Choice of Control Group
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Four doses of BMN 270 will be evaluated and the dose 
escalation decision tree for Cohorts 1-3 is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and the DRB. 
There will be no control group. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy). 
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3
Selection of Study Population 
Up to 15 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation.  
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2.
9.3.1
Inclusion Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
1. Males that are 18 years or older with established severe Haemophilia A as evidenced 
by their medical history.  Patients will be considered as severe if their base FVIII 
level is 1 IU/dL or less
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs) 
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less 
than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within 
the past 12 months 
6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment.  After 6 months, subjects may stop contraception use only if they have 
had 3 consecutive negative semen samples.

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9.3.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study:
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition or AAV5 total antibodies
2. Any evidence of active infection or any immunosuppressive disorder.  
3. HIV positive
4. Significant liver dysfunction as defined by abnormal elevation of:
ALT (alanine transaminase) to 3 times the upper limit of normal;
Bilirubin above 3 times the upper limit of normal;
Alkaline phosphatase above 3 times the upper limit of normal; or
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if 
they had significant fibrosis of 3 or 4 as rated on a scale of 0-4
6. Evidence of any bleeding disorder not related to Haemophilia A
7. Platelet count of < 100 x 109/L
8.
9. Liver cirrhosis of any etiology as assessed by liver ultrasound 
10. Hepatitis B if surface antigen is positive
11. Hepatitis C if RNA is positive
12. Treatment with any IP within 30 days prior to the end of the screening period
13. Any disease or condition at the physician’s discretion that would prevent the patient 
from fully complying with the requirements of the study including possible 
corticosteroid treatment outlined in the protocol. The physician may exclude patients 
unwilling or unable to agree on not using alcohol for the 16-week period following 
the viral infusion.
14. Prior treatment with any gene transfer agent
15. Major surgery planned in the 16-week period following the viral infusion
16. Use of immunosuppressive agents or live vaccines within 30 days before the viral 
infusion

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9.3.3
Removal of Subjects from Treatment or Assessment
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 
BioMarin must be notified of all subject withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following: 
Subject requires medication or medical procedure prohibited by the protocol 
Subject does not adhere to study requirements specified in the protocol 
Subject was erroneously admitted into the study or does not meet entry criteria 
Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study.
9.3.3.1
Study Safety Evaluation Criteria
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis 
per Section 9.1.

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Any ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of 
BMN 270, in the absence of a definitive alternate etiology for the increase
The occurrence of Grade 3 or higher adverse events (excluding ALT elevation) 
assessed as related to study drug, including liver failure and clinical hepatitis
The detection of neutralizing antibodies to hFVIII following BMN 270 infusion 
The detection of AAV vector DNA in the semen of a participant in 3 consecutive 
samples (which are at least 2 weeks apart) more than 52 weeks after BMN 270 
infusion, as discussed in Section 9.7.8.6
The occurrence of a malignancy excluding skin cancers at any point after BMN 270 
infusion 
If the following event occurs in a subject in the study who has received BMN 270 infusion, a 
DRB review and analysis of safety data will be undertaken to determine whether the 
enrollment into the trial will be put on halt:
Grade 2 adverse event assessed as related to study drug that persists for at least 7 days  
9.3.4
Subject Identification and Replacement of Subjects
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Subjects who withdraw from the study will not be replaced. 
9.3.5
Duration of Subject Participation
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks.
9.4
Treatments
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1
Treatments Administered
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 

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9.4.2
Identity of Investigational Product
9.4.2.1
Product Characteristics and Labeling
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer.
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements.
9.4.3
Storage
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 
stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures.
9.4.4
Directions for Administration
After a physical examination performed by the PI or designee, participants will be admitted 
on the day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral 
vein (e.g. the median cubital vein) and flushed with saline. FVIII replacement therapy will 
not be given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions.
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter.
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 ml/min while monitoring the vital signs (pulse, blood pressure, respiration
rate and temperature) at 15 minute (± 5 minutes) intervals. The anticipated maximum
interval from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, 
although the IP has been shown to be stable at room temperature for 6 hours.
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis
at the puncture site will be established by applying pressure according to standard
protocol for infusing FVIII concentrates. Subjects will remain in the clinic for 24 hours to
observe for any immediate toxicity of the procedure. After 24 hours, participants will be

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discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical
Monitor. 
9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study subject. Upon their enrollment into the study, subjects will be assigned a unique subject
number and dose level by the Sponsor.
Cohorts 1 to 3 are enrolled serially and their dose is defined in Section 9.4.6.2 below. 
Escalation is based on FVIII activity 3 weeks after injection. Cohorts may receive the next 
higher dose if subjects in the previous cohort does not meet the activity criteria, or the same 
dose if subjects in the previous cohort meets the activity criteria. Subjects in Cohort 4 will all 
be enrolled at a single dose.
9.4.6
Selection of Doses Used in the Study
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in mice. The dose escalation is half-logs based.    
9.4.6.1
Selection of Timing of Dose for Each Subject
A minimum of three weeks are required between subjects, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next subject will be made as described below. 
9.4.6.2
Selection of Dose for Each Subject
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus potentially decreasing the risk of immune response), and a new 
evaluation of the titer (PCR performed after hairpin removal). 
For Cohorts 1 to 3, approximately three weeks after an injection, the decision to escalate to 
the next dose level will be made based on the review of safety parameters and FVIII activity 
by the Sponsor and the DRB.  
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1)

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at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject
IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.
If the FVIII activity level in the first subject treated in Cohort 3 
IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
 IU/dL and no safety issue is found, then up to four subjects will be enrolled in that cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
ay be enrolled in 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB.  The adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals.
Refer to Figure 9.1.1 for a visual representation of the study design for Cohorts 1-3 
9.4.7
Blinding
This is an open-label study.
9.4.8
Prior and Concomitant Medications
All prescription and over-the-counter medications (including dietary and herbal supplements) 
taken by a subject for 30 days before Screening will be recorded on the designated CRF. The 
Investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF.

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The following medications are prohibited starting 30 days before Screening:
Live vaccines
Systemic immunosuppressive agents
Medications which are predominately metabolized by the liver (e.g., acetaminophen) and 
alcohol should, whenever possible, be avoided for the first 52 weeks of the study, and 
particularly within 48 hours prior to lab work.
9.4.8.1
Concomitant Haemophilia Treatments
Subjects on “on demand” therapy for FVIII will continue their treatment at will. Subjects on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and 
switch to an “on demand” schedule. FVIII can always be taken as needed by the subject, who 
will carefully record his treatment and bleeding episodes in his diary. In addition, 
information on FVIII usage by medical history will be collected (if available) from subjects 
for the 6 month period immediately preceding study enrollment.
9.4.8.2
Glucocorticoid Treatment of Elevated Hepatic Transaminases
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject
will have comprehensive surveillance plan monitoring of LFTs (at local labs, once per week 
for Weeks 1-36, then once every 2 weeks from Week 37-52). LFTs may be monitored more 
or less frequently (and in particular when ALT values are >1.5x ULN) based on discussion 
between the Medical Monitor and the Investigator and review of subject data. 
9.4.8.2.1
Therapeutic Corticosteroids
In general, therapeutic corticosteroids may be initiated when a subject’s ALT value is 
1.5x ULN, or based on review of FVIII and liver enzyme data after consultation between 
the Medical Monitor and the Investigator.
Reports of raised LFTs (defined as ALT
1.5x ULN) should be made to the BioMarin 
medical monitor within 30 minutes of the lab value being available. Local laboratory results 
of LFTs will be used to trigger corticosteroid treatment as needed.  In case of discrepant 
results between local and central laboratories, the Investigator and Medical Monitor will 
decide further action.
Following initiation or completion of therapeutic corticosteroids, if ALT elevation 
1.5x ULN is reported, steroid management decisions will based on discussions between the 
Investigator and Medical Monitor. Modification of the steroid regimen may take into 
consideration possible confounders for the ALT elevation and impact on FVIII expression.

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Treatment with prednisolone will be initiated at a dose of 60 mg per day and then gradually 
tapered (60 mg daily for the first 2 weeks, then 40 mg the next 2 weeks, then 30 mg the next 
two weeks, then 20 mg the next two weeks, then 15 mg for the next week, then 10 mg for the 
next week, then 5 mg for the next week, then stop, for a total treatment of 11 weeks) (refer to 
Table 9.1.5).  
After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be 
measured once a week for 4 weeks to ensure stability in values.
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This 
includes the contraindicated use of NSAIDs during corticosteroid treatment, and specific 
monitoring not already covered by the schedule of events. Hepatitis B status and HCV viral 
load will be rechecked 6 weeks after the start of corticosteroid treatment, and then 1 week 
and 13 weeks after the completion of corticosteroid treatment. All adverse events should be 
reported as outlined in Section 10 of the protocol. 
9.4.9
Treatment Compliance
Study drug will be administered to subjects at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided 
for the study.  Sites will be instructed to return or destroy all used and unused study drug 
containers.
9.5
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data.
9.5.1
Return and Disposition of Clinical Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials.
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 

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appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a Study Drug Return Form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6
Dietary or Other Protocol Restrictions
There are no dietary or other protocol restrictions for this study. 
9.7
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8.
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
 weeks post 
BMN 270 administration. 
9.7.1
Safety and Efficacy Measurements Assessed
The Schedule of Events (Table 9.1.1 through Table 9.1.4) describes the timing of required 
evaluations.
9.7.2
Primary Efficacy Variables
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to expression of FVIII at 5 IU/dL or above, 
i.e., a mild severity. This is associated in natural history studies with clinically superior long 
term outcomes (Den Ujil, 2011, Haemophilia). 
The following assays (assessed by the central laboratory) will be used to measure the primary 
efficacy variable:
FVIII activity (chromogenic FXa assay)
FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time)
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made 
to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved.
The FVIII activity level in both assays and the number of subjects with FVIII activity 
 5 IU/dL in at least one of the two assays will be summarized.

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FVIII activity assays will also be performed at the local laboratory at the time points 
indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4, but will be used in conjunction with 
local lab LFT assessments to monitor subject safety and need for initiation of therapeutic 
corticosteroid dosing; local laboratory FVIII activity assessments will not be used to assess 
efficacy or to measure the primary efficacy outcome of the study.
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.  Details on performing the assays are included in the Laboratory Manual.
9.7.3
Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Subjects will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the subject’s diary or 
other subject records.
9.7.4
Immunogenicity
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
5-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to a retrospective immunogenicity assessment to determine 
anti-FVIII and capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be 
performed on collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.
9.7.5
Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage APTT and/or chromogenic FXa assay (activity).  Individual antigen and activity 
plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity measurements 
will be used to determine PD parameters.
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration),
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 

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concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology.
Sample collection times are indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4.
9.7.6
Exploratory Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1,
Table 9.1.2, Table 9.1.3, and Table 9.1.4 to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to Haemophilia A disease. The exploratory 
genetic/genomic testing is optional.
All biomarker samples collected in this study may be used for exploratory biomarker 
research including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes may be used for exploratory use once the 
primary use has been completed.
On an exploratory basis, samples may be fractionated prior to shedding analysis in order to 
better characterize the presence and location of vector DNA and/or vector capsid within each 
matrix. The fractionation may be performed with samples collected specifically for shedding 
analysis (saliva, blood, semen, urine, faeces), or by using exploratory samples, such as 
plasma, PBMCs, and red blood cells, collected under the study protocol.  
9.7.7
Haemo-QoL-A Quality of Life Assessment
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to 
assess subject quality of life (QoL) during the study.  Assessments will occur at the time 
points listed in the Schedules of Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual.
9.7.8
Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
9.7.8.1
Adverse Events
The occurrence of AEs will be assessed continuously from the time the subject signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1,
Table 9.1.2, Table 9.1.3, and Table 9.1.4.

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9.7.8.2
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, and Table 9.1.4. The scheduled clinical laboratory tests 
are listed in Table 9.7.8.2.1. Refer to the Study Reference Manual for instructions on 
obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant.
All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF.
Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry
Haematology
Urine Tests
Other
Albumin
Haemoglobin 
Appearance
CRP
BUN
Haematocrit 
Color
Calcium
WBC count
pH
Coagulation Screen
including:
Chloride
RBC count
Specific gravity
APTT
Total cholesterol
Platelet count
Ketones
PT/INR
CO2
Differential cell count 
Protein 
TT
CPK
Glucose 
Creatinine
Bilirubin
Glucose 
Nitrite
Phosphorus 
Urobilinogen 
Potassium
Haemoglobin
Total protein
Sodium
Uric Acid
BUN, blood urea nitrogen; CO2, carbon dioxide; CRP, C-reactive protein; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; INR, 
international normalized ratio.

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9.7.8.3
Liver Function and Hepatitis Testing
Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening.   Subjects with documented results showing an absence of active Hepatitis B or 
Hepatitis C infection (as measured by positive surface antigen for hepatitis B or positive 
RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need 
to be screened again.   
Evidence of ongoing Hepatitis B or Hepatitis C infection is exclusionary. Subjects who have 
cleared a Hepatitis B infection or are seronegative do not need to receive the Hepatitis B 
vaccination.  
Subjects will be tested for hepatitis B and hepatitis C reactivation at Week 16.  Subjects who 
receive therapeutic corticosteroids prior to Week 16 do not need to complete the Week 16 
reactivation assessment; instead, they will be tested for hepatitis B and hepatitis C 
reactivation at the time points listed in Table 9.1.5.
A liver ultrasound and liver function testing at Screening will identify any significant hepatic 
dysfunction, which is defined as: 
More than 3x the normal ALT level 
More than 3x the normal bilirubin level 
More than 3x the normal Alkaline phosphatase level. 
INR > 1.4.  
Thrombocytopoenia under 100 x 109/L
Liver ultrasound results indicative of a liver cirrhosis  
Liver function tests will be monitored on a regular basis, at the time points indicated in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, and Table 9.1.4.  At each time point, the following 
LFTs should be assessed: 
Table 9.7.8.3.1:  Liver Function Tests
Liver Function Tests
Alkaline Phosphatase
AST (SGOT)
Total Bilirubin
LDH
ALT (SGPT)
Direct Bilirubin
GGT
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, 
lactate dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic 
transaminase

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Patients with ALT > 1.5 ULN during the study may undergo additional evaluations (e.g., 
imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at 
the discretion of the investigator. 
9.7.8.4
HIV Testing
HIV testing will be performed at Screening.  Subjects with documented negative results 
within the last 30 days prior to screening do not need to be retested. 
9.7.8.5
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE.
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored prior to infusion, during the infusion every 
15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then 
every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).  
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 
and every 52 weeks thereafter; at other visits, brief physical examinations may be performed 
at the discretion of the investigator based on the subject’s clinical condition. Particular 
attention should be given to signs of bleeding, as well as assessing possible hemarthroses.
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems. 
A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 
Height will be recorded at Screening only. Weight will be recorded at Screening and then 
every 6 months thereafter. 
9.7.8.6
Vector Shedding
Vector shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 2007, J.Gene 
Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the literature referenced above, including 
Haemophilia B clinical studies utilizing AAV2 and AAV8, vector was no longer detectable 

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after 40 days in blood, saliva, urine or stool, but in one study was detected in the seminal 
fluid but not in motile sperm (Manno, 2006, Nat.Med.). In these studies, the amount of 
vector present in these bodily fluids involved an extremely small fraction of the infused dose.  
More recent data from an ongoing AAV-FIX study demonstrates persistence of the vector in 
both the blood and the semen for at least 39 weeks (Miesbach, 2016, Haemophilia).
During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily 
samples to look for evidence of vector shedding for possible viral transmission.  Bodily 
fluids will be tested by PCR at the time points indicated in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4. Fluids tested will include:
Blood 
Saliva
Semen
Urine
Stool 
Vector shedding will also be extensively studied in the present clinical trial, every other week 
between Weeks 4-16, then every 4 weeks to Week 52 until at least 3 consecutive negative 
results are obtained.  Testing of semen will continue through Week 12, even if 3 consecutive 
negative results have been recorded in that compartment prior to that timepoint.  Subjects 
who have not had 3 consecutive negative samples by Week 52 should continue to have PCR 
testing every 4 weeks until 3 consecutive negative samples are documented (or upon 
consultation between the Investigator and Medical Monitor). 
Contraception use may need to be extended beyond 26 weeks in individual subjects based on 
observed vector shedding in semen.  After 6 months, subjects may stop contraception use 
only if they have had 3 consecutive negative semen samples. 
Details for sample collection and storage are provided in the Laboratory Manual. 

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10
REPORTING ADVERSE EVENTS
10.1
Safety Parameters and Definitions
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug.
10.1.1 Adverse Events
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a subject administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following:
AEs not previously observed in the subject that emerge during the course of the 
study.
Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study.
Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures).
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE.
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only 
because the subject is a haemophiliac) should not be recorded as AEs but will instead be 
captured in subject diaries.  Bleeding events that occur where a normal 
(ie, non-haemophiliac) patient would bleed, such as bleeding as a result of major trauma, 
should be recorded as adverse events.  All bleeding events which meet criteria for being 
serious should be reported as serious adverse events (SAEs) whether or not they are bleeding 
events that are normal sequelae of haemophilia.
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis.

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10.2
Serious Adverse Events
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria:
Is fatal
Is life threatening 
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
Requires or prolongs inpatient hospitalization.   
Results in persistent or significant disability or incapacity
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of  the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as non-
serious AEs.
10.2.1 Events of Special Interest (EOSI) 
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality: 
Elevation of liver enzymes (ALT) that triggers an initiation or modification of  
corticosteroid treatment
10.3
Methods and Timing for Capturing and Assessing Safety Parameters
10.3.1 Adverse Event Reporting Period
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.2.

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10.3.2 Eliciting Adverse Events
Investigators will seek information on AEs, SAEs, and EOSI at each subject contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the subject’s medical record and on the AE Case Report 
Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.2 for 
SAE definitions).  These assessments must be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS).
10.3.3.1
Seriousness
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.3.3.2
Severity
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1.
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 

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Table 10.3.3.2.1: Adverse Event Grading (Severity) Scale
Grade
Description
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated
Grade 4 and 5 AEs 
should always be 
reported as SAEs
5
Death related to AE
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money.
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden.
10.3.3.3
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1.

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Table 10.3.3.3.1: Causality Attribution Guidance
Relationship
Description
Not Related
Exposure to the IP has not occurred
OR
The administration of the IP and the occurrence of the AE are not 
reasonably related in time 
OR
The AE is considered likely to be related to an etiology other than the 
use of the IP; that is, there are no facts, evidence, or arguments to 
suggest a causal relationship to the IP.
Related
The administration of the IP and the occurrence of the AE are 
reasonably related in time
AND
The AE could possibly be explained  by factors or causes other than 
exposure to the IP
OR
The administration of IP and the occurrence of the AE are reasonably 
related in time 
AND
The AE is more likely explained by exposure to the IP than by other 
factors or causes.
Factors suggestive of a causal relationship could include (but are not limited to):
Plausible temporal relationship
Absence of alternative explanations
Rarity of event in a given patient or disease state
Absence of event prior to study drug exposure
Consistency with study product pharmacology
Known relationship to underlying mechanism of study drug action
Similarity to adverse reactions seen with related drug products
Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug

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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities.
10.4
Procedures for Recording Adverse Events
10.4.1 Recording Adverse Events on a eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations.
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries).
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology.
10.4.1.1
Diagnosis versus Signs and Symptoms
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE (or SAE, as appropriate) eCRF, replacing the original 
entries where appropriate.
10.4.1.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF.
10.4.1.3
Persistent or Recurrent Adverse Events
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF.

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A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF.
10.4.1.4
Abnormal Laboratory Values
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable.
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the AE eCRF.
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met:
Accompanied by clinical symptoms
Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation) 
Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or
treatment).
The abnormality suggests a disease and/or organ toxicity
The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.)
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed.

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10.4.1.5
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches).
10.4.1.6
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF.
10.4.1.7
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2).
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to:
Perform a protocol-mandated efficacy measurement
Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
Hospitalization solely for the purpose of insertion of an in-dwelling IV catheter (such 
as a Port-a-Cath or other brand) for administration of study drug will not be 
considered an SAE. 
Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8
Deaths
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 

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is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event.  The Investigator must make every effort to 
follow the subject’s partner (with that partner’s consent) through resolution of the pregnancy 
(delivery or termination) and to report the resolution on the Pregnancy Follow-up Form in the 
study reference materials. In the event of pregnancy in the partner of a study subject, the 
Investigator should make every reasonable attempt to obtain the woman’s consent for release 
of protected health information.
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5
Reporting Requirements
10.5.1 Expedited Reporting Requirements
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF  and submitting  to BPV within 24 hours of the site 
becoming aware of the event. Investigators should not wait to collect information that fully 
documents the event before notifying BPV of an SAE.  BioMarin may be required to report 
certain SAEs to regulatory authorities within 7 calendar days of being notified about the 
event; therefore, it is important that Investigators submit any information requested by 
BioMarin as soon as it becomes available.
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations.
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 

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becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF.
10.5.2 Ethics Committee Reporting Requirements
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required.
10.6
Follow-up of Subjects after Adverse Events
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the subject is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the subject’s medical record to facilitate source data verification.
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report.
10.7
Post-Study Adverse Events
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment.
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study. 
10.8
Urgent Safety Measures
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 

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investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.” 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours.
Examples of situations that may require urgent safety measures include discovery of the 
following:
Immediate need to revise the IP administration (eg, modified dose amount or 
frequency not defined in protocol)
Lack of study scientific value, or detrimental study conduct or management
Discovery that the quality or safety of the IP does not meet established safety 
requirements
10.9
BioMarin Pharmacovigilance Contact Information
Contact information for BioMarin Pharmacovigilance is as follows:
BioMarin Pharmaceutical Inc.
Address
105 Digital Drive
Novato, CA 94949
Phone:
Fax:
E-mail:
drugsafety@bmrn.com
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows:
Name:
, MD
Address:
105 Digital Drive
Novato, CA 94949 USA
Phone:
E-mail:
PI
PI
PI
PI
PI

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11
APPROPRIATENESS OF MEASUREMENTS
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures.
The chromogenic FXa assay and the one-stage APTT assay are both validated and utilize CE 
marked reagents.  The exploratory FVIII activity assay will be used for exploratory purposes 
only.

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12
STUDY PROCEDURES
12.1
Prestudy
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed.
12.2
Screening Visit
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LFTs, haematology, urine tests, coagulation screen, and CRP do 
not need to be repeated at Baseline. 
The following procedures will be performed during the Screening Period:
Full medical history, including haemophilia A history, Hepatitis B, Hepatitis C, and 
HIV. 
Complete Physical Examination
Height and weight
Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature) 
Assessment of Adverse Events and Concomitant Medications
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
Electrocardiogram
Chest X-ray
Liver Ultrasound
Samples for hFVIII Assays
o
Baseline hFVIII activity – chromogenic FXa (plasma)
o
Baseline hFVIII activity level – one-stage APTT assay
o
hFVIII coagulation activity exploratory assay
o
hFVIII inhibitor level (Bethesda assay with Nijmegen modification)
o
hFVIII total antibody assay
o
hFVIII antigen (ELISA)

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Blood sample for AAV5 Assays 
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay 
Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested)
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
Urine Tests (refer to Table 9.7.8.2.1)
Liver Function Tests (refer to Table 9.7.8.3.1)
Von Willebrand Factor Antigen (VWF:Ag)  
Blood samples for Biomarker testing (including HLA genotyping, FVIII genotyping 
status, TNF  and IL10a single nucleotide polymorphisms) 
12.2.1 “Smart Rescreening” Visit
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study:
Vital signs
Assessment of Adverse Events and Concomitant Medications 
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification)
Blood sample for AAV5 Assays 
AAV5 antibody titer
AAV5 transduction inhibition assay 
Blood chemistry, haematology, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 

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Urine Tests (refer to Table 9.7.8.2.1)
Liver Function Tests (refer to Table 9.7.8.3.1) 
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period:
Physical examination
Assessment of Adverse Events and Concomitant Medications 
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
Distribution of subject diaries and training in diary completion
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
Urine Tests (refer to Table 9.7.8.2.1)
Liver Function Tests (refer to Table 9.7.8.3.1) 
PBMC collection for CTL baseline
Direct Thrombin test
PCR of vector DNA in blood, saliva, urine, semen, and stools 
Exploratory biomarker assessments 
Haemo-QoL-A QoL assessment
12.4
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each subject. Subjects will remain in the clinic for 
24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
Physical examination
Assessment of Adverse Events and Concomitant Medications 
Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
o
AAV5 antibody titer
o
AAV5 transduction inhibition assay 
BMN 270 Infusion 
Vital Signs

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o
Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the subject’s stay in 
the clinic.
12.5
BMN 270 Infusion Follow-Up Visits
After BMN 270 has been infused, subjects will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Once per week (Weeks 1 through 16) 
The following procedures will be performed at one visit per week from Weeks 1 through 16: 
Physical examination
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
Vital Signs
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
Samples for FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.
o
Central assessment of FVIII activity level should be performed 1x/week 
from Week 1 through Week 16 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 

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FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
PBMC collection
12.5.2 Week 1 – Day 2 and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed:
PCR of vector DNA in blood, saliva, urine, semen, and stools (Day 2 and Day 4)
Samples for FVIII Assays (Day 4 only) – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  
Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – central laboratory 
assessment
Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – local laboratory 
assessment
FVIII activity level (Day 4 only) – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
12.5.3 Week 1 – Day 8 
On Day 8, the following procedures will be performed: 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
Direct Thrombin test 
Haemo-QoL-A QoL assessment

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12.5.4 Every 2 Weeks
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedures will be 
performed:
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
(not assessed at Week 14)
PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at Week 
2) 
o
Collection to occur until at least 3 consecutive negative results are 
obtained.  Semen samples should continue to be collected and tested 
through Week 12, even if 3 consecutive negative results in that 
compartment have been recorded prior to that timepoint. 
12.5.5 Weeks 4, 8, 12, and 16 
At Weeks 4, 8, 12, and 16, the following procedures will be performed:
Urine Tests (refer to Table 9.7.8.2.1)  
VWF:Ag
FVIII antibody titer
Exploratory biomarker assessments 
12.5.6 Week 16 
At Week 16, the following procedures will be performed: 
Test for Hepatitis B and Hepatitis C reactivation
o
Subjects will be tested for hepatitis B and hepatitis C reactivation at Week 
16.  Subjects who receive therapeutic corticosteroids prior to Week 16 do 
not need to complete the Week 16 reactivation assessment; instead, they 
will be tested for hepatitis B and hepatitis C reactivation at the time points 
listed in Table 9.1.5.
12.5.7 Weeks 8 and 16 
At Weeks 8 and 16, the following procedures will be performed:
AAV5 antibody titer
12.5.8 Weeks 2, 3, 4, and 16 
At Weeks 2, 3, 4, and 16, the following procedure will be performed: 
Haemo-QoL-A QoL assessment

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12.5.9 Week 13
At Week 13, the following procedure will be performed: 
Direct Thrombin test
12.6
Safety Follow-Up – Weeks 17-36 
After the Post-Infusion Follow-Up visits are complete, subjects will return to the study site
for Safety Follow-Up visits from Weeks 17 through Week 36 (± 48 hours), when the 
following procedures will be completed: 
12.6.1 Once per week (Weeks 17 through 36)
Once per week from Week 17 through Week 36, the following procedures will be performed: 
Physical examination
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
Vital Signs
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)

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o
FVIII activity level (chromogenic FXa assay)
12.6.2 Once per week (Weeks 17 through 20) 
Once per week from Week 17 through Week 20, the following procedures will be performed: 
PBMC collection
12.6.3 Every 2 weeks (Weeks 21 through 36) 
Every 2 weeks (Weeks 22, 24, 26, 28, 30, 32, 34, and 36), the following procedures will be 
performed:
PBMC collection
12.6.4 Every 4 Weeks
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed: 
Exploratory biomarker assessments (Weeks 20 and 24 only) 
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
Urine Tests (refer to Table 9.7.8.2.1)
VWF:Ag
AAV5 antibody titer
PCR of vector DNA in blood, saliva, urine, semen, and stools 
o
Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period. 
12.6.5 Every 8 Weeks
Every 8 weeks (Weeks 20, 28, and 36), the following procedure will be performed: 
FVIII antibody titer
12.6.6 Week 26
At Week 26, the following procedure will be performed: 
Direct Thrombin test
Weight
12.6.7 Week 28
At Week 28, the following procedure will be performed: 
Haemo-QoL-A QoL assessment

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12.7
 Safety Follow-Up – Weeks 37-52 
Subjects will return every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) from 
Week 37-52 (± 1 week), when the following procedures will be completed: 
12.7.1 Once per visit
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed: 
Physical examination
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
Vital Signs
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently based (and in particular when 
ALT values are >1.5x ULN) on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
12.7.2 Every 4 Weeks
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed: 

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Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
Urine Tests (refer to Table 9.7.8.2.1)
AAV5 antibody titer
VWF:Ag
PCR of vector DNA in blood, saliva, urine, semen, and stools 
o
Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period.  
Subjects who have not had 3 consecutive negative samples by Week 52 
should continue to have PCR testing every 4 weeks until 3 consecutive 
negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor). 
12.7.3 Every 8 Weeks  
Every 8 weeks (Weeks 44 and 52), the following procedure will be performed: 
PBMC collection
FVIII antibody titer
12.7.4 Week 38 and 52 
At Week 38 and Week 52, the following procedure will be performed: 
Direct Thrombin test
12.7.5 Week 52
At Week 52, the following procedure will be performed: 
Haemo-QoL-A QoL assessment
Weight
12.8
Safety Follow-Up – Years 2-5 
During Years 2-5 of Safety Follow-up, subjects will be assessed every 3 months (± 2 weeks). 
At these times, the following procedures will be completed:
12.8.1 Every Visit
Every 3 months (± 2 weeks), the following procedures will be performed: 
Physical examination
o
Complete Physical Examination will be performed every 52 weeks; Brief 
Physical Examinations may be performed at other visits.

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Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
Vital Signs
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
Urine Tests (refer to Table 9.7.8.2.1) 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (FXa chromogenic assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
AAV5 antibody titer
FVIII antibody titer
PBMC collection
VWF:Ag
Direct Thrombin test

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12.8.2 Every Other Visit (Every 6 Months) 
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the 
end of Year 1 of the Safety Follow-up period), the following procedure will be performed: 
Haemo-QoL-A QOL assessment
Weight
12.9
Early Termination Visit
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit.
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
Physical examination
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
Vital Signs
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1)
Urine Tests (refer to Table 9.7.8.2.1)
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment
FVIII Assays – central laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
FVIII antigen (ELISA)
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 

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AAV5 antibody titer
FVIII antibody titer
PBMC collection
VWF:Ag
Direct Thrombin test
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing at the ETV is not required if at least 3 consecutive samples 
are clear during the Post-Infusion Follow-Up period.
Haemo-QoL-A QOL assessment
12.10 End of Study
The study will end after the last subject completes the last Safety Follow-Up visit 
(Week 260). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study subjects may be 
compromised.

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13
DATA QUALITY ASSURANCE
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan.

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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS.
14.1.1 Interim Analyses
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all subjects having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16).
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
Missing data will not be imputed. 
14.2
Primary and Secondary Efficacy Analysis
The subjects will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of subjects, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined.
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
IU/dL by chromogenic FXa and/or one-stage APTT assay as 
measured by the central laboratory at 16 weeks following study treatment.  hFVIII activity 
will be assessed weekly during the study period.  We can only assess the true steady state of 
hFVIII protein produced from BMN 270 after a minimum of 72 hours has elapsed since the 
last infusion of FVIII protein concentrates.
14.3
Immunogenicity
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons 
14.4
Pharmacodynamic Analyses
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage APTT and/or chromogenic FXa assay (activity level), will be used for plasma 

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profiles; FVIII activity will be used to determine PD parameters.  Traditional PK analysis is 
not applicable.
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics. 
14.5
Safety Analysis
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF.
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of subjects who report hepatitis will be presented.
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided. 
Detailed statistical methods will be provided in the SAP.
14.6
Determination of Sample Size
No formal sample size calculations based on statistical power were performed.
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 15 subjects may be dosed in the study; the actual number of 
subjects will depend on the criteria for dose escalation. 
14.7
Analysis Populations
The Safety analysis population is defined as all enrolled subjects who receive any study drug. 
The analysis of safety data will be performed on Safety Set.

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The Full Analysis Set (FAS) is defined as all enrolled subjects who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis.
14.8
Changes in the Conduct of the Study or Planned Analyses
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation.
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active subjects must again provide informed consent.
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail.

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15
DATA REVIEW BOARD
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established.
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available subject safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene 
for further assessment of subject safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites.

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16
COMPENSATION, INSURANCE AND INDEMNITY
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected.
The Investigator should contact BioMarin immediately upon notification that a study subject
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the subject’s health insurance company or other third party 
payer for the cost of this medical treatment. If the subject has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law.

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17
CASE REPORT FORMS AND SOURCE DOCUMENTS
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy.
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable. 
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator.
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to 
their medical records, and subjects will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
subject records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification.
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed. 
Before a subject’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee,
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 

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completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents.

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STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees.
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files.

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RETENTION OF RECORDS
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained.

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USE OF INFORMATION AND PUBLICATION
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP). 

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21
REFERENCES
Bainbridge, JW, Smith, AJ, Barker, SS, Robbie, S et. al. Effect of gene therapy on visual 
function in Leber's congenital amaurosis. N Engl J Med 358[21], 2231-2239. 2008.
Berntorp, E, Peake, I, Budde, U, Laffan, M et. al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia 18 Suppl 6, 1-13. 2012.
Croteau, GA, Martin, DB, Camp, J, Yost, M et. al. Evaluation of exposure and health care 
worker response to nebulized administration of tgAAVCF to patients with cystic fibrosis. 
Ann Occup Hyg 48[8], 673-681. 2004.
D'Avola, D. Phase 1 Clinical Trial of Liver Directed Gene Therapy with rAAV5-PBGD in 
Acute Intermittent Porphyria: Preliminary Safety Data. J Hepatol 60[S58]. 2014.
Den Ujil, Mauser Bunschoten, Roosendaal, Schutgens et. al. Clinical Severity of haemophilia 
A: does the classification of the 1950s still stand? Haemophilia 17, 849-853. 2011.
George, LA, Sullivan, S, Teitel, J, Cuker, A et al.  Preliminary results of a phase 1/2 trial of 
SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent 
factor IX activity levels at the lowest dose cohort.  Haemophilia 22[Suppl. 4], 151-152.
2016.
Hay, CR, DiMichele, DM. The principal results of the International Immune Tolerance 
Study: a randomized dose comparison. Blood 119[6], 1335-1344. 2012.
Heller CG & Clermont Y.  Kinetics of the germinal epithelium in man.  Recent Prog Horm 
Res.  1964;20:545-571.
Heller CG, Heller GV, Rowley MJ.  Human spermatogenesis: an estimate of the duration of 
each cell association and each cell type.  Excerpta Med Int Congr Ser.  1969;184:1012-1018.
Kaufman, RJ, Powell, JS. Molecular approaches for improved clotting factors for hemophilia
1. Blood 122[22], 3568-3574. 2013.
Maguire, AM, High, KA, Auricchio, A, Wright, JF et. al. Age-dependent effects of RPE65 
gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 
374[9701], 1597-1605. 2009.
Mahlangu, J, Powell, JS, Ragni, MV, Chowdary, P et. al. Phase 3 study of recombinant factor 
VIII Fc fusion protein in severe hemophilia A
8. Blood 123[3], 317-325. 2014.

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Manno, CS, Chew, AJ, Hutchison, S, Larson, PJ et. al. AAV-mediated factor IX gene 
transfer to skeletal muscle in patients with severe hemophilia B
1. Blood 101[8], 2963-2972. 2003.
Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006.
Mannucci, PM, Tuddenham, EG. The hemophilias--from royal genes to gene therapy
1. N Engl J Med 344[23], 1773-1779. 2001.
McIntosh, J, Lenting, PJ, Rosales, C, Lee, D et. al. Therapeutic levels of FVIII following a 
single peripheral vein administration of rAAV vector encoding a novel human factor VIII 
variant. Blood 121[17], 3335-3344. 2013.
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016.
Mingozzi, F and High, KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013.
Monahan, P, Walsh CE, Powell JS, Konkle BA et al.  Update on a phase 1/2 open-label trial 
of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for 
hemophilia B.  J Thromb Haemostasis 13[Suppl 2], 1-997.  2015.
Nagel, K, Walker, I, Decker, K, Chan, AK et. al. Comparing bleed frequency and factor 
concentrate use between haemophilia A and B patients. Haemophilia 17[6], 872-874. 2011.
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992.
Nathwani, AC, McIntosh, J, Davidoff, AM. An update on gene therapy for hemophilia. Curr 
Hematol Rep 4[4], 287-293. 2005.
Nathwani, AC, Gray, JT, Ng, CY, Zhou, J et. al. Self-complementary adeno-associated virus 
vectors containing a novel liver-specific human factor IX expression cassette enable highly 
efficient transduction of murine and nonhuman primate liver. Blood 107[7], 2653-2661.
2006.
Nathwani, AC, Rosales, C, McIntosh, J, Rastegarlari, G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011.

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Nathwani, AC, Tuddenham, EG, Rangarajan, S, Rosales, C et. al. Adenovirus-associated 
virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365[25], 2357-2365.
2011.
Nathwani, AC, Reiss, UM, Tuddenham, EG, Rosales, C et. al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014.
Paneda, A, Lopez-Franco, E, Kaeppel, C, Unzu, C et. al. Safety and liver transduction 
efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute 
intermittent porphyria. Hum Gene Ther 24[12], 1007-1017. 2013.
Pasi, J, Wong, W, Rangarajan, S, Wilde, J et al.  Interim results of an open-label, phase 1/2 
study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A.  Haemophilia 
22[Suppl. 4], 151-152.  2016.
Schenk-Braat, EA, van Mierlo, MM, Wagemaker, G, Bangma, CH et. al. An inventory of 
shedding data from clinical gene therapy trials. J Gene Med 9[10], 910-921. 2007.
Simonelli, F, Maguire, AM, Testa, F, Pierce, EA et. al. Gene therapy for Leber's congenital 
amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18[3], 
643-650. 2010.
Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS et. al. Guidelines for the 
management of hemophilia. Haemophilia 19[1], e1-47. 2013.
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010.
Watkins, PB, Kaplowitz, N, Slattery, JT, Colonese, CR et al.  Aminotransferase Elevations in 
Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized Controlled 
Trial.  JAMA 296[1], 87-93.  2006.
White, GC, Rosendaal, F, Aledort, FM, Lusher, JM et al.  Definitions in hemophilia.  
Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific 
and standardization committee of the International society on Thrombosis and Haemostasis.  
Thromb Haemost. 85[3], 560.  2001.

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22
INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Patients 
In accordance with FDA Form 1572, the Investigator will ensure that:
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients.
He or she will personally conduct or supervise the study.
He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and IRB 
review and approval in 21 CFR Part 56 are met. 
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64.
He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug.
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments
He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68.
He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients.
He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312.

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23
SIGNATURE PAGE
Protocol Title: A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII in Patients with Severe Haemophilia A
Protocol Number: 270-201, Amendment 5
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
E6 ICH, as stated in the protocol, and other information supplied to me.
Investigator Signature
Date
Printed name:
Accepted for the Sponsor:
Medical Monitor Signature
Date
Printed name:
, MD,
, Clinical Sciences
PI
PI
PI
PI
PI

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24 PROTOCOL AMENDMENT TEXT REVISIONS
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See pages 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font.
Section No./Title
Text Revisions
Rationale
2/Synopsis (Criteria 
for Evaluation)
No major toxicity is expected based on preclinical studies in mice and monkeys. Each subject will have comprehensive 
surveillance monitoring of LFTs (at local labs, twice once per week for Weeks 1-2036, then once per week from Week 21-36, 
and then once every 2 weeks from Week 37-52) during Year 1. LFTs will be monitored every three months for up to 5 years 
post-dose in the safety extension; the frequency and duration of LFT testing may be changed based on discussion between the 
Medical Monitor and the Investigator and review of subject data.
1
7/Introduction
Gene therapy offers the potential of a cure through disease-modifying therapy by continuous endogenous production of human 
FVIII following a single administration of vector.
5
Tables 9.1.1, 9.1.2, 
9.1.3, 9.1.4
Schedules of Assessments and footnotes were updated to be consistent with other changes made elsewhere in the protocol.
1, 2, 3, 5
9.4.8.2/Glucocorticoid 
Treatment of Elevated 
Hepatic 
Transaminases
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject will have comprehensive 
surveillance plan monitoring of LFTs (at local labs, twice once per week for Weeks 1-3620, then once per week from Week 21-
36, and then once every 2 weeks from Week 37-52).  LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data. 
1
9.7.6/Exploratory 
Biomarker
Assessments
On an exploratory basis, samples may be fractionated prior to shedding analysis in order to better characterize the presence and 
location of vector DNA and/or vector capsid within each matrix. The fractionation may be performed with samples collected 
specifically for shedding analysis (saliva, blood, semen, urine, faeces), or by using exploratory samples, such as plasma, 
PBMCs, and red blood cells, collected under the study protocol.
4
9.7.8.3/Liver Function 
and Hepatitis Testing
Patients with persistent ALT > 1.5 ULN during the study and no other etiology identified may undergo additional evaluations 
(e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the 
investigator.
5

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Section No./Title
Text Revisions
Rationale
9.7.8.6/Vector 
Shedding
Vector shedding will also be extensively studied in the present clinical trial, every other week between Weeks 4-16, then every 
4 weeks to Week 52 until at least 3 consecutive negative results are obtained.  Testing of semen will continue through Week 12, 
even if 3 consecutive negative results have been recorded in that compartment prior to that timepoint.
3
10.4.1.1/Diagnosis 
versus Signs and 
Symptoms
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter sign(s) and/or symptom(s).  If a 
diagnosis subsequently becomes available, then this diagnosis should be entered on the AE (or SAE, as appropriate) eCRF, 
replacing the original entries where appropriate.
5
10.4.1.9/Pregnancy
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the pregnancy by entering the 
information on the Pregnancy eCRF and submitting to BPV within 24 hours of the site becoming aware of the event.  
The Investigator must make every effort to follow the subject’s partner (with that partner’s consent) through resolution of the 
pregnancy (delivery or termination) and to report the resolution on the Pregnancy Follow-up Form in the study reference 
materials.
5
12.5.1/Once per Week 
(Weeks 1-16)
The following procedures will be performed at one visit per week from Weeks 1 through 16:
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) 
based on discussion between the Medical Monitor and the Investigator and review of subject data.
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
PMBC collection
1, 2
12.5.2/Twice per 
Week (Weeks 1-16)
The following procedures will be performed twice per week from Weeks 1 through 16:
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
Local assessment of liver function tests should be performed on Day 8 during Week 1, and then 2x/week 
from Week 2 through Week 16
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) 
based on discussion between the Medical Monitor and the Investigator and review of subject data.
1

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Section No./Title
Text Revisions
Rationale
FVIII activity level – local laboratory assessment
o
FVIII activity level (APTT)
o
FVIII activity level (chromogenic FXa assay)
Local assessment of FVIII activity level should be performed on Day 8 during Week 1, and then 
2x/week from Week 2 through Week 16
12.5.4/Every 2 Weeks
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedures will be performed:
PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at Week 2)
o
Collection to occur until at least 3 consecutive negative results are obtained.  Semen samples should 
continue to be collected and tested through Week 12, even if 3 consecutive negative results in that 
compartment have been recorded prior to that timepoint.
3
12.5.5/Weeks 4, 8, 12, 
and 16
At Weeks 4, 8, 12, and 16, the following procedures will be performed:
PBMC collection
2
12.6.1/Once per week 
(Weeks 17 through 
36)
Once per week from Week 17 through Week 36, the following procedures will be performed:
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) 
based on discussion between the Medical Monitor and the Investigator and review of subject data.
FVIII activity level – local laboratory assessment
o
FVIII activity level (one-stage APTT)
o
FVIII activity level (chromogenic FXa assay)
1
12.6.2/Twice Once per 
Week (Weeks 17 
through 20)
Twice Once per week from Week 17 through Week 20, the following procedures will be performed:
PBMC collection
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
1, 2

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Section No./Title
Text Revisions
Rationale
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data.
FVIII activity level – local laboratory assessment
o
FVIII activity level (APTT)
o
FVIII activity level (chromogenic FXa assay)
12.6.3/Once per week
Every Two Weeks 
(Weeks 21 through 
36)
Once per week from Week 21 through Week 36 Every two weeks (Weeks 22, 24, 26, 28, 30, 32, 34, and 36), the following 
procedures will be performed:
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment
o
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) 
based on discussion between the Medical Monitor and the Investigator and review of subject data.
FVIII activity level – local laboratory assessment
o
FVIII activity level (APTT)
o
FVIII activity level (chromogenic FXa assay)
PBMC collection
1, 2
12.6.4/Every 4 Weeks
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed:
PBMC collection
2
References
Heller CG & Clermont Y.  Kinetics of the germinal epithelium in man.  Recent Prog Horm Res.  1964;20:545-571.
Heller CG, Heller GV, Rowley MJ.  Human spermatogenesis: an estimate of the duration of each cell association and each cell 
type.  Excerpta Med Int Congr Ser.  1969;184:1012-1018.
3

 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer 
of Human Factor VIII in Patients with Severe Haemophilia A 
Protocol Number: 
270-201 
Active Investigational 
Product: 
AAV5-hFVIII-SQ 
IND/European Union Drug 
Regulating Authorities 
Clinical Trials (EudraCT) 
Number: 
2014-003880-38 
 
Indication: 
Haemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 1/2 
Sponsor's Responsible 
Medical Monitor: 
, MD 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Duration of Subject 
Participation: 
Approximately 264 weeks 
Dose: 
Varied 
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
10 February 2015 
Date of Amendment 1: 
06 March 2015 
Date of Amendment 2: 
26 May 2015 
Date of Amendment 3: 
06 November 2015 
Date of Amendment 4: 
02 September 2016 
 
Property of BioMarin 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin. 
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code 
of Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving 
of essential documents 
PI
PI

 
270-201 – Amendment 4 
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2 September 2016 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 4 
Date: 2 September 2016 
 
RATIONALE AND SUMMARY OF MAJOR CHANGES 
A summary of major changes covered by Amendment 4 to the BMN 270-201 protocol is 
provided below.   
1. The requirement for prophylactic corticosteroids has been removed and the threshold for 
starting therapeutic corticosteroids has been changed from alanine aminotransferase 
(ALT) ≥ 1.5x baseline value to ≥ 1.5x upper limit of normal (ULN). 
Rationale:  Previous FIX gene-therapy clinical studies have demonstrated an association 
between increases in ALT and declines in FIX expression, which are thought to be due to a 
cell-mediated immune response to transduced hepatocytes (Manno, 2006, Nat.Med.) 
Mingozzi, 2013, Blood; (Nathwani, 2014, N.Engl.J.Med.); (Nathwani, 2011, Mol.Ther.).  In 
one study (Nathwani, 2014, N.Engl.J.Med.); (Nathwani, 2011, Mol.Ther.), partial rescue of 
FIX expression was observed with the initiation of corticosteroids.  Based on these results, as 
a conservative measure to preserve FVIII activity, the BMN 270-201 protocol set the 
threshold for initiating a therapeutic course of corticosteroids at ≥ 1.5x baseline.  Further, 
following this event in the first subject, all subsequent subjects were to receive prophylactic 
corticosteroid therapy.  To date, however, in clinical study 270-201, mild asymptomatic 
elevations in ALT largely near or slightly above the ULN have been observed following 
dosing, but in general, have not been associated with a concomitant drop in FVIII expression.  
These observations are consistent with preliminary clinical trial data reported from recent 
AAV-FIX gene therapy studies (George, 2016, Haemophilia; Miesbach, 2016, Haemophilia), 
which demonstrate that subjects with mild elevations in ALT did not have associated 
concomitant loss in FIX activity; in one study (George, 2016, Haemophilia), subjects did not 
require corticosteroid dosing (no hepatic transaminases >1.5x ULN).  Given the fact that 
elevations in ALT values of 1.5x baseline could represent normal fluctuations in liver 
enzymes (Watkins, 2006, JAMA), the threshold for initiating corticosteroids is being 
amended to ≥ 1.5x the ULN.  Adjusting the threshold to ≥ 1.5x ULN will avoid unnecessary 
prolonged exposure to corticosteroids at lower levels of ALT elevation.  Given the lack of 
association between changes in liver enzymes and FVIII activity, the 270-201 protocol has 
been amended to provide increased flexibility and clinical discretion and to recommend 
initiation of corticosteroids if there is a rise in ALT greater than 1.5x ULN or in consultation 

 
270-201 – Amendment 4 
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2 September 2016 
between  the investigator and the medical monitor based on the pattern of FVIII activity 
and/or changes in liver enzymes as well as an ongoing review of efficacy and safety data 
from subjects on-study to date. 
To maintain adequate surveillance of hepatocyte injury and FVIII expression, liver enzymes 
and FVIII levels will be monitored at regular intervals (at local labs, twice per week for 
Weeks 1-20, then once per week from Week 21-36, and then once every 2 weeks from 
Week 37-52) to ensure that any elevations in ALT and decreases in FVIII are observed early 
which may support intervention with corticosteroids.  The monitoring schedule and 
corticosteroid regimen may be adjusted as needed based on individual subject data upon 
discussion between the investigator and the medical monitor. 
2. An additional cohort of subjects has been added.  For Cohort 4, 3 subjects will be 
enrolled at the dose of 4E13 vector genomes (vg) per kilogram. If FVIII activity in these 
3 subjects is ≥ 5% at 8 weeks and no safety issue is found, an additional 3 subjects may 
be enrolled in this cohort. 
Rationale: In order to fully understand the dose-response relationship of BMN 270, an 
additional cohort of subjects will be enrolled at a dose of 4E13 vg/kg, a dose level which is 
intermediate between the high (6E13 vg/kg) and mid (2E13 vg/kg) dose levels. A dose level 
of 4E13 vg/kg was chosen in order to target FVIII levels within the normal range, which is 
expected to prevent the need for exogenous FVIII administration under most circumstances, 
such as peri-surgically or following serious trauma (White, 2001, Thromb Haemost).  The 
current dose of 6E13 vg/kg has resulted in FVIII levels above the upper limit of normal in 
2 of 7 treated patients, which suggests that a lower dose could provide more optimal FVIII 
expression and activity levels.  The 4E13 dose is expected to be effective based on clinical 
experience to date in 270-201 as improvements in FVIII activity and  an acceptable safety 
profile were observed  in both Cohort 2 (2E13) and Cohort 3 (6E13). 
3. The enrollment stopping criterion related to serum ALT levels has been changed from a 
5-fold increase from baseline after BMN 270 administration to: 
ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of 
BMN 270 in the absence of a definitive alternate etiology for the increase. 
Rationale:  Given that 270-201 is a first in human study, a 5-fold ALT increase from 
baseline was considered, at study initiation, to be an appropriately conservative approach to 
enhancing patient safety.  Clinical experience to date with BMN 270 demonstrates mild 
asymptomatic increases in ALT from baseline values, which have not to date exceeded 
Common Terminology Criteria for Adverse Events (CTCAE) grade 1 toxicity level (up to 
3x ULN).  Most ALT increases from baseline were within the normal range or slightly 

 
270-201 – Amendment 4 
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2 September 2016 
greater than the ULN.  Given that the fluctuations in liver enzymes observed above baseline 
values in treated subjects are potentially in-line with normal variations found in healthy 
volunteers (Watkins, 2006, JAMA) and as safety data to date generated with AAV vectors 
with tropism to the liver (Nathwani, 2014, N.Engl.J.Med.); Pasi, 2016, Haemophilia; 
Monahan, 2015, J. Thromb Haemostasis; George, 2016, Haemophilia; Miesbach, 2016, 
Haemophilia; (Manno, 2006, Nat.Med.); (Nathwani, 2011, Mol.Ther.), have found reversible 
and, in most cases, mild elevations in ALT without signs of significant hepatic injury, the 
ALT enrollment stopping criteria has been modified to 5x the ULN with a duration of at least 
2 consecutive weeks.  This criterion is in line with FDA guidance on drug-induced liver 
injury.  To support patient safety, monitoring of liver enzymes will be performed frequently 
and at regular intervals (at local labs, twice per week for Weeks 1-20, then once per week 
from Week 21-36, and then once every 2 weeks from Week 37-52) to ensure that any 
elevations in ALT are observed early, with repeat testing to confirm the abnormality.  In 
addition, when considering whether to dose subsequent subjects following an elevation in 
ALT in any treated subject, other factors that may have directly caused the rise in ALT (eg, 
excessive alcohol use or ALT rise from non-liver origin such as from excessive physical 
strain) will be considered to fully evaluate the etiology of the increase. 
4. Frequency of monitoring of vector shedding assessment (by polymerase chain reaction 
[PCR]) during the Post-Infusion Follow-Up period (Weeks 1 to 16) has been reduced to 
every other week between Week 4 and Week 16. 
Rationale:  In the Post-Infusion Follow-Up period, collection every 2 weeks after Week 4 is 
sufficient, as clinical study data generated to date demonstrates that the earliest biofluid to 
clear is urine, but not earlier than Week 4.  A visit every week presents an unnecessary 
burden on subjects given the slow clearance in most fluids. 
5. Frequency of monitoring of the vector shedding assessment (by PCR) in the Safety 
Follow-Up period (after Week 16) has been changed to include assessments every 
4 weeks between Weeks 20 and 52. 
Rationale: More frequent testing after week 20 is needed in order to better characterize the 
time point at which vector shedding has ceased.  Per protocol, testing of vector shedding in 
any fluid compartment can be stopped after 3 consecutive negative tests.  In the case of 
vector shedding in the semen, more frequent testing will avoid prolonged and unnecessary 
contraception use. 

 
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2 September 2016 
6. The enrollment stopping criterion around vector shedding has been modified.  Enrollment 
in the study will be put on halt if there is persistent detection (defined as 3 consecutive 
positive samples) of AAV vector DNA in the semen of a participant more than 52 weeks 
after BMN 270 administration.   
Rationale: The original enrollment stopping criterion related to vector shedding had set a 
threshold of 26 weeks if detected in the semen, based on expected clearance from AAV 
clinical studies (Nathwani, 2014, N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 
2007, J.Gene Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the literature referenced above, 
including Haemophilia B clinical studies utilizing AAV2 and AAV8, vector was no longer 
detectable after 40 days in blood, saliva, urine or stool, but in one study was detected in the 
seminal fluid for 16 weeks, but not in motile sperm (Manno, 2006, Nat.Med.).  In these 
studies, the amount of vector present in these bodily fluids involved an extremely small 
fraction of the infused dose. More recent data from an ongoing AAV5-FIX study 
demonstrates persistence of the vector in both the blood and the semen for at least 39 weeks 
(Miesbach, 2016, Haemophilia).  Similarly, clinical study data from 270-201 has 
demonstrated that subjects show a residual, but progressively declining level of vector DNA 
in the semen with very low copies identified past week 26 in one subject to date 
(2 copies/5μL qPCR sample at week 28 with 2 prior negative values).  The slow clearance 
from the semen mirrors clearance from the blood compartment and as the semen values are 
declining with a very low copy level at week 28, shedding in semen is expected to clear by 
week 40.  The modified enrollment stopping criterion is deemed appropriate to allow for 
complete clearance from the semen while controlling the potential risk to patient safety that 
may be posed by the continued persistence of the vector DNA in semen. Subjects will 
continue effective contraception use until at least 3 consecutive semen samples are negative 
for vector DNA. 
7. Stopping criterion regarding Grade 2 related events has been changed.  The occurrence of 
a Grade 2 related adverse event persisting for at least 7 days will now trigger a Data 
Review Board (DRB) review of safety data to determine whether an enrollment halt is 
warranted, rather than triggering an automatic enrollment halt. 
Rationale:  The original stopping criterion was set very conservatively, in the absence of any 
clinical data for BMN 270 at the start of the first-in-human study.  Given the safety profile 
observed to date in 9 subjects dosed with BMN 270, an automatic enrollment halt based on a 
related Grade 2 event of 7 days duration is not warranted.  To date, no subject has 
experienced a Grade 2 related event lasting 7 days or more.  As such, a prolonged Grade 2 
event assessed by the investigator as related to BMN 270 will trigger a DRB review of study 

 
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2 September 2016 
safety; the DRB will be consulted to evaluate the event as well as the totality of safety data 
and may choose to halt enrollment or not based upon the results of that review. 
8. Testing of von Willebrand factor Antigen (VWF:Ag) has been added as an assessment (at 
Screening and the same time points that FVIII activity is measured during the study). 
Rationale:  As fluctuations in FVIII levels are commonly observed and may be related to 
changes in VWF levels (e.g. increase in VWF secondary to exercise), following VWF levels 
at regular intervals over the course of the study will enable a more complete assessment of 
any on-study changes in FVIII levels. 
9. Testing of creatine phosphokinase (CPK) has been added to routine blood chemistry 
assessments during the study.  CPK testing may be performed at other intervals based on 
PI assessment.  
Rationale: CPK will allow for a more complete assessment of elevations in ALT and/or 
alanine aminotransferase (AST) by potentially differentiating between muscle and liver as 
the source of the enzymes.  An elevation of CPK may indicate muscle injury and not hepatic 
injury.    
10. An exploratory Direct Thrombin assay has been added at Baseline, Week 1, and every 
3 months thereafter. 
Rationale:  To better understand the relationship between FVIII levels and the downstream 
clotting cascade following administration of BMN 270, a direct thrombin assay will be 
performed.   
11. The identity of the medical monitor has been changed. 
12. Minor edits for clarity and consistency have been incorporated. 
Specific changes included in this amendment, including the Synopsis, since Amendment 3 
(approved 6 November 2015) are outlined in Section 24. 

 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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TITLE OF STUDY:  
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of BMN 270, an Adenovirus-
Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
PROTOCOL NUMBER: 
270-201 
STUDY SITES: 
Approximately 6-10 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 1/2 
STUDY RATIONALE: 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an essential 
cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to a new 
mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% 
of wild type activity and the mild form is 5-40% activity. The clinical manifestations of severe HA 
remain frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or recombinant 
human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, and at the time 
of a bleed, to prevent or control bleeding episodes, respectively. The half-life for FVIII (12 to 
18 hours for most approved products) necessitates frequent infusions, and although a major advance 
in the treatment of HA, it remains common for severe HA patients to continue to have multiple 
bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up to 30 to 
50 episodes/year for on demand treatment). The consequence of multiple bleeding events is the 
development of an underlying pathology that contributes to debilitating multiple-joint arthropathy and 
substantially increased risk of death. Chemical modification (e.g. direct conjugation of polyethylene 
glycol (PEG) polymers) and bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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by approximately 50%, and thus, show promise in reduced dosing and maintaining activity levels 
above 1% trough. However, these longer acting FVIIIs remain dependent on multiple infusions to 
maintain critical levels of FVIII activity in severe HA patients. There is therefore a strong unmet need 
for a fully preventive treatment of HA to give patients a FVIII level compatible with a normal and 
haemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous production 
of active FVIII following a single intravenous administration of a vector with the appropriate gene 
sequence. Haemophilia A is well suited for a gene replacement approach because clinical 
manifestations are attributable to the lack of a single gene product (FVIII) that circulates in minute 
amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not essential, and 
modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml induces an 
increase in activity of 1%) can ameliorate the severe form of the disease.  Thus, relatively small 
changes in endogenous FVIII activity results in clinically relevant improvements in disease 
phenotype. Finally, the response to gene transduction can be assessed using validated quantitative 
rather than qualitative endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific tissues 
such as the liver (for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical 
trial for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild is achievable following a single peripheral vein administration of AAV-8 vector. 
Several participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in bleeding. 
Thus, gene therapy treatment has resulted in a substantial improvement in their quality of life.  
 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a liver-selective promoter (Figure 1). 
 
 
 
 
 
 
 
 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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Figure 1. hFVIII-SQ Vector Genome Schematic 
 
 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, potentially 
life-long expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
The clinical study 270-201 is a first-in-human study designed to assess the relationship of vector dose 
to the augmentation of residual FVIII activity, and whether these levels are sufficient to alter the 
clinical phenotype. The relationship of dose to safety will be correlated to the activity of hFVIII in 
patients with severe HA. 
OBJECTIVES:  
The primary objectives of the study are: 
• 
To assess the safety of a single intravenous administration of a recombinant AAV5 encoding 
human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• 
To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of 
normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and magnitude 
of AAV-mediated FVIII activity in individuals with haemophilia A will be determined and 
correlated to an appropriate BMN 270 dose. 
The secondary objectives of the study are: 
• 
To describe the immune response to the FVIII transgene and AAV capsid proteins following 
systemic administration of AAV5-hFVIII-SQ 
• 
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during the 
study 
• 
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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Dossier: 
 
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during the study 
STUDY DESIGN AND PLAN:  
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe haemophilia 
A. Eligible patients will enter the dose escalation part of the study followed by a 16-week 
Post-Infusion Follow-Up period during which safety and efficacy assessments will be taken. After the 
primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed for approximately 
5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and 
do not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. 
Participants will be enrolled into one of up to four cohorts according to dose level:  
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv) 
Cohort 2:  2E13 vg per kilogram, iv 
Cohort 3:  6E13 vg per kilogram, iv 
Cohort 4:  4E13 vg per kilogram, iv 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of 
mice and monkeys.  The starting dose has a significant safety margin (10-fold) from no observed 
adverse effect level (NOAEL) in non-human primates.  
The first 3 cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between 
cohorts. Dose escalation may occur after a single subject has been safely dosed if the resulting FVIII 
activity at the Week 3 visit is < 5 IU/dL in both the aPTT and chromogenic assays. Three weeks is 
expected to be the time the expression will be close to the maximum.  This escalation paradigm is 
intended to minimize the subject numbers exposed to subtherapeutic doses. 
Cohorts 1-3  
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study, the Data Review Board (DRB).  
If the FVIII activity reaches ≥ 5 IU/dL at the Week 3 visit, then the remaining subjects in the cohort 
will be enrolled without the need to wait for 3 weeks between subjects. 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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Subject 1 will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram of body 
weight. If the FVIII activity level does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then no 
further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with Subject 2 at 
the next dose (2E13 vg/kg).  
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥ 5 IU/dL at the Week 
3 visit in both assays, then no further subjects will be dosed in Cohort 2 and enrollment into Cohort 3 
(6E13) will initiate with the next subject. If the FVIII activity level in the first subject treated in 
Cohort 3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then the Data Review Board 
(DRB) will recommend whether to continue to add subjects to the cohort and/or whether to continue 
the study. 
For the first subject treated in each of the first 3 cohorts, if the activity level reaches ≥5 IU/dL and no 
safety issue is found, then up to four subjects will be enrolled in the Cohort, though, the adaptive 
nature of this trial allows the DRB to recommend allocating subjects to the cohorts based on activity 
levels of FVIII and safety signals.  
 
Cohort 4 
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects is ≥ 5% 
at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical monitor 
and the DRB.  The adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals. 
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of vector 
is not a likely treatment option and these subjects have effectively a single opportunity for therapy 
using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post dose. Safety 
will be evaluated for approximately 5 years after dosing.  Any safety signal may trigger a review of 
the data and possible additional immunogenicity studies that include an assessment of cellular 
immune responses using collected peripheral blood mononuclear cells (PBMC). 
NUMBER OF SUBJECTS PLANNED:  
Up to 15 subjects may enroll into the study; the actual number of subjects will depend on the FVIII 
activity levels seen in each Cohort. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
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1. Males that are 18 years or older with established severe haemophilia A as evidenced by their 
medical history.  Patients will be considered as severe if their base FVIII level is 1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days 
(EDs) 
3. Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the previous 
12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 
12 months 
6. Sexually active patients must be willing to use an acceptable method of contraception such as 
double barrier, including hormonal contraception for at least 6 months post-treatment.  After 
6 months, subjects may stop contraception use only if they have had 3 consecutive negative 
semen samples. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition or AAV5 total antibodies 
2. Any evidence of active infection or any immunosuppressive disorder.   
3. HIV positive 
4. Significant liver dysfunction as defined by abnormal elevation of: 
• 
ALT (alanine transaminase) to 3 times the upper limit of normal; 
• 
Bilirubin above 3 times the upper limit of normal; 
• 
Alkaline phosphatase above 3 times the upper limit of normal; or 
• 
INR (international normalized ratio) ≥ 1.4 
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if they had 
significant fibrosis of 3 or 4 as rated on a scale of 0-4 
6. Evidence of any bleeding disorder not related to Haemophilia A 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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7. Platelet count of < 100 x 109/L 
8. Creatinine ≥ 1.5 mg/dL 
9. Liver cirrhosis of any etiology as assessed by liver ultrasound  
10. Hepatitis B if surface antigen is positive 
11. Hepatitis C if RNA is positive 
12. Treatment with any IP within 30 days prior to the end of the screening period 
13. Any disease or condition at the physician’s discretion that would prevent the patient from fully 
complying with the requirements of the study including possible corticosteroid treatment outlined 
in the protocol.  The physician may exclude patients unwilling or unable to agree on not using 
alcohol for the 16-week period following the viral infusion. 
14. Prior treatment with any vector or gene transfer agent 
15. Major surgery planned in the 16-week period following the viral infusion 
16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral 
infusion 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
The study is open label with comparison of FVIII activity to baseline values. No reference therapy 
will be evaluated in this study. 
DURATION OF TREATMENT:  
BMN 270 is given as a single dose by intravenous infusion. 
CRITERIA FOR EVALUATION: 
The following safety outcome measurements will be assessed: 
Safety: 
• 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
• 
Change in clinical laboratory tests (serum chemistry and haematology) 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding 
• 
Liver function tests (LFTs, including ALT, AST, GGT, LDH, bilirubin, alkaline phosphatase) 
• 
Immune response to FVIII transgene and AAV capsid proteins 
No major toxicity is expected based on preclinical studies in mice and monkeys. Each subject will 
have comprehensive surveillance monitoring of LFTs (at local labs, twice per week for Weeks 1-20, 
then once per week from Week 21-36, and then once every 2 weeks from Week 37-52) during Year 1. 
LFTs will be monitored every three months for up to 5 years post-dose in the safety extension; the 
frequency and duration of LFT testing may be changed based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.   
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the study 
is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration. 
  
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Subjects will be asked 
to keep a subject diary to record the details in these areas.   
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage 
APTT and/or chromogenic FXa assay (activity level), will be used for plasma profiles; FVIII activity 
will be used to determine PD parameters.  Traditional PK analysis is not applicable. 
Pharmacodynamics: 
If supported by the FVIII activity data, non-compartmental analysis and observation will be used to 
estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss (time 
to steady state), C(t) and AUC(0-t) where t is 16 weeks.   
STATISTICAL METHODS:  
The sample size is based upon clinical considerations and could detect a strong clinical efficacy 
signal. Up to 15 subjects may be dosed in the study.  The subjects will be followed in a longitudinal 
manner and all the relevant information will be collected. The analysis of the data will be descriptive 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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in nature but data collected in a longitudinal manner may be analyzed using longitudinal methods 
such as mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as biologically 
active FVIII at ≥ 5 IU/dL by chromogenic FXa assay and/or one-stage APTT assay at 16 weeks 
following study treatment. FVIII activity will be assessed weekly during the study period.  We can 
only assess the true steady state of FVIII protein produced from BMN 270 after a minimum of 
72 hours has elapsed since the last infusion of FVIII protein concentrates. 
Analysis of neutralizing antibody response and other immunological parameters as well as vector 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses. 

 
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3 TABLE OF CONTENTS 
2 SYNOPSIS ...........................................................................................................................7 
3 TABLE OF CONTENTS ...................................................................................................16 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................22 
5 ETHICS..............................................................................................................................24 
5.1 Institutional Review Board or Independent Ethics Committee ................................24 
5.2 Ethical Conduct of Study ..........................................................................................24 
5.3 Subject Information and Informed Consent ..............................................................25 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................26 
7 INTRODUCTION .............................................................................................................27 
7.1 Nonclinical Studies ...................................................................................................27 
7.2 Previous Clinical Studies ..........................................................................................29 
7.3 Study Rationale .........................................................................................................30 
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic ..............................................32 
7.4 Summary of Overall Risks and Benefits ...................................................................32 
8 STUDY OBJECTIVES ......................................................................................................34 
9 INVESTIGATIONAL PLAN ............................................................................................35 
9.1 Overall Study Design and Plan .................................................................................35 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3 ...............36 
Table 9.1.1: Schedule of Events – Screening and Infusion ......................................38 
Table 9.1.4:  Schedule of Events – Safety Follow-Up .............................................45 
Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids .............................47 
9.2 Discussion of Study Design, Including Choice of Control Group ............................48 
9.3 Selection of Study Population ...................................................................................48 
9.3.1 
Inclusion Criteria .........................................................................................48 
9.3.2 
Exclusion Criteria ........................................................................................49 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................49 
9.3.4 
Subject Identification and Replacement of Subjects ...................................51 
9.3.5 
Duration of Subject Participation ................................................................51 
9.4 Treatments .................................................................................................................51 

 
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9.4.1 
Treatments Administered ............................................................................51 
9.4.2 
Identity of Investigational Product ..............................................................52 
9.4.3 
Storage .........................................................................................................52 
9.4.4 
Directions for Administration .....................................................................52 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................53 
9.4.6 
Selection of Doses Used in the Study .........................................................53 
9.4.7 
Blinding .......................................................................................................54 
9.4.8 
Prior and Concomitant Medications ............................................................54 
9.4.9 
Treatment Compliance ................................................................................56 
9.5 Investigational Product Accountability .....................................................................56 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................56 
9.6 Dietary or Other Protocol Restrictions......................................................................57 
9.7 Safety and Efficacy Variables ...................................................................................57 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................57 
9.7.2 
Primary Efficacy Variables .........................................................................57 
9.7.3 
Secondary Efficacy Variables .....................................................................58 
9.7.4 
Immunogenicity ...........................................................................................58 
9.7.5 
Pharmacodynamics ......................................................................................58 
9.7.6 
Exploratory Biomarker Assessments ..........................................................59 
9.7.7 
Haemo-QoL-A Quality of Life Assessment ................................................59 
9.7.8 
Safety Variables ..........................................................................................59 
10 REPORTING ADVERSE EVENTS .................................................................................64 
10.1 Safety Parameters and Definitions ............................................................................64 
10.1.1 Adverse Events ............................................................................................64 
10.2 Serious Adverse Events ............................................................................................65 
10.2.1 Events of Special Interest (EOSI) ...............................................................65 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................65 
10.3.1 Adverse Event Reporting Period .................................................................65 
10.3.2 Eliciting Adverse Events .............................................................................66 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................66 

 
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10.4 Procedures for Recording Adverse Events ...............................................................69 
10.4.1 Recording Adverse Events on a eCRF ........................................................69 
10.5 Reporting Requirements ...........................................................................................72 
10.5.1 Expedited Reporting Requirements .............................................................72 
10.5.2 Ethics Committee Reporting Requirements ................................................73 
10.6 Follow-up of Subjects after Adverse Events .............................................................73 
10.7 Post-Study Adverse Events .......................................................................................73 
10.8 Urgent Safety Measures ............................................................................................73 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................74 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................75 
12 STUDY PROCEDURES ...................................................................................................76 
12.1 Prestudy .....................................................................................................................76 
12.2 Screening Visit ..........................................................................................................76 
12.2.1 “Smart Rescreening” Visit ..........................................................................77 
12.3 Baseline Visit ............................................................................................................78 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................78 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................79 
12.5.1 Once per week (Weeks 1 through 16) .........................................................79 
12.5.2 Twice per week (Weeks 1 through 16) .......................................................80 
12.5.3 Week 1 – Day 2 and Day 4 ..........................................................................80 
12.5.4 Week 1 – Day 8 ...........................................................................................81 
12.5.5 Every 2 Weeks .............................................................................................81 
12.5.6 Weeks 4, 8, 12, and 16 ................................................................................81 
12.5.7 Week 16 .......................................................................................................81 
12.5.8 Weeks 8 and 16 ...........................................................................................82 
12.5.9 Weeks 2, 3, 4, and 16 ..................................................................................82 
12.5.10 Week 13 .......................................................................................................82 
12.6 Safety Follow-Up – Weeks 17-36 .............................................................................82 
12.6.1 Once per week (Weeks 17 through 36) .......................................................82 
12.6.2 Twice per week (Weeks 17 through 20) .....................................................83 

 
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12.6.3 Once per week (Weeks 21 through 36) .......................................................83 
12.6.4 Every 4 Weeks .............................................................................................83 
12.6.5 Every 8 Weeks .............................................................................................84 
12.6.6 Week 26 .......................................................................................................84 
12.6.7 Weeks 28 .....................................................................................................84 
12.7 Safety Follow-Up – Weeks 37-52 .............................................................................84 
12.7.1 Once per visit ...............................................................................................84 
12.7.2 Every 4 Weeks .............................................................................................85 
12.7.3 Every 8 Weeks .............................................................................................85 
12.7.4 Week 38 and 52 ...........................................................................................85 
12.7.5 Week 52 .......................................................................................................86 
12.8 Safety Follow-Up – Years 2-5 ..................................................................................86 
12.8.1 Every Visit ...................................................................................................86 
12.8.2 Every Other Visit (Every 6 Months) ...........................................................87 
12.9 Early Termination Visit ............................................................................................87 
12.10 End of Study .............................................................................................................88 
13 DATA QUALITY ASSURANCE .....................................................................................89 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................90 
14.1 Statistical and Analytical Plans .................................................................................90 
14.1.1 Interim Analyses ..........................................................................................90 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........90 
14.2 Primary and Secondary Efficacy Analysis................................................................90 
14.3 Immunogenicity ........................................................................................................90 
14.4 Pharmacodynamic Analyses .....................................................................................90 
14.5 Safety Analysis .........................................................................................................91 
14.6 Determination of Sample Size ..................................................................................91 
14.7 Analysis Populations .................................................................................................91 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................92 
15 DATA REVIEW BOARD .................................................................................................93 
16 COMPENSATION, INSURANCE AND INDEMNITY ..................................................94 

 
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17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................95 
18 STUDY MONITORING AND AUDITING .....................................................................97 
19 RETENTION OF RECORDS ...........................................................................................98 
20 USE OF INFORMATION AND PUBLICATION ...........................................................99 
21 REFERENCES ................................................................................................................100 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................103 
22.1 Conduct of Study and Protection of Human Patients .............................................103 
23 SIGNATURE PAGE .......................................................................................................104 
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................105 

 
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LIST OF TABLES 
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................38 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) ............................41 
Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) .....................................43 
Table 9.1.4:  Schedule of Events – Safety Follow-Up .............................................................45 
Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids .............................................47 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................60 
Table 9.7.8.3.1:  Liver Function Tests .....................................................................................61 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................67 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................68 
 
LIST OF FIGURES 
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic .............................................................32 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3...............................36 
 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAV 
Abbreviations 
adeno-associated virus 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine transaminase 
APTT 
activated partial thromboplastin time 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DRB 
Data Review Board 
eCRF 
electronic case report form 
ED 
exposure days 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FVIII 
coagulation factor VIII 
FXa 
coagulation factor Xa 
GCP 
Good Clinical Practice 
HA 
Haemophilia A 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 
IND 
Investigational New Drug (application) 

 
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INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
ULN 
upper limit of normal 
vg 
vector genomes 
VWF:Ag 
von Willebrand factor Antigen 
 
Investigational Product (IP): 
Definition of Terms:  
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 

 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin or its designee. The Investigator will provide the IRB/IEC/REB 
with all appropriate material, including the protocol, Investigator’s Brochure (IB), the 
Informed Consent Form (ICF) including compensation procedures, and any other written 
information provided to the subjects, including all ICFs translated to a language other than 
the native language of the clinical site. The study will not be initiated and Investigational 
Product (IP) supplies will not be shipped to the site until appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol, the ICF and all subject 
recruitment materials are obtained in writing by the Investigator and copies are received at 
BioMarin or its designee. The approval document should refer to the study by protocol title 
and BioMarin protocol number (if possible), identify the documents reviewed, and include 
the date of the review and approval. BioMarin will ensure that the appropriate reports on the 
progress of the study are made to the IRB/IEC/REB and BioMarin by the Investigator in 
accordance with applicable guidance documents and governmental regulations. 
5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 

 
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eligible subjects for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability. 
This study will be conducted in accordance with the following: 
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6) 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the subjects will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF, and if applicable, a 
copy of the approved subject information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed. 
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject. 

 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of subjects in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 
Liver function tests (LFTs) will be performed at the local laboratories associated with the 
study sites.  Local laboratory results of LFTs will be used to trigger corticosteroid treatment 
as needed (refer to Section 9.4.8.2).  In case of discrepant results between local and central 
laboratories, the Investigator and Medical Monitor will decide further action.  Safety labs 
evaluations (including LFTs) will be performed at the central lab, while bioanalytical 
samples will be performed at the appropriate specialty lab.  Refer to the Laboratory Manual 
for more details. 

 
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7 
INTRODUCTION 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.). 
Chemical modification or bioengineering of FVIII may improve half-life to 18-19 hours 
(Kaufman, 2013, Blood). However, these long acting FVIII variants do not eliminate the 
need for lifelong FVIII protein administration (Hay, 2012, Blood).  
Gene therapy offers the potential of a cure through continuous endogenous production of 
human FVIII following a single administration of vector. Haemophilia A is well suited for 
this approach because its clinical manifestations are attributable to the lack of a single gene 
product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. Tightly 
regulated control of gene expression is not essential and a modest increase in the level of 
FVIII (a plasma level of 2 ng/ml protein leads to a 1% expression) can ameliorate the severe 
phenotype (Srivastava, 2013, Haemophilia.); thus the therapeutic goal for gene therapy is a 
modest increase in hFVIII. Finally, the consequences of gene transfer can be assessed using 
simple quantitative rather than qualitative endpoints that can be easily assayed in most 
clinical laboratories. 
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 
7.1 
Nonclinical Studies 
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 

 
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nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints. 
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in FVIII KO x Rag2 mice given matched IU 
levels of Refacto®.   
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.   
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed. 
The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 

 
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the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence closely matching that of 
the protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Nathwani, 2006, Blood). Despite 
distribution to non-liver organs, no expression of Factor IX was detected in these tissues.  
Additionally, distribution to the testis was observed in another study in monkeys given an 
AAV5-codon-optimized human porphobilinogen deaminase; however, vector genomes in the 
semen were only transiently observed within one week but not thereafter (Paneda, 2013, 
Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents 10-fold safety factor from the 
no observed adverse effect level (NOAEL) in the GLP enabling nonclinical toxicology study 
in mice.  
7.2 
Previous Clinical Studies 
This is the first clinical study for BMN 270. 
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Engl.J.Med.), 
(Nathwani, 2014, N.Engl.J.Med.). The large size of the FVIII cDNA was shortened and a 
preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013, 
Blood). 

 
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AAV serotype 5 is being tested in other clinical trials and was reportedly well tolerated 
without treatment-related serious adverse events in a recent phase 1 study for treatment of 
Acute Intermittent Porphyria (D'Avola, 2014, J.Hepatol.). In addition, AAV using other 
serotypes have been used in 105 clinical studies to date and no safety issue specific to the 
vector was ever reported.   
7.3 
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Mannucci, 2001, N.Engl.J.Med.).  It is caused by deficiency in the activity 
of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic coagulation cascade. 
This disorder can be either inherited, due to a new mutation or an acquired immunologic 
process, leading to insufficient quantities of FVIII or a dysfunctional FVIII, but all are 
characterized by a defective coagulation process. . The clinical phenotype of HA patients is 
largely governed by the level of residual expression. Severe HA is classified as FVIII activity 
less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild type activity 
and the mild form is 5-40% activity. The clinical manifestations of severe HA remain 
frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-4 times per 
week, and at the time of a bleed, to prevent or control bleeding episodes, respectively. The 
half-life for FVIII (12-18 hours for most approved products) necessitates frequent infusions, 
and although a major advance in the treatment of HA, it remains common for severe HA 
patients to continue to have multiple bleeding events on treatment (mean of 
1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year for on demand 
treatment) (Nagel, 2011, Haemophilia.).  The consequence of multiple bleeding events is the 
development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death (Nagel, 2011, Haemophilia).  Chemical 
modification (e.g. direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by approximately 
50%, and thus, show promise in reduced dosing and maintaining activity levels above 1% 
trough (Stonebraker, 2010, Haemophilia.), (Mahlangu, 2014, Blood). However, these longer 
acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive 
treatment of HA to give patients a FVIII level compatible with a normal and 
haemorrhage-free life.  

 
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Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Mannucci, 2001, 
N.Engl.J.Med.). They have an excellent and well defined safety profile, and can direct long 
term transgene expression with tropism for specific tissues such as the liver (Nathwani, 2005, 
Curr.Hematol.Rep.) for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene 
therapy clinical trial for a related disorder, haemophilia B, has established that stable 
(>36 months) expression of human factor IX at levels that are sufficient for conversion of 
their bleeding phenotype from severe to moderate or mild is achievable following a single 
peripheral vein administration of AAV-8 vector (Nathwani, 2014, N.Engl.J.Med.).  Several 
participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in 
bleeding. Thus, gene therapy treatment has resulted in a substantial improvement in their 
quality of life (Nathwani, 2011, Mol.Ther.), (Bainbridge, 2008, N.Engl.J.Med.), (Maguire, 
2009, Lancet); (Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a liver-selective promoter (Figure 7.3.1).  

 
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Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active FVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of FVIII in patients with severe 
HA. 
7.4 
Summary of Overall Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based 
on prior human studies with peripheral injections of AAV vectors, there is no known safety 
risk of AAV gene therapy. However, a mild asymptomatic transaminitis was observed at 
week 7-12 after administration in humans with an AAV8-FIX, providing the rationale for the 
following surveillance plan (Nathwani, 2011, Mol.Ther.). Each subject will have a 
comprehensive surveillance plan that monitors LFTs during the study. 
For additional information on safety findings in 270-201, refer to current version of the 
Investigator’s Brochure. 
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose 
that maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the 
possibility of a sub-therapeutic effect. With this consideration in mind, the starting dose 
6E12 vg/kg was selected using overall data from the pre-clinical studies conducted in mice 
(normal and disease model, Rag2 -/- x FVIII -/-) and monkey. A detectable pharmacological 
response based on activity was observed at 6E12 vg/kg. A 10-fold safety margin based upon 
the NOAEL was observed in the GLP 13-week study in normal mouse at the highest dose 
administered. A 30-fold safety margin in an 8-week dose response study in disease model 
mice based on histology was observed at the highest dose administered. No BMN 270-related 

 
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changes in clinical observations or chemistry was observed in the monkey at doses up to 
6E13 vg/kg, a 10-fold safety margin after 8-weeks. Overall, no BMN 270-related findings, 
except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model 
mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to subjects with the best chance of 
benefiting the subject therapeutically. 

 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are: 
• To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII 
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270 
dose. 
The secondary objectives of the study are: 
• To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of AAV5-hFVIII-SQ 
• To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study 
• To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled into one of up to four cohorts according to dose level:  
• Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single 
intravenous dose (iv) 
• Cohort 2:  2E13 vg per kilogram, iv 
• Cohort 3:  6E13 vg per kilogram, iv 
• Cohort 4:  4E13 vg per kilogram, iv 
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys.  The starting dose has a significant safety margin (10-fold) 
from no observed adverse effect level (NOAEL) in mice.  
The first three cohorts will be enrolled sequentially, allowing a period of 3 weeks or more 
between cohorts. Dose escalation may occur after a single subject in a cohort has been safely 
dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both assays. Three 
weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic 
doses.  The decision to escalate to the next dose level will be made based on the review of 
safety parameters and FVIII activity by the Sponsor and a panel of investigators participating 
in the study.    
Cohorts 1-3  
If the FVIII activity reaches ≥5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects. 

 
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme for Cohorts 1 to 3 
 
 
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1) 
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.  
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in the Cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals. 
Cohort 4
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.   
   

 
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There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB.  The adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals. 
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a likely treatment option and these subjects have effectively a single opportunity 
for therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dosing. Any safety signal 
may trigger a review of the data and possible additional immunogenicity studies that include 
an assessment of cellular immune responses using collected peripheral blood mononuclear 
cells (PBMC). Additionally, if any of the events listed in Section 9.3.3.1 occur, enrollment 
into the trial will be halted to complete an extensive safety analysis. Notification of the study 
enrollment halt will be sent by the Sponsor to the participating sites via telephone and email 
immediately after becoming aware of a safety concern. This will ensure no additional 
subjects are dosed until the signal has been completely evaluated. If, following safety review 
by the Data Review Board (DRB) and the Sponsor, it is deemed appropriate to restart dosing, 
a request to restart dosing with pertinent data will be submitted to the health authority. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 and Table 9.1.4 for Safety Follow-up. 
Table 9.1.5, dealing with therapeutic corticosteroid use in the event of elevated LFTs, is 
discussed in Section 9.4.8.2. 
 

 
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Table 9.1.1: Schedule of Events – Screening and Infusion 
Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion Visit 
(Day 1)k 
Screeningi 
(Day -28 to Day -1) 
Smart Rescreeningi  
(Day -28 to Day -1) 
Baseline (Day -7 
to Day -1)h 
Informed consent 
X 
 
 
 
Medical History 
X 
 
 
 
Physical Exama 
X 
 
X 
X 
Height and Weighta 
X 
 
 
 
Vital Signs 
X 
X 
 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
Documentation of bleeding episodes and FVIII usage (by either subject or 
clinical information) 
X 
X 
X 
 
Distribution of subject diaries and training in their use 
 
 
X 
 
Electrocardiogram 
X 
 
 
 
Chest X-ray 
X 
 
 
 
Liver Ultrasound 
X 
 
 
 
hFVIII Assaysb 
X 
Xj 
 
 
AAV5 Assaysc 
X 
X 
 
X 
Screen for Hepatitis B, Hepatitis C, HIVd 
X 
 
 
 
Blood chemistry, haematology, coagulation screen, and CRPe 
X 
X 
X 
 
Urine Testse 
X 
X 
X 
 
Liver Function Testse 
X 
X 
X 
 
PBMC collection for CTL baseline 
 
 
X 
 
Von Willebrand Factor Antigen (VWF:Ag) 
X 
 
 
 
Direct Thrombin Test 
 
 
X 
 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
 
 
X 
 

 
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Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion Visit 
(Day 1)k 
Screeningi 
(Day -28 to Day -1) 
Smart Rescreeningi  
(Day -28 to Day -1) 
Baseline (Day -7 
to Day -1)h 
Biomarker testingf 
X 
 
 
 
Exploratory biomarker assessmentsg 
 
 
X 
 
Haemo-QoL-A Quality of Life (QoL) assessment 
 
 
X 
 
BMN 270 Infusion 
 
 
 
X 
a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height will be 
recorded at Screening only.  Weight will be recorded at Screening and then every 6 months thereafter. 
b Includes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay 
with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).   
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction 
inhibition, in vitro transduction inhibition and AAV5 total antibody assays).  The assessment on the day of the infusion visit must be performed before the BMN 270 
infusion is given. 
d Patients with documented negative results within the last 30 days do not need to be retested. 
e Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests. 
f Includes HLA genotyping, FVIII genotyping, TNFα and IL10a single nucleotide polymorphisms. 
g Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
exploratory genetic/genomic testing on these samples is optional. 
h Should the screening visit occur within 7 days of the drug infusion, physical examination, blood chemistry, LFTs, haematology, urine tests, coagulation screen, and CRP 
do not need to be repeated at Baseline. 
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion 
prior to the closing of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion 
within 90 days of signing the original consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures.  
Subjects may not undergo smart rescreening more than once. 
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening. 

 
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k Assessments on the day of infusion must be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, 
during the infusion every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 
4 hour intervals (± 15 minutes). 

 
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) 
Assessment 
Follow-Up After BMN 270 Administration – Weeks* 
Week 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
D2 
D4 
D8 
Physical exama 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary for 
bleeding and FVIII use) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, 
and CRPb     
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Urine Testsb 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Liver Function Tests (local)b 
 
X 
X 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
FVIII assays (local)c 
 
X 
X 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Liver Function Tests (central)b 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PCR of vector DNA in blood, saliva, urine, semen, 
and stoolse 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Exploratory biomarker assessmentsf 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Haemo-QoL-A QoL assessment 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
AAV5 antibody titer 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Testing for reactivation of hepatitis B and hepatitis 
C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
PBMC collection  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Von Willebrand Factor Antigen (VWF:Ag)  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Direct Thrombin test 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 

 
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* Visit windows are ± 48 hours (and include the Day 4 visit) 
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.5. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTs may be monitored more or less frequently (and in 
particular when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data.  Patients with persistent 
ALT > 1.5 ULN during the study and no other etiology identified may undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional 
blood tests, and/or liver biopsy) at the discretion of the investigator. 
c Includes hFVIII activity level (APTT and FXa chromogenic assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances 
in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.   
d Includes hFVIII activity level (APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII 
activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.   
e Collection to occur on Day 2 and 4 following BMN 270 infusion, and then until at least 3 consecutive negative results are obtained. 
f Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
exploratory genetic/genomic testing on these samples is optional. 
g Testing for reactivation of hepatitis B and hepatitis C at Week 16 should be performed only in subjects who have not received therapeutic corticosteroids prior to 
Week 16; subjects who have received therapeutic corticosteroids will have hepatitis B and hepatitis C testing at the time points indicated in Table 9.1.5. 

 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up (Week 17-32) 
Assessment 
Follow-Up After BMN 270 Administration – Weeks* 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary for 
bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, 
and CRPb     
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urine Testsb 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Liver Function Tests (local)b 
XX 
XX 
XX 
XX 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c 
XX 
XX 
XX 
XX 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests (central)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
PCR of vector DNA in blood, saliva, urine, semen, and 
stoolse 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Exploratory biomarker assessmentsf 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Haemo-QoL-A QoL assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
AAV5 antibody titer 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PBMC collection  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Von Willebrand Factor Antigen (VWF:Ag)  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Direct Thrombin test 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
* Visit windows are ± 48 hours 
a Brief physical examination should be done at all weekly visits.  Refer to Section 9.7.8.5. 

 
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b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTs may be monitored more or less frequently (and in 
particular when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data.  Patients with persistent 
ALT > 1.5 ULN during the study and no other etiology identified may undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional 
blood tests, and/or liver biopsy) at the discretion of the investigator. 
c Includes hFVIII activity level (APTT and FXa chromogenic assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances 
in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.   
d Includes hFVIII activity level (APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII 
activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances in which FVIII 
activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.   
e Collection to occur until at least 3 consecutive negative results are obtained. 
f Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
exploratory genetic/genomic testing on these samples is optional. 

 
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Table 9.1.4:  Schedule of Events – Safety Follow-Up 
Assessment 
Year 1 – Weeks* 
Years 
2-5 
ETV 
33 
34 
35 
36 
38 
40 
42 
44 
46 
48 
50 
52 
Q3M 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta 
 
 
 
 
 
 
 
 
 
 
 
X 
Xa 
 
Assessment of Adverse Events and Concomitant 
Medications (including review of subject diary for 
bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, coagulation screen, and 
CRPb 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Urine Testsb 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Liver Function Tests (local)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (local)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests (central)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assays (central)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AAV5 antibody titer 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
FVIII antibody titer 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
PBMC Collection (for determination of FVIII and 
Capsid specific CTL activity) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Von Willebrand Factor Antigen (VWF:Ag) 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Direct Thrombin Test 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and 
stoolse 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

 
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Haemo-QoL-A QoL assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
Xf 
X 
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52 and ± 2 weeks for visits in Years 2-5. 
a Complete physical examination should be performed at Week 52 and every 52 weeks thereafter; brief physical exam may be performed at other study visits.  Refer to 
Section 9.7.8.5.  During Years 2-5, weight should be performed every 6 months. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver function tests.  LFTs may be monitored more or less frequently (and in 
particular when ALT values are >1.5x ULN) based on discussion between the Medical Monitor and the Investigator and review of subject data. Patients with persistent 
ALT > 1.5 ULN during the study and no other etiology identified may undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, additional 
blood tests, and/or liver biopsy) at the discretion of the investigator. 
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be 
made to obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several 
weeks, assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.   
d Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII 
coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator.  A d-dimer may be considered under circumstances 
in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.   
e Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period.  Subjects who have not 
had 3 consecutive negative samples by Week 52 should continue to have PCR testing every 4 weeks until 3 consecutive negative samples are documented (or upon 
consultation between the Investigator and Medical Monitor). 
f Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 6 months) starting with the Week 78 visit (ie, 
26 weeks after the Week 52 visit at the end of Year 1 of the Safety Follow-up period). 

 
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Table 9.1.5:  Schedule of Events – Therapeutic Corticosteroids 
 
Steroid Treatment Periodd 
Post-Steroid Periodc 
 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11b 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
13 
Therapeutic 
corticosteroids 
(dose in 
mg/day) a  
60 mg 
60 mg 
40 mg 
40 mg 
30 mg 
30 mg 
20 mg 
20 mg 
15 mg 
10 mg 
5 mg 
 
 
 
 
 
FVIII activity 
testing  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Liver function 
testing 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Hepatitis B 
testing 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
HCV Viral 
Load 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
a Therapeutic corticosteroids may be initiated when a subject’s ALT value is ≥ 1.5x ULN or based on review of FVIII and liver enzyme data after consultation between 
the Investigator and the Medical Monitor. 
b Following initiation or completion of steroid regimen, if ALT elevation  ≥ 1.5x ULN is reported, steroid management decisions will based on discussions between the 
Investigator and Medical Monitor.  Modification of the steroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII 
expression. 
c After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values.  If these 
assessments are already being done as part of normal study follow-up, they do not need to be duplicated. 
d Regardless of the assessments listed in the Schedule of Assessments (Table 9.1.2, Table 9.1.3, or Table 9.1.4), subjects initiated on corticosteroids will only be required 
to have laboratory evaluations on a weekly basis. 
 
 

 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Four doses of BMN 270 will be evaluated and the dose 
escalation decision tree for Cohorts 1-3 is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and the DRB. 
There will be no control group. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy).  
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3 
Selection of Study Population 
Up to 15 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation.  
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe Haemophilia A as evidenced by 
their medical history.  Patients will be considered as severe if their base FVIII level is 
1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs) 
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the previous 
12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within the past 
12 months 
6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment.  After 6 months, subjects may stop contraception use only if they have 
had 3 consecutive negative semen samples. 

 
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9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition or AAV5 total antibodies 
2. Any evidence of active infection or any immunosuppressive disorder.   
3. HIV positive 
4. Significant liver dysfunction as defined by abnormal elevation of: 
• ALT (alanine transaminase) to 3 times the upper limit of normal; 
• Bilirubin above 3 times the upper limit of normal; 
• Alkaline phosphatase above 3 times the upper limit of normal; or 
• INR (international normalized ratio) ≥ 1.4.  
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if they 
had significant fibrosis of 3 or 4 as rated on a scale of 0-4 
6. Evidence of any bleeding disorder not related to Haemophilia A 
7. Platelet count of < 100 x 109/L 
8. Creatinine ≥ 1.5 mg/dL 
9. Liver cirrhosis of any etiology as assessed by liver ultrasound  
10. Hepatitis B if surface antigen is positive 
11. Hepatitis C if RNA is positive 
12. Treatment with any IP within 30 days prior to the end of the screening period 
13. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study including possible corticosteroid 
treatment outlined in the protocol.  The physician may exclude patients unwilling or 
unable to agree on not using alcohol for the 16-week period following the viral infusion. 
14. Prior treatment with any gene transfer agent 
15. Major surgery planned in the 16-week period following the viral infusion 
16. Use of immunosuppressive agents or live vaccines within 30 days before the viral 
infusion 
9.3.3 Removal of Subjects from Treatment or Assessment 
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 

 
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A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 
BioMarin must be notified of all subject withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following: 
• Subject requires medication or medical procedure prohibited by the protocol 
• Subject does not adhere to study requirements specified in the protocol 
• Subject was erroneously admitted into the study or does not meet entry criteria 
• Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study. 
9.3.3.1 
Study Safety Evaluation Criteria 
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis 
per Section 9.1.   
• 
Any ALT elevation > 5x ULN for at least 2 consecutive weeks after administration of 
BMN 270, in the absence of a definitive alternate etiology for the increase   

 
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• The occurrence of Grade 3 or higher adverse events (excluding ALT elevation) 
assessed as related to study drug, including liver failure and clinical hepatitis 
• The detection of neutralizing antibodies to hFVIII following BMN 270 infusion 
• The detection of AAV vector DNA in the semen of a participant in 3 consecutive 
samples (which are at least 2 weeks apart) more than 52 weeks after BMN 270 
infusion, as discussed in Section 9.7.8.5  
• The occurrence of a malignancy excluding skin cancers at any point after BMN 270 
infusion 
If the following event occurs in a subject in the study who has received BMN 270 infusion, a 
DRB review and analysis of safety data will be undertaken to determine whether the 
enrollment into the trial will be put on halt: 
• Grade 2 adverse event assessed as related to study drug that persists for at least 7 days  
9.3.4 Subject Identification and Replacement of Subjects 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Subjects who withdraw from the study will not be replaced. 
9.3.5 Duration of Subject Participation 
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks. 
9.4 
Treatments 
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 

 
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9.4.2 Identity of Investigational Product 
9.4.2.1 
Product Characteristics and Labeling 
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 
stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4 Directions for Administration 
After a physical exam performed by the PI or designee, participants will be admitted on the 
day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral vein 
(e.g. the median cubital vein) and flushed with saline. FVIII replacement therapy will not be 
given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 ml/min while monitoring the vital signs (pulse, blood pressure, respiration 
rate and temperature) at 15 minute (± 5 minutes) intervals. The anticipated maximum 
interval from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, 
although the IP has been shown to be stable at room temperature for 6 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard 
protocol for infusing FVIII concentrates. Subjects will remain in the clinic for 24 hours to 
observe for any immediate toxicity of the procedure. After 24 hours, participants will be 

 
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discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
9.4.5 Method of Assigning Subjects to Treatment Groups 
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study subject. Upon their enrollment into the study, subjects will be assigned a unique subject 
number and dose level by the Sponsor. 
Cohorts 1 to 3 are enrolled serially and their dose is defined in Section 9.4.6.2 below. 
Escalation is based on FVIII activity 3 weeks after injection. Cohorts may receive the next 
higher dose if subjects in the previous cohort does not meet the activity criteria, or the same 
dose if subjects in the previous cohort meets the activity criteria. Subjects in Cohort 4 will all 
be enrolled at a single dose. 
9.4.6 Selection of Doses Used in the Study 
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in mice. The dose escalation is half-logs based.    
9.4.6.1 
Selection of Timing of Dose for Each Subject 
A minimum of three weeks are required between subjects, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next subject will be made as described below.  
9.4.6.2 
Selection of Dose for Each Subject 
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus potentially decreasing the risk of immune response), and a new 
evaluation of the titer (PCR performed after hairpin removal). 
For Cohorts 1 to 3, approximately three weeks after an injection, the decision to escalate to 
the next dose level will be made based on the review of safety parameters and FVIII activity 
by the Sponsor and the DRB.  
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1) 

 
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at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.  
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each of the first 3 cohorts, if the activity level reaches 
≥5 IU/dL and no safety issue is found, then up to four subjects will be enrolled in that cohort, 
though the adaptive nature of this trial allows the DRB to recommend allocating subjects to 
the cohorts based on activity levels of FVIII and safety signals.   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects 
is ≥ 5% at 8 weeks and if no safety issue is found, an additional 3 subjects may be enrolled in 
this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical 
monitor and the DRB.  The adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals. 
Refer to Figure 9.1.1 for a visual representation of the study design for Cohorts 1-3 
9.4.7 Blinding 
This is an open-label study. 
9.4.8 Prior and Concomitant Medications 
All prescription and over-the-counter medications (including dietary and herbal supplements) 
taken by a subject for 30 days before Screening will be recorded on the designated CRF. The 
Investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF. 

 
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The following medications are prohibited starting 30 days before Screening: 
• Live vaccines 
• Systemic immunosuppressive agents 
Medications which are predominately metabolized by the liver (e.g., acetaminophen) and 
alcohol should, whenever possible, be avoided for the first 52 weeks of the study, and 
particularly within 48 hours prior to lab work. 
9.4.8.1 
Concomitant Haemophilia Treatments 
Subjects on “on demand” therapy for FVIII will continue their treatment at will.  Subjects on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and 
switch to an “on demand” schedule. FVIII can always be taken as needed by the subject, who 
will carefully record his treatment and bleeding episodes in his diary.  In addition, 
information on FVIII usage by medical history will be collected (if available) from subjects 
for the 6 month period immediately preceding study enrollment. 
9.4.8.2 
Glucocorticoid Treatment of Elevated Hepatic Transaminases 
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject 
will have comprehensive surveillance plan monitoring of LFTs (at local labs, twice per week 
for Weeks 1-20, then once per week from Week 21-36, and then once every 2 weeks from 
Week 37-52).  LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and the 
Investigator and review of subject data.  
9.4.8.2.1 Therapeutic Corticosteroids 
In general, therapeutic corticosteroids may be initiated when a subject’s ALT value is 
≥ 1.5x ULN, or based on review of FVIII and liver enzyme data after consultation between 
the Medical Monitor and the Investigator.   
Reports of raised LFTs (defined as ALT ≥ 1.5x ULN) should be made to the BioMarin 
medical monitor within 30 minutes of the lab value being available.  Local laboratory results 
of LFTs will be used to trigger corticosteroid treatment as needed.  In case of discrepant 
results between local and central laboratories, the Investigator and Medical Monitor will 
decide further action.  
Following initiation or completion of therapeutic corticosteroids, if ALT elevation ≥  1.5x  
ULN is reported, steroid management decisions will based on discussions between the 

 
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Investigator and Medical Monitor. Modification of the steroid regimen may take into 
consideration possible confounders for the ALT elevation and impact on FVIII expression.   
Treatment with prednisolone will be initiated at a dose of 60 mg per day and then gradually 
tapered (60 mg daily for the first 2 weeks, then 40 mg the next 2 weeks, then 30 mg the next 
two weeks, then 20 mg the next two weeks, then 15 mg for the next week, then 10 mg for the 
next week, then 5 mg for the next week, then stop, for a total treatment of 11 weeks) (refer to 
Table 9.1.5).  
After discontinuation of corticosteroids, weekly labs for ALT and FVIII levels will be 
measured once a week for 4 weeks to ensure stability in values. 
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This 
includes the contraindicated use of NSAIDs during corticosteroid treatment, and specific 
monitoring not already covered by the schedule of events. Hepatitis B status and HCV viral 
load will be rechecked 6 weeks after the start of corticosteroid treatment, and then 1 week 
and 13 weeks after the completion of corticosteroid treatment. All adverse events should be 
reported as outlined in Section 10 of the protocol. 
9.4.9 Treatment Compliance 
Study drug will be administered to subjects at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided 
for the study.  Sites will be instructed to return or destroy all used and unused study drug 
containers. 
9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 

 
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drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a Study Drug Return Form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study. 
9.7 
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8. 
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post 
BMN 270 administration.  
9.7.1 Safety and Efficacy Measurements Assessed 
The Schedule of Events (Table 9.1.1 through Table 9.1.4) describes the timing of required 
evaluations. 
9.7.2 Primary Efficacy Variables 
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to expression of FVIII at 5 IU/dL or above, 
i.e., a mild severity. This is associated in natural history studies with clinically superior long 
term outcomes (Den Ujil, 2011, Haemophilia). 
The following assays (assessed by the central laboratory) will be used to measure the primary 
efficacy variable: 
• FVIII activity (chromogenic FXa assay) 
• FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time) 
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made 
to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 

 
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The FVIII activity level in both assays and the number of subjects with FVIII activity 
≥ 5 IU/dL in at least one of the two assays will be summarized. 
FVIII activity assays will also be performed at the local laboratory at the time points 
indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4, but will be used in conjunction with 
local lab LFT assessments to monitor subject safety and need for initiation of therapeutic 
corticosteroid dosing; local laboratory FVIII activity assessments will not be used to assess 
efficacy or to measure the primary efficacy outcome of the study. 
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.  Details on performing the assays are included in the Laboratory Manual. 
9.7.3 Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Subjects will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the subject’s diary or 
other subject records. 
9.7.4 Immunogenicity 
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
5-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to a retrospective immunogenicity assessment to determine 
anti-FVIII and capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be 
performed on collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4. 
9.7.5 Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage APTT and/or chromogenic FXa assay (activity).  Individual antigen and activity 
plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity measurements 
will be used to determine PD parameters. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), 
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 

 
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be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology. 
Sample collection times are indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4. 
9.7.6 Exploratory Biomarker Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1, 
Table 9.1.2, Table 9.1.3, and Table 9.1.4 to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to Haemophilia A disease.  The exploratory 
genetic/genomic testing is optional. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes may be used for exploratory use once the 
primary use has been completed.   
9.7.7 Haemo-QoL-A Quality of Life Assessment 
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to 
assess subject quality of life (QoL) during the study.  Assessments will occur at the time 
points listed in the Schedules of Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual. 
9.7.8 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
9.7.8.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the subject signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1, 
Table 9.1.2, Table 9.1.3, and Table 9.1.4. 
9.7.8.2 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, and Table 9.1.4. The scheduled clinical laboratory tests 

 
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are listed in Table 9.7.8.2.1. Refer to the Study Reference Manual for instructions on 
obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF. 
Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Haematology 
Urine Tests 
Other 
Albumin 
Haemoglobin  
Appearance 
CRP 
BUN 
Haematocrit  
Color 
 
Calcium 
WBC count 
pH 
Coagulation Screen 
including: 
Chloride 
RBC count 
Specific gravity 
APTT 
Total cholesterol 
Platelet count 
Ketones 
PT/INR 
CO2 
Differential cell count  
Protein  
TT 
CPK 
 
Glucose  
 
Creatinine 
 
Bilirubin 
 
Glucose 
 
Nitrite 
 
Phosphorus 
 
Urobilinogen 
 
Potassium 
 
Haemoglobin 
 
Total protein 
 
 
 
Sodium 
 
 
 
Uric Acid 
 
 
 
BUN, blood urea nitrogen; CO2, carbon dioxide; CRP, C-reactive protein; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; INR, 
international normalized ratio. 
 

 
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9.7.8.3 
Liver Function and Hepatitis Testing 
Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening.   Subjects with documented results showing an absence of active Hepatitis B or 
Hepatitis C infection (as measured by positive surface antigen for hepatitis B or positive 
RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need 
to be screened again.   
Evidence of ongoing Hepatitis B or Hepatitis C infection is exclusionary. Subjects who have 
cleared a Hepatitis B infection or are seronegative do not need to receive the Hepatitis B 
vaccination.  
Subjects will be tested for hepatitis B and hepatitis C reactivation at Week 16.  Subjects who 
receive therapeutic corticosteroids prior to Week 16 do not need to complete the Week 16 
reactivation assessment; instead, they will be tested for hepatitis B and hepatitis C 
reactivation at the time points listed in Table 9.1.5. 
A liver ultrasound and liver function testing at Screening will identify any significant hepatic 
dysfunction, which is defined as: 
• More than 3x the normal ALT level 
• More than 3x the normal bilirubin level 
• More than 3x the normal Alkaline phosphatase level. 
• INR > 1.4.  
• Thrombocytopoenia under 100 x 109/L 
• Liver ultrasound results indicative of a liver cirrhosis  
Liver function tests will be monitored on a regular basis, at the time points indicated in 
Table 9.1.1, Table 9.1.2, Table 9.1.3, and Table 9.1.4.  At each time point, the following 
LFTs should be assessed: 
Table 9.7.8.3.1:  Liver Function Tests 
Liver Function Tests 
Alkaline Phosphatase 
AST (SGOT) 
Total Bilirubin 
LDH 
ALT (SGPT) 
Direct Bilirubin 
GGT 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; LDH, 
lactate dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic 
transaminase 
 

 
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Patients with persistent ALT > 1.5 ULN during the study and no other etiology identified 
may undergo additional evaluations (e.g., imaging studies including MRI or ultrasound, 
additional blood tests, and/or liver biopsy) at the discretion of the investigator. 
9.7.8.4 
HIV Testing 
HIV testing will be performed at Screening.  Subjects with documented negative results 
within the last 30 days prior to screening do not need to be retested. 
9.7.8.5 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE. 
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored prior to infusion, during the infusion every 
15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then 
every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).  
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 
and every 52 weeks thereafter; at other visits, brief physical examinations may be performed 
at the discretion of the investigator based on the subject’s clinical condition. Particular 
attention should be given to signs of bleeding, as well as assessing possible hemarthroses. 
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems. 
A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 
Height will be recorded at Screening only.  Weight will be recorded at Screening and then 
every 6 months thereafter. 
9.7.8.6 
Vector Shedding 
Vector shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 2007, J.Gene 
Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the literature referenced above, including 
Haemophilia B clinical studies utilizing AAV2 and AAV8, vector was no longer detectable 

 
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after 40 days in blood, saliva, urine or stool, but in one study was detected in the seminal 
fluid but not in motile sperm (Manno, 2006, Nat.Med.).  In these studies, the amount of 
vector present in these bodily fluids involved an extremely small fraction of the infused dose.  
More recent data from an ongoing AAV-FIX study demonstrates persistence of the vector in 
both the blood and the semen for at least 39 weeks (Miesbach, 2016, Haemophilia). 
During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily 
samples to look for evidence of vector shedding for possible viral transmission.  Bodily 
fluids will be tested by PCR at the time points indicated in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.  Fluids tested will include: 
• Blood 
• Saliva 
• Semen 
• Urine 
• Stool 
Vector shedding will also be extensively studied in the present clinical trial, every other week 
between Weeks 4-16, then every 4 weeks to Week 52 until at least 3 consecutive negative 
results are obtained.  Subjects who have not had 3 consecutive negative samples by Week 52 
should continue to have PCR testing every 4 weeks until 3 consecutive negative samples are 
documented (or upon consultation between the Investigator and Medical Monitor). 
Contraception use may need to be extended beyond 26 weeks in individual subjects based on 
observed vector shedding in semen.  After 6 months, subjects may stop contraception use 
only if they have had 3 consecutive negative semen samples. 
Details for sample collection and storage are provided in the Laboratory Manual. 

 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a subject administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
• AEs not previously observed in the subject that emerge during the course of the 
study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only 
because the subject is a haemophiliac) should not be recorded as AEs but will instead be 
captured in subject diaries.  Bleeding events that occur where a normal 
(ie, non-haemophiliac) patient would bleed, such as bleeding as a result of major trauma, 
should be recorded as adverse events.  All bleeding events which meet criteria for being 
serious should be reported as serious adverse events (SAEs) whether or not they are bleeding 
events that are normal sequelae of haemophilia. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 

 
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10.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening  
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires or prolongs inpatient hospitalization.   
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
• 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of  the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as non-
serious AEs. 
10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• 
Elevation of liver enzymes (ALT) that triggers an initiation or modification of  
corticosteroid treatment 
10.3 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.3.1 Adverse Event Reporting Period 
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.2.  

 
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10.3.2 Eliciting Adverse Events 
Investigators will seek information on AEs, SAEs, and EOSI at each subject contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the subject’s medical record and on the AE Case Report 
Form (eCRF). 
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.2 for 
SAE definitions).  These assessments must be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.3.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.3.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1. 
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 

 
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Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden. 
 
10.3.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1. 

 
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Table 10.3.3.3.1:  Causality Attribution Guidance 
Relationship 
Description 
Not Related 
• 
Exposure to the IP has not occurred 
• 
OR 
• 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
• 
OR 
• 
The AE is considered likely to be related to an etiology other than the 
use of the IP; that is, there are no facts, evidence, or arguments to 
suggest a causal relationship to the IP. 
Related 
• 
The administration of the IP and the occurrence of the AE are 
reasonably related in time 
• 
The AE could possibly be explained  by factors or causes other than 
exposure to the IP 
AND 
 
OR 
• 
The administration of IP and the occurrence of the AE are reasonably 
related in time  
• 
The AE is more likely explained by exposure to the IP than by other 
factors or causes. 
AND 
 
Factors suggestive of a causal relationship could include (but are not limited to): 
• Plausible temporal relationship 
• Absence of alternative explanations 
• Rarity of event in a given patient or disease state 
• Absence of event prior to study drug exposure 
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 

 
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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.4.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE eCRF, replacing the original entries where 
appropriate. 
10.4.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF. 

 
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A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.4.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the AE eCRF. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed. 

 
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10.4.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.4.1.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.4.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
• Perform a protocol-mandated efficacy measurement 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
• Hospitalization solely for the purpose of insertion of an in-dwelling IV catheter (such 
as a Port-a-Cath or other brand) for administration of study drug will not be 
considered an SAE. 
• Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 

 
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is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9 
Pregnancy 
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event.  The Investigator must make every effort to 
follow the subject’s partner through resolution of the pregnancy (delivery or termination) and 
to report the resolution on the Pregnancy Follow-up Form in the study reference materials. In 
the event of pregnancy in the partner of a study subject, the Investigator should make every 
reasonable attempt to obtain the woman’s consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5 
Reporting Requirements 
10.5.1 Expedited Reporting Requirements 
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF  and submitting  to BPV within 24 hours of the site 
becoming aware of the event.  Investigators should not wait to collect information that fully 
documents the event before notifying BPV of an SAE.  BioMarin may be required to report 
certain SAEs to regulatory authorities within 7 calendar days of being notified about the 
event; therefore, it is important that Investigators submit any information requested by 
BioMarin as soon as it becomes available. 
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations. 
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 

 
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becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF. 
10.5.2 Ethics Committee Reporting Requirements 
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required. 
10.6 
Follow-up of Subjects after Adverse Events 
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the subject is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the subject’s medical record to facilitate source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.7 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study.  
10.8 
Urgent Safety Measures 
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 

 
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investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• Immediate need to revise the IP administration (eg, modified dose amount or 
frequency not defined in protocol) 
• Lack of study scientific value, or detrimental study conduct or management 
• Discovery that the quality or safety of the IP does not meet established safety 
requirements 
10.9 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
, MD  
Address: 
105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
E-mail: 
 
PI
PI
PI
PI
PI

 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic FXa assay and the APTT assays are both validated and utilize CE marked 
reagents.  The exploratory FVIII activity assay will be used for exploratory purposes only. 

 
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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed. 
12.2 
Screening Visit 
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LFTs, haematology, urine tests, coagulation screen, and CRP do 
not need to be repeated at Baseline.  
The following procedures will be performed during the Screening Period: 
• Full medical history, including haemophilia A history, Hepatitis B, Hepatitis C, and 
HIV.  
• Complete Physical Exam  
• Height and weight 
• Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature)  
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
• Electrocardiogram 
• Chest X-ray 
• Liver Ultrasound 
• Samples for hFVIII Assays 
o Baseline hFVIII activity – chromogenic FXa (plasma) 
o Baseline hFVIII activity level – one-stage APTT assay 
o hFVIII coagulation activity exploratory assay 
o hFVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay 
o hFVIII antigen (ELISA) 

 
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• Blood sample for AAV5 Assays 
o AAV5 antibody titer 
o AAV5 transduction inhibition assay 
• Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested) 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Function Tests (refer to Table 9.7.8.3.1) 
• Von Willebrand Factor Antigen (VWF:Ag)  
• Blood samples for Biomarker testing (including HLA genotyping, FVIII genotyping 
status, TNFα and IL10a single nucleotide polymorphisms) 
12.2.1 “Smart Rescreening” Visit 
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study: 
• 
Vital signs 
• 
Assessment of Adverse Events and Concomitant Medications 
• 
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
• 
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification) 
• Blood sample for AAV5 Assays 
 AAV5 antibody titer 
 AAV5 transduction inhibition assay 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 

 
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• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Function Tests (refer to Table 9.7.8.3.1) 
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
• Distribution of subject diaries and training in diary completion 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Function Tests (refer to Table 9.7.8.3.1) 
• PBMC collection for CTL baseline 
• Direct Thrombin test 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
• Exploratory biomarker assessments 
• Haemo-QoL-A QoL assessment 
12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each subject.  Subjects will remain in the clinic for 
24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
o AAV5 antibody titer 
o AAV5 transduction inhibition assay 
• BMN 270 Infusion 
• Vital Signs 

 
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o Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the subject’s stay in 
the clinic. 
12.5 
BMN 270 Infusion Follow-Up Visits 
After BMN 270 has been infused, subjects will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Once per week (Weeks 1 through 16)  
The following procedures will be performed at one visit per week from Weeks 1 through 16: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
o LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
• Samples for FVIII Assays – central laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
o Central assessment of FVIII activity level should be performed 1x/week 
from Week 1 through Week 16 

 
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12.5.2 Twice per week (Weeks 1 through 16) 
The following procedures will be performed twice per week from Weeks 1 through 16: 
• Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o Local assessment of liver function tests should be performed on Day 8 
during Week 1, and then 2x/week from Week 2 through Week 16 
o LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
• FVIII activity level – local laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
 Local assessment of FVIII activity level should be performed on 
Day 8 during Week 1, and then 2x/week from Week 2 through 
Week 16 
12.5.3 Week 1 – Day 2 and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed: 
• 
PCR of vector DNA in blood, saliva, urine, semen, and stools (Day 2 and Day 4) 
• Samples for FVIII Assays (Day 4 only) – central laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  
• Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – central laboratory 
assessment 
• Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – local laboratory 
assessment 
• FVIII activity level (Day 4 only) – local laboratory assessment 
o FVIII activity level (APTT) 

 
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o FVIII activity level (chromogenic FXa assay) 
12.5.4 Week 1 – Day 8 
On Day 8, the following procedures will be performed: 
• 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
• 
Direct Thrombin test 
• 
Haemo-QoL-A QoL assessment 
12.5.5 Every 2 Weeks 
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedures will be 
performed: 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
(not assessed at Week 14) 
• PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at Week 
2) 
o Collection to occur until at least 3 consecutive negative results are 
obtained 
12.5.6 Weeks 4, 8, 12, and 16 
At Weeks 4, 8, 12, and 16, the following procedure will be performed: 
• PBMC collection 
• Urine Tests (refer to Table 9.7.8.2.1)  
• VWF:Ag 
• FVIII antibody titer 
• Exploratory biomarker assessments 
12.5.7 Week 16 
At Week 16, the following procedure will be performed: 
• Test for Hepatitis B and Hepatitis C reactivation 
o Subjects will be tested for hepatitis B and hepatitis C reactivation at Week 
16.  Subjects who receive therapeutic corticosteroids prior to Week 16 do 
not need to complete the Week 16 reactivation assessment; instead, they 
will be tested for hepatitis B and hepatitis C reactivation at the time points 
listed in Table 9.1.5. 

 
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12.5.8 Weeks 8 and 16 
At Weeks 8 and 16, the following procedures will be performed: 
• AAV5 antibody titer 
12.5.9 Weeks 2, 3, 4, and 16 
At Weeks 2, 3, 4, and 16, the following procedure will be performed: 
• Haemo-QoL-A QoL assessment 
12.5.10Week 13 
At Week 13, the following procedure will be performed: 
• Direct Thrombin test 
12.6 
Safety Follow-Up – Weeks 17-36 
After the Post-Infusion Follow-Up visits are complete, subjects will return to the study site 
for Safety Follow-Up visits from Weeks 17 through Week 36 (± 48 hours), when the 
following procedures will be completed: 
12.6.1 Once per week (Weeks 17 through 36) 
Once per week from Week 17 through Week 36, the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
o LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
• FVIII Assays – central laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 

 
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Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
12.6.2 Twice per week (Weeks 17 through 20) 
Twice per week from Week 17 through Week 20, the following procedures will be 
performed: 
• Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
• FVIII activity level – local laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
12.6.3 Once per week (Weeks 21 through 36) 
Once per week from Week 21 through Week 36, the following procedures will be performed: 
• Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
• FVIII activity level – local laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
12.6.4 Every 4 Weeks  
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed: 
• Exploratory biomarker assessments (Weeks 20 and 24 only) 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• Urine Tests (refer to Table 9.7.8.2.1)  
• VWF:Ag 
• AAV5 antibody titer 
• PBMC collection 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 

 
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o Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period. 
12.6.5 Every 8 Weeks  
Every 8 weeks (Weeks 20, 28, and 36), the following procedure will be performed: 
• FVIII antibody titer 
12.6.6 Week 26 
At Week 26, the following procedure will be performed: 
• Direct Thrombin test 
• Weight 
12.6.7 Weeks 28  
At Week 28, the following procedure will be performed: 
• Haemo-QoL-A QoL assessment 
12.7 
 Safety Follow-Up – Weeks 37-52 
Subjects will return every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) from 
Week 37-52 (± 1 week), when the following procedures will be completed: 
12.7.1 Once per visit 
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data. 
• FVIII activity level – local laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
• Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 

 
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o LFTs may be monitored more or less frequently based (and in particular when 
ALT values are >1.5x ULN) on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
• FVIII Assays – central laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
12.7.2 Every 4 Weeks  
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed: 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• Urine Tests (refer to Table 9.7.8.2.1)  
• AAV5 antibody titer 
• VWF:Ag 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up period.  
Subjects who have not had 3 consecutive negative samples by Week 52 
should continue to have PCR testing every 4 weeks until 3 consecutive 
negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor). 
12.7.3 Every 8 Weeks  
Every 8 weeks (Weeks 44 and 52), the following procedure will be performed: 
• PBMC collection 
• FVIII antibody titer 
12.7.4 Week 38 and 52 
At Week 38 and Week 52, the following procedure will be performed: 
• Direct Thrombin test 

 
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12.7.5 Week 52  
At Week 52, the following procedure will be performed: 
• Haemo-QoL-A QoL assessment 
• Weight 
12.8 
Safety Follow-Up – Years 2-5 
During Years 2-5 of Safety Follow-up, subjects will be assessed every 3 months (± 2 weeks). 
At these times, the following procedures will be completed: 
12.8.1 Every Visit 
Every 3 months (± 2 weeks), the following procedures will be performed: 
• Physical exam 
o Complete Physical Exam will be performed every 52 weeks; Brief 
Physical Exams may be performed at other visits. 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
• FVIII activity level – local laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
• Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
o LFTs may be monitored more or less frequently (and in particular when ALT 
values are >1.5x ULN) based on discussion between the Medical Monitor and 
the Investigator and review of subject data. 
• FVIII Assays – central laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (FXa chromogenic assay) 

 
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o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
• AAV5 antibody titer 
• FVIII antibody titer 
• PBMC collection 
• VWF:Ag 
• Direct Thrombin test 
12.8.2 Every Other Visit (Every 6 Months) 
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the 
end of Year 1 of the Safety Follow-up period), the following procedure will be performed: 
• Haemo-QoL-A QOL assessment 
• Weight 
12.9 
Early Termination Visit 
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
• FVIII activity level – local laboratory assessment 

 
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o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
• Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
• FVIII Assays – central laboratory assessment 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
• AAV5 antibody titer 
• FVIII antibody titer 
• PBMC collection 
• VWF:Ag 
• Direct Thrombin test 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing at the ETV is not required if at least 3 consecutive samples 
are clear during the Post-Infusion Follow-Up period. 
• Haemo-QoL-A QOL assessment 
12.10 End of Study 
The study will end after the last subject completes the last Safety Follow-Up visit 
(Week 260). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study subjects may be 
compromised. 

 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all subjects having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16). 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Missing data will not be imputed.  
14.2 
Primary and Secondary Efficacy Analysis 
The subjects will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of subjects, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined. 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay as 
measured by the central laboratory at 16 weeks following study treatment.  hFVIII activity 
will be assessed weekly during the study period.  We can only assess the true steady state of 
hFVIII protein produced from BMN 270 after a minimum of 72 hours has elapsed since the 
last infusion of FVIII protein concentrates.   
14.3 
Immunogenicity 
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons   
14.4 
Pharmacodynamic Analyses 
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage APTT and/or chromogenic FXa assay (activity level), will be used for plasma 

 
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profiles; FVIII activity will be used to determine PD parameters.  Traditional PK analysis is 
not applicable. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics.  
14.5 
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of subjects who report hepatitis will be presented. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided.  
Detailed statistical methods will be provided in the SAP. 
14.6 
Determination of Sample Size 
No formal sample size calculations based on statistical power were performed. 
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 15 subjects may be dosed in the study; the actual number of 
subjects will depend on the criteria for dose escalation.  
14.7 
Analysis Populations 
The Safety analysis population is defined as all enrolled subjects who receive any study drug. 
The analysis of safety data will be performed on Safety Set. 

 
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The Full Analysis Set (FAS) is defined as all enrolled subjects who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis. 
14.8 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active subjects must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 

 
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15 
DATA REVIEW BOARD 
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established. 
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available subject safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene 
for further assessment of subject safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites. 

 
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16 
COMPENSATION, INSURANCE AND INDEMNITY 
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the subject’s health insurance company or other third party 
payer for the cost of this medical treatment. If the subject has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law. 

 
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17 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy. 
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to 
their medical records, and subjects will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
subject records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification. 
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a subject’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 

 
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completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 

 
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18 
STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 

 
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19 
RETENTION OF RECORDS 
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained. 

 
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20 
USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  

 
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21 
REFERENCES 
Bainbridge, JW, Smith, AJ, Barker, SS, Robbie, S et. al. Effect of gene therapy on visual 
function in Leber's congenital amaurosis. N Engl J Med 358[21], 2231-2239. 2008. 
Berntorp, E, Peake, I, Budde, U, Laffan, M et. al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia 18 Suppl 6, 1-13. 2012. 
Croteau, GA, Martin, DB, Camp, J, Yost, M et. al. Evaluation of exposure and health care 
worker response to nebulized administration of tgAAVCF to patients with cystic fibrosis. 
Ann Occup Hyg 48[8], 673-681. 2004. 
D'Avola, D. Phase 1 Clinical Trial of Liver Directed Gene Therapy with rAAV5-PBGD in 
Acute Intermittent Porphyria: Preliminary Safety Data. J Hepatol 60[S58]. 2014. 
Den Ujil, Mauser Bunschoten, Roosendaal, Schutgens et. al. Clinical Severity of haemophilia 
A: does the classification of the 1950s still stand? Haemophilia 17, 849-853. 2011. 
George, LA, Sullivan, S, Teitel, J, Cuker, A et al.  Preliminary results of a phase 1/2 trial of 
SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent 
factor IX activity levels at the lowest dose cohort.  Haemophilia 22[Suppl. 4], 151-152.  
2016. 
Hay, CR, DiMichele, DM. The principal results of the International Immune Tolerance 
Study: a randomized dose comparison 
12. Blood 119[6], 1335-1344. 2012. 
Kaufman, RJ, Powell, JS. Molecular approaches for improved clotting factors for hemophilia 
1. Blood 122[22], 3568-3574. 2013. 
Maguire, AM, High, KA, Auricchio, A, Wright, JF et. al. Age-dependent effects of RPE65 
gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 
374[9701], 1597-1605. 2009. 
Mahlangu, J, Powell, JS, Ragni, MV, Chowdary, P et. al. Phase 3 study of recombinant factor 
VIII Fc fusion protein in severe hemophilia A 
8. Blood 123[3], 317-325. 2014. 
Manno, CS, Chew, AJ, Hutchison, S, Larson, PJ et. al. AAV-mediated factor IX gene 
transfer to skeletal muscle in patients with severe hemophilia B 
1. Blood 101[8], 2963-2972. 2003. 

 
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Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006. 
Mannucci, PM, Tuddenham, EG. The hemophilias--from royal genes to gene therapy 
1. N Engl J Med 344[23], 1773-1779. 2001. 
McIntosh, J, Lenting, PJ, Rosales, C, Lee, D et. al. Therapeutic levels of FVIII following a 
single peripheral vein administration of rAAV vector encoding a novel human factor VIII 
variant. Blood 121[17], 3335-3344. 2013. 
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016. 
Mingozzi, F and High, KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013. 
Monahan, P, Walsh CE, Powell JS, Konkle BA et al.  Update on a phase 1/2 open-label trial 
of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for 
hemophilia B.  J Thromb Haemostasis 13[Suppl 2], 1-997.  2015. 
Nagel, K, Walker, I, Decker, K, Chan, AK et. al. Comparing bleed frequency and factor 
concentrate use between haemophilia A and B patients 
1. Haemophilia 17[6], 872-874. 2011. 
Nathwani, AC, Gray, JT, Ng, CY, Zhou, J et. al. Self-complementary adeno-associated virus 
vectors containing a novel liver-specific human factor IX expression cassette enable highly 
efficient transduction of murine and nonhuman primate liver 
3. Blood 107[7], 2653-2661. 2006. 
Nathwani, AC, McIntosh, J, Davidoff, AM. An update on gene therapy for hemophilia. Curr 
Hematol Rep 4[4], 287-293. 2005. 
Nathwani, AC, Reiss, UM, Tuddenham, EG, Rosales, C et. al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014. 
Nathwani, AC, Rosales, C, McIntosh, J, Rastegarlari, G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011. 
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992. 

 
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Nathwani, AC, Tuddenham, EG, Rangarajan, S, Rosales, C et. al. Adenovirus-associated 
virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365[25], 2357-2365. 
2011. 
Paneda, A, Lopez-Franco, E, Kaeppel, C, Unzu, C et. al. Safety and liver transduction 
efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute 
intermittent porphyria. Hum Gene Ther 24[12], 1007-1017. 2013. 
Pasi, J, Wong, W, Rangarajan, S, Wilde, J et al.  Interim results of an open-label, phase 1/2 
study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A.  Haemophilia 
22[Suppl. 4], 151-152.  2016. 
Schenk-Braat, EA, van Mierlo, MM, Wagemaker, G, Bangma, CH et. al. An inventory of 
shedding data from clinical gene therapy trials. J Gene Med 9[10], 910-921. 2007. 
Simonelli, F, Maguire, AM, Testa, F, Pierce, EA et. al. Gene therapy for Leber's congenital 
amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18[3], 
643-650. 2010. 
Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS et. al. Guidelines for the 
management of hemophilia 
128. Haemophilia 19[1], e1-47. 2013. 
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010. 
 
Watkins, PB, Kaplowitz, N, Slattery, JT, Colonese, CR et al.  Aminotransferase Elevations in 
Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized Controlled 
Trial.  JAMA 296[1], 87-93.  2006. 
White, GC, Rosendaal, F, Aledort, FM, Lusher, JM et al.  Definitions in hemophilia.  
Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific 
and standardization committee of the International society on Thrombosis and Haemostasis.  
Thromb Haemost. 85[3], 560.  2001. 
 
 
 
 

 
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22 
INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Patients  
In accordance with FDA Form 1572, the Investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and IRB 
review and approval in 21 CFR Part 56 are met.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312. 

 
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23 
SIGNATURE PAGE 
Protocol Title: A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII in Patients with Severe Haemophilia A 
Protocol Number: 270-201, Amendment 4 
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
E6 ICH, as stated in the protocol, and other information supplied to me. 
 
 
 
 
Investigator Signature 
 
Date 
 
 
Printed name:  
 
 
 
 
Accepted for the Sponsor: 
 
 
 
 
Medical Monitor Signature 
 
Date 
 
Printed name: 
, MD, 
, Clinical Sciences 
 
DocuSign Envelope ID: 1E1A3B42-CDC5-483C-B36C-B51007AC035E
PI
PI
PI
PI
PI
PI

 
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24 PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See pages 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font. 
Section No./Title 
Text Revisions 
Rationale 
2/Synopsis/Study 
Rationale 
Figure 1. BMN 270 transgene construct, ~5.0 kbph FVIII-SQ Vector Genome Schematic 
[an updated version of Figure 1 was provided in this protocol amendment] 
12 
2/Synopsis/Objectives 
The primary objectives of the study are: 
• 
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of FVIII at or above 5% of normal activity 
(>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and magnitude of AAV-mediated FVIII activity in 
individuals with haemophilia A will be determined and correlated to an appropriate BMN 270 dose. 
12 
2/Synopsis/Study 
Design & Plan 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and do not have transduction 
inhibition activity to AAV5 will be eligible to enroll in the study. Participants will be enrolled into one of up to threefour cohorts 
according to dose level:  
Cohort 1:  6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous dose (iv) 
Cohort 2:  2E13 vg per kilogram, iv 
Cohort 3:  6E13 vg per kilogram, iv 
Cohort 4:  4E13 vg per kilogram, iv 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of mice and monkeys.  The 
starting dose has a significant safety margin (10-fold) from no observed adverse effect level (NOAEL) in non-human primates.  
Cohorts 1-3  
The first 3 cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between cohorts. Dose escalation may occur 
after a single subject has been safely dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both the aPTT and 
chromogenic assays. Three weeks is expected to be the time the expression will be close to the maximum.  This escalation 
paradigm is intended to minimize the subject numbers exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of mice and monkeys.  The 
starting dose has a significant safety margin (10-fold) from no observed adverse effect level (NOAEL) in non-human primates.   
2 

 
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Section No./Title 
Text Revisions 
Rationale 
… 
For the first subject treated in each Cohortof the first 3 cohorts, if the activity level reaches ≥5 IU/dL and no safety issue is found, 
then up to four subjects will be enrolled in the Cohort. Although the optimum design of this study is three cohorts of 4 subjects, 
though, the adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts based on activity levels of 
FVIII and safety signals.  
Cohort 4 
 
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects is ≥ 5% at 8 weeks and if no safety 
issue is found, an additional 3 subjects may be enrolled in this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical monitor and the DRB.  The adaptive 
nature of this trial allows the DRB to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals. 
 
2/Synopsis/Number of 
Subjects Planned 
Up to 1215 subjects may enroll into the study; the actual number of subjects will depend on the FVIII activity levels seen in each 
Cohort. 
2 
2/Synopsis/Diagnosis 
and All Criteria for 
Inclusion and 
Exclusion 
Individuals eligible to participate in this study must meet all of the following criteria: 
6.  Sexually active patients must be willing to use an acceptable method of contraception such as double barrier, including 
hormonal contraception for at least 6 months post-treatment.  After 6 months, subjects may stop contraception use only if they 
have had 3 consecutive negative semen samples. 
 
6 
2/Synopsis/Criteria for 
Evaluation 
Safety: 
No major toxicity is expected based on preclinical studies in mice and monkeys. An asymptomatic transaminitis was observed at 
week 7-12 after administration in humans with an AAV8-FIX, providing the rationale for the following surveillance plan. Each 
subject will have comprehensive surveillance monitoring LFTs of LFTs (at local labs, twice per week for Weeks 1-20, then once a 
per week from dose to completion of Week 6, 3 times per week from Weeks 7 to 1221-36, and then once a week from Weeks 13 to 
16. If a subject’s ALT is found to be greater than 1.5x his baselineevery 2 weeks from Week 37-52) during these periods, then 
Year 1. LFTs will be monitored three times per week or until the ALT returns to baseline. LFTs will be monitored every other 
month for the first year and then every three months for up to 5 years post-dose in the safety extension; the frequency and duration 
of LFT testing may be changed if dictated by ongoing safety evaluations based on discussion between the Medical Monitor and the 
Investigator and review of subject data. 
1, 3, 12 

 
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Section No./Title 
Text Revisions 
Rationale 
2/Synopsis/Statistical 
Methods 
The sample size is based upon clinical considerations and could detect a strong clinical efficacy signal. Up to 1215 subjects may 
be dosed in the study… 
2 
Figure 7.3.1 
BMN 270 Transgene Construct, ~5.0 kbph FVIII-SQ Vector Genome Schematic 
[An updated version of Figure 7.3.1 has been provided in this protocol amendment] 
12 
7.4/Summary of 
Overall Risks and 
Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based on prior human studies with 
peripheral injections of AAV vectors, there is no known safety risk of AAV gene therapy. However, a mild asymptomatic 
transaminitis was observed at week 7-12 after administration in humans with an AAV8-FIX, providing the rationale for the 
following surveillance plan (Nathwani, 2011, Mol.Ther.). Each subject will have a comprehensive surveillance plan that monitors 
LFTs once a week from dose to completion of Week 6, 3 times per week from Weeks 7 to 12, and once a week from Weeks 13 to 
16.  If a subject’s ALT is found to be greater than 1.5x baseline during these periods, then LFTs will be monitored three times per 
week or until the ALT returns to baseline.  LFTs will be monitored every other month for the first year and then every three 
months for up to 5 years post-dose in the safety extension.  study. 
For additional information on safety findings in 270-201, refer to current version of the Investigator’s Brochure. 
1, 3, 12 
9.1/Overall Study 
Design and Plan 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and do not have transduction 
inhibition activity to AAV5 will be eligible to enroll in the study. Participants will be enrolled into one of up to threefour cohorts 
according to dose level:  
• 
Cohort 1:  6E12 vector genomes [vg/kg] per kilogram of body weight, given as a single intravenous dose (iv) 
• 
Cohort 2:  2E13 vg/kg per kilogram, iv 
• 
Cohort 3:  6E13 vg/kg per kilogram, iv 
• 
Cohort 4:  4E13 vg per kilogram, iv 
Cohort 4   
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects is ≥ 5% at 8 weeks and if no safety 
issue is found, an additional 3 subjects may be enrolled in this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical monitor and the DRB.  The adaptive 
1, 2, 12 

 
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Section No./Title 
Text Revisions 
Rationale 
nature of this trial allows the DRB to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals. 
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of vector is not a likely treatment 
option and these subjects have effectively a single opportunity for therapy using this AAV capsid. Efficacy will be determined by 
FVIII activity at 16 weeks post dose. Safety will be evaluated for approximately 5 years after dosing. Any safety signal may 
trigger a review of the data and possible additional immunogenicity studies that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMC). Additionally, if any of the events listed in Section 9.3.3.1 
occur, enrollment into the trial will be halted to complete an extensive safety analysis. Notification of the study enrollment halt 
will be sent by the Sponsor to the participating sites via telephone and email immediately after becoming aware of a safety 
concern. This will ensure no additional subjects are dosed until the signal has been completely evaluated. If, following safety 
review by the Data Review Board (DRB) and the Sponsor, it is deemed appropriate to restart dosing, a request to restart dosing 
with pertinent data will be submitted to the health authority. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, Baseline and BMN 270 Infusion, in 
Table 9.1.2 for Post-Infusion Follow-up, and in Table 9.1.3 and Table 9.1.4 for Safety Follow-up. 
Table 9.1.5, dealing with steroid prophylaxis therapeutic corticosteroid use in the event of elevated LFTs, is discussed in Section 
9.4.8.2. 
Figure 9.1.1 
The figure title was updated. 
12 
Tables 9.1.1, 9.1.2, 
9.1.3, 9.1.4, and 9.1.5 
All tables and footnotes were updates to reflect the changes in the protocol amendment.  These changes are also reflected as 
changes in Section 12 and are detailed below. 
1, 4, 5, 6, 
7, 8, 9, 10, 
12 
9.2/Discussion of 
Study Design, 
Including Choice of 
Control Group 
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe haemophilia A.  
ThreeFour doses of BMN 270 will be evaluated and the dose escalation decision tree for Cohorts 1-3 is summarized in 
Figure 9.1.1.   
2 
9.3/Selection of Study 
Population 
Up to 1215 severe haemophilia A patients may enroll into the study; the actual number of patients will depend on the criteria for 
dose escalation.  
2 

 
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Section No./Title 
Text Revisions 
Rationale 
9.3.1/Inclusion 
Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
6.  Sexually active patients must be willing to use an acceptable method of contraception such as double barrier, including 
hormonal contraception for at least 6 months post-treatment.  After 6 months, subjects may stop contraception use only if they 
have had 3 consecutive negative semen samples. 
6 
9.3.3.1/Study Safety 
Evaluation Criteria 
If any of the following events occur in a subject in the study who has received BMN 270 infusion, enrollment into the trial will be 
put on halt to complete an extensive safety analysis per Section 9.1.   
• 
A 5-fold increase from baseline in Any ALT elevation > 5x ULN for at least 2 consecutive weeks after BMN 270 
administration of BMN 270, in the absence of a definitive alternate etiology for the increase   
• 
The occurrence of Grade 3 or higher adverse events (excluding ALT elevation) assessed as related to study drug, 
including liver failure and clinical hepatitis 
• 
Grade 2 adverse event assessed as related to study drug that persists for at least 7 days 
• 
The persistent detection of the AAV vector genomeDNA in the semen of a participant in 3 consecutive samples (which 
are at least 2 weeks apart) more than 2652 weeks after BMN 270 infusion, as discussed in Section 9.7.8.5  
If  the following event occurs in a subject in the study who has received BMN 270 infusion, a DRB review and analysis of safety 
data will be undertaken to determine whether the enrollment into the trial will be put on halt: 
Grade 2 adverse event assessed as related to study drug that persists for at least 7 days 
3, 6, 7, 12 
9.4.5/Method of 
Assigning Subjects to 
Treatment Groups 
Cohorts 1 to 3 are enrolled serially and their dose is defined in Section 9.4.6.2 below. Escalation is based on FVIII activity 3 
weeks after injection. Cohorts may receive the next higher dose if subjects in the previous cohort does not meet the activity 
criteria, or the same dose if subjects in the previous cohort meets the activity criteria. Subjects in Cohort 4 will all be enrolled at a 
single dose. 
2 
9.4.6.2/Selection of 
Dose for Each Subject 
For Cohort 4, 3 subjects will be enrolled at 4E13 vg/kg.  If FVIII activity in these 3 subjects is ≥ 5% at 8 weeks and if no safety 
issue is found, an additional 3 subjects may be enrolled in this cohort.   
There will be an ongoing review of individual patient safety and efficacy data by the medical monitor and the DRB.  The adaptive 
nature of this trial allows the DRB to recommend allocating subjects to the cohorts based on activity levels of FVIII and safety 
signals. 
Refer to Figure 9.1.1 for a visual representation of the study design. for Cohorts 1-3 
2, 12 

 
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Section No./Title 
Text Revisions 
Rationale 
9.4.8/Prior and 
Concomitant 
Medications 
All prescription and over-the-counter medications (including dietary and herbal supplements) taken by a subject for 30 days before 
Screening will be recorded on the designated CRF.… 
Medications which are predominately metabolized by the liver (e.g., acetaminophen) and alcohol should, whenever possible, be 
avoided for the first 52 weeks of the study, and particularly within 48 hours prior to lab work. 
12 
9.4.8.1/Concomitant 
Haemophilia 
Treatments 
Subjects on “on demand” therapy for FVIII will continue their treatment at will.  Subjects on prophylactic FVIII therapy will 
discontinue their treatment starting the day of infusion and switch to an “on demand” schedule. FVIII can always be taken as 
needed by the subject, who will carefully record his treatment and bleeding episodes in his diary.  In addition, information on 
FVIII usage by medical history will be collected (if available) from subjects for the 6 month period immediately preceding study 
enrollment. 
12 
9.4.8.2/Glucocorticoid 
Treatment of Elevated 
Hepatic 
Transaminases 
During the Post-Infusion Follow-up Period and the Safety Follow-Up Period, each subject will have comprehensive surveillance 
plan monitoring LFTs once a week from dose to completion of Week 6, 3 timesof LFTs (at local labs, twice per week fromfor 
Weeks 7 to 121-20, then once per week from Week 21-36, and then once a week from Weeks 13 to 16.  Ifevery 2 weeks from 
Week 37-52).  LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based on 
discussion between the Medical Monitor and the Investigator and review of subject data. 
1, 3 
9.4.8.2.1/Therapeutic 
Corticosteroids 
In general, therapeutic corticosteroids may be initiated when a subject’s ALT value is found to be greater than 1.5x his baseline 
during these periods, then LFTs will be monitored three times per week until the ALT returns to baseline.≥ 1.5x ULN, or based on 
review of FVIII and liver enzyme data after consultation between the Medical Monitor and the Investigator.   
Reports of abnormalraised LFTs (defined as 1.5x the subject’s baseline ALT level≥ 1.5x ULN) should be made to the BioMarin 
medical monitor within 30 minutes of the lab value being available, and .  Local laboratory results of LFTs will be used to trigger 
corticosteroid treatment as needed.  In case of discrepant results between local and central laboratories, the Investigator and 
Medical Monitor will decide further action.  
Following initiation or completion of therapeutic corticosteroids, if ALT elevation ≥ 1.5x ULN is reported, steroid management 
decisions will based on discussions between the Investigator and Medical Monitor. Modification of the steroid regimen may take 
into consideration possible confounders for the ALT elevation and impact on FVIII expression.   
Treatment with prednisolone will be initiated immediately at a dose of 60 mg per day and then gradually tapered (60 mg daily for 
the first 2 weeks, then 40 mg the next 2 weeks, then 30 mg the next two weeks, then 20 mg the next two weeks, then 15 mg for the 
next week, then 10 mg for the next week, then 5 mg for the next week, then stop, for a total treatment of 811 weeks). Local 
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laboratory results of LFTs will be used) (refer to Table 9.1.5trigger corticosteroid treatment as needed.  In case of discrepant 
results between local and central laboratories, the Investigator and Medical Monitor will decide further action.).  
• 
If a glucocorticoid treatment is startedAfter discontinuation of corticosteroids, weekly labs for a subject at any point of 
the study, the following stepsALT and FVIII levels will be taken:  
o 
A prophylactic glucocorticoid treatment will be started for subsequent subjects scheduled to be dosed. 
Subjects will receive prednisolone 40 mg per day starting at measured once a week 3, for a duration of 4 
weeks, then tapered by 5 mg every two weeks for 8 weeks (until 20 mg/day is reached), then tapered 5 mg 
per week for 3 weeks, for a total duration of 15 weeks (refer to ). 
Subjects already dosed who have not yet reached Week 17 to ensure stability in the study will be evaluated for the use of 
prophylactic steroids after discussion between the Investigator and the Medical Monitor. 
Once prophylactic glucocorticoid treatments have been initiated, then all subjects (who have not already passed that period in the 
study) will have 3x/week LFT assessments during the 6-week period when a liver response is expected based on the liver response 
in the original subject, if this period is different from the 3x/weekly LFT assessments already planned for Weeks 7-12.   
Subjects who have already passed that 6-week period in the study will continue to have the regularly scheduled LFT assessments 
as planned in the protocolvalues. 
Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in 
consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid 
treatment, and specific monitoring not already covered by the schedule of events. Hepatitis B status and HCV viral load will be 
rechecked at6 weeks after the end start of corticosteroid treatment, and then 1 week and 13 weeks after the completion of 
corticosteroid treatment. All adverse events should be reported as outlined in Section 10 of the protocol. 
9.7.2/Primary Efficacy 
Variables 
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis after BMN 270 dose. The efficacy 
goal of the protocol is to ascertain the dose range of BMN 270 required to convert severe HA patients to stable expression of FVIII 
at 5 IU/dL or above, i.e., a mild severity. This is associated in natural history studies with clinically superior long term outcomes, 
(Den Ujil, 2011, Haemophilia). 
The following assays (assessed by the central laboratory) will be used to measure the primary efficacy variable: 
• 
FVIII activity (chromogenic FXa assay) 
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• 
FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time) 
… 
FVIII activity assays will also be performed at the local laboratory at the time points indicated in Table 9.1.2, Table 9.1.3, and 
Table 9.1.4, but will be used in conjunction with local lab LFT assessments to monitor subject safety and need for initiation of 
therapeutic corticosteroid dosing; local laboratory FVIII activity assessments will not be used to assess efficacy or to measure the 
primary efficacy outcome of the study. 
9.7.6/Exploratory 
Biomarker 
Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1, Table 9.1.2, Table 9.1.3, and Table 9.1.4 
to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The exploratory 
genetic/genomic testing on these exploratory samples is optional. 
All biomarker samples collected in this study may be used for exploratory biomarker research including evaluation of additional 
biomarkers not specifically listed in the protocol.  In addition, samples collected for other purposes may be used for exploratory 
use once the primary use has been completed.  No additional genetic or genomic testing will be conducted on any sample (other 
than testing specified in the protocol). 
12 
Table 
9.7.8.2.1/Clinical 
Laboratory Tests 
This table has been updated as part of this protocol amendment. 
1, 3, 9, 12 
9.7.8.3/Liver Function 
and Hepatitis Testing 
9.7.8.3 Liver Function and Hepatitis Testing at Screening 
Subjects will be tested for hepatitis B and hepatitis C reactivation at Week 16.  Subjects who receive therapeutic corticosteroids 
prior to Week 16 do not need to complete the Week 16 reactivation assessment; instead, they will be tested for hepatitis B and 
hepatitis C reactivation at the time points listed in Table 9.1.5. 
... 
Liver function tests will be monitored on a regular basis, at the time points indicated in Table 9.1.1, Table 9.1.2, Table 9.1.3, and 
Table 9.1.4.  At each time point, the following LFTs should be assessed: 
Table 9.7.8.3.1:  Liver Function Tests 
[this table has been added as part of this protocol amendment] 
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Patients with persistent ALT > 1.5 ULN during the study and no other etiology identified may undergo additional evaluations 
(e.g., imaging studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the investigator. 
9.7.8.4/HIV Testing 
HIV testing will be performed at Screening.  Subjects with documented negative results within the last 30 days prior to screening 
do not need to be retested. 
12 
9.7.8.5/Vital Signs, 
Physical Examinations 
and Other 
Observations Related 
to Safety 
A complete physical examination is necessary during Screening/Baseline, at Week 16 and 52 and every 52 weeks thereafter; at 
other visits, brief physical examinations may be performed at the discretion of the investigator based on the subject’s clinical 
condition. Particular attention should be given to signs of bleeding, as well as assessing possible hemarthroses…. 
Weight and hHeight will be recorded at Screening only.  Weight will be recorded at Screening and then every 6 months thereafter. 
 
9.7.8.6/Vector 
Shedding 
9.7.8.6 ViralVector Shedding 
ViralVector shedding has been extensively studied in all similar clinical trials performed to date. (Nathwani, 2014, 
N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 2007, J.Gene Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the 
literature referenced above, including Haemophilia B clinical studies utilizing AAV2 and AAV8, vector was no longer detectable 
after 40 days in blood, saliva, urine or stool.  However, vector persisted , but in semen for 16 weeksone study was detected in the 
seminal fluid but not in motile sperm (Manno, 2006, Nat.Med.).  In all casesthese studies, the amount of vector present in these 
bodily fluids involved an extremely small fraction of the infused dose.  More recent data from an ongoing AAV-FIX study 
demonstrates persistence of the vector in both the blood and the semen for at least 39 weeks (Miesbach, 2016, Haemophilia). 
Viral shedding will also be extensively studied in the present clinical trial, every week up to 16 weeks, then every 4 weeks to one 
year, then every three months, until at least 3 consecutive negative results are obtained.  During the Post-Infusion Follow-Up 
period, subjects will undergo testing of various bodily samples to look for evidence of viralvector shedding for possible viral 
transmission.  Bodily fluids will be tested by PCR at the time points indicated in Table 9.1.2, Table 9.1.3, and Table 9.1.4…. 
Vector shedding will also be extensively studied in the present clinical trial, every other week between Weeks 4-16, then every 4 
weeks to Week 52 until at least 3 consecutive negative results are obtained.  Subjects who have not had 3 consecutive negative 
samples by Week 52 should continue to have PCR testing every 4 weeks until 3 consecutive negative samples are documented (or 
upon consultation between the Investigator and Medical Monitor). 
Contraception use may need to be extended beyond 26 weeks in individual subjects based on observed vector shedding in semen.  
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After 6 months, subjects may stop contraception use only if they have had 3 consecutive negative semen samples. 
10.2.1/Events of 
Special Interest 
(EOSI) 
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, irrespective of seriousness, severity or 
causality:  
Elevation of liver enzymes (ALT) that triggers a an initiation or modification of  corticosteroid treatment 
12 
10.4.1.3/Persistent or 
Recurrent Adverse 
Events 
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, without resolution, between subject 
evaluation time points.  SuchEvents that change in severity necessitate the recording of an event additional AE.  AEs that do not 
have a change in severity should be recorded only once on the AE eCRF unless its severity increases or decreases (in which case it 
should be recorded again on the AE eCRF).. 
7, 12 
10.4.1.4/Abnormal 
Laboratory Values 
A clinical laboratory abnormality is considered clinically significant and should be documented as AE if anyan AE if not refuted 
by a repeat test to confirm the abnormality and any one or more of the following conditions is met: 
• 
The laboratory abnormality persists upon repeat confirmatory testing.  
12 
10.9/BioMarin 
Pharmacovigilance 
Contact Inforamtion 
Contact information for the medical monitor is as follows: 
Name:  
 
Address: 105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
E-mail:  
 
11 
12.2/Screening Visit 
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion while baseline assessments will take 
place within 7 days of BMN 270 infusion (Day 1). Should the screening visit occur within 7 days of the drug infusion, physical 
examination, vital signs, blood chemistry, LFTs, haematology, urine tests, coagulation screen, and CRP do not need to be repeated 
at Baseline.  
The following procedures will be performed during the Screening Period: 
• 
Complete Physical Exam (including height and weight) 
• 
Height and weight 
1, 3, 8, 12 
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• 
Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• 
Urine Tests (refer to Table 9.7.8.2.1) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) 
• 
Von Willebrand Factor Antigen (VWF:Ag)  
12.2.1/”Smart 
Rescreening” Visit 
If a patient has to be screened again because the original assessments have fallen out of the 28 + 14 day period allowed for 
Screening (refer to Section 12.2), then only the following assessments need to be performed (rather than the full list indicated in 
Section 12.2) for the patient to be successfully re-screened for the study: 
• 
Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• 
Urine Tests (refer to Table 9.7.8.2.1) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) 
1, 3, 12 
12.3/Baseline Visit 
The following procedures will be performed during the Baseline Period: 
• 
Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• 
Urine Tests (refer to Table 9.7.8.2.1) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) 
• 
Direct Thrombin test 
• 
PCR of vector genomesDNA in blood, saliva, urine, semen, and stools 
1, 3, 10, 12 
12.5.1/BMN 270 
Infusion Follow-Up 
Visits/Once per Week 
The following procedures will be performed at one visit per week from Weeks 1 through 16: 
• 
Blood chemistry, haematology, urine tests, coagulation screen, and CRP 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
o 
Each subject will have comprehensive surveillance plan monitoring LFTs once a week from dose to 
completion of Week 6, 3 times per week (every other day excluding weekends) from Weeks 7 to 12, and 
once a week from Weeks 13 to 16.  If a subject’s ALT is found to be greater than 1.5x baseline during these 
periods, then LFTs will be monitored three times per week or until the ALT returns to baseline. 
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o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
Samples for FVIII Assays – central laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
o 
FVIII coagulation activity exploratory assay 
o 
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o 
FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 
Central assessment of FVIII activity level should be performed 1x/week from Week 1 through Week 16 
12.5.2/Twice per week 
(Weeks 1 through 16) 
The following procedures will be performed twice per week from Weeks 1 through 16: 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o 
Local assessment of liver function tests should be performed on Day 8 during Week 1, and then 2x/week 
from Week 2 through Week 16 
o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII activity level – local laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
 
Local assessment of FVIII activity level should be performed on Day 8 during Week 1, and then 
2x/week from Week 2 through Week 16 
1, 3 
12.5.3/Week 1 – Day 
2 and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed: 
• 
PCR of vector genomesDNA in blood, saliva, urine, semen, and stools (Day 2 and Day 4) 
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• 
Samples for FVIII Assays (Day 4 only) – central laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
o 
FVIII coagulation activity exploratory assay 
o 
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o 
FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved.  
• 
Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – central laboratory assessment 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) (Day 4 only) – local laboratory assessment 
• 
FVIII activity level (Day 4 only) – local laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
12.5.4/Week 1 – Day 
8 
On Day 8, the following procedures will be performed: 
• 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
• 
Direct Thrombin test 
• 
Haemo-QoL-A QoL assessment 
4, 10, 12 
12.5.5/Every 2 Weeks 
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedure procedures will be performed: 
• 
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) (not assessed at Week 14) 
• 
Exploratory biomarker assessments 
• 
PCR of vector DNA in blood, saliva, urine, semen, and stools (not collected at Week 2) 
o 
Collection to occur until at least 3 consecutive negative results are obtained 
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12.5.5/Weeks 1, 3, and 
6 
At Weeks 1, 3, and 6, the following procedure will be performed: 
• 
Test for Hepatitis B and Hepatitis C reactivation 
1, 3, 12 
12.5.6/Weeks 4, 8, 12, 
and 16 
At Weeks 4, 8, 12, and 16, the following procedure will be performed: 
• 
PBMC collection 
• 
Urine Tests (refer to Table 9.7.8.2.1)  
• 
VWF:Ag 
• 
FVIII antibody titer 
• 
Exploratory biomarker assessments 
8, 12 
12.5.7/Week 16 
At Week 16, the following procedure will be performed: 
• 
Test for Hepatitis B and Hepatitis C reactivation 
Subjects will be tested for hepatitis B and hepatitis C reactivation at Week 16.  Subjects who receive therapeutic 
corticosteroids prior to Week 16 do not need to complete the Week 16 reactivation assessment; instead, they will 
be tested for hepatitis B and hepatitis C reactivation at the time points listed in Table 9.1.5. 
1, 3, 12 
12.5.10/Weeks 1, 2, 3, 
4 and 16 
At Weeks 1, 2, 3, 4, and 16, the following procedure will be performed: 
• 
Haemo-QoL-A QoL assessment 
12 
12.5.11/Week 13 
At Week 13, the following procedure will be performed: 
• 
Direct Thrombin test 
 
10 
12.6/Safety Follow-
Up – Year 1 
Section 12.6 and its subsections (describing assessments to be performed during the Week 17-52 Safety Follow-Up Period) have 
been deleted and replaced with the new Section 12.6 (for Weeks 17-36) and Section 12.7 (for Weeks 37-52). 
12 
12.6/Safety Follow-
Up – Weeks 17-36 
After the 16 weekly Post-Infusion Follow-Up visits are complete, subjects will return to the study site atfor Safety Follow-Up 
visits from Weeks 20, 28,17 through Week 36, 44, and 52 (± 1 week (± 48 hours), when the following procedures will be 
completed: 
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12.6.1/Once per week 
(Weeks 17 through 
36) 
Once per week from Week 17 through Week 36, the following procedures will be performed: 
• 
Physical exam 
• 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and FVIII 
use) 
• 
Vital Signs 
• 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPLiver Function Tests (refer to Table 9.7.8.3.1) – 
central laboratory assessment 
o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based on 
discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII Assays – central laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
o 
FVIII coagulation activity exploratory assay 
o 
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o 
FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved. 
3, 12 
12.6.2/Twice per week 
(Weeks 17 through 
20) 
Twice per week from Week 17 through Week 20, the following procedures will be performed: 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII activity level – local laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
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12.6.3/Once per week 
(Weeks 21 through 
36) 
Once per week from Week 21 through Week 36, the following procedures will be performed: 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII activity level – local laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
3 
12.6.4/Every 4 Weeks 
Every 4 weeks (Weeks 20, 24, 28, 32, and 36), the following procedures will be performed: 
• 
Exploratory biomarker assessments (Weeks 20 and 24 only) 
• 
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• 
Urine Tests (refer to Table 9.7.8.2.1)  
• 
VWF:Ag 
• 
AAV5 antibody titer 
• 
PBMC collection 
• 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
o 
Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are clear during the 
Post-Infusion Follow-Up period. 
5, 8, 9 
12.6.5/Every 8 Weeks 
Every 8 weeks (Weeks 20, 28, and 36), the following procedure will be performed: 
• 
FVIII antibody titer 
 
12 
12.6.6/Week 26 
At Week 26, the following procedure will be performed: 
• 
Direct Thrombin test 
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• 
Weight 
 
12.6.7/Weeks 28 
At Week 28, the following procedure will be performed: 
• 
Haemo-QoL-A QoL assessment 
 
12 
12.7/Safety Follow-up 
– Weeks 37-52 
Subjects will return every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) from Week 37-52 (± 1 week), when the following 
procedures will be completed: 
 
12 
12.7.1/Once per visit 
At Weeks 38, 40, 42, 44, 46, 48, 50, and 52, the following procedures will be performed: 
• 
Physical exam 
• 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and FVIII 
use) 
• 
Vital Signs 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based 
on discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII activity level – local laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
o 
LFTs may be monitored more or less frequently based (and in particular when ALT values are >1.5x ULN) on 
discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII Assays – central laboratory assessment 
o 
FVIII activity level (APTT) 
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o 
FVIII activity level (chromogenic FXa assay) 
o 
FVIII coagulation activity exploratory assay 
o 
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o 
FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72-hour interval without FVIII use is achieved 
12.7.2/Every 4 Weeks 
Every 4 weeks (Weeks 40, 44, 48, and 52), the following procedures will be performed: 
• 
Blood chemistry, haematology, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• 
Urine Tests (refer to Table 9.7.8.2.1)  
• 
AAV5 antibody titer 
• 
VWF:Ag 
• 
PCR of vector genomesDNA in blood, saliva, urine, semen, and stools 
Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are clear during the 
Post-Infusion Follow-Up period.  Subjects who have not had 3 consecutive negative samples by Week 52 should 
continue to have PCR testing every 4 weeks until 3 consecutive negative samples are documented (or upon 
consultation between the Investigator and Medical Monitor). 
5, 8, 9, 12 
12.7.3/Every 8 Weeks 
Every 8 weeks (Weeks 44 and 52), the following procedure will be performed: 
• 
PBMC collection 
• 
FVIII antibody titer 
12 
12.7.4/Week 38 and 
52 
At Weeks 28 andWeek 38 and Week 52, the following procedure will be performed: 
• 
Direct Thrombin test 
10 
12.7.5/Week 52 
At Week 52, the following procedure will be performed: 
• 
Haemo-QoL-A QoL assessment 
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• 
Weight 
12.8.1/Safety Follow-
Up (Years 2-5): Every 
Visit 
Every 3 months (± 2 weeks), the following procedures will be performed: 
• 
Vital Signs 
• 
Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• 
Urine Tests (refer to Table 9.7.8.2.1) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based on 
discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII activity level – local laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
o 
LFTs may be monitored more or less frequently (and in particular when ALT values are >1.5x ULN) based on 
discussion between the Medical Monitor and the Investigator and review of subject data. 
• 
FVIII Assays – central laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (FXa chromogenic assay) 
o 
FVIII coagulation activity exploratory assay 
o 
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o 
FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain 
FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 
• 
VWF:Ag 
1, 3, 8, 10, 
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• 
Direct Thrombin test  
• 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
o 
Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are clear during the 
Post-Infusion Follow-Up period. 
• 
Vital Signs 
12.8.2/Every Other 
Visit (Every 6 
Months) 
• 
Weight 
 
12.9/Early 
Termination Visit 
At the Early Termination visit, as many of the following assessments as possible should be done: 
• 
Vital Signs 
• 
Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
• 
Urine Tests (refer to Table 9.7.8.2.1) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – local laboratory assessment 
• 
FVIII activity level – local laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
• 
Liver Function Tests (refer to Table 9.7.8.3.1) – central laboratory assessment 
• 
FVIII Assays – central laboratory assessment 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
o 
FVIII coagulation activity exploratory assay 
o 
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o 
FVIII antigen (ELISA) 
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
1, 3, 5, 6, 
8, 10, 12 

 
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2 September 2016 
Section No./Title 
Text Revisions 
Rationale 
activity measurements when a 72-hour interval without FVIII use is achieved. 
• 
VWF:Ag 
• 
Direct Thrombin test 
• 
PCR of vector genomesDNA in blood, saliva, urine, semen, and stools 
o 
Sample testing at the ETV is not required if at least 3 consecutive samples are clear during the Post-Infusion 
Follow-Up period. 
• 
Vital Signs 
14.2/Primary and 
Secondary Efficacy 
Analysis 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as mixed effect model which takes into 
account the correlation among the observation taken at various time points within a participant. Efficacy is a secondary endpoint, 
defined as biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay as measured by the central 
laboratory at 16 weeks following study treatment.  hFVIII activity will be assessed weekly during the study period.  We can only 
assess the true steady state of hFVIII protein produced from BMN 270 after a minimum of 72 hours has elapsed since the last 
infusion of FVIII protein concentrates. 
1, 3, 12 
14.6/Determination of 
Sample Size 
The sample size is determined based upon clinical consideration and could detect a strong clinical efficacy signal. Up to 1215 
subjects may be dosed in the study; the actual number of subjects will depend on the criteria for dose escalation. 
2 
 

 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study 
of BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene 
Transfer of Human Factor VIII in Patients with Severe Haemophilia A 
Protocol Number: 
270-201 
Active Investigational 
Product: 
AAV5-hFVIII-SQ 
IND/European Union 
Drug Regulating 
Authorities Clinical Trials 
(EudraCT) Number: 
2014-003880-38 
 
Indication: 
Haemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 1/2 
Sponsor's Responsible 
Medical Monitor: 
, MD, PhD 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Duration of Subject 
Participation: 
Approximately 264 weeks 
Dose: 
Varied 
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
10 February 2015 
Date of Amendment 1: 
06 March 2015 
Date of Amendment 2: 
26 May 2015 
Date of Amendment 3: 
06 November 2015 
 
 
Property of BioMarin 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written approval from BioMarin. 
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. Code 
of Federal Regulations and the International Conference on Harmonisation Guidelines, including the archiving 
of essential documents 
PI
PI

 
270-201 – Amendment 3 
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06 November 2015 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 3 
Date: 06 November 2015 
 
RATIONALE AND SUMMARY OF MAJOR CHANGES 
A summary of major changes covered by Amendment 3 to the BMN 270-201 protocol is 
provided below.   
1. If a subject develops hepatic transaminases elevated 1.5x above his baseline during 
the study, changes to subject management, including the use of prophylactic 
glucocorticoids and a change to the frequency of liver function testing, will be 
adopted.  
 
Rationale: Previous clinical trials using AAV2-FIX and AAV8-FIX have shown some 
occurrences of elevation of liver enzymes 5-12 weeks after dosing. Such elevation was 
correlated with a loss of transgene expression in these clinical trials. As the present trial is a 
First-in-Human (FIH) for the combination of this vector serotype and Factor VIII, the 
occurrence of such a liver response is unknown as well as the possible consequences on gene 
expression. Occurrences of liver enzyme elevation in previous clinical trial were readily 
managed by a tapered regimen of low dose steroids.  By including prophylactic 
corticosteroids for all subsequent subjects as well as shifting the surveillance monitoring 
period to coincide with the initial liver response, reductions in transgene expression may be 
avoided. 
2. Added as an exclusion criterion any subject with major surgery planned during the 
16-week period following viral infusion. 
Rationale:   A major surgery, such as hip replacement, planned during the initial 16-week 
follow up period would jeopardize the subject’s safety, as it is unknown what his expression 
level of factor VIII would be at this time.  
3. Added a “smart rescreening” option for subjects who are successfully screened but do 
not undergo Baseline assessments and Infusion within the 28 + 14 day window 
required by the protocol.  
Rationale: Reducing the number of screening assessments for a smart rescreen poses minimal 
risk to the subject and keeps the subject below the statutory 12 week blood volume threshold. 
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 

 
270-201 – Amendment 3 
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06 November 2015 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.   Subjects may not undergo smart rescreening more than once. 
4. Clarified that subjects who have cleared a Hepatitis B infection or are seronegative 
will not be required to receive the hepatitis vaccination as a requirement for enrolling 
in the study. 
Rationale:   Subjects who have cleared the infection or are seronegative have a very low 
chance of becoming seropositive during the trial. Most Haemophilia A patients are already 
vaccinated, and the risk is too low to mandate the vaccination.  
5. Minor edits for clarity and consistency have been incorporated. 
Specific changes included in this amendment, including the Synopsis, since Amendment 2 
(approved 26 May 2015) are outlined in Section 24. 

 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study of BMN 270, an Adenovirus-
Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
PROTOCOL NUMBER: 
270-201 
STUDY SITES: 
Approximately 6-10 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 1/2 
STUDY RATIONALE: 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an essential 
cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to a new 
mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of 
wild type activity and the mild form is 5-40% activity. The clinical manifestations of severe HA 
remain frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or recombinant 
human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, and at the time of 
a bleed, to prevent or control bleeding episodes, respectively. The half-life for FVIII (12 to 18 hours 
for most approved products) necessitates frequent infusions, and although a major advance in the 
treatment of HA, it remains common for severe HA patients to continue to have multiple bleeding 
events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year 
for on demand treatment). The consequence of multiple bleeding events is the development of an 
underlying pathology that contributes to debilitating multiple-joint arthropathy and substantially 
increased risk of death. Chemical modification (e.g. direct conjugation of polyethylene glycol (PEG) 
polymers) and bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
approximately 50%, and thus, show promise in reduced dosing and maintaining activity levels above 
1% trough. However, these longer acting FVIIIs remain dependent on multiple infusions to maintain 
critical levels of FVIII activity in severe HA patients. There is therefore a strong unmet need for a fully 
preventive treatment of HA to give patients a FVIII level compatible with a normal and 
haemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous production 
of active FVIII following a single intravenous administration of a vector with the appropriate gene 
sequence. Haemophilia A is well suited for a gene replacement approach because clinical 
manifestations are attributable to the lack of a single gene product (FVIII) that circulates in minute 
amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not essential, and 
modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml induces an increase 
in activity of 1%) can ameliorate the severe form of the disease.  Thus, relatively small changes in 
endogenous FVIII activity results in clinically relevant improvements in disease phenotype. Finally, 
the response to gene transduction can be assessed using validated quantitative rather than qualitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific tissues 
such as the liver (for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical 
trial for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild is achievable following a single peripheral vein administration of AAV-8 vector. 
Several participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in bleeding. 
Thus, gene therapy treatment has resulted in a substantial improvement in their quality of life.  
 
 
 
 
 
 
 
 
 
 
 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII under the 
control of a liver-selective promoter (Figure 1). 
Figure 1. BMN 270 transgene construct, ~5.0 kbp 
 
 
 
 
 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, potentially 
life-long expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
The clinical study BMN 270-201 is a first-in-human study designed to assess the relationship of vector 
dose to the augmentation of residual FVIII activity, and whether these levels are sufficient to alter the 
clinical phenotype. The relationship of dose to safety will be correlated to the activity of hFVIII in 
patients with severe HA. 
OBJECTIVES:  
The primary objectives of the study are: 
• 
To assess the safety of a single intravenous administration of a recombinant AAV5 encoding 
human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• 
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of FVIII at or 
above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose. 
The secondary objectives of the study are: 
• 
To describe the immune response to the FVIII transgene and AAV capsid proteins following 
systemic administration of AAV5-hFVIII-SQ 
• 
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during the 
study 
• 
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study 
4970 
251 bp  
SFSQNPPVKRHQ

 
270-201 – Amendment 3 
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06 November 2015 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STUDY DESIGN AND PLAN:  
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe haemophilia 
A. Eligible patients will enter the dose escalation part of the study followed by a 16-week 
Post-Infusion Follow-Up period during which safety and efficacy assessments will be taken. After the 
primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed for approximately 
5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and do 
not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. Participants 
will be enrolled into one of up to three cohorts according to dose level:  
1. 6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous dose 
(iv) 
2. 2E13 vg per kilogram, iv 
3. 6E13 vg per kilogram, iv 
Cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between cohorts. Dose 
escalation may occur after a single subject has been safely dosed if the resulting FVIII activity at the 
Week 3 visit is < 5 IU/dL in both the aPTT and chromogenic assays. Three weeks is expected to be the 
time the expression will be close to the maximum.  This escalation paradigm is intended to minimize 
the subject numbers exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of 
mice and monkeys.  The starting dose has a significant safety margin (10-fold) from no observed 
adverse effect level (NOAEL) in non-human primates.   
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study, the Data Review Board (DRB).  
If the FVIII activity reaches ≥ 5 IU/dL at the Week 3 visit, then the remaining subjects in the cohort 
will be enrolled without the need to wait for 3 weeks between subjects. 
Subject 1 will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram of body 
weight. If the FVIII activity level does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then no 
further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with Subject 2 at 
the next dose (2E13 vg/kg).  
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥ 5 IU/dL at the Week 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
3 visit in both assays, then no further subjects will be dosed in Cohort 2 and enrollment into Cohort 3 
(6E13) will initiate with the next subject. If the FVIII activity level in the first subject treated in Cohort 
3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then the Data Review Board (DRB) will 
recommend whether to continue to add subjects to the cohort and/or whether to continue the study. 
For the first subject treated in each Cohort, if the activity level reaches ≥5 IU/dL and no safety issue is 
found, then up to four subjects will be enrolled in the Cohort. Although the optimum design of this 
study is three cohorts of 4 subjects, the adaptive nature of this trial allows the DRB to recommend 
allocating subjects to the cohorts based on activity levels of FVIII and safety signals.  
Because subjects develop neutralizing immunity upon exposure to the capsid, re-challenge of vector is 
not a likely treatment option and these subjects have effectively a single opportunity for therapy using 
this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post dose. Safety will be 
evaluated for approximately 5 years after dosing.  Any safety signal may trigger a review of the data 
and possible additional immunogenicity studies that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMC). 
NUMBER OF SUBJECTS PLANNED:  
Up to 12 subjects may enroll into the study; the actual number of subjects will depend on the FVIII 
activity levels seen in each Cohort. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe haemophilia A as evidenced by their 
medical history.  Patients will be considered as severe if their base FVIII level is 1 IU/dL or 
less 
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days 
(EDs) 
3. Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 
0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 
12 months 

 
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06 November 2015 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
6. Sexually active patients must be willing to use an acceptable method of contraception such as 
double barrier, including hormonal contraception for at least 6 months post-treatment 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition or AAV5 total antibodies 
2. Any evidence of active infection or any immunosuppressive disorder.   
3. HIV positive 
4. Significant liver dysfunction as defined by abnormal elevation of: 
• 
ALT (alanine transaminase) to 3 times the upper limit of normal; 
• 
Bilirubin above 3 times the upper limit of normal; 
• 
Alkaline phosphatase above 3 times the upper limit of normal; or 
• 
INR (international normalized ratio) ≥ 1.4 
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if they had 
significant fibrosis of 3 or 4 as rated on a scale of 0-4 
6. Evidence of any bleeding disorder not related to Haemophilia A 
7. Platelet count of < 100 x 109/L 
8. Creatinine ≥ 1.5 mg/dL 
9. Liver cirrhosis of any etiology as assessed by liver ultrasound  
10. Hepatitis B if surface antigen is positive 
11. Hepatitis C if RNA is positive 
12. Treatment with any IP within 30 days prior to the end of the screening period 
13. Any disease or condition at the physician’s discretion that would prevent the patient from fully 
complying with the requirements of the study including possible corticosteroid treatment 
outlined in the protocol.  The physician may exclude patients unwilling or unable to agree on 
not using alcohol for the 16-week period following the viral infusion. 
14. Prior treatment with any vector or gene transfer agent 

 
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06 November 2015 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
15. Major surgery planned in the 16-week period following the viral infusion 
16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral 
infusion 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
The study is open label with comparison of FVIII activity to baseline values. No reference therapy will 
be evaluated in this study. 
DURATION OF TREATMENT:  
BMN 270 is given as a single dose by intravenous infusion. 
CRITERIA FOR EVALUATION: 
The following safety outcome measurements will be assessed: 
Safety: 
• 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
• 
Change in clinical laboratory tests (serum chemistry and haematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding 
• 
Liver function tests (LFTs, including ALT, AST, GGT, LDH, bilirubin, alkaline phosphatase) 
• 
Immune response to FVIII transgene and AAV capsid proteins 
No major toxicity is expected based on preclinical studies in mice and monkeys. An asymptomatic 
transaminitis was observed at week 7-12 after administration in humans with an AAV8-FIX, providing 
the rationale for the following surveillance plan. Each subject will have comprehensive surveillance 
monitoring LFTs once a week from dose to completion of Week 6, 3 times per week from Weeks 7 to 
12, and once a week from Weeks 13 to 16. If a subject’s ALT is found to be greater than 1.5x his 
baseline during these periods, then LFTs will be monitored three times per week or until the ALT 
returns to baseline. LFTs will be monitored every other month for the first year and then every three 
months for up to 5 years post-dose in the safety extension; the frequency and duration of LFT testing 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
may be changed if dictated by ongoing safety evaluations. 
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.   
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the study is 
to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration. 
  
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Subjects will be asked 
to keep a subject diary to record the details in these areas.   
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage APTT 
and/or chromogenic FXa assay (activity level), will be used for plasma profiles; FVIII activity will be 
used to determine PD parameters.  Traditional PK analysis is not applicable. 
Pharmacodynamics: 
If supported by the FVIII activity data, non-compartmental analysis and observation will be used to 
estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss (time 
to steady state), C(t) and AUC(0-t) where t is 16 weeks.   
STATISTICAL METHODS:  
The sample size is based upon clinical considerations and could detect a strong clinical efficacy signal. 
Up to 12 subjects may be dosed in the study.  The subjects will be followed in a longitudinal manner 
and all the relevant information will be collected. The analysis of the data will be descriptive in nature 
but data collected in a longitudinal manner may be analyzed using longitudinal methods such as mixed 
effect model which takes into account the correlation among the observation taken at various time 
points within a participant. Efficacy is a secondary endpoint, defined as biologically active FVIII at 
≥ 5 IU/dL by chromogenic FXa assay and/or one-stage APTT assay at 16 weeks following study 
treatment. FVIII activity will be assessed weekly during the study period.  We can only assess the true 
steady state of FVIII protein produced from BMN 270 after a minimum of 72 hours has elapsed since 
the last infusion of FVIII protein concentrates. 
Analysis of neutralizing antibody response and other immunological parameters as well as viral 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses. 

 
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3 TABLE OF CONTENTS 
2 SYNOPSIS ...........................................................................................................................4 
3 TABLE OF CONTENTS ...................................................................................................12 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................17 
5 ETHICS..............................................................................................................................19 
5.1 Institutional Review Board or Independent Ethics Committee ................................19 
5.2 Ethical Conduct of Study ..........................................................................................19 
5.3 Subject Information and Informed Consent ..............................................................20 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................21 
7 INTRODUCTION .............................................................................................................22 
7.1 Nonclinical Studies ...................................................................................................22 
7.2 Previous Clinical Studies ..........................................................................................24 
7.3 Study Rationale .........................................................................................................25 
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp .........................................26 
7.4 Summary of Overall Risks and Benefits ...................................................................27 
8 STUDY OBJECTIVES ......................................................................................................29 
9 INVESTIGATIONAL PLAN ............................................................................................30 
9.1 Overall Study Design and Plan .................................................................................30 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme ............................................31 
Table 9.1.1: Schedule of Events – Screening and Infusion ......................................33 
Table 9.1.3:  Schedule of Events – Safety Follow-Up .............................................37 
Table 9.1.4:  Schedule of Events – Steroid Prophylaxis ..........................................38 
9.2 Discussion of Study Design, Including Choice of Control Group ............................39 
9.3 Selection of Study Population ...................................................................................39 
9.3.1 
Inclusion Criteria .........................................................................................39 
9.3.2 
Exclusion Criteria ........................................................................................40 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................41 
9.3.4 
Subject Identification and Replacement of Subjects ...................................42 
9.3.5 
Duration of Subject Participation ................................................................42 
9.4 Treatments .................................................................................................................42 

 
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9.4.1 
Treatments Administered ............................................................................42 
9.4.2 
Identity of Investigational Product ..............................................................42 
9.4.3 
Storage .........................................................................................................43 
9.4.4 
Directions for Administration .....................................................................43 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................44 
9.4.6 
Selection of Doses Used in the Study .........................................................44 
9.4.7 
Blinding .......................................................................................................45 
9.4.8 
Prior and Concomitant Medications ............................................................45 
9.4.9 
Treatment Compliance ................................................................................47 
9.5 Investigational Product Accountability .....................................................................47 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................47 
9.6 Dietary or Other Protocol Restrictions......................................................................47 
9.7 Safety and Efficacy Variables ...................................................................................47 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................48 
9.7.2 
Primary Efficacy Variables .........................................................................48 
9.7.3 
Secondary Efficacy Variables .....................................................................48 
9.7.4 
Immunogenicity ...........................................................................................48 
9.7.5 
Pharmacodynamics ......................................................................................49 
9.7.6 
Exploratory Biomarker Assessments ..........................................................49 
9.7.7 
Haemo-QoL-A Quality of Life Assessment ................................................49 
9.7.8 
Safety Variables ..........................................................................................49 
10 REPORTING ADVERSE EVENTS .................................................................................54 
10.1 Safety Parameters and Definitions ............................................................................54 
10.1.1 Adverse Events ............................................................................................54 
10.2 Serious Adverse Events ............................................................................................55 
10.2.1 Events of Special Interest (EOSI) ...............................................................55 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................55 
10.3.1 Adverse Event Reporting Period .................................................................55 
10.3.2 Eliciting Adverse Events .............................................................................55 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................56 

 
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10.4 Procedures for Recording Adverse Events ...............................................................58 
10.4.1 Recording Adverse Events on a eCRF ........................................................58 
10.5 Reporting Requirements ...........................................................................................61 
10.5.1 Expedited Reporting Requirements .............................................................61 
10.5.2 Ethics Committee Reporting Requirements ................................................62 
10.6 Follow-up of Subjects after Adverse Events .............................................................62 
10.7 Post-Study Adverse Events .......................................................................................62 
10.8 Urgent Safety Measures ............................................................................................63 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................64 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................65 
12 STUDY PROCEDURES ...................................................................................................66 
12.1 Prestudy .....................................................................................................................66 
12.2 Screening Visit ..........................................................................................................66 
12.2.1 “Smart Rescreening” Visit ..........................................................................67 
12.3 Baseline Visit ............................................................................................................68 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................68 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................69 
12.5.1 Every Visit ...................................................................................................69 
12.5.2 Week 1 – Day 2 and Day 4 ..........................................................................70 
12.5.3 Every 2 Weeks .............................................................................................70 
12.5.4 Weeks 4, 8, 12, and 16 ................................................................................70 
12.5.5 Weeks 1, 3, and 6 ........................................................................................70 
12.5.6 Weeks 8 and 16 ...........................................................................................70 
12.5.7 Weeks 1, 2, 3, 4, and 16 ..............................................................................70 
12.6 Safety Follow-Up – Year 1 .......................................................................................71 
12.6.1 Every Visit ...................................................................................................71 
12.6.2 Weeks 28 and 52 .........................................................................................71 
12.7 Safety Follow-Up – Years 2-5 ..................................................................................72 
12.7.1 Every Visit ...................................................................................................72 
12.7.2 Every Other Visit (Every 6 Months) ...........................................................73 

 
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12.8 Early Termination Visit ............................................................................................73 
12.9 End of Study..............................................................................................................74 
13 DATA QUALITY ASSURANCE .....................................................................................75 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................76 
14.1 Statistical and Analytical Plans .................................................................................76 
14.1.1 Interim Analyses ..........................................................................................76 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........76 
14.2 Primary and Secondary Efficacy Analysis................................................................76 
14.3 Immunogenicity ........................................................................................................76 
14.4 Pharmacodynamic Analyses .....................................................................................76 
14.5 Safety Analysis .........................................................................................................77 
14.6 Determination of Sample Size ..................................................................................77 
14.7 Analysis Populations .................................................................................................77 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................78 
15 DATA REVIEW BOARD .................................................................................................79 
16 COMPENSATION, INSURANCE AND INDEMNITY ..................................................80 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................81 
18 STUDY MONITORING AND AUDITING .....................................................................83 
19 RETENTION OF RECORDS ...........................................................................................84 
20 USE OF INFORMATION AND PUBLICATION ...........................................................85 
21 REFERENCES ..................................................................................................................86 
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................89 
22.1 Conduct of Study and Protection of Human Patients ...............................................89 
23 SIGNATURE PAGE .........................................................................................................90 
24 PROTOCOL AMENDMENT TEXT REVISIONS ..........................................................91 

 
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LIST OF TABLES 
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................33 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up .................................................35 
Table 9.1.3:  Schedule of Events – Safety Follow-Up .............................................................37 
Table 9.1.4:  Schedule of Events – Steroid Prophylaxis ..........................................................38 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................51 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................56 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................57 
 
LIST OF FIGURES 
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp ........................................................26 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme ............................................................31 
 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAV 
Abbreviations 
adeno-associated virus 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine transaminase 
APTT 
activated partial thromboplastin time 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
DMC 
Data Monitoring Committee 
DRB 
Data Review Board 
eCRF 
electronic case report form 
ED 
exposure days 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FVIII 
coagulation factor VIII 
FXa 
coagulation factor Xa 
GCP 
Good Clinical Practice 
HA 
Haemophilia A 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 

 
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IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
vg 
vector genomes 
 
Investigational Product (IP): 
Definition of Terms:  
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 

 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin or its designee. The Investigator will provide the IRB/IEC/REB 
with all appropriate material, including the protocol, Investigator’s Brochure (IB), the 
Informed Consent Form (ICF) including compensation procedures, and any other written 
information provided to the subjects, including all ICFs translated to a language other than 
the native language of the clinical site. The study will not be initiated and Investigational 
Product (IP) supplies will not be shipped to the site until appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol, the ICF and all subject 
recruitment materials are obtained in writing by the Investigator and copies are received at 
BioMarin or its designee. The approval document should refer to the study by protocol title 
and BioMarin protocol number (if possible), identify the documents reviewed, and include 
the date of the review and approval. BioMarin will ensure that the appropriate reports on the 
progress of the study are made to the IRB/IEC/REB and BioMarin by the Investigator in 
accordance with applicable guidance documents and governmental regulations. 
5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 

 
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eligible subjects for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability. 
This study will be conducted in accordance with the following: 
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6) 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the subjects will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF , and if applicable, 
a copy of the approved subject information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed. 
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject. 

 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of subjects in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 
Liver function tests (LFTs) will be performed at the local laboratories associated with the 
study sites.  Local laboratory results of LFTs will be used to trigger corticosteroid treatment 
as needed (refer to Section 9.4.8.2).  In case of discrepant results between local and central 
laboratories, the Investigator and Medical Monitor will decide further action.  Safety labs 
evaluations (including LFTs) will be performed at the central lab, while bioanalytical 
samples will be performed at the appropriate specialty lab.  Refer to the Laboratory Manual 
for more details. 

 
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7 
INTRODUCTION 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.). 
Chemical modification or bioengineering of FVIII may improve half-life to 18-19 hours 
(Kaufman, 2013, Blood). However, these long acting FVIII variants do not eliminate the 
need for lifelong FVIII protein administration (Hay, 2012, Blood).  
Gene therapy offers the potential of a cure through continuous endogenous production of 
human FVIII following a single administration of vector. Haemophilia A is well suited for 
this approach because its clinical manifestations are attributable to the lack of a single gene 
product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. Tightly 
regulated control of gene expression is not essential and a modest increase in the level of 
FVIII (a plasma level of 2ng/ml protein leads to a 1% expression) can ameliorate the severe 
phenotype (Srivastava, 2013, Haemophilia.); thus the therapeutic goal for gene therapy is a 
modest increase in hFVIII. Finally, the consequences of gene transfer can be assessed using 
simple quantitative rather than qualitative endpoints that can be easily assayed in most 
clinical laboratories. 
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 
7.1 
Nonclinical Studies 
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 

 
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nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints. 
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in FVIII KO x Rag2 mice given matched IU 
levels of Refacto®.   
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.   
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed. 
The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 

 
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the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence closely matching that of 
the protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Nathwani, 2006, Blood). Despite 
distribution to non-liver organs, no expression of Factor IX was detected in these tissues.  
Additionally, distribution to the testis was observed in another study in monkeys given an 
AAV5-codon-optimized human porphobilinogen deaminase; however, vector genomes in the 
semen were only transiently observed within one week but not thereafter (Paneda, 2013, 
Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents 10-fold safety factor from the 
no observed adverse effect level (NOAEL) in the GLP enabling nonclinical toxicology study 
in mice.  
7.2 
Previous Clinical Studies 
This is the first clinical study for BMN 270. 
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Engl.J.Med.), 
(Nathwani, 2014, N.Engl.J.Med.). The large size of the FVIII cDNA was shortened and a 
preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013, 
Blood). 

 
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AAV serotype 5 is being tested in other clinical trials and was reportedly well tolerated 
without treatment-related serious adverse events in a recent phase 1 study for treatment of 
Acute Intermittent Porphyria (D'Avola, 2014, J.Hepatol.). In addition, AAV using other 
serotypes have been used in 105 clinical studies to date and no safety issue specific to the 
vector was ever reported.   
7.3 
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Mannucci, 2001, N.Engl.J.Med.).  It is caused by deficiency in the activity 
of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic coagulation cascade. 
This disorder can be either inherited, due to a new mutation or an acquired immunologic 
process, leading to insufficient quantities of FVIII or a dysfunctional FVIII, but all are 
characterized by a defective coagulation process. . The clinical phenotype of HA patients is 
largely governed by the level of residual expression. Severe HA is classified as FVIII activity 
less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild type activity 
and the mild form is 5-40% activity. The clinical manifestations of severe HA remain 
frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-4 times per 
week, and at the time of a bleed, to prevent or control bleeding episodes, respectively. The 
half-life for FVIII (12-18 hours for most approved products) necessitates frequent infusions, 
and although a major advance in the treatment of HA, it remains common for severe HA 
patients to continue to have multiple bleeding events on treatment (mean of 1 to 7 
episodes/year with prophylaxis and up to 30 to 50 episodes/year for on demand treatment) 
(Nagel, 2011, Haemophilia.).  The consequence of multiple bleeding events is the 
development of an underlying pathology that contributes to debilitating multiple-joint 
arthropathy and substantially increased risk of death (Nagel, 2011, Haemophilia).  Chemical 
modification (e.g. direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by approximately 
50%, and thus, show promise in reduced dosing and maintaining activity levels above 1% 
trough (Stonebraker, 2010, Haemophilia.), (Mahlangu, 2014, Blood). However, these longer 
acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive 
treatment of HA to give patients a FVIII level compatible with a normal and 
haemorrhage-free life.  

 
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Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Mannucci, 2001, 
N.Engl.J.Med.). They have an excellent and well defined safety profile, and can direct long 
term transgene expression with tropism for specific tissues such as the liver (Nathwani, 2005, 
Curr.Hematol.Rep.) for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene 
therapy clinical trial for a related disorder, haemophilia B, has established that stable (>36 
months) expression of human factor IX at levels that are sufficient for conversion of their 
bleeding phenotype from severe to moderate or mild is achievable following a single 
peripheral vein administration of AAV-8 vector (Nathwani, 2014, N.Engl.J.Med.).  Several 
participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in 
bleeding. Thus, gene therapy treatment has resulted in a substantial improvement in their 
quality of life (Nathwani, 2011, Mol.Ther.), (Bainbridge, 2008, N.Engl.J.Med.), (Maguire, 
2009, Lancet); (Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII 
under the control of a liver-selective promoter (Figure 7.3.1).  
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp 
 
 
 
 
 
4970 
4374 
251 bp  
SFSQNPPVLKRHQ

 
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BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active FVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of FVIII in patients with severe 
HA. 
7.4 
Summary of Overall Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based 
on prior human studies with peripheral injections of AAV vectors, there is no known safety 
risk of AAV gene therapy. However, a mild asymptomatic transaminitis was observed at 
week 7-12 after administration in humans with an AAV8-FIX, providing the rationale for the 
following surveillance plan (Nathwani, 2011, Mol.Ther.). Each subject will have a 
comprehensive surveillance plan that monitors LFTs once a week from dose to completion of 
Week 6, 3 times per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a 
subject’s ALT is found to be greater than 1.5x baseline during these periods, then LFTs will 
be monitored three times per week or until the ALT returns to baseline.  LFTs will be 
monitored every other month for the first year and then every three months for up to 5 years 
post-dose in the safety extension.   
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose 
that maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the 
possibility of a sub-therapeutic effect. With this consideration in mind, the starting dose 
6E12 vg/kg was selected using overall data from the pre-clinical studies conducted in mice 
(normal and disease model, Rag2 -/- x FVIII -/-) and monkey. A detectable pharmacological 
response based on activity was observed at 6E12 vg/kg. A 10-fold safety margin based upon 
the NOAEL was observed in the GLP 13-week study in normal mouse at the highest dose 
administered. A 30-fold safety margin in an 8-week dose response study in disease model 
mice based on histology was observed at the highest dose administered. No BMN 270-related 
changes in clinical observations or chemistry was observed in the monkey at doses up to 
6E13 vg/kg, a 10-fold safety margin after 8-weeks. Overall, no BMN 270-related findings, 
except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model 
mouse and monkey, respectively. 

 
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Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to subjects with the best chance of 
benefiting the subject therapeutically. 

 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are: 
• To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII 
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270 
dose. 
The secondary objectives of the study are: 
• To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of AAV5-hFVIII-SQ 
• To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study 
• To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled into one of up to three cohorts according to dose level:  
1. 6E12 vg/kg of body weight, given as a single intravenous dose (iv) 
2. 2E13 vg/kg, iv 
3. 6E13 vg/kg, iv 
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys.  The starting dose has a significant safety margin (10-fold) 
from no observed adverse effect level (NOAEL) in mice.   
Cohorts will be enrolled sequentially, allowing a period of 3 weeks or more between cohorts. 
Dose escalation may occur after a single subject in a cohort has been safely dosed if the 
resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both assays. Three weeks is 
expected to be the time the expression will be close to the maximum.  This escalation 
paradigm is intended to minimize the subject numbers exposed to subtherapeutic doses.  The 
decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and a panel of investigators participating in the 
study.    
If the FVIII activity reaches ≥5 IU/dL at the Week 3 visit, then the remaining subjects in the 
cohort will be enrolled without the need to wait for 3 weeks between subjects. 

 
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme 
 
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1) 
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.  
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each Cohort, if the activity level reaches ≥5 IU/dL and no 
safety issue is found, then up to four subjects will be enrolled in the Cohort. Although the 
optimum design of this study is three cohorts of 4 subjects, the adaptive nature of this trial 
allows the DRB to recommend allocating subjects to the cohorts based on activity levels of 
FVIII and safety signals.  Because subjects develop neutralizing immunity upon exposure to 
the capsid, re-challenge of vector is not a likely treatment option and these subjects have 
effectively a single opportunity for therapy using this AAV capsid. Efficacy will be 
determined by FVIII activity at 16 weeks post dose. Safety will be evaluated for 
approximately 5 years after dosing. Any safety signal may trigger a review of the data and 
possible additional immunogenicity studies that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMC). Additionally, if any 
of the events listed in Section 9.3.3.1 occur, enrollment into the trial will be halted to 

 
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complete an extensive safety analysis. Notification of the study halt will be sent by the 
Sponsor to the participating sites via telephone and email immediately after becoming aware 
of a safety concern. This will ensure no additional subjects are dosed until the signal has been 
completely evaluated. If, following safety review by the Data Review Board (DRB) and the 
Sponsor, it is deemed appropriate to restart dosing, a request to restart dosing with pertinent 
data will be submitted to the health authority. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 for Safety Follow-up. 
Table 9.1.4, dealing with steroid prophylaxis in the event of elevated LFTs, is discussed in 
Section 9.4.8.2. 
 

 
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Table 9.1.1: Schedule of Events – Screening and Infusion 
Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion Visit 
(Day 1)k 
Screeningi 
(Day -28 to Day -1) 
Smart Rescreeningi  
(Day -28 to Day -1) 
Baseline (Day 
-7 to Day -1)h 
Informed consent 
X 
 
 
 
Medical History 
X 
 
 
 
Physical Exama 
X 
 
X 
X 
Vital Signs 
X 
X 
 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
Documentation of bleeding episodes and FVIII usage (by either subject or 
clinical information) 
X 
X 
X 
 
Distribution of subject diaries and training in their use 
 
 
X 
 
Electrocardiogram 
X 
 
 
 
Chest X-ray 
X 
 
 
 
Liver Ultrasound 
X 
 
 
 
hFVIII Assaysb 
X 
Xj 
 
 
AAV5 Assaysc 
X 
X 
 
X 
Screen for Hepatitis B, Hepatitis C, HIVd 
X 
 
 
 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPe 
X 
X 
X 
 
PBMC collection for CTL baseline 
 
 
X 
 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
 
 
X 
 
Biomarker testingf 
X 
 
 
 
Exploratory biomarker assessmentsg 
 
 
X 
 
Haemo-QoL-A Quality of Life (QoL) assessment 
 
 
X 
 
BMN 270 Infusion 
 
 
 
X 

 
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a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height and 
weight will be recorded at Screening only. 
b Includes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay 
with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).   
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction 
inhibition, in vitro transduction inhibition and AAV5 total antibody assays).  The assessment on the day of the infusion visit must be performed before the BMN 270 
infusion is given. 
d Patients with documented negative results within the last 30 days do not need to be retested. 
e Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
f Includes HLA genotyping, FVIII genotyping, TNFα and IL10a single nucleotide polymorphisms. 
g Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 
h Should the screening visit occur within 7 days of the drug infusion, physical examination, blood chemistry, haematology, urine tests, coagulation screen, and CRP do not 
need to be repeated at Baseline. 
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion 
prior to the closing of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion 
within 90 days of signing the original consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures.  
Subjects may not undergo smart rescreening more than once. 
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening. 
k Assessments on the day of infusion should be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, 
during the infusion every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 
hour intervals (± 15 minutes). 

 
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up 
Assessment 
Follow-Up After BMN 270 Administration - Weeks* 
Week 1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
D2 
D4 
D8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exama 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant 
Medications  (including review of subject diary 
for bleeding and FVIII use) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, 
coagulation screen, and CRPb     
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII  assaysc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, 
semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker assessmentse 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Haemo-QoL-A QoL assessment 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
AAV5 antibody titer 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Testing for reactivation of hepatitis B and 
hepatitis C 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PBMC collection  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
* Visit windows are ±48 hours (and include the Day 4 visit) 
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included.  Each subject will have comprehensive surveillance plan monitoring LFTs once a week from dose to 
completion of Week 6, 3 times per week (every other day excluding weekends) from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a subject’s ALT is found 
to be greater than 1.5x baseline during these periods, then LFTs will be monitored three times per week or until the ALT returns to baseline. 

 
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c Includes hFVIII activity level (APTT and FXa chromogenic assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity 
exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved. 
d Collection to occur on Day 2 and 4 following BMN 270 infusion, and then weekly until at least 3 consecutive negative results are obtained. 
e Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 

 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up 
Assessment 
Year 1 - Weeks* 
Years 2-
5* 
ETV (early 
termination visit) 
20 
28 
36 
44 
52 
Q3M 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications (including review 
of subject diary for bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPb 
X 
X 
X 
X 
X 
X 
X 
FVIII assaysc 
X 
X 
X 
X 
X 
X 
X 
AAV5 antibody titer 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer 
X 
X 
X 
X 
X 
X 
X 
PBMC Collection (for determination of FVIII and Capsid specific CTL 
activity) 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
Haemo-QoL-A QoL assessment 
 
X 
 
 
X 
Xe 
X 
* Visit windows are ±1 week for visits in Year 1, and ± 2 weeks for visits in Years 2-5. 
a Complete physical examination should be performed at Weeks 52 and every 52 weeks thereafter; brief physical exam may be performed at other study visits.  Refer to 
Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII 
coagulation activity exploratory assay, and hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved. 
d Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are cleared during the Post-Infusion Follow-Up period. 
e Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 6 months) starting with the Week 78 visit (ie, 26 
weeks after the Week 52 visit at the end of Year 1 of the Safety Follow-up period). 

 
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Table 9.1.4:  Schedule of Events – Steroid Prophylaxis 
 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week 
12 
Week 
13 
Week 
14 
Week 
15 
Week 
16 
Week 
17 
Week 
23-25 
Prophylactic steroids 
(dose in mg/day) a  
40 mg 
40 mg 
40 mg 
40 mg 
35 mg 
35 mg 
30 mg 
30 mg 
25 mg 
25 mg 
20 mg 
20 mg 
15 mg 
10 mg 
5 mg 
 
Hepatitis B testingb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Liver function testingc  
Weekly, then 3x/week during the 6-week period when a liver response is expected based on the liver response in the original subject 
 
a Steroid prophylaxis will be started in all subjects not yet dosed
b The subject’s hepatitis B status should be rechecked 6-8 weeks after the end of corticosteroid treatment, using the same tests performed for hepatitis B status at 
Screening. 
 following the first subject who develops elevated liver function tests (defined as 1.5x baseline ALT) 
during the study.  Subjects already dosed who have not yet reached Week 17 in the study will be evaluated for the use of prophylactic steroids after discussion between 
the Investigator and the Medical Monitor.  Deviations from this prophylactic steroid dosing regimen must be approved by the Medical Monitor. 
c Reports of abnormal LFTs (defined as 1.5x the subject’s baseline ALT) should be made to the BioMarin medical monitor within 30 minutes of the lab value being 
available. 
 

 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Three doses of BMN 270 will be evaluated and the dose 
escalation decision tree is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and the DRB. 
There will be no control group. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy).  
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3 
Selection of Study Population 
Up to 12 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation.  
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe Haemophilia A as evidenced 
by their medical history.  Patients will be considered as severe if their base FVIII 
level is  1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs) 
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less 
than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within 
the past 12 months 
6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment. 

 
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9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition or AAV5 total antibodies 
2. Any evidence of active infection or any immunosuppressive disorder.   
3. HIV positive 
4. Significant liver dysfunction as defined by abnormal elevation of: 
• ALT (alanine transaminase) to 3 times the upper limit of normal; 
• Bilirubin above 3 times the upper limit of normal; 
• Alkaline phosphatase above 3 times the upper limit of normal; or 
• INR (international normalized ratio) ≥ 1.4.  
5. Potential participants who have had a liver biopsy in the past 3 years are excluded if 
they had significant fibrosis of 3 or 4 as rated on a scale of 0-4 
6. Evidence of any bleeding disorder not related to Haemophilia A 
7. Platelet count of < 100 x 109/L 
8. Creatinine ≥ 1.5 mg/dL 
9. Liver cirrhosis of any etiology as assessed by liver ultrasound  
10. Hepatitis B if surface antigen is positive 
11. Hepatitis C if RNA is positive 
12. Treatment with any IP within 30 days prior to the end of the screening period 
13. Any disease or condition at the physician’s discretion that would prevent the patient 
from fully complying with the requirements of the study including possible 
corticosteroid treatment outlined in the protocol.  The physician may exclude patients 
unwilling or unable to agree on not using alcohol for the 16-week period following 
the viral infusion. 
14. Prior treatment with any gene transfer agent 
15. Major surgery planned in the 16-week period following the viral infusion 
16. Use of immunosuppressive agents or live vaccines within 30 days before the viral 
infusion 

 
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9.3.3 Removal of Subjects from Treatment or Assessment 
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 
BioMarin must be notified of all subject withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or BioMarin may withdraw a subject from the study 
include, but are not limited to, the following: 
• Subject requires medication or medical procedure prohibited by the protocol 
• Subject does not adhere to study requirements specified in the protocol 
• Subject was erroneously admitted into the study or does not meet entry criteria 
• Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study. 
9.3.3.1 
Study Safety Evaluation Criteria 
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis 
per Section 9.1.   

 
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• 
A 5-fold increase from baseline in ALT after BMN 270 administration 
• The occurrence of Grade 3 or higher adverse events assessed as related to study drug, 
including liver failure and clinical hepatitis 
• Grade 2 adverse event assessed as related to study drug that persists for at least 7 days 
• The detection of neutralizing antibodies to hFVIII following BMN 270 infusion 
• The persistent detection of the AAV vector genome in the semen of a participant 
more than 26 weeks after BMN 270 infusion, as discussed in Section 9.7.8.5  
• The occurrence of a malignancy excluding skin cancers at any point after BMN 270 
infusion 
9.3.4 Subject Identification and Replacement of Subjects 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Subjects who withdraw from the study will not be replaced. 
9.3.5 Duration of Subject Participation 
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks. 
9.4 
Treatments 
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
9.4.2 Identity of Investigational Product 
9.4.2.1 
Product Characteristics and Labeling 
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 

 
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The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 
stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4 Directions for Administration 
After a physical exam performed by the PI or designee, participants will be admitted on the 
day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral vein 
(e.g. the median cubital vein) and flushed with saline. FVIII replacement therapy will not be 
given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 ml/min while monitoring the vital signs (pulse, blood pressure, respiration 
rate and temperature) at 15 minute (± 5 minutes) intervals. The anticipated maximum 
interval from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, 
although the IP has been shown to be stable at room temperature for 6 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard 
protocol for infusing FVIII concentrates. Subjects will remain in the clinic for 24 hours to 
observe for any immediate toxicity of the procedure. After 24 hours, participants will be 
discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 

 
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9.4.5 Method of Assigning Subjects to Treatment Groups 
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study subject. Upon their enrollment into the study, subjects will be assigned a unique subject 
number and dose level by the Sponsor. 
Cohorts are enrolled serially and their dose is defined in Section 9.4.6.2 below. Escalation is 
based on FVIII activity 3 weeks after injection. Cohorts may receive the next higher dose if 
subjects in the previous cohort does not meet the activity criteria, or the same dose if subjects 
in the previous cohort meets the activity criteria.  
9.4.6 Selection of Doses Used in the Study 
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in mice. The dose escalation is half-logs based.    
9.4.6.1 
Selection of Timing of Dose for Each Subject 
A minimum of three weeks are required between subjects, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next subject will be made as described below.  
9.4.6.2 
Selection of Dose for Each Subject 
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus potentially decreasing the risk of immune response), and a new 
evaluation of the titer (PCR performed after hairpin removal). 
Approximately three weeks after an injection, the decision to escalate to the next dose level 
will be made based on the review of safety parameters and FVIII activity by the Sponsor and 
the DRB.  
Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vg/kg of body weight. 
If the FVIII activity level does not reach 5 IU/dL or greater (expressed as % in Figure 9.1.1) 
at the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 1 and 
enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg/kg). 
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL at 
the Week 3 visit in both assays, then no further subjects will be dosed in Cohort 2 and 
enrollment into Cohort 3 (6E13) will initiate with the next subject.  

 
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If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at 
the Week 3 visit in both assays, then the DRB will recommend whether to continue to add 
subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each Cohort, if the activity level reaches ≥5 IU/dL and no 
safety issue is found, then up to four subjects will be enrolled in the Cohort. Although the 
optimum design of this study is three cohorts of 4 subjects, the adaptive nature of this trial 
allows the DRB to recommend allocating subjects to the cohorts based on activity levels of 
FVIII and safety signals. 
Refer to Figure 9.1.1 for a visual representation of the study design. 
9.4.7 Blinding 
This is an open-label study. 
9.4.8 Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a subject for 30 days before 
Screening will be recorded on the designated CRF. The Investigator may prescribe additional 
medications during the study, as long as the prescribed medication is not prohibited by the 
protocol. In the event of an emergency, any needed medications may be prescribed without 
prior approval, but the medical monitor must be notified of the use of any contraindicated 
medications immediately thereafter. Any concomitant medications added or discontinued 
during the study should be recorded on the CRF. 
The following medications are prohibited starting 30 days before Screening: 
• Live vaccines 
• Systemic immunosuppressive agents 
9.4.8.1 
Concomitant Haemophilia Treatments 
Subjects on “on demand” therapy for FVIII will continue their treatment at will.  Subjects on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and 
switch to an “on demand” schedule. FVIII can always be taken as needed by the subject, who 
will carefully record his treatment and bleeding episodes in his diary. 
9.4.8.2 
Glucocorticoid Treatment of Elevated Hepatic Transaminases 
During the Post-Infusion Follow-up Period, each subject will have comprehensive 
surveillance plan monitoring LFTs once a week from dose to completion of Week 6, 3 times 
per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a subject’s ALT is 

 
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found to be greater than 1.5x his baseline during these periods, then LFTs will be monitored 
three times per week until the ALT returns to baseline.  
Reports of abnormal LFTs (defined as 1.5x the subject’s baseline ALT level) should be made 
to the BioMarin medical monitor within 30 minutes of the lab value being available, and 
treatment with prednisolone will be initiated immediately at a dose of 60 mg per day and then 
gradually tapered (60 mg daily for the first 2 weeks, then 40 mg the next 2 weeks, then 
30 mg the next two weeks, then 20 mg the next two weeks, then stop, for a total treatment of 
8 weeks). Local laboratory results of LFTs will be used to trigger corticosteroid treatment as 
needed.  In case of discrepant results between local and central laboratories, the Investigator 
and Medical Monitor will decide further action. 
If a glucocorticoid treatment is started for a subject at any point of the study, the following 
steps will be taken:  
• A prophylactic glucocorticoid treatment will be started for subsequent subjects 
scheduled to be dosed. Subjects will receive prednisolone 40 mg per day starting at 
week 3, for a duration of 4 weeks, then tapered by 5 mg every two weeks for 8 weeks 
(until 20 mg/day is reached), then tapered 5 mg per week for 3 weeks, for a total 
duration of 15 weeks (refer to 4). 
o Subjects already dosed who have not yet reached Week 17 in the study 
will be evaluated for the use of prophylactic steroids after discussion 
between the Investigator and the Medical Monitor. 
• Once prophylactic glucocorticoid treatments have been initiated, then all subjects 
(who have not already passed that period in the study) will have 3x/week LFT 
assessments during the 6-week period when a liver response is expected based on the 
liver response in the original subject, if this period is different from the 3x/weekly 
LFT assessments already planned for Weeks 7-12.   
o Subjects who have already passed that 6-week period in the study will 
continue to have the regularly scheduled LFT assessments as planned in 
the protocol. 
• Management and monitoring of reactions to corticosteroids should be determined by 
the Investigator’s clinical judgment in consultation with the Sponsor’s Medical 
Monitor. This includes the contraindicated use of NSAIDs during corticosteroid 
treatment, and specific monitoring not already covered by the schedule of events. 
Hepatitis B status will be rechecked at the end of the corticosteroid treatment. All 
adverse events should be reported as outlined in Section 10 of the protocol. 

 
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9.4.9 Treatment Compliance 
Study drug will be administered to subjects at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided 
for the study.  Sites will be instructed to return or destroy all used and unused study drug 
containers. 
9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a Study Drug Return Form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study. 
9.7 
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8. 
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post 
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9.7.1 Safety and Efficacy Measurements Assessed 
The Schedule of Events (Table 9.1.1) describes the timing of required evaluations. 
9.7.2 Primary Efficacy Variables 
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to stable expression of FVIII at 5 IU/dL or 
above, i.e., a mild severity. This is associated in natural history studies with clinically 
superior long term outcomes, (Den Ujil, 2011, Haemophilia). 
The following assays will be used to measure the primary efficacy variable: 
• FVIII activity (chromogenic FXa assay) 
• FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time) 
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made 
to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved. 
The FVIII activity level in both assays and the number of subjects with FVIII activity 
≥ 5  IU/dL in at least one of the two assays will be summarized. 
Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3.  Details on 
performing the assays are included in the Laboratory Manual. 
9.7.3 Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Subjects will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the subject’s diary or 
other subject records. 
9.7.4 Immunogenicity 
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
5-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to a retrospective immunogenicity assessment to determine 
anti-FVIII and capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be 
performed on collected PBMCs. 

 
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Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3. 
9.7.5 Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage APTT and/or chromogenic FXa assay (activity).  Individual antigen and activity 
plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity measurements 
will be used to determine PD parameters. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), 
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology. 
Sample collection times are indicated in Table 9.1.2 and Table 9.1.3. 
9.7.6 Exploratory Biomarker Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1 and 
Table 9.1.2 to evaluate biochemical, molecular, cellular, and genetic/genomic aspects 
relevant to Haemophilia A disease.  The genetic/genomic testing on these exploratory 
samples is optional. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes may be used for exploratory use once the 
primary use has been completed.  No additional genetic or genomic testing will be conducted 
on any sample (other than testing specified in the protocol). 
9.7.7 Haemo-QoL-A Quality of Life Assessment 
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to 
assess subject quality of life (QoL) during the study.  Assessments will occur at the time 
points listed in the Schedules of Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual. 
9.7.8 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 

 
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9.7.8.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the subject signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1.   
9.7.8.2 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1. The scheduled clinical laboratory tests are listed in Table 9.7.8.2.1. Refer to the 
Study Reference Manual for instructions on obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF. 

 
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Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Haematology 
Urine Tests 
Other 
Albumin  
Haemoglobin  
Appearance 
CRP 
Alkaline phosphatase  
Haematocrit  
Color 
 
ALT (SGPT) 
WBC count 
pH 
Coagulation Screen 
including: 
AST (SGOT) 
RBC count 
Specific gravity 
APTT 
Direct bilirubin 
Platelet count 
Ketones 
PT/INR 
Total bilirubin 
Differential cell count  
Protein  
TT 
BUN 
 
Glucose  
 
Calcium 
 
Bilirubin 
 
Chloride 
 
Nitrite 
 
Total cholesterol 
 
Urobilinogen 
 
CO2 
 
Haemoglobin 
 
Creatinine 
 
 
 
Glucose 
 
 
 
GGT 
 
 
 
LDH 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Total protein  
 
 
 
Sodium  
 
 
 
Uric acid  
 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon 
dioxide; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; 
SGPT, serum glutamic-pyruvic transaminase; WBC, white blood cell; TT, thrombin time; INR, international 
normalized ratio. 
 
9.7.8.3 
Liver function and Hepatitis Testing at Screening 
Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening.   Subjects with documented results showing an absence of active Hepatitis B or 
Hepatitis C infection (as measured by positive surface antigen for hepatitis B or positive 
RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need 
to be screened again.   

 
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Evidence of ongoing Hepatitis B or Hepatitis C infection is exclusionary. Subjects who have 
cleared a Hepatitis B infection or are seronegative do not need to receive the Hepatitis B 
vaccination.  
A liver ultrasound and liver function testing at Screening will identify any significant hepatic 
dysfunction, which is defined as: 
• More than 3x the normal ALT level 
• More than 3x the normal bilirubin level 
• More than 3x the normal Alkaline phosphatase level. 
• INR > 1.4.  
• Thrombocytopoenia under 100 x 109/L 
• Liver ultrasound results indicative of a liver cirrhosis  
9.7.8.4 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE. 
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored prior to infusion, during the infusion every 
15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for 6 hours and then 
every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes).  
A complete physical examination is necessary during Screening/Baseline; thereafter, brief 
physical examinations may be performed at the discretion of the investigator based on the 
subject’s clinical condition. Particular attention should be given to signs of bleeding, as well 
as assessing possible hemarthroses. 
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems. 
A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 
Weight and height will be recorded at Screening only. 

 
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9.7.8.5 
Viral Shedding 
Viral shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Engl.J.Med.); (Manno, 2006, Nat.Med.); (Schenk-Braat, 2007, J.Gene 
Med.); (Croteau, 2004, Ann.Occup.Hyg.). In the literature referenced above, vector was no 
longer detectable after 40 days in blood, saliva, urine or stool.  However, vector persisted in 
semen for 16 weeks in the seminal fluid but not in motile sperm (Manno, 2006, Nat.Med.).  
In all cases, the amount of vector present in these bodily fluids involved an extremely small 
fraction of the infused dose.  
Viral shedding will also be extensively studied in the present clinical trial, every week up to 
16 weeks, then every 4 weeks to one year, then every three months, until at least 
3 consecutive negative results are obtained.  During the Post-Infusion Follow-Up period, 
subjects will undergo testing of various bodily samples to look for evidence of viral shedding 
for possible viral transmission.  Bodily fluids will be tested by PCR at the time points 
indicated in Table 9.1.2 and Table 9.1.3.  Fluids tested will include: 
• Blood 
• Saliva 
• Semen 
• Urine 
• Stool 
Details for sample collection and storage are provided in the Laboratory Manual. 

 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a subject administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
• AEs not previously observed in the subject that emerge during the course of the 
study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only 
because the subject is a haemophiliac) should not be recorded as AEs but will instead be 
captured in subject diaries.  Bleeding events that occur where a normal 
(ie, non-haemophiliac) patient would bleed, such as bleeding as a result of major trauma, 
should be recorded as adverse events.  All bleeding events which meet criteria for being 
serious should be reported as serious adverse events (SAEs) whether or not they are bleeding 
events that are normal sequelae of haemophilia. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 

 
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10.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening  
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires or prolongs inpatient hospitalization.   
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
• 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of  the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as non-
serious AEs. 
10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• 
Elevation of liver enzymes (ALT) that triggers a corticosteroid treatment 
10.3 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.3.1 Adverse Event Reporting Period 
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.2.  
10.3.2 Eliciting Adverse Events 
Investigators will seek information on AEs, SAEs, and EOSI at each subject contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 

 
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and EOSI, should be recorded in the subject’s medical record and on the AE Case Report 
Form (eCRF). 
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.2 for 
SAE definitions).  These assessments must be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.3.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.3.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1. 
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden. 

 
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10.3.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1. 
Table 10.3.3.3.1:  Causality Attribution Guidance 
Relationship 
Description 
Not Related 
• 
Exposure to the IP has not occurred 
• 
OR 
• 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
• 
OR 
• 
The AE is considered likely to be related to an etiology other than 
the use of the IP; that is, there are no facts, evidence, or arguments 
to suggest a causal relationship to the IP. 
Related 
• 
The administration of the IP and the occurrence of the AE are 
reasonably related in time 
• 
The AE could possibly be explained  by factors or causes other 
than exposure to the IP 
AND 
 
OR 
• 
The administration of IP and the occurrence of the AE are 
reasonably related in time  
• 
The AE is more likely explained by exposure to the IP than by 
other factors or causes. 
AND 
 
Factors suggestive of a causal relationship could include (but are not limited to): 
• Plausible temporal relationship 
• Absence of alternative explanations 
• Rarity of event in a given patient or disease state 
• Absence of event prior to study drug exposure 
• Consistency with study product pharmacology 

 
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• Known relationship to underlying mechanism of study drug action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.4.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE eCRF, replacing the original entries where 
appropriate. 
10.4.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 

 
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10.4.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points.  Such an event should be recorded only once on the AE eCRF unless 
its severity increases or decreases (in which case it should be recorded again on the AE 
eCRF). 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.4.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the AE eCRF. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as AE if any of the following conditions is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
• The laboratory abnormality persists upon repeat confirmatory testing.  
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 

 
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explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed. 
10.4.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.4.1.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.4.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
• Perform a protocol-mandated efficacy measurement 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
• Hospitalization solely for the purpose of insertion of an in-dwelling IV catheter (such 
as a Port-a-Cath or other brand) for administration of study drug will not be 
considered an SAE. 
• Receive scheduled therapy (study drug or otherwise) for the study indication 

 
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10.4.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9 
Pregnancy 
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event.  The Investigator must make every effort to 
follow the subject’s partner through resolution of the pregnancy (delivery or termination) and 
to report the resolution on the Pregnancy Follow-up Form in the study reference materials. In 
the event of pregnancy in the partner of a study subject, the Investigator should make every 
reasonable attempt to obtain the woman’s consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5 
Reporting Requirements 
10.5.1 Expedited Reporting Requirements 
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF  and submitting  to BPV within 24 hours of the site 
becoming aware of the event.  Investigators should not wait to collect information that fully 
documents the event before notifying BPV of an SAE.  BioMarin may be required to report 
certain SAEs to regulatory authorities within 7 calendar days of being notified about the 
event; therefore, it is important that Investigators submit any information requested by 
BioMarin as soon as it becomes available. 

 
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The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations. 
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF. 
10.5.2 Ethics Committee Reporting Requirements 
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required. 
10.6 
Follow-up of Subjects after Adverse Events 
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the subject is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the subject’s medical record to facilitate source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.7 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each subject to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study.  

 
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10.8 
Urgent Safety Measures 
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• Immediate need to revise the IP administration (eg, modified dose amount or 
frequency not defined in protocol) 
• Lack of study scientific value, or detrimental study conduct or management 
• Discovery that the quality or safety of the IP does not meet established safety 
requirements 

 
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10.9 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
, MD, PhD 
Address: 
105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
E-mail: 
 
PI
PI
PI
PI
PI

 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic FXa assay and the APTT assays are both validated and utilize CE marked 
reagents.  The exploratory FVIII activity assay will be used for exploratory purposes only. 

 
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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed. 
12.2 
Screening Visit 
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, haematology, urine tests, coagulation screen, and CRP do not 
need to be repeated at Baseline.  
The following procedures will be performed during the Screening Period: 
• Full medical history, including haemophilia A history, Hepatitis B, Hepatitis C, and 
HIV.  
• Complete Physical Exam (including height and weight) 
• Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature)  
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
• Electrocardiogram 
• Chest X-ray 
• Liver Ultrasound 
• Samples for hFVIII Assays 
o Baseline hFVIII activity – chromogenic FXa (plasma) 
o Baseline hFVIII activity level – one-stage APTT assay 
o hFVIII coagulation activity exploratory assay 
o hFVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay 
o hFVIII antigen (ELISA) 

 
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• Blood sample for AAV5 Assays 
o AAV5 antibody titer 
o AAV5 transduction inhibition assay 
• Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested) 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• Blood samples for Biomarker testing (including HLA genotyping, FVIII genotyping 
status, TNFα and IL10a single nucleotide polymorphisms) 
12.2.1 “Smart Rescreening” Visit 
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study: 
• 
Vital signs 
• 
Assessment of Adverse Events and Concomitant Medications 
• 
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
• 
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification) 
• Blood sample for AAV5 Assays 
 AAV5 antibody titer 
 AAV5 transduction inhibition assay 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 

 
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12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
• Distribution of subject diaries and training in diary completion 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• PBMC collection for CTL baseline 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
• Exploratory biomarker assessments 
• Haemo-QoL-A QoL assessment 
12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each subject.  Subjects will remain in the clinic for 
24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
o AAV5 antibody titer 
o AAV5 transduction inhibition assay 
• BMN 270 Infusion 
• Vital Signs 
o Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the subject’s stay in 
the clinic. 

 
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12.5 
BMN 270 Infusion Follow-Up Visits 
After BMN 270 has been infused, subjects will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Every Visit 
Every week (Weeks 1 through 16), the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
o Each subject will have comprehensive surveillance plan monitoring LFTs 
once a week from dose to completion of Week 6, 3 times per week (every 
other day excluding weekends) from Weeks 7 to 12, and once a week from 
Weeks 13 to 16.  If a subject’s ALT is found to be greater than 1.5x 
baseline during these periods, then LFTs will be monitored three times per 
week or until the ALT returns to baseline. 
• Samples for FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
• FVIII antibody titer 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Collection to occur weekly until at least 3 consecutive negative results are 
obtained 

 
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12.5.2 Week 1 – Day 2 and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed: 
• 
PCR of vector genomes in blood, saliva, urine, semen, and stools (Day 2 and Day 4) 
• Samples for FVIII Assays (Day 4 only) 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved.  
12.5.3 Every 2 Weeks 
Every 2 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedure will be 
performed: 
• Exploratory biomarker assessments 
12.5.4 Weeks 4, 8, 12, and 16 
At Weeks 4, 8, 12, and 16, the following procedure will be performed: 
• PBMC collection 
12.5.5 Weeks 1, 3, and 6 
At Weeks 1, 3, and 6, the following procedure will be performed: 
• Test for Hepatitis B and Hepatitis C reactivation 
12.5.6 Weeks 8 and 16 
At Weeks 8 and 16, the following procedure will be performed: 
• AAV5 antibody titer 
12.5.7 Weeks 1, 2, 3, 4, and 16 
At Weeks 1, 2, 3, 4, and 16, the following procedure will be performed: 
• Haemo-QoL-A QoL assessment 

 
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12.6 
Safety Follow-Up – Year 1 
After the 16 weekly infusion follow-up visits are complete, subjects will return to the study 
site at Weeks 20, 28, 36, 44, and 52 (± 1 week), when the following procedures will be 
completed: 
12.6.1 Every Visit 
At Weeks 20, 28, 36, 44, and 52, the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
• AAV5 antibody titer 
• FVIII antibody titer 
• PBMC collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up 
period. 
12.6.2 Weeks 28 and 52 
At Weeks 28 and 52, the following procedure will be performed: 
• Haemo-QoL-A QoL assessment 

 
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12.7 
 Safety Follow-Up – Years 2-5 
During Years 2-5 of Safety Follow-up, subjects will be assessed every 3 months (± 2 weeks). 
At these times, the following procedures will be completed: 
12.7.1 Every Visit 
Every 3 months (± 2 weeks), the following procedures will be performed: 
• Physical exam 
o Complete Physical Exam will be performed every 52 weeks; Brief 
Physical Exams may be performed at other visits. 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (FXa chromogenic assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
• AAV5 antibody titer 
• FVIII antibody titer 
• PBMC collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if at least 
3 consecutive samples are clear during the Post-Infusion Follow-Up 
period. 
• Vital Signs 

 
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12.7.2 Every Other Visit (Every 6 Months) 
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the 
end of Year 1 of the Safety Follow-up period), the following procedure will be performed: 
• Haemo-QoL-A QOL assessment 
12.8 
Early Termination Visit 
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII antigen (ELISA) 
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts 
should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved. 
• AAV5 antibody titer 
• FVIII antibody titer 
• PBMC collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing at the ETV is not required if at least 3 consecutive samples 
are clear during the Post-Infusion Follow-Up period. 
• Vital Signs 

 
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• Haemo-QoL-A QOL assessment 
12.9 
End of Study 
The study will end after the last subject completes the last Safety Follow-Up visit 
(Week 260). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study subjects may be 
compromised. 

 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all subjects having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16). 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Missing data will not be imputed.  
14.2 
Primary and Secondary Efficacy Analysis 
The subjects will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of subjects, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined. 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay at 
16 weeks following study treatment.  hFVIII activity will be assessed weekly during the 
study period.  We can only assess the true steady state of hFVIII protein produced from 
BMN 270 after a minimum of 72 hours has elapsed since the last infusion of FVIII protein 
concentrates. 
14.3 
Immunogenicity 
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons   
14.4 
Pharmacodynamic Analyses 
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage APTT and/or chromogenic FXa assay (activity level), will be used for plasma 

 
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profiles; FVIII activity will be used to determine PD parameters.  Traditional PK analysis is 
not applicable. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics.  
14.5 
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-subject listing will 
be provided for those subjects who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of subjects who report hepatitis will be presented. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided.  
Detailed statistical methods will be provided in the SAP. 
14.6 
Determination of Sample Size 
No formal sample size calculations based on statistical power were performed. 
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 12 subjects may be dosed in the study; the actual number of 
subjects will depend on the criteria for dose escalation.  
14.7 
Analysis Populations 
The Safety analysis population is defined as all enrolled subjects who receive any study drug. 
The analysis of safety data will be performed on Safety Set. 

 
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The Full Analysis Set (FAS) is defined as all enrolled subjects who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis. 
14.8 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active subjects must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 

 
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15 
DATA REVIEW BOARD 
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established. 
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available subject safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene 
for further assessment of subject safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites. 

 
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16 
COMPENSATION, INSURANCE AND INDEMNITY 
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the subject’s health insurance company or other third party 
payer for the cost of this medical treatment. If the subject has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law. 

 
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CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy. 
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and subject records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Subjects must also allow access to 
their medical records, and subjects will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
subject records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification. 
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a subject’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 

 
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completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 

 
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STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 

 
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RETENTION OF RECORDS 
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained. 

 
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USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  

 
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21 
REFERENCES 
Bainbridge, JW, Smith, AJ, Barker, SS, Robbie, S et. al. Effect of gene therapy on visual 
function in Leber's congenital amaurosis. N Engl J Med 358[21], 2231-2239. 2008. 
Berntorp, E, Peake, I, Budde, U, Laffan, M et. al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia 18 Suppl 6, 1-13. 2012. 
Croteau, GA, Martin, DB, Camp, J, Yost, M et. al. Evaluation of exposure and health care 
worker response to nebulized administration of tgAAVCF to patients with cystic fibrosis. 
Ann Occup Hyg 48[8], 673-681. 2004. 
D'Avola, D. Phase 1 Clinical Trial of Liver Directed Gene Therapy with rAAV5-PBGD in 
Acute Intermittent Porphyria: Preliminary Safety Data. J Hepatol 60[S58]. 2014. 
Den Ujil, Mauser Bunschoten, Roosendaal, Schutgens et. al. Clinical Severity of haemophilia 
A: does the classification of the 1950s still stand? Haemophilia 17, 849-853. 2011. 
Hay, CR, DiMichele, DM. The principal results of the International Immune Tolerance 
Study: a randomized dose comparison 
12. Blood 119[6], 1335-1344. 2012. 
Kaufman, RJ, Powell, JS. Molecular approaches for improved clotting factors for hemophilia 
1. Blood 122[22], 3568-3574. 2013. 
Maguire, AM, High, KA, Auricchio, A, Wright, JF et. al. Age-dependent effects of RPE65 
gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 
374[9701], 1597-1605. 2009. 
Mahlangu, J, Powell, JS, Ragni, MV, Chowdary, P et. al. Phase 3 study of recombinant factor 
VIII Fc fusion protein in severe hemophilia A 
8. Blood 123[3], 317-325. 2014. 
Manno, CS, Chew, AJ, Hutchison, S, Larson, PJ et. al. AAV-mediated factor IX gene 
transfer to skeletal muscle in patients with severe hemophilia B 
1. Blood 101[8], 2963-2972. 2003. 
Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006. 
Mannucci, PM, Tuddenham, EG. The hemophilias--from royal genes to gene therapy 
1. N Engl J Med 344[23], 1773-1779. 2001. 

 
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McIntosh, J, Lenting, PJ, Rosales, C, Lee, D et. al. Therapeutic levels of FVIII following a 
single peripheral vein administration of rAAV vector encoding a novel human factor VIII 
variant. Blood 121[17], 3335-3344. 2013. 
Nagel, K, Walker, I, Decker, K, Chan, AK et. al. Comparing bleed frequency and factor 
concentrate use between haemophilia A and B patients 
1. Haemophilia 17[6], 872-874. 2011. 
Nathwani, AC, Gray, JT, Ng, CY, Zhou, J et. al. Self-complementary adeno-associated virus 
vectors containing a novel liver-specific human factor IX expression cassette enable highly 
efficient transduction of murine and nonhuman primate liver 
3. Blood 107[7], 2653-2661. 2006. 
Nathwani, AC, McIntosh, J, Davidoff, AM. An update on gene therapy for hemophilia. Curr 
Hematol Rep 4[4], 287-293. 2005. 
Nathwani, AC, Reiss, UM, Tuddenham, EG, Rosales, C et. al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014. 
Nathwani, AC, Rosales, C, McIntosh, J, Rastegarlari, G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011. 
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992. 
Nathwani, AC, Tuddenham, EG, Rangarajan, S, Rosales, C et. al. Adenovirus-associated 
virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365[25], 2357-2365. 
2011. 
Paneda, A, Lopez-Franco, E, Kaeppel, C, Unzu, C et. al. Safety and liver transduction 
efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute 
intermittent porphyria. Hum Gene Ther 24[12], 1007-1017. 2013. 
Pipe, SW. Go long! A touchdown for factor VIII? Blood 116[2], 153-154. 2010. 
Schenk-Braat, EA, van Mierlo, MM, Wagemaker, G, Bangma, CH et. al. An inventory of 
shedding data from clinical gene therapy trials. J Gene Med 9[10], 910-921. 2007. 
Simonelli, F, Maguire, AM, Testa, F, Pierce, EA et. al. Gene therapy for Leber's congenital 
amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18[3], 
643-650. 2010. 

 
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Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS et. al. Guidelines for the 
management of hemophilia 
128. Haemophilia 19[1], e1-47. 2013. 
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010. 
 
 
 

 
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22 
INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Patients  
In accordance with FDA Form 1572, the Investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and IRB 
review and approval in 21 CFR Part 56 are met.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312. 

 
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SIGNATURE PAGE 
Protocol Title: A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study of 
BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII in Patients with Severe Haemophilia A 
Protocol Number: 270-201, Amendment 3 
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
E6 ICH, as stated in the protocol, and other information supplied to me. 
 
 
 
 
Investigator Signature 
 
Date 
 
 
Printed name:  
 
 
 
 
Accepted for the Sponsor: 
 
Printed name: 
, MD, PhD, 
, Clinical Sciences 
 
PI
PI
PI

 
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24 PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See pages 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font. 
Section No./Title 
Text Revisions 
Rationale 
2/Synopsis/Study 
Rationale 
Treatment of severe HA presently consists of intravenous injection of plasma derived or recombinant human FVIII protein 
(rhFVIII) concentrates both as prophylaxis 2-3 times per week, and at the time of a bleed, to prevent or control bleeding 
episodes, respectively. The half-life for rhFVIII (under 24FVIII (12 to 18 hours for most approved products) necessitates 
frequent infusions, and although a major advance in the treatment of HA, it remains common for severe HA patients to continue 
to have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year 
for on demand treatment). 
1, 5 
2/Synopsis/Study 
Design and Plan 
PatientsCohorts will be enrolled sequentially every, allowing a period of 3 weeks or more between cohorts. Dose escalation may 
occur after a single patientsubject has been safely dosed if the resulting FVIII activity at the Week 3 visit is < 5 IU/dL in both the 
aPTT and chromogenic assays. Three weeks is expected to be the time the expression will be close to the maximum.  This 
escalation paradigm is intended to minimize the patientsubject numbers exposed to subtherapeutic doses. 
Approximately three weeks after an injection, the decision to escalate to the next dose level will be made based on the review of 
safety parameters and FVIII activity by the Sponsor and a panel of investigators participating in the study., the Data Review 
Board (DRB).  
If the FVIII activity isreaches ≥ 5 IU/dL at the Week 3 visit, then the other patients ofremaining subjects in the dose groupcohort 
will be enrolled without waitingthe need to wait for 3 weeks between patientssubjects. 
Patient Subject 1 will be dosed by intravenous perfusion infusion with 6E12 vector genomes [vg] per kilogram of body weight. 
If the FVIII activity level does not reach ≥ 5 IU/dL at 21 days the Week 3 visit in both assays, then a higher no further subjects 
will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with Subject 2 at the next dose (2E13 vg per kilogram) will 
be used for the next patient./kg).  
If the activity level does not reach ≥ 5 IU/dL after Patient 2, then the highest dose (6E13 vg per kilogram) will be used for the 
next patient. FVIII activity level in the first subject treated in Cohort 2 does not reach ≥ 5 IU/dL at the Week 3 visit in both 
assays, then no further subjects will be dosed in Cohort 2 and enrollment into Cohort 3 (6E13) will initiate with the next subject. 
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then 
the Data Review Board (DRB) will recommend whether to continue to add subjects to the cohort and/or whether to continue the 
study. 
5 

 
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Section No./Title 
Text Revisions 
Rationale 
For the first subject treated in each dose Cohort, if the activity level reaches ≥5 IU/dL and no safety issue is found, then up to 
four patients will receive subjects will be enrolled in the Cohort. Although the optimum design of this dose.  If at any time study 
is three cohorts of 4 subjects, the adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts 
based on activity levels reach 10 IU/dL or higher, no further dose escalation will take place, but additional patients will then be 
dosed at this dose level for a total of 6 patients per dose. Of FVIII and safety signals.  
Because patientssubjects develop neutralizing immunity upon exposure to the capsid, re-challenge of vector is not a likely 
treatment option and these patientssubjects have effectively a single opportunity for therapy using this AAV capsid. Efficacy 
will be determined by FVIII activity at 16 weeks post dose. Safety will be evaluated for approximately 5 years after dose dosing.  
Any safety signal will may trigger a review of the data and possible additional analysis including immunogenicity studies that 
include an assessment of cellular immune responses using collected peripheral blood mononuclear collection. Cells (PBMC). 
2/Synopsis/Number of 
Subjects Planned 
Up to 12 patientssubjects may enroll into the study; the actual number of patientssubjects will depend on the criteria for dose 
escalation. A total of 6 patients may be enrolled at a single dose level VIII activity levels seen in each Cohort. 
5 
2/Synopsis/Diagnosis 
and All Criteria for 
Inclusion and Exclusion 
Individuals eligible to participate in this study must meet all of the following criteria: 
• 
Males that are 18 years or older with established severe haemophilia A as evidenced by their medical history.  Patients 
will be considered as severe if their base FVIII baseline level is 1 IU/dL or less 
• 
Treated/exposed to FVIII concentrates or cryoprecipitates cryoprecipitate for a minimum of 150 exposure days (EDs) 
• 
No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 12 months using and results from a 
modified Nijmegen Bethesda assay higher of less than 0.6 Bethesda Unit Units (BU) on 2 consecutive occasions at least 
one week apart within the past 12 months 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
• 
Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction inhibition andora AAV5 
total antibodies 
• 
Patients that are HIV positive are excluded. 
• 
Significant liver dysfunction as defined by abnormal elevation of: 
1, 2, 5 

 
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Section No./Title 
Text Revisions 
Rationale 
o 
ALT (alanine transaminase) to 3 times the upper limit of normal, bilirubin, ; 
o 
Bilirubin above 3 times the upper limit of normal; 
o 
Alkaline phosphatase, above 3 times the upper limit of normal; or 
o 
an INR (international normalized ratio) of≥ 1.4 
• 
Treatment with any IP within 30 days prior to the end of the screening visit period 
• 
Any disease or condition at the physician’s discretion that would prevent the patient from fully complying with the 
requirements of the study. including possible corticosteroid treatment outlined in the protocol.  The physician may 
exclude patients unwilling or unable to agree on not using alcohol for the 16-week period following the viral infusion. 
• 
Receipt of Prior treatment with any vector or gene transfer agent 
• 
Major surgery planned in the 16-week period following the viral infusion 
• 
Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral infusion 
2/Synopsis/Duration of 
Treatment 
BMN 270 is given as a single dose by intravenous perfusion infusion. 
5 
2/Synopsis/Criteria for 
Evaluation 
Safety: 
The following safety outcome measurements will be assessed: 
• 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
• 
Change in clinical laboratory tests (serum chemistry and haematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding 
• 
Liver function tests (LFTLFTs, including ALT, AST, GGT, LDH, bilirubin, alkaline phosphatase) 
• 
Immune response to FVIII transgene and AAV capsid proteins 
 
No major toxicity is expected based on preclinical studies in mice and monkeys. An asymptomatic transaminitis was observed at 
1, 5 

 
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Section No./Title 
Text Revisions 
Rationale 
week 8-107-12 after administration in humans with an AAV8-FIX, providing the rationale for the following surveillance plan. 
Each patient subject will have comprehensive surveillance plan monitoring LFTs once a week from dose to completion of Week 
6, 3 times per week from Weeks 7 to 12, and once a week from Weeks 13 to 16. If a patient’s subject’s ALT is found to be 
greater than 1.5x his baseline during these periods, then LFTs will be monitored three times per week or until the ALT returns to 
baseline. LFTs will be monitored every other month for the first year and then every three months for up to 5 years post-dose in 
the safety extension; the frequency and duration of LFT testing may be changed if dictated by ongoing safety evaluations. 
There will be a detailed monitoring plan for assessment of cellular and humoral responses to AAV5 capsid and FVIII protein.   
2/Synopsis/Statistical 
Methods 
Efficacy is a secondary endpoint, defined as biologically active FVIII at ≥ 5 IU/dL by chromogenic FXa assay and/or one-stage 
APTT assay between 1 to at 16 weeks following study treatment. 
5 
4/List of Abbreviations 
eCRF CSR - electronic case clinical study report form 
eCRF - electronic case report form 
PBMC - peripheral blood mononuclear cells 
5 
6/Investigators and 
Study Administrative 
Structure 
Liver function tests (LFTs) will be performed at the local laboratories associated with the study sites.  Local laboratory results of 
LFTs will be used to trigger corticosteroid treatment as needed (refer to Section 9.4.8.2Laboratory evaluations will be performed 
at the local laboratories associated with the study sites.).  In case of discrepant results between local and central laboratories, the 
Investigator and Medical Monitor will decide further action.  Safety labs evaluations (including LFTs) will be performed at the 
central lab, while bioanalytical samples will be performed at the appropriate specialty lab.  Refer to the Laboratory Manual for 
more details. 
1 
7/Introduction 
Chemical modification or bioengineering of FVIII may improve half-life to around 2018-19 hours (Pipe, 2010, Blood),Kaufman, 
2013, Blood). However, these long acting FVIII variants do not eliminate the need for lifelong FVIII protein administration or 
problems of FVIII inhibitor formation, which occurs in 30% of patients on standard FVIII replacement therapy (Nathwani, 1992, 
Baillieres Clin.Haematol.).(Hay, 2012, Blood). 
5 
7.1/Nonclinical Studies 
BMN 270 related correction of bleeding times showed a dose relationship that was similar to that observed in FVIII KO x Rag2 
mice given matched IU levels of Refacto®. 
Additionally, the BMN 270 transgene product has a final sequence closely matching that of the protein replacement treatment, 
Refacto® and therefore the safety profile of the BMN 270 transgene product is anticipated to be similar to Refacto® and have no 
5 

 
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Section No./Title 
Text Revisions 
Rationale 
unique FVIII-specific target organs of toxicity. 
Liver targeted distribution of a similar AAV5 Factor IX gene therapy product was observed in the rhesus macaque monkey with 
low levels of vector genomes detected in spleen, kidney and testis (Paneda, 2009, Hum.Gene Ther.).Nathwani 2006, Blood). 
This dose represents > 3010-fold safety factor from the no observed adverse effect level (NOAEL) in the GLP enabling 
nonclinical studies toxicology study in mice. 
7.2/Previous Clinical 
Studies 
AAV serotype 5 is also used being tested in other clinical trials and has shown good safety was reportedly well tolerated without 
treatment-related serious adverse events in a recent phase 1 study for treatment of Acute Intermittent Porphyria (D’Avola. 2014, 
J Hepatology). In addition, AAV using other serotypes have been used in 105 clinical studies to date and no safety issue specific 
to the vector was ever reported. 
5 
7.3/Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males (Nathwani, 1992, 
Baillieres Clin. Haematol Mannucci, 2001, NEJM). 
Treatment of severe HA presently consists of intravenous injection of plasma derived or recombinant human FVIII protein 
(rhFVIII) concentrates both as prophylaxis 2-34 times per week, and at the time of a bleed, to prevent or control bleeding 
episodes, respectively. The half-life for rhFVIII (under 24FVIII (12-18 hours for most approved products) necessitates frequent 
infusions, and although a major advance in the treatment of HA, it remains common for severe HA patients to continue to have 
multiple bleeding events on treatment (mean of 1 to 7 episodes/year with prophylaxis and up to 30 to 50 episodes/year for on 
demand treatment) (Nagel, 2011, Haemophilia).   
Several different gene transfer strategies for FVIII replacement have been evaluated, but adeno-associated viral (AAV) vectors 
show the greatest promise (Pipe, 2010, Blood).Mannucci, 2001, NEJM). 
Indeed, an on-going gene therapy clinical trial for a related disorder, haemophilia B, has established that stable (>36 months) 
expression of human factor IX at levels that are sufficient for conversion of their bleeding phenotype from severe to moderate or 
mild is achievable following a single peripheral vein administration of AAV-8 vector (Nathwani, 20112014, NEJM). 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, potentially life-long expression of 
active hFVIII FVIII in the plasma, synthesized from vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-
human study designed to assess the relationship of vector dose to the augmentation of residual FVIII activity, and whether these 
1, 5 

 
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Section No./Title 
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Rationale 
levels are sufficient to alter the clinical phenotype. The relationship of dose to safety will be correlated to the activity of hFVIII 
FVIII in patients with severe HA. 
7.4/Summary of Overall 
Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based on prior human studies with 
peripheral injections of AAV vectors, there is no known safety risk of AAV gene therapy. However, a mild asymptomatic 
transaminitis was observed at week 8-107-12 after administration in humans with an AAV8-FIX, providing the rationale for the 
following surveillance plan (Manno, 2006, Nature Med.). Nathwani, 2011, Mol.Ther.). Each patientsubject will have a 
comprehensive surveillance plan monitoring that monitors LFTs once a week from dose to completion of Week 6, 3 times per 
week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s subject’s ALT is found to be greater than 1.5x 
baseline during these periods, then LFTs will be monitored three times per week or until the ALT returns to baseline. 
Dose selection: The benefit of this study can only be enhanced by selecting a starting dose that potentially could contribute to a 
better maximizes the opportunity of observing a therapeutic effect, and therefore, reducing the possibility of a sub-therapeutic 
effect. 
Overall, no BMN 270-related findings, except expected formation of anti-AAV5 antibodies, were observed at the highest 
administered doses of 6E13, 2E14 and 6E13 vg/kg in the normal mouse, disease model mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 6E12 vg/kg should not pose any 
risk or safety concerns to patients but may potentially benefit the patient subjects with the best chance of benefiting the subject 
therapeutically. 
1, 5 
9/Investigational Plan 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and do not have transduction 
inhibition activity to AAV5 will be eligible to enroll in the study. Participants will be enrolled sequentially into one of up to 
three cohorts according to dose level:  
1. 6E12 vector genomes [vg] per kilogram/kg of body weight, given as a single intravenous dose (iv) 
2. 2E13 vg per kilogram/kg, iv 
3. 6E13 vg per kilogram/kg, iv 
Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose escalation may occur after a single patient 
has been safely dosed if the resulting FVIII activity at Week 3 is < 5 IU/dL. Three weeks is expected to be the time the 
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expression will be close to the maximum.  This escalation paradigm is intended to minimize the patient numbers exposed to 
subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of mice and monkeys.  The 
starting dose has a significant safety margin (10-fold) from no observed adverse effect level (NOAEL) in non-human primates 
mice.   
Approximately three weeks after an injection, Cohorts will be enrolled sequentially, allowing a period of 3 weeks or more 
between cohorts. Dose escalation may occur after a single subject in a cohort has been safely dosed if the resulting FVIII activity 
at the Week 3 visit is < 5 IU/dL in both assays. Three weeks is expected to be the time the expression will be close to the 
maximum.  This escalation paradigm is intended to minimize the subject numbers exposed to subtherapeutic doses.  The 
decision to escalate to the next dose level will be made based on the review of safety parameters and FVIII activity by the 
Sponsor and a panel of investigators participating in the study. 
If the FVIII activity isreaches ≥5 IU/dL at the Week 3 visit, then the other patients ofremaining subjects in the dose groupcohort 
will be enrolled without waitingthe need to wait for 3 weeks between patientssubjects. 
Subject 1 (Cohort 1) will be dosed by intravenous perfusion infusion with 6E12 vector genomes [vg] per kilogram/kg of body 
weight. If the FVIII activity level does not reach ≥5 IU/dL or greater (expressed as % in Figure 9.1.1) at 21 days the Week 3 visit 
in both assays, then a higher no further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with Subject 
2 at the next dose (2E13 vg per kilogram) will be used for the next patient. /kg). 
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL after Patient 2at the Week 3 visit in 
both assays, then the highest dose (6E13 vg per kilogram)no further subjects will be used for dosed in Cohort 2 and enrollment 
into Cohort 3 (6E13) will initiate with the next patient. Subject.  
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then 
the DRB will recommend whether to continue to add subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each dose Cohort, if the activity level reaches ≥5 IU/dL and if no safety issue is found, then up to 
four patients will receive subjects will be enrolled in the Cohort. Although the optimum design of this dose.  If at any time study 
is three cohorts of 4 subjects, the adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts 
based on activity levels reach 10 IU/dL or higher, no further dose escalation will take place, but additional patients will then be 

 
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dosed at this dose level for a total of 6 patients per dose. 
of FVIII and safety signals.  Because patientssubjects develop neutralizing immunity upon exposure to the capsid, re-challenge 
of vector is not a likely treatment option and these patientssubjects have effectively a single opportunity for therapy using this 
AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post dose. Safety will be evaluated for approximately 5 
years after dose. dosing. Any safety signal will may trigger a review of the data and possible additional analysis including 
immunogenicity studies that include an assessment of cellular immune responses using collected peripheral blood mononuclear 
collection. cells (PBMC). 
Table 9.1.4, dealing with steroid prophylaxis in the event of elevated LFTs, is discussed in Section 9.4.8.2. 
Table 9.1.1/Schedule of 
Events/Screening and 
Infusion/Assessment 
Distribution of subject diaries and training in their use 
Mononuclear cell PBMC collection for CTL baseline 
Haemo-QoL-A Quality of Life (QoL) assessment 
5 
Table 9.1.1/Schedule of 
Events/Screening and 
Infusion/Rescreening 
Added this new column 
3 
Table 9.1.1/Schedule of 
Events/Screening and 
Infusion/Footnotes 
f Includes HLA typing genotyping, FVIII mutation status genotyping, TNFα and IL10a single nucleotide polymorphisms. 
h Should the screening visit occur within 7 days of the drug infusion, physical examination, vital signs, blood chemistry, 
haematology, urine tests, coagulation screen, and CRP do not need to be repeated at Baseline. 
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to 
complete the Baseline assessments and Infusion prior to the closing of the original Screening window.  Subjects who undergo 
smart rescreening must complete the rescreening assessments and receive the infusion within 90 days of signing the original 
consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening. 
k Assessments on the day of infusion should be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs 
will be monitored prior to the infusion, during the infusion every 15 minutes (± 5 minutes), following the infusion hourly (± 5 
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minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals (± 15 minutes). 
Table 9.1.2/Schedule of 
Events/Post-Infusion 
Follow-Up/Assessment 
Assessment of Adverse Events and Concomitant Medications  (including review of subject diary for bleeding and FVIII use) 
hFVIII activity FVIII  assaysc 
hFVIII FVIII antibody titer 
Haemo-QoL-A QoL assessment 
Mononuclear cell PBMC collection 
5 
Table 9.1.2/Schedule of 
Events/Post-Infusion 
Follow-Up/Follow-Up 
After BMN270 
Administration - Weeks 
Expanded Week 1 column to include D2, D4, and D8. 
5 
Table 9.1.2/Schedule of 
Events/Post-Infusion 
Follow-Up/Footnotes 
* Visit windows are ±48 hours (and include the Day 4 visit) 
c Includes hFVIII activity level (APTT and FXa chromogenic assay), hFVIII activity confirmation (frozen plasma), Bethesda 
assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII 
antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved. 
d Collection to occur on Day 1, 3, 72 and 4 following BMN 270 infusion, and then weekly until at least 3 consecutive negative 
results are obtained. 
1, 5 
Table 9.1.3/Schedule of 
Events/Safety Follow-
Up/Assessment 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and FVIII use) 
hFVIII activity FVIII assaysc 
hFVIII FVIII antibody titer 
Mononuclear Cell PBMC Collection (for determination of FVIII and Capsid specific CTL activity) 
Haemo-QoL-A QoL assessment 
5 
Table 9.1.3/Schedule of 
Events/Safety Follow-
* Visit windows are ±72 hours1 week for visits in Year 1, and ± 2 weeks for visits in Years 2-5. 
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Up/Footnotes 
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), hFVIII activity confirmation (frozen plasma), 
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and 
hFVIII antigen (ELISA).  If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to 
obtain FVIII activity measurements when a 72 hour interval without FVIII use is achieved. 
e Haemo-QoL-A QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 
6 months) starting with the Week 78 visit (ie, 26 weeks after the Week 52 visit at the end of Year 1 of the Safety Follow-up 
period). 
Table 9.1.4/Schedule of 
Events/Steroid 
Prophylaxis 
This table was added as part of this amendment. 
1 
9.2/Discussion of Study 
Design, Including 
Choice of Control Group 
The decision to escalate to the next dose level will be made based on the review of safety parameters and FVIII activity by the 
Sponsor and a panel of investigators participating in the study. the DRB. 
There will be no control group. Parameters for each patientsubject will be compared to a pre-treatment assessment of safety 
(liver function) and efficacy (number of bleeds, use of replacement therapy).  
5 
9.3/Selection of Study 
Population 
Up to 12 severe haemophilia A patients may enroll into the study; the actual number of patients will depend on the criteria for 
dose escalation. A total of 6 patients may be enrolled at a single dose level. 
5 
9.3.1/Inclusion Criteria 
• 
Males that are 18 years or older with established severe Haemophilia A as evidenced by their medical history.  Patients 
will be considered as severe if their base FVIII baseline level is  1 IU/dL or less 
• 
Treated/exposed to FVIII concentrates or cryoprecipitates cryoprecipitate for a minimum of 150 exposure days (EDs) 
• 
No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 12 months using and results from a 
modified Nijmegen Bethesda assay higher of less than 0.6 Bethesda Unit Units (BU) 2 consecutive occasions at least 
one week apart within the past 12 months 
5 
9.3.1/Exclusion Criteria 
• 
Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction inhibition and or AAV5 total 
antibodies 
• 
Patients that are HIV positive are excluded. 
• 
Significant liver dysfunction as defined by abnormal elevation of: 
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o 
 ALT (alanine transaminase) to 3 times the upper limit of normal, bilirubin, ; 
o 
Bilirubin above 3 times the upper limit of normal; 
o 
Alkaline phosphatase, above 3 times the upper limit of normal; or 
o 
 an INR (international normalized ratio) of≥ 1.4.  
• 
Treatment with any IP within 30 days prior to the end of the screening visit period 
• 
Any disease or condition at the physician’s discretion that would prevent the patient from fully complying with the 
requirements of the study. including possible corticosteroid treatment outlined in the protocol.  The physician may 
exclude patients unwilling or unable to agree on not using alcohol for the 16-week period following the viral infusion. 
• 
Receipt of Prior treatment with any vector or gene transfer agent 
• 
Major surgery planned in the 16-week period following the viral infusion 
• 
Use of immunosuppressive agents or live vaccines within 30 days before the viral infusion 
9.3.3.1/Study Safety 
Evaluation Criteria 
If any of the following events occur (except the persistence of AAV5) in a patientsubject in the study who has received BMN 
270 infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis per Section 9.1. 
• 
A 5-fold increase from baseline in ALT after BMN 270 administration 
• 
The occurrence of other drug-Grade 3 or higher adverse events assessed as related Grade III-IV toxicity to study drug, 
including liver failure and clinical hepatitis 
• 
Drug-Grade 2 adverse event assessed as related Grade II toxicity to study drug that persists for at least 7 days 
• 
The occurrence detection of neutralizing antibodies to hFVIII following BMN 270 infusion 
The occurrence of a malignancy excluding skin cancers at any point after BMN 270 infusion that is assessed as possibly, 
probably, or definitely related to the study agent 
5 
9.3.5/Subject 
Identification and 
Replacement of Subjects 
Patients Subjects who withdraw from the study after Week 16 will not be replaced. 
5 
9.4.2.1/Product 
Characteristics and 
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 2 mL polypropylene cryovial. 
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Labeling 
Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 
9.4.4/Directions for 
Administration 
FVIII protein concentrate replacement therapy will not be given since venipuncture is a minimally invasive procedure in these 
individuals under ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. Prepared drug will be kept at room 
temperature prior to administration. An electric syringe pump will be used to infuse through an in-line, low protein binding 
0.22 micron filter. BMN 270 will be infused through the catheter using an appropriate infusion pump at a constant rate of 4 
ml/min while monitoring the vital signs (pulse, blood pressure, respiration rate and temperature) at 15 minute (± 5 minutes) 
intervals. The anticipated maximum interval from initiation of thawing of BMN 270 to completion of the infusion is 4 hours., 
although the IP has been shown to be stable at room temperature for 6 hours. 
Patients Subjects will remain hospitalized in the clinic for 24 hours to observe for any immediate toxicity of the procedure. 
After 24 hours of hospitalization, participants will be discharged from the clinic unless toxicity has been observed in which 
case hospitalization the stay in the clinic may be extended or the subject may transfer to an outpatient a separate facility may 
occur based on the evaluation and judgment of the Principal Investigator after consultation with the Medical Monitor. 
5 
9.4.5/Method of 
Assigning Subjects to 
Treatment Groups 
Patients Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be enrolled into the study. 
Approval by the Sponsor will be required prior to enrollment of each study patientsubject. Upon their enrollment into the study, 
patientssubjects will be assigned a unique patientsubject number and dose level by the Sponsor. 
PatientsCohorts are enrolled serially and their dose is defined in Section 9.4.6.2 below. Escalation is based on FVIII activity 
3 weeks after injection. PatientsCohorts may receive the next higher dose if subjects in the previous patient cohort does not meet 
the activity criteria, or the same dose if subjects in the previous patient cohort meets the activity criteria. Up to 6 patients can 
have the same dose, for a total of 12 patients in this study. 
5 
9.4.6/Selection of Doses 
Used in the Study 
The starting dose was based on the expression of hFVIII observed in nonclinical studies of mice and monkeys. The starting dose 
has a significant safety margin (10-fold) from NOAEL in non-human primates. Mice. The dose escalation is half-logs based. 
5 
9.4.6.2/Selection of 
Dose for Each Subject 
The starting dose was determined by expression of hFVIII observed in mice and monkeys and a scale up factor based on 
previous experience, an improved purification process over previous trials (thus potentially decreasing the risk of immune 
response), and a new evaluation of the titer (PCR performed after hairpin removal). 
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Approximately three weeks after an injection, the decision to escalate to the next dose level will be made based on the review of 
safety parameters and FVIII activity by the Sponsor and a panel of investigators participating in the study the DRB.  
Patient Subject 1 (Cohort 1) will be dosed by intravenous infusion with 6E12 vector genomes [vg] per kilogram/kg of body 
weight. If the FVIII activity level does not reach ≥5 IU/dL or greater (expressed as % in Figure 9.1.1) at 21 days the Week 3 visit 
in both assays, then a higher no further subjects will be dosed in Cohort 1 and enrollment into Cohort 2 will initiate with Subject 
2 at the next dose (2E13 vg per kilogram) will be used for the next patient. /kg). 
If the FVIII activity level in the first subject treated in Cohort 2 does not reach ≥5 IU/dL after Patient 2at the Week 3 visit in 
both assays, then the highest dose (6E13 vg per kilogram)no further subjects will be used for dosed in Cohort 2 and enrollment 
into Cohort 3 (6E13) will initiate with the next patient. Subject.  
If the FVIII activity level in the first subject treated in Cohort 3 does not reach ≥ 5 IU/dL at the Week 3 visit in both assays, then 
the DRB will recommend whether to continue to add subjects to the cohort and/or whether to continue the study.  
For the first subject treated in each dose Cohort, if the activity level reaches ≥5 IU/dL and if no safety issue is found, then up to 
four patients will receive subjects will be enrolled in the Cohort. Although the optimum design of this dose.  If at any time study 
is three cohorts of 4 subjects, the adaptive nature of this trial allows the DRB to recommend allocating subjects to the cohorts 
based on activity levels reach 10 IU/dL or higher, no further dose escalation will take place, but additional patients will then be 
dosed at this dose level for a total of 6 patients per dose of FVIII and safety signals. 
9.4.8/Prior and 
Concomitant 
Medications 
The following medications are prohibited starting 30 days before Screening: 
• 
Systemic immunosuppressive agents 
5 
9.4.8.2/Glucocorticoid 
Treatment of Elevated 
Hepatic Transaminases 
Reports of abnormal LFTs (defined as 1.5x the patient’s subject’s baseline ALT level) should be made to the BioMarin medical 
monitor within 24 hours30 minutes of the lab value being available.  If the LFTs are abnormal, , and treatment with prednisolone 
will be initiated immediately at a dose of 60 mg per day and then gradually tapered (60 mg daily for the first week2 weeks, then 
40 mg the second week next 2 weeks, then 30 mg the third week next two weeks, then 20 mg the fourth week next two weeks, 
then stop) will be , for a total treatment of 8 weeks). Local laboratory results of LFTs will be used to trigger corticosteroid 
treatment as needed.  In case of discrepant results between local and central laboratories, the Investigator and Medical Monitor 
will decide further action. 
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If a glucocorticoid treatment is started for a subject at any point of the study, the following steps will be taken:  
• 
A prophylactic glucocorticoid treatment will be started for subsequent subjects scheduled to be dosed. Subjects will 
receive prednisolone 40 mg per day starting at week 3, for a duration of 4 weeks, then tapered by 5 mg every two weeks 
for 8 weeks (until 20 mg/day is reached), then tapered 5 mg per week for 3 weeks, for a total duration of 15 weeks 
(refer to Table 9.1.4immediately). 
o 
Subjects already dosed who have not yet reached Week 17 in the study will be evaluated for the use of 
prophylactic steroids after discussion between the Investigator and the Medical Monitor 
• 
Once prophylactic glucocorticoid treatments have been initiated, then all subjects (who have not already passed that 
period in the study) will have 3x/week LFT assessments during the 6-week period when a liver response is expected 
based on the liver response in the original subject, if this period is different from the 3x/weekly LFT assessments 
already planned for Weeks 7-12.   
o 
Subjects who have already passed that 6-week period in the study will continue to have the regularly 
scheduled LFT assessments as planned in the protocol. 
Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in 
consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid 
treatment, and specific monitoring not already covered by the schedule of events. Hepatitis B status will be rechecked at the end 
of the corticosteroid treatment. All adverse events should be reported as outlined in section 10 of the protocol. 
9.4.9/Treatment 
Compliance 
Study drug will be administered to patients subjects at the study site by a qualified professional.  The quantity dispensed, 
returned, used, lost, etc. must be recorded on the dispensing log provided for the study.  Sites will be instructed to return or 
destroy all used and unused study drug containers. 
5 
9.5/Investigational 
Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates and quantities) of IP(s) received, 
patients to whom IP is dispensed (patient-by-patient dose specific accounting), and IP lost or accidentally or deliberately 
destroyed. The Investigator or designee must retain all unused or expired study supplies until the study monitor (on-site CRA) 
has confirmed the accountability data. 
5 
9.7.2/Primary Efficacy 
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis after BMN 270 dose. The efficacy 
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Variables 
goal of the protocol is to ascertain the dose range of BMN 270 required to convert severe HA patients to stable expression of 
FVIII at 5 IU/dL or above, i.e., a mild severity. This is associated in natural history studies with clinically superior long term 
outcomes (Nathwani, 1992, Baillieres Clin.Haematol.).Den Uijl, 2011, Haemophilia). 
If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72-hour interval without FVIII use is achieved. 
The FVIII activity level in both assays and the number of patientssubjects with FVIII activity ≥ 5 IU/dL in at least one of the two 
assays will be summarized. 
9.7.3/Secondary 
Efficacy Variables 
Assessment of viral shedding at one week after BMN 270 infusion will also be considered an efficacy variable. 
5 
9.7.4/Immunogenicity 
Immunogenicity assays will be performed on plasma.  The assays will include detection of anti-capsid, and anti-FVIII total 
antibody, and determination of neutralizing antibodies against FVIII. Any increase in total antibody level, especially during the 
time period of 65-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the liver parameters will 
lead to ana retrospective immunogenicity assessment to determine anti-FVIII and capsid specific CTL.  Anti-FVIII and capsid 
specific CTL assays will be performed on collected PBMCs. 
5 
9.7.6/Exploratory 
Biomarker Assessments 
All biomarker samples collected in this study may be used for exploratory biomarker research including evaluation of additional 
biomarkers not specifically listed in the protocol.  In addition, samples collected for other purposes may be used for exploratory 
use once the primary use has been completed.  No additional genetic or genomic testing will be conducted on any sample (other 
than testing specified in the protocol). 
5 
9.7.7/Haemo-QoL-A 
Quality of Life 
Assessment 
The Haemo-QoL-A is a patient-reported outcome (PRO) questionnaire which will be used to assess subject quality of life (QoL) 
during the study.  Assessments will occur at the time points listed in the Schedules of Assessments. 
5 
Table 9.7.8.2.1/Clinical 
Laboratory 
Tests/Footnotes 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon dioxide; GGT, 
gamma-glutamyltransferase; LDH, lactate dehydrogenase; PT, prothrombin time; APTT, activated partial thromboplastin time; 
RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; T3, 
triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; WBC, white blood cell; TT, thrombin time; INR, 
international normalized ratio. 
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9.7.8.3/Liver Function 
and Hepatitis Testing at 
Screening 
Patients Subjects will be screened for evidence of previous hepatitis B or hepatitis C infection at Screening. If medical records  
Subjects with documented results showing no evidence an absence of active Hepatitis B or Hepatitis C infection from the 
previous 30 days are available, then the Screening tests do not need to be done.   
Evidence of ongoing infection ((as measured by positive surface antigen for hepatitis B or positive RNA testing for hepatitis C) 
will be an exclusion criteria. If these parameters are negative and therefore no active infection is detected, then the patients may 
be included if they were vaccinated (for hepatitis B) or cleared the infection (for hepatitis C) and their liver function is 
acceptable.30 days prior to providing signed informed consent do not need to be screened again.   
Evidence of ongoing Hepatitis B or Hepatitis C infection is exclusionary. Subjects who have cleared a Hepatitis B infection or 
are seronegative do not need to receive the Hepatitis B vaccination.  
A liver ultrasound and liver function testing at Screening will identify any significant hepatic dysfunction, which is defined as: 
• 
More than 3x the normal Alkaline phosphatase above the normal cut off level. 
• 
INR over> 1.4.  
Liver ultrasound results indicative of a liver cirrhosis 
1, 4 
9.7.8.4/Vital Signs, 
Physical Examinations 
and Other Observations 
Related to Safety 
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature will be assessed at Screening, 
Baseline, and at the beginning of each visit during the Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of 
the BMN 270 Infusion, vital signs will be monitored prior to infusion, during the infusion every 15 minutes (± 5 minutes), 
following the infusion hourly (± 5 minutes) for 6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour 
intervals. (± 15 minutes).  
A complete physical examination will include general appearance (head, eyes, ears, nose, and throat), cardiovascular, 
dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems (level of 
consciousness, speech, language, cranial nerves, motor strength, motor tone, abnormal movements, reflexes, upper extremity 
sensation, lower extremity sensations, gait, Romberg, nystagmus, and coordination).. 
5 
9.7.8.5/Viral Shedding 
Viral shedding has been extensively studied in all similar clinical trials performed to date. (Nathwani, 2014, N.Eng.J.Med 
(Supplemental Appendix); Manno, 2006, Nature Med. (Supplemental Appendix); Schenk-Braat, 2007, J Gene Med; Croteau, 
2004, Ann Occup Hyg). It has been constantly shown that In the literature referenced above, vector was not no longer detectable 
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anymore at after 40 days, with its persistence in blood, saliva, urine or stool.  However, vector persisted in semen for 16 weeks 
in the seminal fluid but not in motile sperm (Manno, 2006, Nature Med.).  In addition, it has always all cases, the amount of 
vector present in these bodily fluids involved only an extremely small fraction of the injected infused dose.  
Viral shedding will also be extensively studied in the present clinical trial, every week up to 16 weeks, then every 4 weeks to one 
year, then every three months., until at least 3 consecutive negative results are obtained.  During the Post-Infusion Follow-Up 
period, patients subjects will undergo testing of various bodily fluids samples to look for evidence of viral shedding for possible 
viral transmission.  Bodily fluids will be tested by PCR at the time points indicated in Table 9.1.2 and Table 9.1.3. 
10.1.1/Adverse Events 
Bleeding events that occur where a normal (ie, non-haemophiliac) patient would bleed, such as bleeding as a result of major 
trauma, should be recorded as adverse events. 
5 
10.2/Serious Adverse 
Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 1 or more of the following criteria: 
• 
Requires or prolongs inpatient hospitalization.  Hospitalization for less than 24 hours will not be considered to be an 
SAE. Hospitalization solely for the purpose of insertion of an in-dwelling IV catheter (such as a Port-a-Cath or other 
brand) for administration of study drug will not be considered an SAE. 
5 
10.2.1/Events of Special 
Interest (EOSI) 
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, irrespective of seriousness, severity or 
causality:  
Elevation of liver enzymes triggering (ALT) that triggers a corticosteroid treatment 
5 
10.3.3/Assessment of 
Seriousness, Severity, 
and Causality 
The Investigator responsible for the care of the patientsubject or medically qualified designee will assess AEs for severity, 
relationship to study drug, and seriousness (refer to Section 10.2 for SAE definitions).  These assessments should must be made 
by a study clinician with the training and authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
5 
10.4.1.7/Hospitalization, 
Prolonged 
Hospitalization, or 
Surgery 
There are some hospitalization scenarios that do not require reporting as an SAE when there is no occurrence of an AE.  These 
scenarios include planned hospitalizations or prolonged hospitalizations to: 
• 
Hospitalization solely for the purpose of insertion of an in-dwelling IV catheter (such as a Port-a-Cath or other brand) 
for administration of study drug will not be considered an SAE. 
5 

 
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10.4.1.9/Pregnancy 
Pregnancy in partner should be reported within 24 hours of the site becoming aware of the pregnancy by faxing entering the 
information on the Pregnancy Form in the study reference materials eCRF and submitting to BPV. within 24 hours of the site 
becoming aware of the event.  The Investigator must make every effort to follow the patient subject’s partner through resolution 
of the pregnancy (delivery or termination) and to report the resolution on the Pregnancy Follow-up Form in the study reference 
materials. In the event of pregnancy in the partner of a study patientsubject, the Investigator should make every reasonable 
attempt to obtain the woman’s consent for release of protected health information. 
5 
10.5.1/Expedited 
Reporting Requirements  
The reporting period for SAEs begins after informed consent is obtained and the first administration of study drug is given.  It 
continues for approximately 5 years or until study discontinuation/termination, whichever is longer.  
5 
12.2/Screening Visit 
The following procedures will be performed during the Screening Period: 
• 
Full medical history, including haemophilia A history, Hepatitis B, Hepatitis C, and HIV. Patients with documented 
negative results within the last 30 days do not need to be retested. 
• 
Samples for hFVIII Assays 
o 
AAV5 transduction inhibition assays assay 
• 
Screen for Hepatitis B, Hepatitis C, and HIV if required (Patientssubjects with documented negative results within the 
last 30 days prior to informed consent being obtained do not need to be retested) 
• 
Blood samples for Biomarker testing (including HLA typing genotyping, FVIII mutation genotyping status, TNFα and 
IL10a single nucleotide polymorphisms) 
4, 5 
12.2.1/”Smart 
Rescreening” Visit 
Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion within 90 days of 
signing the original consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all 
screening procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 28 + 14 day period allowed for 
Screening (refer to Section 12.2), then only the following assessments need to be performed (rather than the full list indicated in 
Section 12.2) for the patient to be successfully re-screened for the study: 
• 
Vital signs 
3, 5 

 
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• 
Assessment of Adverse Events and Concomitant Medications 
• 
Documentation of bleeding episodes and FVIII usage (by either subject or clinical information) 
• 
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) 
• 
Blood sample for AAV5 Assays 
o 
AAV5 antibody titer 
o 
AAV5 transduction inhibition assay 
Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to Table 9.7.8.2.1) 
12.3/Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following procedures will be performed 
during the Baseline Period: 
• 
Samples for FVIII Assays 
o 
FVIII activity chromogenic FXa (plasma)  
o 
FVIII activity level APTT One stage assay  
o 
FVIII coagulation activity exploratory assay 
o 
FVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o 
FVIII antibody assay 
o 
FVIII antigen (ELISA) 
• 
Distribution of subject diaries and training in diary completion 
• 
Mononuclear cell PBMC collection for CTL baseline 
• 
Haemo-QoL-A QoL assessment 
5 
12.4/Treatment 
Visit/BMN 270 Infusion 
Visit (Day 1) 
There will be one treatment visit for each patient.  Patients subject.  Subjects will be hospitalized remain in the clinic for 24 
hours for the BMN 270 Infusion Visit.  
5 

 
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12.5.1/Every Visit 
Every week (Weeks 1 through 16), the following procedures will be performed: 
• 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and FVIII 
use) 
• 
Samples for FVIII Assays 
o 
FVIII activity confirmation (Frozen plasma) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved. 
• 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
o 
Collection to occur on Day 1, 3, 7 following BMN 270 infusion, and then weekly until at least 
3 consecutive negative results are obtained 
1, 5 
12.5.3/Week 1 – Day 2 
and Day 4 
On Day 2 and Day 4 of Week 1, the following procedures will be performed: 
• 
PCR of vector genomes in blood, saliva, urine, semen, and stools (Day 2 and Day 4) 
• 
Samples for FVIII Assays (Day 4 only) 
o 
FVIII activity level (APTT) 
o 
FVIII activity level (chromogenic FXa assay) 
o 
FVIII coagulation activity exploratory assay 
o 
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o 
FVIII antigen (ELISA) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved.  
5 
12.5.4/Every 2 Weeks 
Every 42 weeks (Weeks 2, 4, 6, 8, 10, 12, 14 and 16), the following procedure will be performed: 
• 
Mononuclear cell Exploratory biomarker assessments 
5 
12.5.5/Weeks 4, 8, 12, 
At Weeks 4, 8, 12, and 16, the following procedure will be performed: 
5 

 
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and 16 
• 
PBMC collection 
12.5.7/Weeks 8 and 16 
At Weeks 1, 8, and 16, the following procedure will be performed: 
• 
AAV5 antibody titer 
5 
12.5.8/Weeks 1, 2, 3, 4, 
and 16 
At Weeks 1, 2, 3, 4, and 16, the following procedure will be performed: 
• 
Haemo-QoL-A QoL assessment 
5 
12.6/Safety Follow-Up – 
Year 1 
After the 16 weekly infusion follow-up visits are complete, subjects will return to the study site at Weeks 20, 28, 36, 44, and 52 
(± 48 hours1 week), when the following procedures will be completed: 
5 
12.6.1/Every Visit 
At Weeks 20, 28, 36, 44, and 52, the following procedures will be performed: 
• 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and FVIII 
use) 
• 
FVIII Assays 
o 
FVIII activity confirmation (Frozen plasma) 
Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved. 
• 
Mononuclear cell PBMC collection 
• 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
o 
Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are clear during 
the Post-Infusion Follow-Up period. 
5 
12.6.2/Weeks 28 and 52 
At Weeks 28 and 52, the following procedure will be performed: 
• 
Haemo-QoL-A QoL assessment 
5 
12.7/Safety Follow-Up 
During Years 2-5 of Safety Follow-up, patients subjects will be assessed every 3 months (± 72 hours2 weeks). At these times, 
the following procedures will be completed: 
5 
12.7.1/Every Visit 
Every 3 months (± 72 hours 2 weeks), the following procedures will be performed: 
5 

 
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• 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and FVIII 
use) 
• 
FVIII Assays 
o 
FVIII activity confirmation (Frozen plasma) 
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved. 
• 
Mononuclear cell PBMC collection 
• 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
o 
Sample testing during Safety Follow-Up is not required if at least 3 consecutive samples are clear during 
the Post-Infusion Follow-Up period. 
12.7.2/Every Other Visit 
(Every 6 months) 
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the end of Year 1 of the Safety Follow-up 
period), the following procedure will be performed: 
• 
Haemo-QoL-A QOL assessment 
5 
12.8/Early Termination 
Visit 
If a patient subject leaves the study prior to the Week 270260 visit, the patient subject will be asked to return to the study site 
and complete an Early Termination visit.  At the Early Termination visit, as many of the following assessments as possible 
should be done: 
• 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and FVIII 
use) 
o 
Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o 
FVIII activity confirmation (Frozen plasma) 
o 
FVIII antigen (ELISA) 
 Note: If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII 
activity measurements when a 72-hour interval without FVIII use is achieved. 
• 
Mononuclear cell PBMC collection 
• 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
5 

 
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o 
Sample testing at the ETV is not required if at least 3 consecutive samples are clear during the 
Post-Infusion Follow-Up period. 
• 
Haemo-QoL-A QOL assessment 
12.9/End of Study 
The study will end after the last patientsubject completes the last Safety Follow-Up visit (Week 270260). 
5 
13/Data Quality 
Assurance 
BioMarin personnel or designees will visit the study site prior to initiation of the study to review with the site personnel 
information about the IP, protocol and other regulatory document requirements, any applicable randomization procedures, 
source document requirements, CRFs eCRFs, monitoring requirements, and procedures for reporting AEs, including SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with regulatory documentation, with a focus on 
accurate and complete recording of data on CRFs eCRFs from source documents, adherence to protocol, randomization (if 
applicable), SAE reporting and drug accountability records.  
The designated clinical data management group will enter or transfer CRF data into a study database. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a predefined analysis plan. 
5 
14.2/Primary and 
Secondary Efficacy 
Analysis 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as mixed effect model which takes 
into account the correlation among the observation taken at various time points within a participant. Efficacy is a secondary 
endpoint, defined as biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay between 1 to at 
16 weeks following study treatment. 
5 
14.3/Immunogenicity 
Analysis of neutralizing antibody response and other immunological parameters will be primarily descriptive and involve both 
inter-participant and intra-participant comparisons across doses. 
5 
14.6/Determination of 
Sample Size 
No formal sample size calculations based on statistical power were performed. 
The sample size is determined based upon clinical consideration and could detect a strong clinical efficacy signal. Up to 
12 patientssubjects may be dosed in the study; the actual number of patientssubjects will depend on the criteria for dose 
escalation. A total of 6 patients may be enrolled at a single dose level. 
5 
15/Data Review Board 
DATA MONITORING COMMITTEEREVIEW BOARD 
5 
21/References 
Den Uijl IEM, Mauser Bunschoten EP, Roosendaal EG, Schutgens REG et al.  Clinical severity of haemophilia A: does the 
5 

 
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classification of the 1950s still stand?  Haemophilia.  2001; 17(6):849-853. 
 
Hay CRM, DiMichele DM.  The principal results of the International Immune Tolerance Study:  A randomized dose 
comparison.  Blood 2012; 119 [6]:1335-1344. 
Kaufman RJ, Powell JS. Molecular approaches for improved clotting factors for hemophilia. Blood 2013; 122: 3568–74. 
Mannucci PM & Tuddenham EGD.  The Hemophilias - From Royal Genes to Gene Therapy.  NEJM 2001; 344:1773-1779. 
 
Nathwani AC, Gray JT, Ng CY, et al.  Self-complementary adeno-associated virus vectors containing a novel liver-specific 
human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver.  Blood.  2006; 
107(7):2653-2661. 
 

 
 
BioMarin is a registered trademark of BioMarin Pharmaceutical Inc. 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study 
of BMN 270, an Adenovirus-Associated Virus Vector–Mediated 
Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
Protocol Number: 
270-201 
Active Investigational 
Product: 
AAV5-hFVIII-SQ 
IND/European Union 
Drug Regulating 
Authorities Clinical Trials 
(EudraCT) Number: 
2014-003880-38 
 
Indication: 
Haemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 1/2 
Sponsor's Responsible 
Medical Monitor: 
 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Duration of Patient 
Participation: 
Approximately 264 weeks 
Dose: 
Varied 
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
10 February 2015 
Date of Amendment 1: 
06 March 2015 
Date of Amendment 2: 
26 May 2015 
Property of BioMarin 
CONFIDENTIAL 
 
May not be divulged, published, or otherwise disclosed to others without prior written approval from 
BioMarin. 
 
This study will be conducted according to the principles of Good Clinical Practice as described in the 
U.S. Code of Federal Regulations and the International Conference on Harmonisation Guidelines, 
including the archiving of essential documents. 
 
PI
PI

 
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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment: 2 
Date: 26 May 2015 
 
RATIONALE AND SUMMARY OF MAJOR CHANGES 
A summary of major changes covered by Amendment 2 to the BMN 270-201 protocol is 
provided below.   
1. Exclusion criterion changed from “Evidence of detectable viral load of HIV” to 
“Patients that are HIV positive are excluded.”  In addition, the following exclusion 
criterion was added:  “Any evidence of active infection or any immunosuppressive 
disorder.” 
Rationale:  The criteria were amended to exclude patients with any disease or condition that 
may jeopardise patient safety.  
 
2. The Overall Study Design and Plan changed to include details of Sponsor actions 
should any of the criteria listed in Section 9.3.3.1 occur. 
Rationale:  Sponsor actions pertaining to the criteria listed in Section 9.3.3.1 reflect a more 
conservative approach considering this is a first-in-man trial. 
3. Expedited Reporting Requirements have been updated to include SUSAR reporting in 
accordance with European Directive 2001/20/EC. 
Rationale:  The protocol was amended to include the Sponsor’s responsibility to ensure that 
all relevant information about SUSARs is reported to the competent authorities in all the 
Member States concerned, and to the Ethics Committee in compliance with current 
legislation.  
 
4. Removed “Exploratory FVIII activity assay” from Primary Efficacy Variables 
section. 
Rationale:  The Exploratory FVIII activity assay is currently used for exploratory purposes 
only and not to direct patient management. 
 
5. Expanded description of Data Review Board (DRB) in Section 15 to include 
notification of all DRB meetings and meeting outcomes to participating sites. 
Rationale:  In view of the multiple sites involved, the DRB meetings and meeting outcomes 
will be used to disseminate data (safety and efficacy) to participating sites.  
 
 

 
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6. Removed requirement of FVIII Treatment Washout period. 
Rationale:  While washout periods are used in some Haemophilia studies, after discussion 
with Investigators and Experts, it was recommended to remove the washout period. 
Removing the washout period allows for continued prophylactic treatment up to the day of 
the infusion and may reduce the risk of a bleeding episode prior to BMN 270 treatment.  
Specific changes included in this amendment, including the Synopsis, since Amendment 1 
(approved 06 March 2015) are outlined in Section 24. 

 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study of BMN 270, an Adenovirus-
Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
PROTOCOL NUMBER: 
270-201 
STUDY SITES: 
Approximately 6-10 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 1/2 
STUDY RATIONALE: 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an essential 
cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to a new 
mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of 
wild type activity and the mild form is 5-40% activity. The clinical manifestations of severe HA 
remain frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or recombinant 
FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, and at the time of a 
bleed, to prevent or control bleeding episodes, respectively. The half-life for rhFVIII (under 24 hours 
for most approved products) necessitates frequent infusions, and although a major advance in the 
treatment of HA, it remains common for severe HA patients to continue to have multiple bleeding 
events on treatment (mean of 1 to 7 episodes/year with prophylaxis up to 30 to 50 for on demand 
treatment).  The consequence of multiple bleeding events is the development of an underlying 
pathology that contributes to debilitating multiple-joint arthropathy and substantially increased risk of 
death. Chemical modification (e.g. direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by approximately 50%, and 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
thus, show promise in reduced dosing and maintaining activity levels above 1% trough. However, 
these longer acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive treatment 
of HA to give patients a FVIII level compatible with a normal and haemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous production 
of active FVIII following a single intravenous administration of a vector with the appropriate gene 
sequence. Haemophilia A is well suited for a gene replacement approach because clinical 
manifestations are attributable to the lack of a single gene product (FVIII) that circulates in minute 
amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not essential, and 
modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml induces an increase 
in activity of 1%) can ameliorate the severe form of the disease.  Thus, relatively small changes in 
endogenous FVIII activity results in clinically relevant improvements in disease phenotype. Finally, 
the response to gene transduction can be assessed using validated quantitative rather than qualitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific tissues 
such as the liver (for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical 
trial for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild is achievable following a single peripheral vein administration of AAV-8 vector. 
Several participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in bleeding. 
Thus, gene therapy treatment has resulted in a substantial improvement in their quality of life.  
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII under the 
control of a liver-selective promoter (Figure 1).  
Figure 1. BMN 270 transgene construct, ~5.0 kbp 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, potentially 
life-long expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
The clinical study BMN 270-201 is a first-in-human study designed to assess the relationship of vector 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
dose to the augmentation of residual FVIII activity, and whether these levels are sufficient to alter the 
clinical phenotype. The relationship of dose to safety will be correlated to the activity of hFVIII in 
patients with severe HA. 
OBJECTIVES:  
The primary objectives of the study are: 
• 
To assess the safety of a single intravenous administration of a recombinant AAV5 encoding 
human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• 
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of FVIII at or 
above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose. 
The secondary objectives of the study are: 
• 
To describe the immune response to the FVIII transgene and AAV capsid proteins following 
systemic administration of AAV5-hFVIII-SQ 
• 
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during the 
study 
• 
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STUDY DESIGN AND PLAN:  
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe haemophilia 
A. Eligible patients will enter the dose escalation part of the study followed by a 16-week 
Post-Infusion Follow-Up period during which safety and efficacy assessments will be taken. After the 
primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed for approximately 
5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and do 
not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. Participants 
will be enrolled sequentially into one of up to three cohorts according to dose level:  
1. 6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous dose 
(iv) 
2. 2E13 vg per kilogram, iv 
3. 6E13 vg per kilogram, iv 
 
Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose escalation may 
occur after a single patient has been safely dosed if the resulting FVIII activity at Week 3 is < 5 IU/dL. 
Three weeks is expected to be the time the expression will be close to the maximum.  This escalation 
paradigm is intended to minimize the patient numbers exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of 
mice and monkeys.  The starting dose has a significant safety margin (10-fold) from no observed 
adverse effect level (NOAEL) in non-human primates.   
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study.  
If the FVIII activity is ≥ 5 IU/dL, then the other patients of the dose group will be enrolled without 
waiting for 3 weeks between patients. 
Patient 1 will be dosed by intravenous perfusion with 6E12 vector genomes [vg] per kilogram of body 
weight. If the activity level does not reach ≥ 5 IU/dL at 21 days, then a higher dose (2E13 vg per 
kilogram) will be used for the next patient.  
If the activity level does not reach ≥ 5 IU/dL after Patient 2, then the highest dose (6E13 vg per 
kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and no safety issue is found, then up to four 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no further dose 
escalation will take place, but additional patients will then be dosed at this dose level for a total of 
6 patients per dose. 
Because patients develop neutralizing immunity upon exposure to the capsid, re-challenge of vector is 
not a treatment option and these patients have effectively a single opportunity for therapy using this 
AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post dose. Safety will be 
evaluated for approximately 5 years after dose.  Any safety signal will trigger a review of the data and 
possible additional analysis including mononuclear collection. 
NUMBER OF PATIENTS PLANNED:  
Up to 12 patients may enroll into the study; the actual number of patients will depend on the criteria 
for dose escalation. A total of 6 patients may be enrolled at a single dose level. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe haemophilia A as evidenced by their 
medical history.  Patients will be considered as severe if their FVIII baseline level is 1 IU/dL 
or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitates for a minimum of 150 exposure 
days (EDs) 
3. Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 12 months 
using a modified Nijmegen Bethesda assay higher than 0.6 Bethesda Unit (BU) 
6. Sexually active patients must be willing to use an acceptable method of contraception such as 
double barrier, including hormonal contraception for at least 6 months post-treatment 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition and AAV5 total antibodies  
2. Any evidence of active infection or any immunosuppressive disorder.   

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
3. Patients that are HIV positive are excluded. 
4. Significant liver dysfunction as defined by abnormal elevation of ALT (alanine transaminase) 
to 3 times the upper limit of normal, bilirubin, alkaline phosphatase, or an INR (international 
normalized ratio) of 1.4. Potential participants who have had a liver biopsy in the past 3 years 
are excluded if they had significant fibrosis of 3 or 4 as rated on a scale of 0-4 
5. Evidence of any bleeding disorder not related to Haemophilia A 
6. Platelet count of < 100 x 109/L 
7. Creatinine ≥ 1.5 mg/dL 
8. Liver cirrhosis of any etiology as assessed by liver ultrasound  
9. Hepatitis B if surface antigen is positive 
10. Hepatitis C if RNA is positive 
11. Treatment with any IP within 30 days prior to the screening visit 
12. Any disease or condition at the physician’s discretion that would prevent the patient from fully 
complying with the requirements of the study.  The physician may exclude patients unwilling 
or unable to agree on not using alcohol for the 16-week period following the viral infusion. 
13. Receipt of any vector or gene transfer agent 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each patient will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
The study is open label with comparison of FVIII activity to baseline values. No reference therapy will 
be evaluated in this study. 
DURATION OF TREATMENT:  
BMN 270 is given as a single dose by intravenous perfusion. 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
CRITERIA FOR EVALUATION: 
The following safety outcome measurements will be assessed: 
Safety: 
• 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
• 
Change in clinical laboratory tests (serum chemistry and haematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding 
• 
Liver function tests (LFT) 
 
No major toxicity is expected based on preclinical studies in mice and monkeys. An asymptomatic 
transaminitis was observed at week 8-10 after administration with an AAV8-FIX, providing the 
rationale for the following surveillance plan. Each patient will have comprehensive surveillance plan 
monitoring LFTs once a week from dose to completion of Week 6, 3 times per week from Weeks 7 to 
12, and once a week from Weeks 13 to 16.  If a patient’s ALT is found to be greater than 1.5x baseline 
during these periods, then LFTs will be monitored three times per week or until the ALT returns to 
baseline. LFTs will be monitored every other month for the first year and then every three months for 
up to 5 years post-dose in the safety extension. 
There will be a detailed monitoring plan for assessment of cellular and humoral responses to AAV5 
capsid and FVIII protein.   
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the study is 
to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration. 
  
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Patients will be asked 
to keep a patient diary to record the details in these areas.   
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage APTT 
and/or chromogenic FXa assay (activity level), will be used for plasma profiles; FVIII activity will be 
Pharmacodynamics: 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
used to determine PD parameters.  Traditional PK analysis is not applicable. 
If supported by the FVIII activity data, non-compartmental analysis and observation will be used to 
estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss (time 
to steady state), C(t) and AUC(0-t) where t is 16 weeks.   
STATISTICAL METHODS:  
The sample size is based upon clinical considerations and could detect a strong clinical efficacy signal. 
Up to 12 patients may be dosed in the study.  The patients will be followed in a longitudinal manner 
and all the relevant information will be collected. The analysis of the data will be descriptive in nature 
but data collected in a longitudinal manner may be analyzed using longitudinal methods such as mixed 
effect model which takes into account the correlation among the observation taken at various time 
points within a participant. Efficacy is a secondary endpoint, defined as biologically active FVIII at 
≥ 5 IU/dL by chromogenic FXa assay and/or one-stage APTT assay between 1 to 16 weeks following 
study treatment. FVIII activity will be assessed weekly during the study period.  We can only assess 
the true steady state of FVIII protein produced from BMN 270 after a minimum of 72 hours has 
elapsed since the last infusion of FVIII protein concentrates. 
Analysis of neutralizing antibody response and other immunological parameters as well as viral 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses. 
 

 
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3 TABLE OF CONTENTS 
1    TITLE PAGE…………………………………………………………………………...…1 
2 SYNOPSIS ...........................................................................................................................4 
3 TABLE OF CONTENTS ...................................................................................................12 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................17 
5 ETHICS..............................................................................................................................19 
5.1 Institutional Review Board or Independent Ethics Committee ................................19 
5.2 Ethical Conduct of Study ..........................................................................................20 
5.3 Patient Information and Informed Consent ...............................................................20 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................21 
7 INTRODUCTION .............................................................................................................22 
7.1 Nonclinical Studies ...................................................................................................23 
7.2 Previous Clinical Studies ..........................................................................................24 
7.3 Study Rationale .........................................................................................................25 
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp .........................................27 
7.4 Summary of Overall Risks and Benefits ...................................................................27 
8 STUDY OBJECTIVES ......................................................................................................29 
9 INVESTIGATIONAL PLAN ............................................................................................30 
9.1 Overall Study Design and Plan .................................................................................30 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme ............................................31 
Table 9.1.1: Schedule of Events – Screening and Infusion ......................................33 
Table 9.1.3:  Schedule of Events – Safety Follow-Up .............................................36 
9.2 Discussion of Study Design, Including Choice of Control Group ............................37 
9.3 Selection of Study Population ...................................................................................37 
9.3.1 
Inclusion Criteria .........................................................................................37 
9.3.2 
Exclusion Criteria ........................................................................................38 
9.3.3 
Removal of Patients from Treatment or Assessment ..................................38 
9.3.4 
Patient Identification and Replacement of Patients .....................................40 
9.3.5 
Duration of Patient Participation .................................................................40 
9.4 Treatments .................................................................................................................40 

 
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9.4.1 
Treatments Administered ............................................................................40 
9.4.2 
Identity of Investigational Product ..............................................................40 
9.4.3 
Storage .........................................................................................................40 
9.4.4 
Directions for Administration .....................................................................41 
9.4.5 
Method of Assigning Patients to Treatment Groups ...................................41 
9.4.6 
Selection of Doses Used in the Study .........................................................42 
9.4.7 
Blinding .......................................................................................................42 
9.4.8 
Prior and Concomitant Medications ............................................................43 
9.4.9 
Treatment Compliance ................................................................................43 
9.5 Investigational Product Accountability .....................................................................44 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................44 
9.6 Dietary or Other Protocol Restrictions......................................................................44 
9.7 Safety and Efficacy Variables ...................................................................................44 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................44 
9.7.2 
Primary Efficacy Variables .........................................................................45 
9.7.3 
Secondary Efficacy Variables .....................................................................45 
9.7.4 
Immunogenicity ...........................................................................................45 
9.7.5 
Pharmacodynamics ......................................................................................46 
9.7.6 
Exploratory Biomarker Assessments ..........................................................46 
9.7.7 
Quality of Life Assessment .........................................................................46 
9.7.8 
Safety Variables ..........................................................................................46 
10 REPORTING ADVERSE EVENTS .................................................................................51 
10.1 Safety Parameters and Definitions ............................................................................51 
10.1.1 Adverse Events ............................................................................................51 
10.2 Serious Adverse Events ............................................................................................51 
10.2.1 Events of Special Interest (EOSI) ...............................................................52 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................52 
10.3.1 Adverse Event Reporting Period .................................................................52 
10.3.2 Eliciting Adverse Events .............................................................................52 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................53 

 
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10.4 Procedures for Recording Adverse Events ...............................................................55 
10.4.1 Recording Adverse Events on a eCRF ........................................................55 
10.5 Reporting Requirements ...........................................................................................58 
10.5.1 Expedited Reporting Requirements .............................................................58 
10.5.2 Ethics Committee Reporting Requirements ................................................59 
10.6 Follow-up of Patients after Adverse Events .............................................................59 
10.7 Post-Study Adverse Events .......................................................................................59 
10.8 Urgent Safety Measures ............................................................................................60 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................61 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................62 
12 STUDY PROCEDURES ...................................................................................................63 
12.1 Prestudy .....................................................................................................................63 
12.2 Screening Visit ..........................................................................................................63 
12.3 Baseline Visit ............................................................................................................64 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................65 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................65 
12.5.1 Every Visit ...................................................................................................65 
12.5.2 Every 4 Weeks .............................................................................................66 
12.5.3 Weeks 1, 3, and 6 ........................................................................................66 
12.5.4 Weeks 1, 8, and 16 ......................................................................................66 
12.5.5 Weeks 1, 2, 3, 4, and 16 ..............................................................................66 
12.6 Safety Follow-Up – Year 1 .......................................................................................66 
12.6.1 Every Visit ...................................................................................................67 
12.6.2 Weeks 28 and 52 .........................................................................................67 
12.7 Safety Follow-Up – Years 2-5 ..................................................................................67 
12.7.1 Every Visit ...................................................................................................67 
12.7.2 Every Other Visit (Every 6 Months) ...........................................................68 
12.8 Early Termination Visit ............................................................................................68 
12.9 End of Study..............................................................................................................69 
13 DATA QUALITY ASSURANCE .....................................................................................70 

 
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14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................71 
14.1 Statistical and Analytical Plans .................................................................................71 
14.1.1 Interim Analyses ..........................................................................................71 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........71 
14.2 Primary and Secondary Efficacy Analysis................................................................71 
14.3 Immunogenicity ........................................................................................................71 
14.4 Pharmacodynamic Analyses .....................................................................................72 
14.5 Safety Analysis .........................................................................................................72 
14.6 Determination of Sample Size ..................................................................................72 
14.7 Analysis Populations .................................................................................................73 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................73 
15 DATA MONITORING COMMITTEE .............................................................................74 
16 COMPENSATION, INSURANCE AND INDEMNITY ..................................................75 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................76 
18 STUDY MONITORING AND AUDITING .....................................................................78 
19 RETENTION OF RECORDS ...........................................................................................79 
20 USE OF INFORMATION AND PUBLICATION ...........................................................80 
21 REFERENCES ..................................................................................................................81 
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................83 
22.1 Conduct of Study and Protection of Human Patients ...............................................83 
23 SIGNATURE PAGE .........................................................................................................84 
24 PROTOCOL AMENDMENT TEXT REVISIONS ..........................................................85 
 
LIST OF TABLES 
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................33 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up .................................................35 
Table 9.1.3:  Schedule of Events – Safety Follow-Up .............................................................36 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................48 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................54 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................54 

 
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LIST OF FIGURES 
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp ........................................................27 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme ............................................................31 
 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAV 
Abbreviations 
adeno-associated virus 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine transaminase 
APTT 
activated partial thromboplastin time 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
eCRF 
electronic case report form 
DMC 
Data Monitoring Committee 
DRB 
Data Review Board 
ED 
exposure days 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FVIII 
coagulation factor VIII 
FXa 
coagulation factor Xa 
GCP 
Good Clinical Practice 
HA 
Haemophilia A 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 

 
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IEC 
independent ethics committee 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LFT 
liver funtion test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
vg 
vector genomes 
 
Investigational Product (IP): 
Definition of Terms:  
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 
 

 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin Pharmaceutical Inc. (BioMarin) or its designee. The 
Investigator will provide the IRB/IEC/REB with all appropriate material, including the 
protocol, Investigator’s Brochure (IB), the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the patients, 
including all ICFs translated to a language other than the native language of the clinical site. 
The study will not be initiated and Investigational Product (IP) supplies will not be shipped 
to the site until appropriate documents from the IRB/IEC/REB confirming unconditional 
approval of the protocol, the ICF and all patient recruitment materials are obtained in writing 
by the Investigator and copies are received at BioMarin or its designee. The approval 
document should refer to the study by protocol title and BioMarin protocol number (if 
possible), identify the documents reviewed, and include the date of the review and approval. 
BioMarin will ensure that the appropriate reports on the progress of the study are made to the 
IRB/IEC/REB and BioMarin by the Investigator in accordance with applicable guidance 
documents and governmental regulations. 

 
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5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible patients for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability. 
This study will be conducted in accordance with the following: 
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6) 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the patients will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each patient will provide written, informed consent before any 
study-related tests or evaluations are performed. 
5.3 
Patient Information and Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each patient prior to entering the patient into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF , and if applicable, 
a copy of the approved patient information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed. 
The Investigator will provide copies of the signed ICF to each patient and will maintain the 
original in the record file of the patient. 

 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to patients. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of patients in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each patient as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 
Laboratory evaluations will be performed at the local laboratories associated with the study 
sites. Refer to the Laboratory Manual for more details. 

 
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7 
INTRODUCTION 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.). 
Chemical modification or bioengineering of FVIII may improve half-life to around 20 hours 
(Pipe, 2010, Blood). However, these long acting FVIII variants do not eliminate the need for 
lifelong FVIII protein administration or problems of FVIII inhibitor formation, which occurs 
in 30% of patients on standard FVIII replacement therapy (Nathwani, 1992, Baillieres 
Clin.Haematol.).  
Gene therapy offers the potential of a cure through continuous endogenous production of 
human FVIII following a single administration of vector. Haemophilia A is well suited for 
this approach because its clinical manifestations are attributable to the lack of a single gene 
product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. Tightly 
regulated control of gene expression is not essential and a modest increase in the level of 
FVIII (a plasma level of 2ng/ml protein leads to a 1% expression) can ameliorate the severe 
phenotype (Srivastava, 2012, Haemophilia); thus the therapeutic goal for gene therapy is a 
modest increase in hFVIII. Finally, the consequences of gene transfer can be assessed using 
simple quantitative rather than qualitative endpoints that can be easily assayed in most 
clinical laboratories. 
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 

 
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7.1 
Nonclinical Studies 
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 
nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints. 
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in mice given matched IU levels of Refacto®.   
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.   
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed. 

 
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The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 
the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence matching that of the 
protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Paneda, 2009, Hum.Gene Ther.). 
Despite distribution to non-liver organs, no expression of Factor IX was detected in these 
tissues.  Additionally, distribution to the testis was observed in another study in monkeys 
given an AAV5-codon-optimized human porphobilinogen deaminase; however, vector 
genomes in the semen were only transiently observed within one week but not thereafter 
(Paneda, 2013, Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents > 30-fold safety factor from 
the no observed adverse effect level (NOAEL) in enabling nonclinical studies.  
7.2 
Previous Clinical Studies 
This is the first clinical study for BMN 270. 
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Eng.J.Med.; 
Nathwani, 2014, N.Eng.J.Med.). The large size of the FVIII cDNA was shortened and a 

 
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preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013, 
Blood). 
AAV serotype 5 is also used in clinical trials and has shown good safety in a recent phase 1 
study for treatment of Acute Intermittent Porphyria (D’Avola. 2014, J Hepatology).  
AAV using other serotypes have been used in 105 clinical studies to date and no safety issue 
specific to the vector was ever reported.   
7.3 
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin. Haematol).  It is caused by deficiency in 
the activity of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic 
coagulation cascade. This disorder can be either inherited, due to a new mutation or an 
acquired immunologic process, leading to insufficient quantities of FVIII or a dysfunctional 
FVIII, but all are characterized by a defective coagulation process. . The clinical phenotype 
of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease 
comprises 1-5% of wild type activity and the mild form is 5-40% activity. The clinical 
manifestations of severe HA remain frequent spontaneous bleeding episodes, predominantly 
in joints and soft tissues, with a substantially increased risk of death from haemorrhage when 
the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life 
for rhFVIII (under 24 hours for most approved products) necessitates frequent infusions, and 
although a major advance in the treatment of HA, it remains common for severe HA patients 
to continue to have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with 
prophylaxis up to 30 to 50 for on demand treatment) (Nagel, 2011, Haemophilia).  The 
consequence of multiple bleeding events is the development of an underlying pathology that 
contributes to debilitating multiple-joint arthropathy and substantially increased risk of death 
(Nagel, 2011, Haemophilia).  Chemical modification (e.g. direct conjugation of polyethylene 
glycol (PEG) polymers) and bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve 
half-life by approximately 50%, and thus, show promise in reduced dosing and maintaining 
activity levels above 1% trough (Stonebraker, 2010, Haemophilia), (Mahlangu, 2014, Blood). 
However, these longer acting FVIIIs remain dependent on multiple infusions to maintain 
critical levels of FVIII activity in severe HA patients. There is therefore a strong unmet need 

 
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for a fully preventive treatment of HA to give patients a FVIII level compatible with a 
normal and haemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Pipe, 2010, Blood). They 
have an excellent and well defined safety profile, and can direct long term transgene 
expression with tropism for specific tissues such as the liver (Nathwani, 2005, Curr.Hematol 
Rep.) for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical trial 
for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from 
severe to moderate or mild is achievable following a single peripheral vein administration of 
AAV-8 vector(Nathwani, 2011, NEJM). Several participants in this trial have been able to 
discontinue factor prophylaxis without suffering spontaneous haemorrhages, even when they 
undertook activities that previously resulted in bleeding. Thus, gene therapy treatment has 
resulted in a substantial improvement in their quality of life (Nathwani, 2011, Mol.Ther.). 
(Bainbridge, 2008, NEJM; Maguire, 2009, Lancet; Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII 
under the control of a liver-selective promoter (Figure 7.3.1).  

 
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Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp 
 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of hFVIII in patients with 
severe HA. 
7.4 
Summary of Overall Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based 
on prior human studies with peripheral injections of AAV vectors, there is no known safety 
risk of AAV gene therapy. However, a mild asymptomatic transaminitis was observed at 
week 8-10 after administration with an AAV8-FIX, providing the rationale for the following 
surveillance plan (Manno, 2006, Nature Med.).  Each patient will have comprehensive 
surveillance plan monitoring LFTs once a week from dose to completion of Week 6, 3 times 
per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is 
found to be greater than 1.5x baseline during these periods, then LFTs will be monitored 
three times per week or until the ALT returns to baseline.  LFTs will be monitored every 
other month for the first year and then every three months for up to 5 years post-dose in the 
safety extension.   
Dose selection:  The benefit of this study can only be enhanced by selecting a starting dose 
that potentially could contribute to a better opportunity of observing a therapeutic effect, and 
therefore, reducing the possibility of a sub-therapeutic effect. With this consideration in 
mind, the starting dose 6E12 vg/kg was selected using overall data from the pre-clinical 
studies conducted in mice (normal and disease model, Rag2 -/- x FVIII -/-) and monkey.  
A detectable pharmacological response based on activity was observed at 6E12 vg/kg. 

 
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A 10-fold safety margin based upon the NOAEL was observed in the GLP 13-week study in 
normal mouse at the highest dose administered.  A 30-fold safety margin in an 8-week dose 
response study in disease model mice based on histology was observed at the highest dose 
administered.  No BMN 270-related changes in clinical observations or chemistry was 
observed in the monkey at doses up to 6E13 vg/kg, a 10-fold safety margin after 8-weeks.  
Overall, no BMN 270-related findings, except expected formation of anti-AAV5 antibodies, 
were observed at the highest administered doses of 6E13, 2E14 and vg/kg in the normal 
mouse, disease model mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to patients but may potentially 
benefit the patient therapeutically. 

 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are: 
• To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII 
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270 
dose. 
The secondary objectives of the study are: 
• To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of AAV5-hFVIII-SQ 
• To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study 
• To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study 
 
 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled sequentially into one of up to three cohorts according to 
dose level:  
1. 6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous 
dose (iv) 
2. 2E13 vg per kilogram, iv 
3. 6E13 vg per kilogram, iv 
Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose 
escalation may occur after a single patient has been safely dosed if the resulting FVIII 
activity at Week 3 is < 5 IU/dL. Three weeks is expected to be the time the expression will be 
close to the maximum.  This escalation paradigm is intended to minimize the patient numbers 
exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys.  The starting dose has a significant safety margin (10-fold) 
from no observed adverse effect level (NOAEL) in non-human primates.   
Approximately three weeks after an injection, the decision to escalate to the next dose level 
will be made based on the review of safety parameters and FVIII activity by the Sponsor and 
a panel of investigators participating in the study.  
If the FVIII activity is ≥5 IU/dL, then the other patients of the dose group will be enrolled 
without waiting for 3 weeks between patients. 
 

 
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme 
 
Patient 1 will be dosed by intravenous perfusion with 6E12 vector genomes [vg] per 
kilogram of body weight. If the activity level does not reach ≥5 IU/dL (expressed as % in 
Figure 9.1.1) at 21 days, then a higher dose (2E13 vg per kilogram) will be used for the next 
patient.  
If the activity level does not reach ≥5 IU/dL after Patient 2, then the highest dose 
(6E13 vg per kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and if no safety issue is found, then up to 
four patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no 
further dose escalation will take place, but additional patients will then be dosed at this dose 
level for a total of 6 patients per dose. 
Because patients develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a treatment option and these patients have effectively a single opportunity for 
therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dose.  Any safety signal 
will trigger a review of the data and possible additional analysis including mononuclear 
collection.  Additionally, if any of the events listed in Section 9.3.3.1 occur, enrollment into 
the trial will be halted to complete an extensive safety analysis.  Notification of the study halt 
will be sent by the Sponsor to the participating sites via telephone and email immediately 
after becoming aware of a safety concern. This will ensure no additional subjects are dosed 
until the signal has been completely evaluated.  If, following safety review by the Data 
Review Board (DRB) and the Sponsor, it is deemed appropriate to restart dosing, a request to 
restart dosing with pertinent data will be submitted to the health authority. 

 
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A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 for Safety Follow-up. 

 
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Table 9.1.1: Schedule of Events – Screening and Infusion 
Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion Visit 
(Day 1) 
Screening (Day 
-28 to  
Day -1) 
Baseline (Day -7 to 
Day -1)h 
Informed consent 
X 
 
 
Medical History 
X 
 
 
Physical Exama 
X 
X 
X 
Vital Signs 
X 
 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
Documentation of bleeding episodes and FVIII usage (by either patient or clinical information) 
X 
X 
 
Electrocardiogram 
X 
 
 
Chest X-ray 
X 
 
 
Liver Ultrasound 
X 
 
 
hFVIII Assaysb 
X 
X 
 
AAV5 Assaysc 
X 
 
X 
Screen for Hepatitis B, Hepatitis C, HIVd 
X 
 
 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPe 
X 
X 
 
Mononuclear cell collection for CTL baseline 
 
X 
 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
 
X 
 
Biomarker testingf 
X 
 
 
Exploratory biomarker assessmentsg 
 
X 
 
Quality of Life (QoL) assessment 
 
X 
 
BMN 270 Infusion 
 
 
X 
a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height and 
weight will be recorded at Screening only. 

 
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b Includes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay 
with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).   
c Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction 
inhibition, in vitro transduction inhibition and AAV5 total antibody assays).  The assessment on the day of the infusion visit must be performed before the BMN 270 
infusion is given. 
d Patients with documented negative results within the last 30 days do not need to be retested. 
e Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
f Includes HLA typing, FVIII mutation status, TNFα and IL10a single nucleotide polymorphisms. 
g Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 
h Should the screening visit occur within 7 days of the drug infusion, physical examination, vital signs, blood chemistry, haematology, urine tests, coagulation screen, and 
CRP do not need to be repeated at Baseline. 
 
 
 

 
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up 
Assessment 
Follow-Up After BMN 270 Administration - Weeks* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPb   X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII activity assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII antibody titer 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker assessmentse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QoL assessment 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
AAV5 antibody titer 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Testing for reactivation of hepatitis B and hepatitis C 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Mononuclear cell collection  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
* Visit windows are ±48 hours 
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included.  Each patient will have comprehensive surveillance plan monitoring LFTs once a week from dose to 
completion of Week 6, 3 times per week (every other day excluding weekends) from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is found 
to be greater than 1.5x baseline during these periods, then LFTs will be monitored three times per week or until the ALT returns to baseline. 
c Includes hFVIII activity level (APTT and FXa chromogenic assay), hFVIII activity confirmation (frozen plasma), Bethesda assay (with Nijmegen modification) for 
hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA). 
d Collection to occur on Day 1, 3, 7 following BMN 270 infusion, and then weekly until 3 consecutive negative results are obtained. 
e Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 

 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up 
Assessment 
Year 1 - Weeks* 
Years 
2-5* 
ETV (early 
termination 
visit) 
20 
28 
36 
44 
52 
Q3M 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPb 
X 
X 
X 
X 
X 
X 
X 
hFVIII activity assaysc 
X 
X 
X 
X 
X 
X 
X 
AAV5 antibody titer 
X 
X 
X 
X 
X 
X 
X 
hFVIII antibody titer 
X 
X 
X 
X 
X 
X 
X 
Mononuclear Cell Collection (for determination of FVIII and Capsid specific CTL activity) 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
QoL assessment 
 
X 
 
 
X 
Xe 
X 
* Visit windows are ±72 hours 
a Complete physical examination should be performed at Weeks 52 and every 52 weeks thereafter; brief physical exam may be performed at other study visits.  Refer to 
Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), hFVIII activity confirmation (frozen plasma), Bethesda assay (with Nijmegen 
modification) for hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA). 
d Sample testing during Safety Follow-Up is not required if 3 consecutive samples are cleared during the Post-Infusion Follow-Up period. 
e QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 6 months) starting with the Week 78 visit (ie, 26 weeks after the 
Week 52 visit at the end of Year 1 of the Safety Follow-up period). 

 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Three doses of BMN 270 will be evaluated and the dose 
escalation decision tree is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and a panel of investigators participating in the 
study.  
There will be no control group. Parameters for each patient will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy).  
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3 
Selection of Study Population 
Up to 12 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation. A total of 6 patients may be enrolled 
at a single dose level. 
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe Haemophilia A as evidenced 
by their medical history.  Patients will be considered as severe if their FVIII baseline 
level is  1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitates for a minimum of 
150 exposure days (EDs) 
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 
12 months using a modified Nijmegen Bethesda assay higher than 0.6 Bethesda Unit 
(BU) 

 
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6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment. 
9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition and AAV5 total antibodies 
2. Any evidence of active infection or any immunosuppressive disorder.   
3. Patients that are HIV positive are excluded. 
4. Significant liver dysfunction as defined by abnormal elevation of ALT (alanine 
transaminase) to 3 times the upper limit of normal, bilirubin, alkaline phosphatase, or 
an INR (international normalized ratio) of 1.4. Potential participants who have had a 
liver biopsy in the past 3 years are excluded if they had significant fibrosis of 3 or 4 
as rated on a scale of 0-4 
5. Evidence of any bleeding disorder not related to Haemophilia A 
6. Platelet count of < 100 x 109/L 
7. Creatinine ≥ 1.5 mg/dL 
8. Liver cirrhosis of any etiology as assessed by liver ultrasound  
9. Hepatitis B if surface antigen is positive 
10. Hepatitis C if RNA is positive 
11. Treatment with any IP within 30 days prior to the screening visit 
12. Any disease or condition at the physician’s discretion that would prevent the patient 
from fully complying with the requirements of the study.  The physician may exclude 
patients unwilling or unable to agree on not using alcohol for the 16-week period 
following the viral infusion. 
13. Receipt of any vector or gene transfer agent 
9.3.3 Removal of Patients from Treatment or Assessment 
Patients may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any patient who requests to be withdrawn. 
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 

 
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BioMarin must be notified of all patient withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or BioMarin may withdraw a patient from the study 
include, but are not limited to, the following: 
• Patient requires medication or medical procedure prohibited by the protocol 
• Patient does not adhere to study requirements specified in the protocol 
• Patient was erroneously admitted into the study or does not meet entry criteria 
• Patient is lost to follow-up 
If a patient fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the patient cannot be reached by telephone, a certified letter should 
be sent to the patient requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each patient, before enrollment into the study, 
that for evaluation of study results, the patient’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each patient. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the patient and the patient will 
be removed from the study. 
9.3.3.1 
Study Safety Evaluation Criteria 
If any of the following events occur (except the persistence of AAV5) in a patient in the 
study who has received BMN 270 infusion, enrollment into the trial will be put on halt to 
complete an extensive safety analysis per Section 9.1.   
• 
A 5-fold increase in ALT after BMN 270 administration 
• The occurrence of other drug-related Grade III-IV toxicity, including liver failure and 
clinical hepatitis 
• Drug-related Grade II toxicity that persists for at least 7 days 
• The occurrence of neutralizing antibodies to hFVIII following BMN 270 infusion 

 
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• The persistent detection of the AAV vector genome in the semen of a participant 
more than 26 weeks after BMN 270 infusion, as discussed in Section 9.7.8.5  
• The occurrence of a malignancy at any point after BMN 270 infusion that is assessed 
as possibly, probably, or definitely related to the study agent 
• Any unexplained serious adverse event ≥ grade 4 assessed as at least possibly related 
to study drug 
9.3.4 Patient Identification and Replacement of Patients 
Each patient will be assigned a unique patient identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Patients who withdraw from the study after Week 16 will not be replaced. 
9.3.5 Duration of Patient Participation 
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks. 
9.4 
Treatments 
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
9.4.2 Identity of Investigational Product 
9.4.2.1 
Product Characteristics and Labeling 
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 

 
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stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4 Directions for Administration 
After a physical exam performed by the PI or designee, participants will be admitted on the 
day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral vein 
(e.g. the median cubital vein) and flushed with saline. FVIII protein concentrate will not be 
given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
will be used to infuse through an in-line, low protein binding 0.22 micron filter. BMN 270 
will be infused through the catheter using an appropriate infusion pump while monitoring 
the vital signs (pulse, blood pressure, respiration rate and temperature) at 15 minute 
(± 5 minutes) intervals. The anticipated maximum interval from initiation of thawing of 
BMN 270 to completion of the infusion is 4 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard 
protocol for infusing FVIII concentrates. Patients will remain hospitalized for 24 hours to 
observe for any immediate toxicity of the procedure. After 24 hours of hospitalization, 
participants will be discharged unless toxicity has been observed in which case 
hospitalization may be extended or transfer to an outpatient facility may occur based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
9.4.5 Method of Assigning Patients to Treatment Groups 
Patients who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study patient. Upon their enrollment into the study, patients will be assigned a unique patient 
number and dose level by the Sponsor. 
Patients are enrolled serially and their dose is defined in Section 9.4.6.2 below. Escalation is 
based on FVIII activity 3 weeks after injection. Patients may receive the next higher dose if 
the previous patient does not meet the activity criteria, or the same dose if the previous 

 
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patient meets the activity criteria. Up to 6 patients can have the same dose, for a total of 
12 patients in this study.  
9.4.6 Selection of Doses Used in the Study 
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in non-human primates. The dose escalation is half-logs based.    
9.4.6.1 
Selection of Timing of Dose for Each Patient 
A minimum of three weeks are required between patients, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next patient will be made as described below.  
9.4.6.2 
Selection of Dose for Each Patient 
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus decreasing the risk of immune response), and a new evaluation of the 
titer (PCR performed after hairpin removal). 
Approximately three weeks after an injection, the decision to escalate to the next dose level 
will be made based on the review of safety parameters and FVIII activity by the Sponsor and 
a panel of investigators participating in the study.  
Patient 1 will be dosed with 6E12 vector genomes [vg] per kilogram of body weight. If the 
activity level does not reach ≥5 IU/dL at 21 days, then a higher dose (2E13 vg per kilogram) 
will be used for the next patient.  
If the activity level does not reach ≥5 IU/dL after Patient 2, then the highest dose 
(6E13 vg per kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and if no safety issue is found, then up to 
four patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no 
further dose escalation will take place, but additional patients will then be dosed at this dose 
level for a total of 6 patients per dose. 
Refer to Figure 9.1.1 for a visual representation of the study design. 
9.4.7 Blinding 
This is an open-label study. 

 
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9.4.8 Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a patient for 30 days before 
Screening will be recorded on the designated CRF. The Investigator may prescribe additional 
medications during the study, as long as the prescribed medication is not prohibited by the 
protocol. In the event of an emergency, any needed medications may be prescribed without 
prior approval, but the medical monitor must be notified of the use of any contraindicated 
medications immediately thereafter. Any concomitant medications added or discontinued 
during the study should be recorded on the CRF. 
The following medications are prohibited starting 30 days before Screening: 
• Live vaccines 
• Immunosuppressive agents 
9.4.8.1 
Concomitant Haemophilia Treatments 
Patients on “on demand” therapy for FVIII will continue their treatment at will. Patients on 
prophylactic FVIII therapy will discontinue their treatment starting the day of infusion and 
switch to an “on demand” schedule. FVIII can always be taken as needed by the patient, who 
will carefully record his treatment and bleeding episodes in his diary. 
9.4.8.2 
Glucocorticoid Treatment of Elevated Hepatic Transaminases 
During the Post-Infusion Follow-up Period, each patient will have comprehensive 
surveillance plan monitoring LFTs once a week from dose to completion of Week 6, 3 times 
per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is 
found to be greater than 1.5x baseline during these periods, then LFTs will be monitored 
three times per week or until the ALT returns to baseline.  
Reports of abnormal LFTs (defined as 1.5x the patient’s baseline level) should be made to 
BioMarin within 24 hours of the lab value being available.  If the LFTs are abnormal, 
treatment with prednisolone initiated at a dose of 60 mg per day and then gradually tapered 
(60 mg daily for the first week, then 40 mg the second week, then 30 mg the third week, then 
20 mg the fourth week, then stop) will be started immediately. 
9.4.9 Treatment Compliance 
Study drug will be administered to patients at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided 
for the study.  Sites will be instructed to return all used and unused study drug containers. 

 
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9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, patients to whom IP is dispensed (patient-by-patient dose 
specific accounting), and IP lost or accidentally or deliberately destroyed. The Investigator or 
designee must retain all unused or expired study supplies until the study monitor (on-site 
CRA) has confirmed the accountability data. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a Study Drug Return Form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study. 
9.7 
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8. 
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post 
BMN 270 administration.  
9.7.1 Safety and Efficacy Measurements Assessed 
The Schedule of Events (Table 9.1.1) describes the timing of required evaluations. 

 
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9.7.2 Primary Efficacy Variables 
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to stable expression of FVIII at 5 IU/dL, 
i.e., a mild severity. This is associated in natural history studies with clinically superior long 
term outcomes (Nathwani, 1992, Baillieres Clin.Haematol.). 
To measure the primary efficacy variable, the following assays will be used: 
• FVIII activity (chromogenic FXa assay) 
• FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time) 
The FVIII activity level and the number of patients with FVIII activity ≥ 5 IU/dL will be 
summarized. 
Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3.  Details on 
performing the assays are included in the Laboratory Manual. 
9.7.3 Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Patients will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the patient’s diary or 
other patient records. 
Assessment of viral shedding at one week after BMN 270 infusion will also be considered an 
efficacy variable.  
9.7.4 Immunogenicity 
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
6-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to an immunogenicity assessment to determine anti-FVIII and 
capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be performed on 
collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3. 

 
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9.7.5 Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage APTT and/or chromogenic FXa assay (activity).  Individual antigen and activity 
plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity measurements 
will be used to determine PD parameters. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), 
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology. 
Sample collection times are indicated in Table 9.1.2 and Table 9.1.3. 
9.7.6 Exploratory Biomarker Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1 and 
Table 9.1.2 to evaluate biochemical, molecular, cellular, and genetic/genomic aspects 
relevant to Haemophilia A disease.  The genetic/genomic testing on these exploratory 
samples is optional. 
9.7.7 Quality of Life Assessment 
A patient-reported outcome (PRO) questionnaire will be used to assess subject quality of life 
(QoL) during the study.  Assessments will occur at the time points listed in the Schedules of 
Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual. 
9.7.8 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
9.7.8.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the patient signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1.   

 
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9.7.8.2 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1. The scheduled clinical laboratory tests are listed in Table 9.7.8.2.1. Refer to the 
Study Reference Manual for instructions on obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
All abnormal clinical laboratory results should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF. 

 
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Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Haematology 
Urine Tests 
Other 
Albumin  
Haemoglobin  
Appearance 
CRP 
Alkaline phosphatase  Haematocrit  
Color 
 
ALT (SGPT) 
WBC count 
pH 
Coagulation Screen 
including: 
AST (SGOT) 
RBC count 
Specific gravity 
APTT 
Direct bilirubin 
Platelet count 
Ketones 
PT/INR 
Total bilirubin 
Differential cell count  Protein  
TT 
BUN 
 
Glucose  
 
Calcium 
 
Bilirubin 
 
Chloride 
 
Nitrite 
 
Total cholesterol 
 
Urobilinogen 
 
CO2 
 
Haemoglobin 
 
Creatinine 
 
 
 
Glucose 
 
 
 
GGT 
 
 
 
LDH 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Total protein  
 
 
 
Sodium  
 
 
 
Uric acid  
 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon 
dioxide; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; 
SGPT, serum glutamic-pyruvic transaminase; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating 
hormone; WBC, white blood cell; TT, thrombin time; INR, international normalized ratio. 
 
9.7.8.3 
Liver function and Hepatitis Testing 
Patients will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening. If medical records showing no evidence of Hepatitis B or Hepatitis C infection 
from the previous 30 days are available, then the Screening tests do not need to be done.   

 
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Evidence of ongoing infection (positive surface antigen for hepatitis B or positive RNA 
testing for hepatitis C) will be an exclusion criteria. If these parameters are negative and 
therefore no active infection is detected, then the patients may be included if they were 
vaccinated (for hepatitis B) or cleared the infection (for hepatitis C) and their liver function is 
acceptable.  
A liver ultrasound and liver function testing at Screening will identify any significant hepatic 
dysfunction, which is defined as: 
• More than 3x the normal ALT level 
• More than 3x the normal bilirubin level 
• Alkaline phosphatase above the normal cut off. 
• INR over 1.4.  
• Thrombocytopoenia under 100 x 109/L 
9.7.8.4 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE. 
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored hourly for 6 hours and then every 2 hours for 6 hours 
and then at 4 hour intervals.  
A complete physical examination is necessary during Screening/Baseline; thereafter, brief 
physical examinations may be performed at the discretion of the investigator based on the 
patient’s clinical condition. Particular attention should be given to signs of bleeding, as well 
as assessing possible hemarthroses. 
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems (level of consciousness, speech, language, cranial 
nerves, motor strength, motor tone, abnormal movements, reflexes, upper extremity 
sensation, lower extremity sensations, gait, Romberg, nystagmus, and coordination). 
A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 

 
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Weight and height will be recorded at Screening only. 
9.7.8.5 
Viral Shedding 
Viral shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Eng.J.Med (Supplemental Appendix); Manno, 2006, Nature Med. 
(Supplemental Appendix); Schenk-Braat, 2007, J Gene Med; Croteau, 2004, Ann Occup 
Hyg). It has been constantly shown that the vector was not detectable anymore at 40 days, 
with its persistence in semen for 16 weeks in the seminal fluid but not in motile sperm 
(Manno, 2006, Nature Med.).  In addition, it has always involved only an extremely small 
fraction of the injected dose.  
Viral shedding will also be extensively studied in the present clinical trial, every week up to 
16 weeks, then every 4 weeks to one year, then every three months.  During the Post-Infusion 
Follow-Up period, patients will undergo testing of various bodily fluids to look for evidence 
of viral shedding for possible viral transmission.  Bodily fluids will be tested by PCR at the 
time points indicated in Table 9.1.2 and Table 9.1.3.  Fluids tested will include: 
• Blood 
• Saliva 
• Semen 
• Urine 
• Stool 
Details for sample collection and storage are provided in the Laboratory Manual. 

 
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10 
REPORTING ADVERSE EVENTS 
10.1     Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a patient administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
• AEs not previously observed in the patient that emerge during the course of the study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only 
because the patient is a haemophiliac) should not be recorded as AEs but will instead be 
captured in patient diaries.  Bleeding events that occur where a normal 
(ie, non-haemophiliac) patient would bleed, such as bleeding as a result of trauma, should be 
recorded as adverse events.  All bleeding events which meet criteria for being serious should 
be reported as serious adverse events (SAEs) whether or not they are bleeding events that are 
normal sequelae of haemophilia. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
10.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening  

 
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Note: Life-threatening refers to an event that places the patient at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires or prolongs inpatient hospitalization.  Hospitalization for less than 24 hours 
will not be considered to be an SAE. Hospitalization solely for the purpose of 
insertion of an in-dwelling IV catheter (such as a Port-a-Cath or other brand) for 
administration of study drug will not be considered an SAE. 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect in the child or fetus of a patient exposed to IP 
prior to conception or during pregnancy 
• 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the patient or require intervention to prevent one of  the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as non-
serious AEs. 
10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• Elevation of liver enzymes triggering a corticosteroid treatment 
10.3 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.3.1 Adverse Event Reporting Period 
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.2.  
10.3.2 Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs and EOSI, at each patient contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the patient’s medical record and on the AE Case Report 
Form (eCRF). 

 
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10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the patient or qualified designee will assess AEs 
for severity, relationship to study drug, and seriousness (refer to Section 10.2 for SAE 
definitions).  These assessments should be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.3.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.3.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1. 
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 

 
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Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden. 
 
10.3.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1. 
Table 10.3.3.3.1:  Causality Attribution Guidance 
Relationship 
Description 
Not Related 
• 
Exposure to the IP has not occurred 
OR 
• 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
OR 
• 
The AE is considered likely to be related to an etiology other than the use 
of the IP; that is, there are no facts, evidence, or arguments to suggest a 
causal relationship to the IP. 
Related 
• 
The administration of the IP and the occurrence of the AE are reasonably 
related in time 
AND 
• 
The AE could possibly be explained  by factors or causes other than 
exposure to the IP 
                                      
 
OR 
• 
The administration of IP and the occurrence of the AE are reasonably 
related in time  
AND 
• 
The AE is more likely explained by exposure to the IP than by other 
factors or causes. 
 

 
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Factors suggestive of a causal relationship could include (but are not limited to): 
• Plausible temporal relationship 
• Absence of alternative explanations 
• Rarity of event in a given patient or disease state 
• Absence of event prior to study drug exposure 
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.4.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE eCRF, replacing the original entries where 
appropriate. 

 
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10.4.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points.  Such an event should be recorded only once on the AE eCRF unless 
its severity increases or decreases (in which case it should be recorded again on the AE 
eCRF). 
A recurrent AE is one that occurs and resolves between patient evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.4.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the AE eCRF. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as AE if any of the following conditions is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
• The laboratory abnormality persists upon repeat confirmatory testing.  
• The abnormality suggests a disease and/or organ toxicity 

 
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• The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed. 
10.4.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.4.1.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.4.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 

 
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• Perform a protocol-mandated efficacy measurement 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
• Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9 
Pregnancy 
Although not an AE per se, pregnancy in the partner of a patient taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by faxing the Pregnancy Form in the study reference materials to BPV.  
The Investigator must make every effort to follow the patient through resolution of the 
pregnancy (delivery or termination) and to report the resolution on the Pregnancy Follow-up 
Form in the study reference materials. In the event of pregnancy in the partner of a study 
patient, the Investigator should make every reasonable attempt to obtain the woman’s 
consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5 
Reporting Requirements 
10.5.1 Expedited Reporting Requirements 
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF  and submitting  to BioMarin Pharmacovigilance (BPV) 

 
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within 24 hours of the site becoming aware of the event.  Investigators should not wait to 
collect information that fully documents the event before notifying BPV of an SAE.  
BioMarin may be required to report certain SAEs to regulatory authorities within 7 calendar 
days of being notified about the event; therefore, it is important that Investigators submit any 
information requested by BioMarin as soon as it becomes available. 
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the 
relevant competent authorities, ethics committees and investigators in accordance with the 
requirements identified in the Clinical Trials Regulations. 
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF. 
The reporting period for SAEs begins after informed consent is obtained and the first 
administration of study drug is given.  It continues for approximately 5 years or until study 
discontinuation/termination, whichever is longer.  
10.5.2 Ethics Committee Reporting Requirements 
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required. 
10.6 
Follow-up of Patients after Adverse Events 
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the patient is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the patient’s medical record to facilitate source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.7 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each patient to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the patient’s personal 
physician(s) believes might be related to prior study treatment. 

 
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The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a patient has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that participated in this 
study.  
10.8 
Urgent Safety Measures 
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect patients against any immediate hazards 
that may affect the safety of patients, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• 
Immediate need to revise the IP administration (eg, modified dose amount or frequency 
not defined in protocol) 
• 
Lack of study scientific value, or detrimental study conduct or management 
• 
Discovery that the quality or safety of the IP does not meet established safety 
requirements 
 
 

 
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10.9 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
 
Address: 
105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
E-mail: 
 
 
PI
PI
PI
PI
PI

 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic FXa assay and the APTT assays are both validated and utilize CE marked 
reagents.  The exploratory FVIII activity assay will be used for exploratory purposes only. 
 

 
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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed. 
12.2 
Screening Visit 
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place a within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, haematology, urine tests, coagulation screen, and CRP do not 
need to be repeated at Baseline.  
The following procedures will be performed during the Screening Period: 
• Full medical history, including haemophilia A history, Hepatitis B, Hepatitis C, and 
HIV. Patients with documented negative results within the last 30 days do not need to 
be retested. 
• Complete Physical Exam (including height and weight) 
• Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature)  
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either patient or clinical 
information) 
• Electrocardiogram 
• Chest X-ray 
• Liver Ultrasound 
• Samples for hFVIII Assays 
o Baseline hFVIII activity – chromogenic FXa (plasma) 
o Baseline hFVIII activity level – one-stage APTT assay 
o hFVIII coagulation activity exploratory assay 
o hFVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay 
o hFVIII antigen (ELISA) 
• Blood sample for AAV5 Assays 

 
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o AAV5 antibody titer 
o AAV5 transduction inhibition assays 
• Screen for Hepatitis B, Hepatitis C, and HIV if required (Patients with documented 
negative results within the last 30 days do not need to be retested) 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• Blood samples for Biomarker testing (HLA typing, FVIII mutation status, TNFα and 
IL10a single nucleotide polymorphisms) 
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either patient or clinical 
information) 
• Samples for FVIII Assays 
o FVIII activity – chromogenic FXa (plasma)  
o FVIII activity level –APTT One stage assay  
o FVIII coagulation activity exploratory assay 
o FVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o FVIII antibody assay 
o FVIII antigen (ELISA) 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• Mononuclear cell collection for CTL baseline 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
• Exploratory biomarker assessments 
• QoL assessment 

 
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12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each patient.  Patients will be hospitalized for 24 hours 
for the BMN 270 Infusion Visit.  The following procedures will be performed during the 
BMN 270 Infusion Visit: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
o AAV5 antibody titer 
o AAV5 transduction inhibition assays 
• BMN 270 Infusion 
• Vital Signs 
o Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the patient’s 
hospitalization. 
12.5 
BMN 270 Infusion Follow-Up Visits 
After BMN 270 has been infused, patients will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Every Visit 
Every week (Weeks 1 through 16), the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
o Each patient will have comprehensive surveillance plan monitoring LFTs 
once a week from dose to completion of Week 6, 3 times per week (every 
other day excluding weekends) from Weeks 7 to 12, and once a week from 
Weeks 13 to 16.  If a patient’s ALT is found to be greater than 1.5x 
baseline during these periods, then LFTs will be monitored three times per 
week or until the ALT returns to baseline. 

 
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• Samples for FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• FVIII antibody titer 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Collection to occur on Day 1, 3, 7 following BMN 270 infusion, and then 
weekly until 3 consecutive negative results are obtained 
• Exploratory biomarker assessments 
12.5.2 Every 4 Weeks 
Every 4 weeks (Weeks 4, 8, 12, and 16), the following procedure will be performed: 
• Mononuclear cell collection 
12.5.3 Weeks 1, 3, and 6 
At Weeks 1, 3, and 6, the following procedure will be performed: 
• Test for Hepatitis B and Hepatitis C reactivation 
12.5.4 Weeks 1, 8, and 16 
At Weeks 1, 8, and 16, the following procedure will be performed: 
• AAV5 antibody titer 
12.5.5 Weeks 1, 2, 3, 4, and 16 
At Weeks 1, 2, 3, 4, and 16, the following procedure will be performed: 
• QoL assessment 
12.6 
Safety Follow-Up – Year 1 
After the 16 weekly infusion follow-up visits are complete, subjects will return to the study 
site at Weeks 20, 28, 36, 44, and 52 (± 48 hours), when the following procedures will be 
completed: 

 
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12.6.1 Every Visit 
At Weeks 20, 28, 36, 44, and 52, the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if 3 consecutive 
samples are clear during the Post-Infusion Follow-Up period. 
12.6.2 Weeks 28 and 52 
At Weeks 28 and 52, the following procedure will be performed: 
• QoL assessment 
12.7 
 Safety Follow-Up – Years 2-5 
During Years 2-5 of Safety Follow-up, patients will be assessed every 3 months (± 72 hours). 
At these times, the following procedures will be completed: 
12.7.1 Every Visit 
Every 3 months (± 72 hours), the following procedures will be performed: 
• Physical exam 

 
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o Complete Physical Exam will be performed every 52 weeks; Brief 
Physical Exams may be performed at other visits. 
• Assessment of Adverse Events and Concomitant Medications 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (FXa chromogenic assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if 3 consecutive 
samples are clear during the Post-Infusion Follow-Up period. 
• Vital Signs 
12.7.2 Every Other Visit (Every 6 Months) 
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the 
end of Year 1 of the Safety Follow-up period), the following procedure will be performed: 
• QOL assessment 
12.8 
Early Termination Visit 
The Early Termination visit will occur on the date the patient withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a patient leaves the study prior to the Week 270 visit, the patient will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 

 
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• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing at the ETV is not required if 3 consecutive samples are 
clear during the Post-Infusion Follow-Up period. 
• Vital Signs 
• QOL assessment 
12.9 
End of Study 
The study will end after the last patient completes the last Safety Follow-Up visit 
(Week 270). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study patients may be 
compromised. 
 

 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
The designated clinical data management group will enter or transfer CRF data into a study 
database. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all patients having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16). 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Missing data will not be imputed.  
14.2 
Primary and Secondary Efficacy Analysis 
The patients will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of patients, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined. 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay 
between 1 to 16 weeks following study treatment.  hFVIII activity will be assessed weekly 
during the study period.  We can only assess the true steady state of hFVIII protein produced 
from BMN 270 after a minimum of 72 hours has elapsed since the last infusion of FVIII 
protein concentrates. 
14.3 
Immunogenicity 
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons 
across doses. 

 
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14.4 
Pharmacodynamic Analyses 
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage APTT and/or chromogenic FXa assay (activity level), will be used for plasma 
profiles; FVIII activity will be used to determine PD parameters.  Traditional PK analysis is 
not applicable. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics.  
14.5 
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-patient listing will 
be provided for those patients who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of patients who report hepatitis will be presented. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided.  
Detailed statistical methods will be provided in the SAP. 
14.6 
Determination of Sample Size 
No formal sample size calculations based on statistical power were performed. 
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 12 patients may be dosed in the study; the actual number of 
patients will depend on the criteria for dose escalation. A total of 6 patients may be enrolled 
at a single dose level. 

 
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14.7 
Analysis Populations 
The Safety analysis population is defined as all enrolled patients who receive any study drug. 
The analysis of safety data will be performed on Safety Set. 
The Full Analysis Set (FAS) is defined as all enrolled patients who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis. 
14.8 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a patient’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on patient risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to patients, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active patients must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 

 
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15 
DATA MONITORING COMMITTEE 
There will be no formal DMC for this study, however a safety and efficacy evaluation board 
(the Data Review Board [DRB]) composed of the investigator representatives and the 
Sponsor will be established. 
The DRB will review safety and efficacy on an ongoing basis. The DRB will meet prior to 
dose escalation or dose expansion to assess available patient safety and efficacy data and 
make recommendations with regards to the conduct of study. Should a safety signal arise, 
including one which may warrant a halt of study enrollment, the DRB will promptly convene 
for further assessment of patient safety. Notification of all DRB meetings and meeting 
outcomes will be sent to participating sites. 
 
 

 
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16 
COMPENSATION, INSURANCE AND INDEMNITY 
There will be no charge to study patients to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study patient’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected. 
The Investigator should contact BioMarin immediately upon notification that a study patient 
has been injured by the IP or by procedures performed as part of the study. Any patient who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The patient should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the patient’s health insurance company or other third party 
payer for the cost of this medical treatment. If the patient has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law. 

 
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17 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each patient. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy. 
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and patient records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Patients must also allow access to 
their medical records, and patients will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
patient records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification. 
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a patient’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 

 
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completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 

 
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18 
STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study patients, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 

 
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19 
RETENTION OF RECORDS 
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, patient charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain patient identifiers for at least 15 years after the completion or discontinuation of 
the study. Patient files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
patient files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained. 

 
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20 
USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  

 
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21 
REFERENCES 
Bainbridge JW, Smith AJ, Barker SS et al. Effect of gene therapy on visual function in Leber's congenital 
amaurosis. N.Engl.J.Med. 2008;358:2231-2239. 
Berntorp E, Halimeh S, Gringeri A, et al.  Management of bleeding disorders in children.  Haemophilia.  
2012; 18 (Suppl. 2):15-23. 
Croteau GA, Martin DB, Camp J et al.  Evaluation of Exposure and Health Care Worker Response to 
Nebulized Administration of tgAAVCF to Patients with Cystic Fibrosis.  Ann. Occup. Hyg. 2004; 
48[8]:673-681. 
D’Avola D, Lopez-Franco E, Harper P, et al.  Phase 1 Clinical Trial of Liver Directed Gene Therapy with 
rAAV5-PBGD in Acute Intermittent Porphyria: Preliminary Safety Data.  J. Hepatology.  2014;60[1]:S58. 
Maguire AM, High KA, Auricchio A et al. Age-dependent effects of RPE65 gene therapy for Leber's 
congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009;374:1597-1605. 
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in 
severe hemophilia A. Blood. 2014; 123: 317-325. 
Manno CS, Chew AJ, Hutchison S, et al.  AAV-mediated factor IX gene transfer to skeletal muscle in 
patients with severe hemophilia B.  Blood.  2003;101:2963-2972. 
Manno CS, Arruda VR, Pierce GF, et al.  Successful transduction of liver in hemophilia by AAV-Factor 
IX and limitations imposed by the host immune response.  Nature Med. 2006;12:342-347 and 
Supplemental Appendix, available at: http://www.nature.com/nm/journal/v12/n3/extref/nm1358-S3.pdf. 
McIntosh J, Lenting PJ, Rosales C, et al.  Therapeutic levels of FVIII following a single peripheral vein 
administration of rAAV vector encoding a novel human factor VIII variant.  Blood.  2013;121:3335-3344. 
Nagel K, Walker I, Decker K, et al. Comparing bleed frequency and factor concentrate use bewteen 
haemophilia A and B patients. Haemophilia. 2011 17: 872-4 
Nathwani AC, Tuddenham EG. Epidemiology of coagulation disorders. Baillieres Clin.Haematol. 
1992;5:383-439. 
Nathwani AC, McIntosh J, Davidoff AM. An update on gene therapy for hemophilia. Curr.Hematol Rep. 
2005;4:287-293. 
Nathwani AC, Rosales C, McIntosh J et al. Long-term Safety and Efficacy Following Systemic 
Administration of a Self-complementary AAV Vector Encoding Human FIX Pseudotyped With Serotype 
5 and 8 Capsid Proteins. Mol.Ther. 2011;19:876-885. 
Nathwani AC, Tuddenham EG, Rangarajan S et al. Adenovirus-associated virus vector-mediated gene 
transfer in hemophilia B. N.Engl.J.Med.  2011;365:2357-2365. 
Nathwani AC, Reiss UM, Tuddenham EGD, et al.  Long-Term Safety and Efficacy of Factor IX Gene 
Therapy in Hemophilia B.  N.Engl.J.Med. 2014;371:1994-2004 and Supplemental Appendix, available at:  
http://www.nejm.org/doi/suppl/10.1056/NEJMoa1407309/suppl_file/nejmoa1407309_appendix.pdf. 

 
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Paneda A, Venrell L, Mauleon I, et al.  Effect of Adeno-Associated Virus Serotype and Genomic Structure 
on Liver Transduction and Biodistribution in Mice of Both Genders.  Hum.Gene Ther.  2009;20:908-917. 
Paneda A, Lopez-Franco E, Kaeppel C, et al.  Safety and Liver Transduction Efficacy of rAAV5-
cohPBGD in Nonhuman Primates: A Potential Therapy for Acute Intermittent Porphyria.  Hum.Gene 
Ther.  2013;24:1007-1017. 
Pipe SW. Go long! A touchdown for factor VIII? Blood. 2010;116:153-154. 
Schenk-Braat EA, van Mierlo MM, Wagemaker G et al.  An inventory of shedding data from clinical gene 
therapy trials.  J Gene Med. 2007; 9:910-921. 
Simonelli F, Maguire AM, Testa F et al. Gene therapy for Leber's congenital amaurosis is safe and 
effective through 1.5 years after vector administration. Mol.Ther. 2010;18:643-650. 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.  Guidelines for the management of hemophilia.  
Haemophilia.  2012:1-47. 
Stonebraker JS, Brooker M, Amand RE, et al. A study of reported factor VIII use around the world. 
Haemophilia. 2010;16:33-46. 

 
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22 
INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Patients  
In accordance with FDA Form 1572, the Investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and IRB 
review and approval in 21 CFR Part 56 are met.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312. 

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26 May 2015 
24 PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See pages 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font. 
Section No./Title 
Text Revisions 
2/Synopsis/(Diagnosis 
and All Criteria for 
Inclusion and 
Exclusion) 
Rationale 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
2.  Any evidence of detectable viral load of active infection or any immunosuppressive disorder
 
.   
1 
2/Synopsis/(Diagnosis 
and All Criteria for 
Inclusion and 
Exclusion) 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
3.  Patients that are HIV positive are excluded
1 
. 
9.1/Overall Study 
Design and Plan 
2 
Additionally, if any of the events listed in Section 9.3.3.1 occur, enrollment into the trial will be halted to complete an extensive 
safety analysis.  Notification of the study halt will be sent by the Sponsor to the participating sites via telephone and email 
immediately after becoming aware of a safety concern. This will ensure no additional subjects are dosed until the signal has been 
completely evaluated.  If, following safety review by the DRB and the Sponsor, it is deemed appropriate to restart dosing, a 
request to restart dosing with pertinent data will be submitted to the health authority. 
9/Investigational 
Plan/(Table 9.1.1 – 
Schedule of Events – 
Screening and Infusion) 
FVIII Treatment Washoutb 
 
6 
9/Investigational 
Plan/(Table 9.1.1 – 
Schedule of Events – 
Screening and 
Infusion)/Footnotes 
b Patients will have a washout period of 72 hours prior to BMN 270 infusion. If a bleeding occurs, another washout period of 72 
hours will be performed. If another bleeding occurs during this second washout period, then the patient may be excluded from 
the study at the physician’s discretion. 
 
6 
9/Investigational 
Plan/(Table 9.1.1 – 
Schedule of Events – 
Screening and 
cbIncludes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory 
assay, hFVIII inhibitor level (Bethesda assay with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen 
(ELISA).  hFVIII assays should be assessed only when the patient has been off FVIII therapy for at least the previous 4 days. 
6 

 
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Section No./Title 
Text Revisions 
Infusion)/Footnotes 
Rationale 
 
9.3.2/Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
2.  Any evidence of detectable viral load of active infection or any immunosuppressive disorder.
1 
   
9.3.2/Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
3.  Patients that are HIV positive are excluded
1 
. 
9.3.3.1/Study Safety 
Evaluation Criteria 
If any of the following events occur (except the persistence of AAV5) in a patient in the study who has received BMN 270 
infusion, enrollment into the trial will be put on halt to complete an extensive safety analysis will be performed and BioMarin and 
the Principal Investigator will discuss pursuing the trial or increasing the time before the next patient is enrolled. per Section 9.1.
2 
   
9.4.8.1/Concomitant 
Haemophilia 
Treatments 
Concomitant 
9.4.8.2    Factor VIII Washout 
Haemophilia Treatments are discussed in the washout section below (Section ). 
Patients will have a washout period of 72 hours prior to the BMN 270 infusion. If a bleeding occurs, another washout period of 
72 hours will be performed. If another bleeding occurs during this second washout period, then the patient may be excluded from 
the study at the physician’s discretion.  
6 
Patients on “on demand” therapy for FVIII will continue their treatment at will. Patients on prophylactic FVIII therapy will 
discontinue their treatment starting the day of infusion and switch to an “on demand” schedule. FVIII can always be taken as 
needed by the patient, who will carefully record his treatment and bleeding episodes in his diary. 
9.7.2/Primary Efficacy 
Variables 
To measure the primary efficacy variable, the following assays will be used: 
• 
FVIII activity (chromogenic FXa assay) 
• 
FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time) 
• 
Exploratory FVIII activity assay 
4 
9.7.8.2/Clinical 
Laboratory 
Assessments 
All abnormal clinical laboratory result pages results 
Admin. 
should be initialed and dated by an Investigator, along with a comment 
regarding whether or not the result is clinically significant. 

 
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Section No./Title 
Text Revisions 
10.1.1/Adverse Events 
Rationale 
• 
Complications that occur as a result of non-drug protocol-imposed interventions (eg, AEs related to screening 
procedures, medication washout, or no-treatment run-in). 
6 
10.5.1/Expedited 
Reporting 
Requirements 
3 
The Sponsor is responsible for identifying, preparing and reporting all SUSARs to the relevant competent authorities, ethics 
committees and investigators in accordance with the requirements identified in the Clinical Trials Regulations. 
11/Appropriateness of 
Measurements 
4 
The chromogenic FXa assay and the APTT assays are both validated and utilize CE marked reagents.  The exploratory FVIII 
activity assay will be used for exploratory purposes only. 
12.2/Screening Visit 
• 
Samples for hFVIII Assays 
o 
Baseline hFVIII activity – chromogenic FXa (plasma) (at least 72 hours off therapy) 
o 
Baseline hFVIII activity level – one-stage APTT assay (at least 72 hours off therapy) 
6 
12.2/Screening Visit 
• 
Screen for Hepatitis B, Hepatitis C, and HIV if required 
Admin. 
(Patients with documented negative results within the last 30 
days do not need to be retested) 
12.3/Baseline Visit 
• 
FVIII Treatment Washout (refer to Section ) 
6 
12.3/Baseline Visit 
• 
Samples for FVIII Assays 
o 
FVIII activity – chromogenic FXa (plasma) (at least 72 hours off therapy) 
o 
FVIII activity level –APTT One stage assay (at least 72 hours off therapy) 
6 
15/Data Monitoring 
Committee 
There will be no formal DMC for this study, however a safety and efficacy evaluation board (the Data Review Board [DRB]) 
composed of the investigators investigator representatives and the 
The primary responsibility of the board will be 
Sponsor will be established. 
Data Review Board [DRB] will review safety and efficacy on an ongoing basis. 
The DRB will meet prior to dose escalation or dose expansion to assess patient’s available patient safety and efficacy data 
accumulated for a particular dose level and to and make recommendations regarding dose escalation. 
5 
with regards to the conduct 
of study. Should a safety signal arise, including one which may warrant a halt of study enrollment, the DRB will promptly 
convene for further assessment of patient safety. Notification of all DRB meetings and meeting outcomes will be sent to 
participating sites. 
 

 
 
BioMarin is a registered trademark of BioMarin Pharmaceutical Inc. 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study 
of BMN 270, an Adenovirus-Associated Virus Vector–Mediated 
Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
Protocol Number: 
270-201 
Active Investigational 
Product: 
AAV5-hFVIII-SQ 
IND/European Union 
Drug Regulating 
Authorities Clinical Trials 
(EudraCT) Number: 
2014-003880-38 
 
Indication: 
Haemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 1/2 
Sponsor's Responsible 
Medical Monitor: 
 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Duration of Patient 
Participation: 
Approximately 264 weeks 
Dose: 
Varied 
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
10 February 2015 
Date of Amendment 1: 
06 March 2015 
Property of BioMarin 
CONFIDENTIAL 
 
May not be divulged, published, or otherwise disclosed to others without prior written approval from 
BioMarin. 
 
This study will be conducted according to the principles of Good Clinical Practice as described in the 
U.S. Code of Federal Regulations and the International Conference on Harmonisation Guidelines, 
including the archiving of essential documents. 
 
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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment:  1 
Date: 06 March 2015 
 
RATIONALE AND SUMMARY OF MAJOR CHANGES 
A summary of major changes covered by Amendment 1 to the BMN 270-201 protocol is 
provided below.   
1. Addition of “Receipt of any vector or gene transfer agent” to exclusion criteria. 
Rationale:  MHRA scientific advice in May 2014 stated that “a rationale has to be provided 
as to why receipt of any vector or gene transfer agent at any time is not an absolute exclusion 
criterion, rather than limiting to any vector/gene transfer agent that had been received in the 
previous 6 months.”   
2. Drug substance “AAV5-SQ-codop-hFVIII” has been revised to “AAV5-hFVIII-SQ.” 
Rationale:  This change was made to remain consistent with drug substance description in the 
IMPD and the IB. 
3. Appendix 1 has been removed. 
Rationale:  Appendix 1 contained a detailed schedule of assessments that is not the schedule 
for this study.  Instead, a reference has been made to the Nathwani 2014 supplemental 
information available online. 
4. Appendix 2 has been removed. 
Rationale:  Appendix 2 contained unpublished data.  Instead, a reference has been added to 
Manno, 2006 supplemental information which includes vector biodistribution data by tissue 
and vector dose. 
5. Inclusion Criterion concerning severe level of FVIII deficiency has been modified to state 
that “Patients will be considered as severe if their FVIII baseline level is 1 IU/dL or less” 
Rationale:  Changed description to more accurately describe patients with severe 
Haemophilia A.  Baseline level is never “reached”; it is historical and based on their 
mutation.   
6. Minor edits for clarity and consistency have been incorporated. 
Specific changes included in this amendment, including the Synopsis, since the original 
protocol (approved 10 February 2015) are outlined in Section 24. 

 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study of BMN 270, an Adenovirus-
Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
PROTOCOL NUMBER: 
270-201 
STUDY SITES: 
Approximately 6-10 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 1/2 
STUDY RATIONALE: 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 
5,000 males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an essential 
cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to a new 
mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of 
wild type activity and the mild form is 5-40% activity. The clinical manifestations of severe HA 
remain frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or recombinant 
FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, and at the time of a 
bleed, to prevent or control bleeding episodes, respectively. The half-life for rhFVIII (under 24 hours 
for most approved products) necessitates frequent infusions, and although a major advance in the 
treatment of HA, it remains common for severe HA patients to continue to have multiple bleeding 
events on treatment (mean of 1 to 7 episodes/year with prophylaxis up to 30 to 50 for on demand 
treatment).  The consequence of multiple bleeding events is the development of an underlying 
pathology that contributes to debilitating multiple-joint arthropathy and substantially increased risk of 
death. Chemical modification (e.g. direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by approximately 50%, and 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
thus, show promise in reduced dosing and maintaining activity levels above 1% trough. However, 
these longer acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive treatment 
of HA to give patients a FVIII level compatible with a normal and haemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous production 
of active FVIII following a single intravenous administration of a vector with the appropriate gene 
sequence. Haemophilia A is well suited for a gene replacement approach because clinical 
manifestations are attributable to the lack of a single gene product (FVIII) that circulates in minute 
amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not essential, and 
modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml induces an increase 
in activity of 1%) can ameliorate the severe form of the disease.  Thus, relatively small changes in 
endogenous FVIII activity results in clinically relevant improvements in disease phenotype. Finally, 
the response to gene transduction can be assessed using validated quantitative rather than qualitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific tissues 
such as the liver (for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical 
trial for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild is achievable following a single peripheral vein administration of AAV-8 vector. 
Several participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in bleeding. 
Thus, gene therapy treatment has resulted in a substantial improvement in their quality of life.  
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII under the 
control of a liver-selective promoter (Figure 1).  
Figure 1. BMN 270 transgene construct, ~5.0 kbp 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, potentially 
life-long expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
The clinical study BMN 270-201 is a first-in-human study designed to assess the relationship of vector 
dose to the augmentation of residual FVIII activity, and whether these levels are sufficient to alter the 
clinical phenotype. The relationship of dose to safety will be correlated to the activity of hFVIII in 
patients with severe HA. 
OBJECTIVES:  
The primary objectives of the study are: 
• 
To assess the safety of a single intravenous administration of a recombinant AAV5 encoding 
human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• 
To determine the dose of AAV5-hFVIII-SQ required to achieve expression of FVIII at or 
above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and 
magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose. 
The secondary objectives of the study are: 
• 
To describe the immune response to the FVIII transgene and AAV capsid proteins following 
systemic administration of AAV5-hFVIII-SQ 
• 
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during the 
study 
• 
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study 
STUDY DESIGN AND PLAN:  
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe haemophilia 
A. Eligible patients will enter the dose escalation part of the study followed by a 16-week 
Post-Infusion Follow-Up period during which safety and efficacy assessments will be taken. After the 
primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed for approximately 
5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and do 
not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. Participants 
will be enrolled sequentially into one of up to three cohorts according to dose level:  
1. 6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous dose 
(iv) 
2. 2E13 vg per kilogram, iv 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
3. 6E13 vg per kilogram, iv 
 
Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose escalation may 
occur after a single patient has been safely dosed if the resulting FVIII activity at Week 3 is < 5 IU/dL. 
Three weeks is expected to be the time the expression will be close to the maximum.  This escalation 
paradigm is intended to minimize the patient numbers exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of 
mice and monkeys.  The starting dose has a significant safety margin (10-fold) from no observed 
adverse effect level (NOAEL) in non-human primates.   
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study.  
If the FVIII activity is ≥ 5 IU/dL, then the other patients of the dose group will be enrolled without 
waiting for 3 weeks between patients. 
Patient 1 will be dosed by intravenous perfusion with 6E12 vector genomes [vg] per kilogram of body 
weight. If the activity level does not reach ≥ 5 IU/dL at 21 days, then a higher dose (2E13 vg per 
kilogram) will be used for the next patient.  
If the activity level does not reach ≥ 5 IU/dL after Patient 2, then the highest dose (6E13 vg per 
kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and no safety issue is found, then up to four 
patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no further dose 
escalation will take place, but additional patients will then be dosed at this dose level for a total of 
6 patients per dose. 
Because patients develop neutralizing immunity upon exposure to the capsid, re-challenge of vector is 
not a treatment option and these patients have effectively a single opportunity for therapy using this 
AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post dose. Safety will be 
evaluated for approximately 5 years after dose.  Any safety signal will trigger a review of the data and 
possible additional analysis including mononuclear collection. 
NUMBER OF PATIENTS PLANNED:  
Up to 12 patients may enroll into the study; the actual number of patients will depend on the criteria 
for dose escalation. A total of 6 patients may be enrolled at a single dose level. 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe haemophilia A as evidenced by their 
medical history.  Patients will be considered as severe if their FVIII baseline level is 1 IU/dL 
or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitates for a minimum of 150 exposure 
days (EDs) 
3. Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 12 months 
using a modified Nijmegen Bethesda assay higher than 0.6 Bethesda Unit (BU) 
6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition and AAV5 total antibodies  
2. Evidence of detectable viral load of HIV  
3. Significant liver dysfunction as defined by abnormal elevation of ALT (alanine transaminase) 
to 3 times the upper limit of normal, bilirubin, alkaline phosphatase, or an INR (international 
normalized ratio) of 1.4. Potential participants who have had a liver biopsy in the past 3 years 
are excluded if they had significant fibrosis of 3 or 4 as rated on a scale of 0-4 
4. Evidence of any bleeding disorder not related to Haemophilia A 
5. Platelet count of < 100 x 109/L 
6. Creatinine ≥ 1.5 mg/dL 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound  
8. Hepatitis B if surface antigen is positive 
9. Hepatitis C if RNA is positive 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
10. Treatment with any IP within 30 days prior to the screening visit 
11. Any disease or condition at the physician’s discretion that would prevent the patient from fully 
complying with the requirements of the study.  The physician may exclude patients unwilling 
or unable to agree on not using alcohol for the 16-week period following the viral infusion. 
12. Receipt of any vector or gene transfer agent 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each patient will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
The study is open label with comparison of FVIII activity to baseline values. No reference therapy will 
be evaluated in this study. 
DURATION OF TREATMENT:  
BMN 270 is given as a single dose by intravenous perfusion. 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
CRITERIA FOR EVALUATION: 
The following safety outcome measurements will be assessed: 
Safety: 
• 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
• 
Change in clinical laboratory tests (serum chemistry and haematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding 
• 
Liver function tests (LFT) 
 
No major toxicity is expected based on preclinical studies in mice and monkeys. An asymptomatic 
transaminitis was observed at week 8-10 after administration with an AAV8-FIX, providing the 
rationale for the following surveillance plan. Each patient will have comprehensive surveillance plan 
monitoring LFTs once a week from dose to completion of Week 6, 3 times per week from Weeks 7 to 
12, and once a week from Weeks 13 to 16.  If a patient’s ALT is found to be greater than 1.5x baseline 
during these periods, then LFTs will be monitored three times per week or until the ALT returns to 
baseline. LFTs will be monitored every other month for the first year and then every three months for 
up to 5 years post-dose in the safety extension. 
There will be a detailed monitoring plan for assessment of cellular and humoral responses to AAV5 
capsid and FVIII protein.   
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the study is 
to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration. 
  
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Patients will be asked 
to keep a patient diary to record the details in these areas.   
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage APTT 
and/or chromogenic FXa assay (activity level), will be used for plasma profiles; FVIII activity will be 
Pharmacodynamics: 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
used to determine PD parameters.  Traditional PK analysis is not applicable. 
If supported by the FVIII activity data, non-compartmental analysis and observation will be used to 
estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss (time 
to steady state), C(t) and AUC(0-t) where t is 16 weeks.   
STATISTICAL METHODS:  
The sample size is based upon clinical considerations and could detect a strong clinical efficacy signal. 
Up to 12 patients may be dosed in the study.  The patients will be followed in a longitudinal manner 
and all the relevant information will be collected. The analysis of the data will be descriptive in nature 
but data collected in a longitudinal manner may be analyzed using longitudinal methods such as mixed 
effect model which takes into account the correlation among the observation taken at various time 
points within a participant. Efficacy is a secondary endpoint, defined as biologically active FVIII at 
≥ 5 IU/dL by chromogenic FXa assay and/or one-stage APTT assay between 1 to 16 weeks following 
study treatment. FVIII activity will be assessed weekly during the study period.  We can only assess 
the true steady state of FVIII protein produced from BMN 270 after a minimum of 72 hours has 
elapsed since the last infusion of FVIII protein concentrates. 
Analysis of neutralizing antibody response and other immunological parameters as well as viral 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses. 
 

 
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3 TABLE OF CONTENTS 
1    TITLE PAGE…………………………………………………………………………...…1 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS ...................................................................................................11 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................15 
5 ETHICS..............................................................................................................................17 
5.1 Institutional Review Board or Independent Ethics Committee ................................17 
5.2 Ethical Conduct of Study ..........................................................................................18 
5.3 Patient Information and Informed Consent ...............................................................18 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................19 
7 INTRODUCTION .............................................................................................................20 
7.1 Nonclinical Studies ...................................................................................................21 
7.2 Previous Clinical Studies ..........................................................................................22 
7.3 Study Rationale .........................................................................................................23 
7.4 Summary of Overall Risks and Benefits ...................................................................25 
8 STUDY OBJECTIVES ......................................................................................................27 
9 INVESTIGATIONAL PLAN ............................................................................................28 
9.1 Overall Study Design and Plan .................................................................................28 
9.2 Discussion of Study Design, Including Choice of Control Group ............................34 
9.3 Selection of Study Population ...................................................................................34 
9.3.1 
Inclusion Criteria .........................................................................................34 
9.3.2 
Exclusion Criteria ........................................................................................35 
9.3.3 
Removal of Patients from Treatment or Assessment ..................................35 
9.3.4 
Patient Identification and Replacement of Patients .....................................37 
9.3.5 
Duration of Patient Participation .................................................................37 
9.4 Treatments .................................................................................................................37 
9.4.1 
Treatments Administered ............................................................................37 
9.4.2 
Identity of Investigational Product ..............................................................37 
9.4.3 
Storage .........................................................................................................37 
9.4.4 
Directions for Administration .....................................................................38 

 
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9.4.5 
Method of Assigning Patients to Treatment Groups ...................................38 
9.4.6 
Selection of Doses Used in the Study .........................................................39 
9.4.7 
Blinding .......................................................................................................39 
9.4.8 
Prior and Concomitant Medications ............................................................40 
9.4.9 
Treatment Compliance ................................................................................40 
9.5 Investigational Product Accountability .....................................................................41 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................41 
9.6 Dietary or Other Protocol Restrictions......................................................................41 
9.7 Safety and Efficacy Variables ...................................................................................41 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................41 
9.7.2 
Primary Efficacy Variables .........................................................................42 
9.7.3 
Secondary Efficacy Variables .....................................................................42 
9.7.4 
Immunogenicity ...........................................................................................42 
9.7.5 
Pharmacodynamics ......................................................................................43 
9.7.6 
Exploratory Biomarker Assessments ..........................................................43 
9.7.7 
Quality of Life Assessment .........................................................................43 
9.7.8 
Safety Variables ..........................................................................................43 
10 REPORTING ADVERSE EVENTS .................................................................................48 
10.1 Safety Parameters and Definitions ............................................................................48 
10.1.1 Adverse Events ............................................................................................48 
10.2 Serious Adverse Events ............................................................................................49 
10.2.1 Events of Special Interest (EOSI) ...............................................................49 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................49 
10.3.1 Adverse Event Reporting Period .................................................................49 
10.3.2 Eliciting Adverse Events .............................................................................50 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................50 
10.4 Procedures for Recording Adverse Events ...............................................................52 
10.4.1 Recording Adverse Events on a eCRF ........................................................52 
10.5 Reporting Requirements ...........................................................................................55 
10.5.1 Expedited Reporting Requirements .............................................................55 

 
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10.5.2 Ethics Committee Reporting Requirements ................................................56 
10.6 Follow-up of Patients after Adverse Events .............................................................56 
10.7 Post-Study Adverse Events .......................................................................................56 
10.8 Urgent Safety Measures ............................................................................................57 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................58 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................59 
12 STUDY PROCEDURES ...................................................................................................60 
12.1 Prestudy .....................................................................................................................60 
12.2 Screening Visit ..........................................................................................................60 
12.3 Baseline Visit ............................................................................................................61 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................62 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................62 
12.5.1 Every Visit ...................................................................................................62 
12.5.2 Every 4 Weeks .............................................................................................63 
12.5.3 Weeks 1, 3, and 6 ........................................................................................63 
12.5.4 Weeks 1, 8, and 16 ......................................................................................63 
12.5.5 Weeks 1, 2, 3, 4, and 16 ..............................................................................63 
12.6 Safety Follow-Up – Year 1 .......................................................................................63 
12.6.1 Every Visit ...................................................................................................64 
12.6.2 Weeks 28 and 52 .........................................................................................64 
12.7 Safety Follow-Up – Years 2-5 ..................................................................................64 
12.7.1 Every Visit ...................................................................................................64 
12.7.2 Every Other Visit (Every 6 Months) ...........................................................65 
12.8 Early Termination Visit ............................................................................................65 
12.9 End of Study..............................................................................................................66 
13 DATA QUALITY ASSURANCE .....................................................................................67 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................68 
14.1 Statistical and Analytical Plans .................................................................................68 
14.1.1 Interim Analyses ..........................................................................................68 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........68 

 
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14.2 Primary and Secondary Efficacy Analysis................................................................68 
14.3 Immunogenicity ........................................................................................................68 
14.4 Pharmacodynamic Analyses .....................................................................................69 
14.5 Safety Analysis .........................................................................................................69 
14.6 Determination of Sample Size ..................................................................................69 
14.7 Analysis Populations .................................................................................................70 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................70 
15 DATA MONITORING COMMITTEE .............................................................................71 
16 COMPENSATION, INSURANCE AND INDEMNITY ..................................................72 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................73 
18 STUDY MONITORING AND AUDITING .....................................................................75 
19 RETENTION OF RECORDS ...........................................................................................76 
20 USE OF INFORMATION AND PUBLICATION ...........................................................77 
21 REFERENCES ..................................................................................................................78 
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................80 
22.1 Conduct of Study and Protection of Human Patients ...............................................80 
23 SIGNATURE PAGE .........................................................................................................81 
24 PROTOCOL AMENDMENT TEXT REVISIONS ..........................................................82 
 
LIST OF TABLES 
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................30 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up .................................................32 
Table 9.1.3:  Schedule of Events – Safety Follow-Up .............................................................33 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................45 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................51 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................51 
 
LIST OF FIGURES 
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp ........................................................25 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme ............................................................29 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAV 
Abbreviations 
adeno-associated virus 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine transaminase 
APTT 
activated partial thromboplastin time 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
eCRF 
electronic case report form 
DMC 
Data Monitoring Committee 
ED 
exposure days 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FVIII 
coagulation factor VIII 
FXa 
coagulation factor Xa 
GCP 
Good Clinical Practice 
HA 
Haemophilia A 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 

 
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IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LFT 
liver funtion test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
vg 
vector genomes 
 
Investigational Product (IP): 
Definition of Terms:  
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 
 

 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin Pharmaceutical Inc. (BioMarin) or its designee. The 
Investigator will provide the IRB/IEC/REB with all appropriate material, including the 
protocol, Investigator’s Brochure (IB), the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the patients, 
including all ICFs translated to a language other than the native language of the clinical site. 
The study will not be initiated and Investigational Product (IP) supplies will not be shipped 
to the site until appropriate documents from the IRB/IEC/REB confirming unconditional 
approval of the protocol, the ICF and all patient recruitment materials are obtained in writing 
by the Investigator and copies are received at BioMarin or its designee. The approval 
document should refer to the study by protocol title and BioMarin protocol number (if 
possible), identify the documents reviewed, and include the date of the review and approval. 
BioMarin will ensure that the appropriate reports on the progress of the study are made to the 
IRB/IEC/REB and BioMarin by the Investigator in accordance with applicable guidance 
documents and governmental regulations. 

 
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5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible patients for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability. 
This study will be conducted in accordance with the following: 
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6) 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the patients will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each patient will provide written, informed consent before any 
study-related tests or evaluations are performed. 
5.3 
Patient Information and Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each patient prior to entering the patient into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF , and if applicable, 
a copy of the approved patient information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed. 
The Investigator will provide copies of the signed ICF to each patient and will maintain the 
original in the record file of the patient. 

 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to patients. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) 
Form FDA 1572 and a Financial Disclosure Form. All sub-Investigators must be listed on 
Form FDA 1572. Financial Disclosure Forms must also be completed for all 
sub-Investigators listed on the Form FDA 1572 who will be directly involved in the treatment 
or evaluation of patients in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each patient as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 
Laboratory evaluations will be performed at the local laboratories associated with the study 
sites. Refer to the Laboratory Manual for more details. 

 
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7 
INTRODUCTION 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.). 
Chemical modification or bioengineering of FVIII may improve half-life to around 20 hours 
(Pipe, 2010, Blood). However, these long acting FVIII variants do not eliminate the need for 
lifelong FVIII protein administration or problems of FVIII inhibitor formation, which occurs 
in 30% of patients on standard FVIII replacement therapy (Nathwani, 1992, Baillieres 
Clin.Haematol.).  
Gene therapy offers the potential of a cure through continuous endogenous production of 
human FVIII following a single administration of vector. Haemophilia A is well suited for 
this approach because its clinical manifestations are attributable to the lack of a single gene 
product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. Tightly 
regulated control of gene expression is not essential and a modest increase in the level of 
FVIII (a plasma level of 2ng/ml protein leads to a 1% expression) can ameliorate the severe 
phenotype (Srivastava, 2012, Haemophilia); thus the therapeutic goal for gene therapy is a 
modest increase in hFVIII. Finally, the consequences of gene transfer can be assessed using 
simple quantitative rather than qualitative endpoints that can be easily assayed in most 
clinical laboratories. 
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 

 
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7.1 
Nonclinical Studies 
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 
nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints. 
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in mice given matched IU levels of Refacto®.   
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.   
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 
6E13 vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined 
potential target organs, immunogenicity, gene expression and activity. No changes in liver 
function were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed. 

 
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The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 
the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence matching that of the 
protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Paneda, 2009, Hum.Gene Ther.). 
Despite distribution to non-liver organs, no expression of Factor IX was detected in these 
tissues.  Additionally, distribution to the testis was observed in another study in monkeys 
given an AAV5-codon-optimized human porphobilinogen deaminase; however, vector 
genomes in the semen were only transiently observed within one week but not thereafter 
(Paneda, 2013, Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents > 30-fold safety factor from 
the no observed adverse effect level (NOAEL) in enabling nonclinical studies.  
7.2 
Previous Clinical Studies 
This is the first clinical study for BMN 270. 
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Eng.J.Med.; 
Nathwani, 2014, N.Eng.J.Med.). The large size of the FVIII cDNA was shortened and a 

 
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preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013, 
Blood). 
AAV serotype 5 is also used in clinical trials and has shown good safety in a recent phase 1 
study for treatment of Acute Intermittent Porphyria (D’Avola. 2014, J Hepatology).  
AAV using other serotypes have been used in 105 clinical studies to date and no safety issue 
specific to the vector was ever reported.   
7.3 
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin. Haematol).  It is caused by deficiency in 
the activity of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic 
coagulation cascade. This disorder can be either inherited, due to a new mutation or an 
acquired immunologic process, leading to insufficient quantities of FVIII or a dysfunctional 
FVIII, but all are characterized by a defective coagulation process. . The clinical phenotype 
of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease 
comprises 1-5% of wild type activity and the mild form is 5-40% activity. The clinical 
manifestations of severe HA remain frequent spontaneous bleeding episodes, predominantly 
in joints and soft tissues, with a substantially increased risk of death from haemorrhage when 
the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life 
for rhFVIII (under 24 hours for most approved products) necessitates frequent infusions, and 
although a major advance in the treatment of HA, it remains common for severe HA patients 
to continue to have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with 
prophylaxis up to 30 to 50 for on demand treatment) (Nagel, 2011, Haemophilia).  The 
consequence of multiple bleeding events is the development of an underlying pathology that 
contributes to debilitating multiple-joint arthropathy and substantially increased risk of death 
(Nagel, 2011, Haemophilia).  Chemical modification (e.g. direct conjugation of polyethylene 
glycol (PEG) polymers) and bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve 
half-life by approximately 50%, and thus, show promise in reduced dosing and maintaining 
activity levels above 1% trough (Stonebraker, 2010, Haemophilia), (Mahlangu, 2014, Blood). 
However, these longer acting FVIIIs remain dependent on multiple infusions to maintain 
critical levels of FVIII activity in severe HA patients. There is therefore a strong unmet need 

 
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for a fully preventive treatment of HA to give patients a FVIII level compatible with a 
normal and haemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Pipe, 2010, Blood). They 
have an excellent and well defined safety profile, and can direct long term transgene 
expression with tropism for specific tissues such as the liver (Nathwani, 2005, Curr.Hematol 
Rep.) for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical trial 
for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from 
severe to moderate or mild is achievable following a single peripheral vein administration of 
AAV-8 vector(Nathwani, 2011, NEJM). Several participants in this trial have been able to 
discontinue factor prophylaxis without suffering spontaneous haemorrhages, even when they 
undertook activities that previously resulted in bleeding. Thus, gene therapy treatment has 
resulted in a substantial improvement in their quality of life (Nathwani, 2011, Mol.Ther.). 
(Bainbridge, 2008, NEJM; Maguire, 2009, Lancet; Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII 
under the control of a liver-selective promoter (Figure 7.3.1).  

 
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Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp 
 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of hFVIII in patients with 
severe HA. 
7.4 
Summary of Overall Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based 
on prior human studies with peripheral injections of AAV vectors, there is no known safety 
risk of AAV gene therapy. However, a mild asymptomatic transaminitis was observed at 
week 8-10 after administration with an AAV8-FIX, providing the rationale for the following 
surveillance plan (Manno, 2006, Nature Med.).  Each patient will have comprehensive 
surveillance plan monitoring LFTs once a week from dose to completion of Week 6, 3 times 
per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is 
found to be greater than 1.5x baseline during these periods, then LFTs will be monitored 
three times per week or until the ALT returns to baseline.  LFTs will be monitored every 
other month for the first year and then every three months for up to 5 years post-dose in the 
safety extension.   
Dose selection:  The benefit of this study can only be enhanced by selecting a starting dose 
that potentially could contribute to a better opportunity of observing a therapeutic effect, and 
therefore, reducing the possibility of a sub-therapeutic effect. With this consideration in 
mind, the starting dose 6E12 vg/kg was selected using overall data from the pre-clinical 
studies conducted in mice (normal and disease model, Rag2 -/- x FVIII -/-) and monkey.  
A detectable pharmacological response based on activity was observed at 6E12 vg/kg. 

 
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A 10-fold safety margin based upon the NOAEL was observed in the GLP 13-week study in 
normal mouse at the highest dose administered.  A 30-fold safety margin in an 8-week dose 
response study in disease model mice based on histology was observed at the highest dose 
administered.  No BMN 270-related changes in clinical observations or chemistry was 
observed in the monkey at doses up to 6E13 vg/kg, a 10-fold safety margin after 8-weeks.  
Overall, no BMN 270-related findings, except expected formation of anti-AAV5 antibodies, 
were observed at the highest administered doses of 6E13, 2E14 and vg/kg in the normal 
mouse, disease model mouse and monkey, respectively. 
Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to patients but may potentially 
benefit the patient therapeutically. 

 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are: 
• To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector.  
• To determine the dose of AAV5-hFVIII-SQ required to achieve expression of hFVIII 
at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270 
dose. 
The secondary objectives of the study are: 
• To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of AAV5-hFVIII-SQ 
• To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study 
• To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study 
 
 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled sequentially into one of up to three cohorts according to 
dose level:  
1. 6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous 
dose (iv) 
2. 2E13 vg per kilogram, iv 
3. 6E13 vg per kilogram, iv 
Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose 
escalation may occur after a single patient has been safely dosed if the resulting FVIII 
activity at Week 3 is < 5 IU/dL. Three weeks is expected to be the time the expression will be 
close to the maximum.  This escalation paradigm is intended to minimize the patient numbers 
exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys.  The starting dose has a significant safety margin (10-fold) 
from no observed adverse effect level (NOAEL) in non-human primates.   
Approximately three weeks after an injection, the decision to escalate to the next dose level 
will be made based on the review of safety parameters and FVIII activity by the Sponsor and 
a panel of investigators participating in the study.  
If the FVIII activity is ≥5 IU/dL, then the other patients of the dose group will be enrolled 
without waiting for 3 weeks between patients. 
 

 
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme 
 
Patient 1 will be dosed by intravenous perfusion with 6E12 vector genomes [vg] per 
kilogram of body weight. If the activity level does not reach ≥5 IU/dL (expressed as % in 
Figure 9.1.1) at 21 days, then a higher dose (2E13 vg per kilogram) will be used for the next 
patient.  
If the activity level does not reach ≥5 IU/dL after Patient 2, then the highest dose 
(6E13 vg per kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and if no safety issue is found, then up to 
four patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no 
further dose escalation will take place, but additional patients will then be dosed at this dose 
level for a total of 6 patients per dose. 
Because patients develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a treatment option and these patients have effectively a single opportunity for 
therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dose.  Any safety signal 
will trigger a review of the data and possible additional analysis including mononuclear 
collection. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 for Safety Follow-up. 

 
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Table 9.1.1: Schedule of Events – Screening and Infusion 
Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion Visit 
(Day 1) 
Screening (Day 
-28 to  Day -1) 
Baseline (Day -7 to 
Day -1)i 
Informed consent 
X 
 
 
Medical History 
X 
 
 
Physical Exama 
X 
X 
X 
Vital Signs 
X 
 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
Documentation of bleeding episodes and FVIII usage (by either patient or clinical information) 
X 
X 
 
Electrocardiogram 
X 
 
 
Chest X-ray 
X 
 
 
Liver Ultrasound 
X 
 
 
FVIII Treatment Washoutb 
 
X 
 
hFVIII Assaysc 
X 
X 
 
AAV5 Assaysd 
X 
 
X 
Screen for Hepatitis B, Hepatitis C, HIVe 
X 
 
 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPf 
X 
X 
 
Mononuclear cell collection for CTL baseline 
 
X 
 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
 
X 
 
Biomarker testingg 
X 
 
 
Exploratory biomarker assessmentsh 
 
X 
 
Quality of Life (QoL) assessment 
 
X 
 
BMN 270 Infusion 
 
 
X 
a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height and 
weight will be recorded at Screening only. 

 
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b Patients will have a washout period of 72 hours prior to BMN 270 infusion. If a bleeding occurs, another washout period of 72 hours will be performed. If another 
bleeding occurs during this second washout period, then the patient may be excluded from the study at the physician’s discretion. 
c Includes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay 
with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).  hFVIII assays should be assessed only when the patient has been off FVIII 
therapy for at least the previous 4 days. 
d Screening (done during Screening) and testing (at Infusion Visit) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction 
inhibition, in vitro transduction inhibition and AAV5 total antibody assays).  The assessment on the day of the infusion visit must be performed before the BMN 270 
infusion is given. 
e Patients with documented negative results within the last 30 days do not need to be retested. 
f Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
g Includes HLA typing, FVIII mutation status, TNFα and IL10a single nucleotide polymorphisms. 
h Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 
i Should the screening visit occur within 7 days of the drug infusion, physical examination, vital signs, blood chemistry, haematology, urine tests, coagulation screen, and 
CRP do not need to be repeated at Baseline. 
 
 
 

 
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up 
Assessment 
Follow-Up After BMN 270 Administration - Weeks* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPb   X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII activity assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII antibody titer 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker assessmentse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QoL assessment 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
AAV5 antibody titer 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Testing for reactivation of hepatitis B and hepatitis C 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Mononuclear cell collection  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
* Visit windows are ±48 hours 
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included.  Each patient will have comprehensive surveillance plan monitoring LFTs once a week from dose to 
completion of Week 6, 3 times per week (every other day excluding weekends) from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is found 
to be greater than 1.5x baseline during these periods, then LFTs will be monitored three times per week or until the ALT returns to baseline. 
c Includes hFVIII activity level (APTT and FXa chromogenic assay), hFVIII activity confirmation (frozen plasma), Bethesda assay (with Nijmegen modification) for 
hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA). 
d Collection to occur on Day 1, 3, 7 following BMN 270 infusion, and then weekly until 3 consecutive negative results are obtained 
e Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 

 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up 
Assessment 
Year 1 - Weeks* 
Years 
2-5* 
ETV (early 
termination 
visit) 
20 
28 
36 
44 
52 
Q3M 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPb 
X 
X 
X 
X 
X 
X 
X 
hFVIII activity assaysc 
X 
X 
X 
X 
X 
X 
X 
AAV5 antibody titer 
X 
X 
X 
X 
X 
X 
X 
hFVIII antibody titer 
X 
X 
X 
X 
X 
X 
X 
Mononuclear Cell Collection (for determination of FVIII and Capsid specific CTL activity) 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
QoL assessment 
 
X 
 
 
X 
Xe 
X 
* Visit windows are ±72 hours 
a Complete physical examination should be performed at Weeks 52 and every 52 weeks thereafter; brief physical exam may be performed at other study visits.  Refer to 
Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), hFVIII activity confirmation (frozen plasma), Bethesda assay (with Nijmegen 
modification) for hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA). 
d Sample testing during Safety Follow-Up is not required if 3 consecutive samples are cleared during the Post-Infusion Follow-Up period. 
e QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 6 months) starting with the Week 78 visit (ie, 26 weeks after the 
Week 52 visit at the end of Year 1 of the Safety Follow-up period). 

 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Three doses of BMN 270 will be evaluated and the dose 
escalation decision tree is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and a panel of investigators participating in the 
study.  
There will be no control group. Parameters for each patient will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy).  
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3 
Selection of Study Population 
Up to 12 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation. A total of 6 patients may be enrolled 
at a single dose level. 
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe Haemophilia A as evidenced by 
their medical history.  Patients will be considered as severe if their FVIII baseline level is  
1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitates for a minimum of 
150 exposure days (EDs) 
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the previous 
12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 
12 months using a modified Nijmegen Bethesda assay higher than 0.6 Bethesda Unit 
(BU) 

 
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6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment. 
9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition and AAV5 total antibodies 
2. Evidence of detectable viral load of HIV  
3. Significant liver dysfunction as defined by abnormal elevation of ALT (alanine 
transaminase) to 3 times the upper limit of normal, bilirubin, alkaline phosphatase, or an 
INR (international normalized ratio) of 1.4. Potential participants who have had a liver 
biopsy in the past 3 years are excluded if they had significant fibrosis of 3 or 4 as rated on 
a scale of 0-4 
4. Evidence of any bleeding disorder not related to Haemophilia A 
5. Platelet count of < 100 x 109/L 
6. Creatinine ≥ 1.5 mg/dL 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound  
8. Hepatitis B if surface antigen is positive 
9. Hepatitis C if RNA is positive 
10. Treatment with any IP within 30 days prior to the screening visit 
11. Any disease or condition at the physician’s discretion that would prevent the patient from 
fully complying with the requirements of the study.  The physician may exclude patients 
unwilling or unable to agree on not using alcohol for the 16-week period following the 
viral infusion. 
12. Receipt of any vector or gene transfer agent 
9.3.3 Removal of Patients from Treatment or Assessment 
Patients may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any patient who requests to be withdrawn. 
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 
BioMarin must be notified of all patient withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 

 
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reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or BioMarin may withdraw a patient from the study 
include, but are not limited to, the following: 
• Patient requires medication or medical procedure prohibited by the protocol 
• Patient does not adhere to study requirements specified in the protocol 
• Patient was erroneously admitted into the study or does not meet entry criteria 
• Patient is lost to follow-up 
If a patient fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the patient cannot be reached by telephone, a certified letter should 
be sent to the patient requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each patient, before enrollment into the study, 
that for evaluation of study results, the patient’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each patient. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the patient and the patient will 
be removed from the study. 
9.3.3.1 
Study Safety Evaluation Criteria 
If any of the following events occur (except the persistence of AAV5) in a patient in the 
study who has received BMN 270 infusion, an extensive safety analysis will be performed 
and BioMarin and the Principal Investigator will discuss pursuing the trial or increasing the 
time before the next patient is enrolled. 
• 
A 5-fold increase in ALT after BMN 270 administration 
• The occurrence of other drug-related Grade III-IV toxicity, including liver failure and 
clinical hepatitis 
• Drug-related Grade II toxicity that persists for at least 7 days 
• The occurrence of neutralizing antibodies to hFVIII following BMN 270 infusion 

 
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• The persistent detection of the AAV vector genome in the semen of a participant 
more than 26 weeks after BMN 270 infusion, as discussed in Section 9.7.8.5  
• The occurrence of a malignancy at any point after BMN 270 infusion that is assessed 
as possibly, probably, or definitely related to the study agent 
• Any unexplained serious adverse event ≥ grade 4 assessed as at least possibly related 
to study drug 
9.3.4 Patient Identification and Replacement of Patients 
Each patient will be assigned a unique patient identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Patients who withdraw from the study after Week 16 will not be replaced. 
9.3.5 Duration of Patient Participation 
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks. 
9.4 
Treatments 
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
9.4.2 Identity of Investigational Product 
9.4.2.1 
Product Characteristics and Labeling 
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 

 
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stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4 Directions for Administration 
After a physical exam performed by the PI or designee, participants will be admitted on the 
day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral vein 
(e.g. the median cubital vein) and flushed with saline. FVIII protein concentrate will not be 
given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
will be used to infuse through an in-line, low protein binding 0.22 micron filter. BMN 270 
will be infused through the catheter using an appropriate infusion pump while monitoring 
the vital signs (pulse, blood pressure, respiration rate and temperature) at 15 minute 
(± 5 minutes) intervals. The anticipated maximum interval from initiation of thawing of 
BMN 270 to completion of the infusion is 4 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard 
protocol for infusing FVIII concentrates. Patients will remain hospitalized for 24 hours to 
observe for any immediate toxicity of the procedure. After 24 hours of hospitalization, 
participants will be discharged unless toxicity has been observed in which case 
hospitalization may be extended or transfer to an outpatient facility may occur based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
9.4.5 Method of Assigning Patients to Treatment Groups 
Patients who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study patient. Upon their enrollment into the study, patients will be assigned a unique patient 
number and dose level by the Sponsor. 
Patients are enrolled serially and their dose is defined in Section 9.4.6.2 below. Escalation is 
based on FVIII activity 3 weeks after injection. Patients may receive the next higher dose if 
the previous patient does not meet the activity criteria, or the same dose if the previous 

 
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patient meets the activity criteria. Up to 6 patients can have the same dose, for a total of 
12 patients in this study.  
9.4.6 Selection of Doses Used in the Study 
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in non-human primates. The dose escalation is half-logs based.    
9.4.6.1 
Selection of Timing of Dose for Each Patient 
A minimum of three weeks are required between patients, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next patient will be made as described below.  
9.4.6.2 
Selection of Dose for Each Patient 
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus decreasing the risk of immune response), and a new evaluation of the 
titer (PCR performed after hairpin removal). 
Approximately three weeks after an injection, the decision to escalate to the next dose level 
will be made based on the review of safety parameters and FVIII activity by the Sponsor and 
a panel of investigators participating in the study.  
Patient 1 will be dosed with 6E12 vector genomes [vg] per kilogram of body weight. If the 
activity level does not reach ≥5 IU/dL at 21 days, then a higher dose (2E13 vg per kilogram) 
will be used for the next patient.  
If the activity level does not reach ≥5 IU/dL after Patient 2, then the highest dose 
(6E13 vg per kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and if no safety issue is found, then up to 
four patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no 
further dose escalation will take place, but additional patients will then be dosed at this dose 
level for a total of 6 patients per dose. 
Refer to Figure 9.1.1 for a visual representation of the study design. 
9.4.7 Blinding 
This is an open-label study. 

 
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9.4.8 Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a patient for 30 days before 
Screening will be recorded on the designated CRF. The Investigator may prescribe additional 
medications during the study, as long as the prescribed medication is not prohibited by the 
protocol. In the event of an emergency, any needed medications may be prescribed without 
prior approval, but the medical monitor must be notified of the use of any contraindicated 
medications immediately thereafter. Any concomitant medications added or discontinued 
during the study should be recorded on the CRF. 
The following medications are prohibited starting 30 days before Screening: 
• Live vaccines 
• Immunosuppressive agents 
Haemophilia treatments are discussed in the washout section below (Section 9.4.8.1). 
9.4.8.1 
Factor VIII Washout 
Patients will have a washout period of 72 hours prior to the BMN 270 infusion. If a bleeding 
occurs, another washout period of 72 hours will be performed. If another bleeding occurs 
during this second washout period, then the patient may be excluded from the study at the 
physician’s discretion.  
9.4.8.2 
Glucocorticoid Treatment of Elevated Hepatic Transaminases 
During the Post-Infusion Follow-up Period, each patient will have comprehensive 
surveillance plan monitoring LFTs once a week from dose to completion of Week 6, 3 times 
per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is 
found to be greater than 1.5x baseline during these periods, then LFTs will be monitored 
three times per week or until the ALT returns to baseline.  
Reports of abnormal LFTs (defined as 1.5x the patient’s baseline level) should be made to 
BioMarin within 24 hours of the lab value being available.  If the LFTs are abnormal, 
treatment with prednisolone initiated at a dose of 60 mg per day and then gradually tapered 
(60 mg daily for the first week, then 40 mg the second week, then 30 mg the third week, then 
20 mg the fourth week, then stop) will be started immediately. 
9.4.9 Treatment Compliance 
Study drug will be administered to patients at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided 
for the study.  Sites will be instructed to return all used and unused study drug containers. 

 
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9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, patients to whom IP is dispensed (patient-by-patient dose 
specific accounting), and IP lost or accidentally or deliberately destroyed. The Investigator or 
designee must retain all unused or expired study supplies until the study monitor (on-site 
CRA) has confirmed the accountability data. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a Study Drug Return Form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study. 
9.7 
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8. 
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post 
BMN 270 administration.  
9.7.1 Safety and Efficacy Measurements Assessed 
The Schedule of Events (Table 9.1.1) describes the timing of required evaluations. 

 
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9.7.2 Primary Efficacy Variables 
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to stable expression of FVIII at 5 IU/dL, 
i.e., a mild severity. This is associated in natural history studies with clinically superior long 
term outcomes (Nathwani, 1992, Baillieres Clin.Haematol.). 
To measure the primary efficacy variable, the following assays will be used: 
• FVIII activity (chromogenic FXa assay) 
• FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time) 
• Exploratory FVIII activity assay  
The FVIII activity level and the number of patients with FVIII activity ≥ 5 IU/dL will be 
summarized. 
Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3.  Details on 
performing the assays are included in the Laboratory Manual. 
9.7.3 Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Patients will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the patient’s diary or 
other patient records. 
Assessment of viral shedding at one week after BMN 270 infusion will also be considered an 
efficacy variable.  
9.7.4 Immunogenicity 
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
6-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to an immunogenicity assessment to determine anti-FVIII and 
capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be performed on 
collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3. 

 
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9.7.5 Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by 
one-stage APTT and/or chromogenic FXa assay (activity).  Individual antigen and activity 
plasma plots will be prepared to assess changes over 16 weeks.  FVIII activity measurements 
will be used to determine PD parameters. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), 
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology. 
Sample collection times are indicated in Table 9.1.2 and Table 9.1.3. 
9.7.6 Exploratory Biomarker Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1 and 
Table 9.1.2 to evaluate biochemical, molecular, cellular, and genetic/genomic aspects 
relevant to Haemophilia A disease.  The genetic/genomic testing on these exploratory 
samples is optional. 
9.7.7 Quality of Life Assessment 
A patient-reported outcome (PRO) questionnaire will be used to assess subject quality of life 
(QoL) during the study.  Assessments will occur at the time points listed in the Schedules of 
Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual. 
9.7.8 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
9.7.8.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the patient signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1.   

 
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9.7.8.2 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1. The scheduled clinical laboratory tests are listed in Table 9.7.8.2.1. Refer to the 
Study Reference Manual for instructions on obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
All abnormal clinical laboratory result pages should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF. 

 
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Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Haematology 
Urine Tests 
Other 
Albumin  
Haemoglobin  
Appearance 
CRP 
Alkaline phosphatase  Haematocrit  
Color 
 
ALT (SGPT) 
WBC count 
pH 
Coagulation Screen 
including: 
AST (SGOT) 
RBC count 
Specific gravity 
APTT 
Direct bilirubin 
Platelet count 
Ketones 
PT/INR 
Total bilirubin 
Differential cell count  Protein  
TT 
BUN 
 
Glucose  
 
Calcium 
 
Bilirubin 
 
Chloride 
 
Nitrite 
 
Total cholesterol 
 
Urobilinogen 
 
CO2 
 
Haemoglobin 
 
Creatinine 
 
 
 
Glucose 
 
 
 
GGT 
 
 
 
LDH 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Total protein  
 
 
 
Sodium  
 
 
 
Uric acid  
 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon 
dioxide; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; 
SGPT, serum glutamic-pyruvic transaminase; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating 
hormone; WBC, white blood cell; TT, thrombin time; INR, international normalized ratio. 
 
9.7.8.3 
Liver function and Hepatitis Testing 
Patients will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening. If medical records showing no evidence of Hepatitis B or Hepatitis C infection 
from the previous 30 days are available, then the Screening tests do not need to be done.   

 
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Evidence of ongoing infection (positive surface antigen for hepatitis B or positive RNA 
testing for hepatitis C) will be an exclusion criteria. If these parameters are negative and 
therefore no active infection is detected, then the patients may be included if they were 
vaccinated (for hepatitis B) or cleared the infection (for hepatitis C) and their liver function is 
acceptable.  
A liver ultrasound and liver function testing at Screening will identify any significant hepatic 
dysfunction, which is defined as: 
• More than 3x the normal ALT level 
• More than 3x the normal bilirubin level 
• Alkaline phosphatase above the normal cut off. 
• INR over 1.4.  
• Thrombocytopoenia under 100 x 109/L 
9.7.8.4 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE. 
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored hourly for 6 hours and then every 2 hours for 6 hours 
and then at 4 hour intervals.  
A complete physical examination is necessary during Screening/Baseline; thereafter, brief 
physical examinations may be performed at the discretion of the investigator based on the 
patient’s clinical condition. Particular attention should be given to signs of bleeding, as well 
as assessing possible hemarthroses. 
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems (level of consciousness, speech, language, cranial 
nerves, motor strength, motor tone, abnormal movements, reflexes, upper extremity 
sensation, lower extremity sensations, gait, Romberg, nystagmus, and coordination). 
A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 

 
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Weight and height will be recorded at Screening only. 
9.7.8.5 
Viral Shedding 
Viral shedding has been extensively studied in all similar clinical trials performed to date. 
(Nathwani, 2014, N.Eng.J.Med (Supplemental Appendix); Manno, 2006, Nature Med. 
(Supplemental Appendix); Schenk-Braat, 2007, J Gene Med; Croteau, 2004, Ann Occup 
Hyg). It has been constantly shown that the vector was not detectable anymore at 40 days, 
with its persistence in semen for 16 weeks in the seminal fluid but not in motile sperm 
(Manno, 2006, Nature Med.).  In addition, it has always involved only an extremely small 
fraction of the injected dose.  
Viral shedding will also be extensively studied in the present clinical trial, every week up to 
16 weeks, then every 4 weeks to one year, then every three months.  During the Post-Infusion 
Follow-Up period, patients will undergo testing of various bodily fluids to look for evidence 
of viral shedding for possible viral transmission.  Bodily fluids will be tested by PCR at the 
time points indicated in Table 9.1.2 and Table 9.1.3.  Fluids tested will include: 
• Blood 
• Saliva 
• Semen 
• Urine 
• Stool 
Details for sample collection and storage are provided in the Laboratory Manual. 

 
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10 
REPORTING ADVERSE EVENTS 
10.1     Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a patient administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
• AEs not previously observed in the patient that emerge during the course of the study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures, medication washout, or no-treatment 
run-in). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only 
because the patient is a haemophiliac) should not be recorded as AEs but will instead be 
captured in patient diaries.  Bleeding events that occur where a normal 
(ie, non-haemophiliac) patient would bleed, such as bleeding as a result of trauma, should be 
recorded as adverse events.  All bleeding events which meet criteria for being serious should 
be reported as serious adverse events (SAEs) whether or not they are bleeding events that are 
normal sequelae of haemophilia. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 

 
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10.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening  
Note: Life-threatening refers to an event that places the patient at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires or prolongs inpatient hospitalization.  Hospitalization for less than 24 hours 
will not be considered to be an SAE. Hospitalization solely for the purpose of 
insertion of an in-dwelling IV catheter (such as a Port-a-Cath or other brand) for 
administration of study drug will not be considered an SAE. 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect in the child or fetus of a patient exposed to IP 
prior to conception or during pregnancy 
• 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the patient or require intervention to prevent one of  the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as non-
serious AEs. 
10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• Elevation of liver enzymes triggering a corticosteroid treatment 
10.3 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.3.1 Adverse Event Reporting Period 
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.2.  

 
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10.3.2 Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs and EOSI, at each patient contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the patient’s medical record and on the AE Case Report 
Form (eCRF). 
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the patient or qualified designee will assess AEs 
for severity, relationship to study drug, and seriousness (refer to Section 10.2 for SAE 
definitions).  These assessments should be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.3.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.3.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1. 
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 

 
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Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden. 
 
10.3.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1. 
Table 10.3.3.3.1:  Causality Attribution Guidance 
Relationship 
Description 
Not Related 
• 
Exposure to the IP has not occurred 
OR 
• 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
OR 
• 
The AE is considered likely to be related to an etiology other than the use 
of the IP; that is, there are no facts, evidence, or arguments to suggest a 
causal relationship to the IP. 
Related 
• 
The administration of the IP and the occurrence of the AE are reasonably 
related in time 
AND 
• 
The AE could possibly be explained  by factors or causes other than 
exposure to the IP 
                                      
 
OR 
• 
The administration of IP and the occurrence of the AE are reasonably 
related in time  
AND 
• 
The AE is more likely explained by exposure to the IP than by other 
factors or causes. 
 

 
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Factors suggestive of a causal relationship could include (but are not limited to): 
• Plausible temporal relationship 
• Absence of alternative explanations 
• Rarity of event in a given patient or disease state 
• Absence of event prior to study drug exposure 
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.4.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE eCRF, replacing the original entries where 
appropriate. 

 
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10.4.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points.  Such an event should be recorded only once on the AE eCRF unless 
its severity increases or decreases (in which case it should be recorded again on the AE 
eCRF). 
A recurrent AE is one that occurs and resolves between patient evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.4.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the AE eCRF. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as AE if any of the following conditions is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
• The laboratory abnormality persists upon repeat confirmatory testing.  
• The abnormality suggests a disease and/or organ toxicity 

 
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• The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed. 
10.4.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.4.1.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.4.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 

 
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• Perform a protocol-mandated efficacy measurement 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
• Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9 
Pregnancy 
Although not an AE per se, pregnancy in the partner of a patient taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by faxing the Pregnancy Form in the study reference materials to BPV.  
The Investigator must make every effort to follow the patient through resolution of the 
pregnancy (delivery or termination) and to report the resolution on the Pregnancy Follow-up 
Form in the study reference materials. In the event of pregnancy in the partner of a study 
patient, the Investigator should make every reasonable attempt to obtain the woman’s 
consent for release of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5 
Reporting Requirements 
10.5.1 Expedited Reporting Requirements 
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF  and submitting  to BioMarin Pharmacovigilance (BPV) 

 
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within 24 hours of the site becoming aware of the event.  Investigators should not wait to 
collect information that fully documents the event before notifying BPV of an SAE.  
BioMarin may be required to report certain SAEs to regulatory authorities within 7 calendar 
days of being notified about the event; therefore, it is important that Investigators submit any 
information requested by BioMarin as soon as it becomes available. 
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF. 
The reporting period for SAEs begins after informed consent is obtained and the first 
administration of study drug is given.  It continues for approximately 5 years or until study 
discontinuation/termination, whichever is longer.  
10.5.2 Ethics Committee Reporting Requirements 
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required. 
10.6 
Follow-up of Patients after Adverse Events 
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the patient is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the patient’s medical record to facilitate source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.7 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each patient to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the patient’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a patient has discontinued or terminated study participation, if the Investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 

 
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also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that participated in this 
study.  
10.8 
Urgent Safety Measures 
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect patients against any immediate hazards 
that may affect the safety of patients, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• 
Immediate need to revise the IP administration (eg, modified dose amount or frequency 
not defined in protocol) 
• 
Lack of study scientific value, or detrimental study conduct or management 
• 
Discovery that the quality or safety of the IP does not meet established safety 
requirements 
 
 

 
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10.9 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
 
Address: 
105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
E-mail: 
 
 
PI
PI
PI
PI
PI

 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
 

 
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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed. 
12.2 
Screening Visit 
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place a within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, haematology, urine tests, coagulation screen, and CRP do not 
need to be repeated at Baseline.  
The following procedures will be performed during the Screening Period: 
• Full medical history, including haemophilia A history, Hepatitis B, Hepatitis C, and 
HIV. Patients with documented negative results within the last 30 days do not need to 
be retested. 
• Complete Physical Exam (including height and weight) 
• Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature)  
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either patient or clinical 
information) 
• Electrocardiogram 
• Chest X-ray 
• Liver Ultrasound 
• Samples for hFVIII Assays 
o Baseline hFVIII activity – chromogenic FXa (plasma) (at least 72 hours 
off therapy) 
o Baseline hFVIII activity level – one-stage APTT assay (at least 72 hours 
off therapy) 
o hFVIII coagulation activity exploratory assay 
o hFVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay 

 
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o hFVIII antigen (ELISA) 
• Blood sample for AAV5 Assays 
o AAV5 antibody titer 
o AAV5 transduction inhibition assays 
• Screen for Hepatitis B, Hepatitis C, and HIV if required  
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• Blood samples for Biomarker testing (HLA typing, FVIII mutation status, TNFα and 
IL10a single nucleotide polymorphisms) 
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either patient or clinical 
information) 
• FVIII Treatment Washout (refer to Section 9.4.8.1) 
• Samples for FVIII Assays 
o FVIII activity – chromogenic FXa (plasma) (at least 72 hours off therapy) 
o FVIII activity level –APTT One stage assay (at least 72 hours off therapy) 
o FVIII coagulation activity exploratory assay 
o FVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o FVIII antibody assay 
o FVIII antigen (ELISA) 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• Mononuclear cell collection for CTL baseline 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
• Exploratory biomarker assessments 
• QoL assessment 

 
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12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each patient.  Patients will be hospitalized for 24 hours 
for the BMN 270 Infusion Visit.  The following procedures will be performed during the 
BMN 270 Infusion Visit: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
o AAV5 antibody titer 
o AAV5 transduction inhibition assays 
• BMN 270 Infusion 
• Vital Signs 
o Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the patient’s 
hospitalization. 
12.5 
BMN 270 Infusion Follow-Up Visits 
After BMN 270 has been infused, patients will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Every Visit 
Every week (Weeks 1 through 16), the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
o Each patient will have comprehensive surveillance plan monitoring LFTs 
once a week from dose to completion of Week 6, 3 times per week (every 
other day excluding weekends) from Weeks 7 to 12, and once a week from 
Weeks 13 to 16.  If a patient’s ALT is found to be greater than 1.5x 
baseline during these periods, then LFTs will be monitored three times per 
week or until the ALT returns to baseline. 

 
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• Samples for FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• FVIII antibody titer 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Collection to occur on Day 1, 3, 7 following BMN 270 infusion, and then 
weekly until 3 consecutive negative results are obtained 
• Exploratory biomarker assessments 
12.5.2 Every 4 Weeks 
Every 4 weeks (Weeks 4, 8, 12, and 16), the following procedure will be performed: 
• Mononuclear cell collection 
12.5.3 Weeks 1, 3, and 6 
At Weeks 1, 3, and 6, the following procedure will be performed: 
• Test for Hepatitis B and Hepatitis C reactivation 
12.5.4 Weeks 1, 8, and 16 
At Weeks 1, 8, and 16, the following procedure will be performed: 
• AAV5 antibody titer 
12.5.5 Weeks 1, 2, 3, 4, and 16 
At Weeks 1, 2, 3, 4, and 16, the following procedure will be performed: 
• QoL assessment 
12.6 
Safety Follow-Up – Year 1 
After the 16 weekly infusion follow-up visits are complete, subjects will return to the study 
site at Weeks 20, 28, 36, 44, and 52 (± 48 hours), when the following procedures will be 
completed: 

 
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12.6.1 Every Visit 
At Weeks 20, 28, 36, 44, and 52, the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if 3 consecutive 
samples are clear during the Post-Infusion Follow-Up period. 
12.6.2 Weeks 28 and 52 
At Weeks 28 and 52, the following procedure will be performed: 
• QoL assessment 
12.7 
 Safety Follow-Up – Years 2-5 
During Years 2-5 of Safety Follow-up, patients will be assessed every 3 months (± 72 hours). 
At these times, the following procedures will be completed: 
12.7.1 Every Visit 
Every 3 months (± 72 hours), the following procedures will be performed: 
• Physical exam 

 
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o Complete Physical Exam will be performed every 52 weeks; Brief 
Physical Exams may be performed at other visits. 
• Assessment of Adverse Events and Concomitant Medications 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (FXa chromogenic assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if 3 consecutive 
samples are clear during the Post-Infusion Follow-Up period. 
• Vital Signs 
12.7.2 Every Other Visit (Every 6 Months) 
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the 
end of Year 1 of the Safety Follow-up period), the following procedure will be performed: 
• QOL assessment 
12.8 
Early Termination Visit 
The Early Termination visit will occur on the date the patient withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a patient leaves the study prior to the Week 270 visit, the patient will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 

 
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• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing at the ETV is not required if 3 consecutive samples are 
clear during the Post-Infusion Follow-Up period. 
• Vital Signs 
• QOL assessment 
12.9 
End of Study 
The study will end after the last patient completes the last Safety Follow-Up visit 
(Week 270). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study patients may be 
compromised. 
 

 
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13 
DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
The designated clinical data management group will enter or transfer CRF data into a study 
database. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all patients having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16). 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Missing data will not be imputed.  
14.2 
Primary and Secondary Efficacy Analysis 
The patients will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of patients, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined. 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay 
between 1 to 16 weeks following study treatment.  hFVIII activity will be assessed weekly 
during the study period.  We can only assess the true steady state of hFVIII protein produced 
from BMN 270 after a minimum of 72 hours has elapsed since the last infusion of FVIII 
protein concentrates. 
14.3 
Immunogenicity 
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons 
across doses. 

 
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14.4 
Pharmacodynamic Analyses 
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage APTT and/or chromogenic FXa assay (activity level), will be used for plasma 
profiles; FVIII activity will be used to determine PD parameters.  Traditional PK analysis is 
not applicable. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics.  
14.5 
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-patient listing will 
be provided for those patients who experience a serious AE (SAE), including death, or 
experience an AE associated with early withdrawal from the study or study drug. Hepatitis is 
of interest, and the percentage of patients who report hepatitis will be presented. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent 
visits. Descriptive statistics for physical examination results and vital signs will also be 
provided.  
Detailed statistical methods will be provided in the SAP. 
14.6 
Determination of Sample Size 
No formal sample size calculations based on statistical power were performed. 
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 12 patients may be dosed in the study; the actual number of 
patients will depend on the criteria for dose escalation. A total of 6 patients may be enrolled 
at a single dose level. 

 
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14.7 
Analysis Populations 
The Safety analysis population is defined as all enrolled patients who receive any study drug. 
The analysis of safety data will be performed on Safety Set. 
The Full Analysis Set (FAS) is defined as all enrolled patients who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis. 
14.8 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a patient’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on patient risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to patients, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active patients must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 

 
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15 
DATA MONITORING COMMITTEE 
There will be no DMC for this study, however a safety and efficacy evaluation board 
composed of the investigators and sponsor will be established. The primary responsibility of 
the board will be to assess patient’s safety and efficacy data accumulated for a particular dose 
level and to make recommendations regarding dose escalation.  
 
 

 
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16 
COMPENSATION, INSURANCE AND INDEMNITY 
There will be no charge to study patients to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study patient’s disease, that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected. 
The Investigator should contact BioMarin immediately upon notification that a study patient 
has been injured by the IP or by procedures performed as part of the study. Any patient who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The patient should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the patient’s health insurance company or other third party 
payer for the cost of this medical treatment. If the patient has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law. 

 
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17 
CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each patient. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy. 
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and patient records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Patients must also allow access to 
their medical records, and patients will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
patient records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification. 
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a patient’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 

 
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completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 

 
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18 
STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study patients, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 

 
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19 
RETENTION OF RECORDS 
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, patient charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain patient identifiers for at least 15 years after the completion or discontinuation of 
the study. Patient files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
patient files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained. 

 
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20 
USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  

 
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21 
REFERENCES 
Bainbridge JW, Smith AJ, Barker SS et al. Effect of gene therapy on visual function in Leber's congenital 
amaurosis. N.Engl.J.Med. 2008;358:2231-2239. 
Berntorp E, Halimeh S, Gringeri A, et al.  Management of bleeding disorders in children.  Haemophilia.  
2012; 18 (Suppl. 2):15-23. 
Croteau GA, Martin DB, Camp J et al.  Evaluation of Exposure and Health Care Worker Response to 
Nebulized Administration of tgAAVCF to Patients with Cystic Fibrosis.  Ann. Occup. Hyg. 2004; 
48[8]:673-681. 
D’Avola D, Lopez-Franco E, Harper P, et al.  Phase 1 Clinical Trial of Liver Directed Gene Therapy with 
rAAV5-PBGD in Acute Intermittent Porphyria: Preliminary Safety Data.  J. Hepatology.  2014;60[1]:S58. 
Maguire AM, High KA, Auricchio A et al. Age-dependent effects of RPE65 gene therapy for Leber's 
congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009;374:1597-1605. 
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in 
severe hemophilia A. Blood. 2014; 123: 317-325. 
Manno CS, Chew AJ, Hutchison S, et al.  AAV-mediated factor IX gene transfer to skeletal muscle in 
patients with severe hemophilia B.  Blood.  2003;101:2963-2972. 
Manno CS, Arruda VR, Pierce GF, et al.  Successful transduction of liver in hemophilia by AAV-Factor 
IX and limitations imposed by the host immune response.  Nature Med. 2006;12:342-347 and 
Supplemental Appendix, available at: http://www.nature.com/nm/journal/v12/n3/extref/nm1358-S3.pdf. 
McIntosh J, Lenting PJ, Rosales C, et al.  Therapeutic levels of FVIII following a single peripheral vein 
administration of rAAV vector encoding a novel human factor VIII variant.  Blood.  2013;121:3335-3344. 
Nagel K, Walker I, Decker K, et al. Comparing bleed frequency and factor concentrate use bewteen 
haemophilia A and B patients. Haemophilia. 2011 17: 872-4 
Nathwani AC, Tuddenham EG. Epidemiology of coagulation disorders. Baillieres Clin.Haematol. 
1992;5:383-439. 
Nathwani AC, McIntosh J, Davidoff AM. An update on gene therapy for hemophilia. Curr.Hematol Rep. 
2005;4:287-293. 
Nathwani AC, Rosales C, McIntosh J et al. Long-term Safety and Efficacy Following Systemic 
Administration of a Self-complementary AAV Vector Encoding Human FIX Pseudotyped With Serotype 
5 and 8 Capsid Proteins. Mol.Ther. 2011;19:876-885. 
Nathwani AC, Tuddenham EG, Rangarajan S et al. Adenovirus-associated virus vector-mediated gene 
transfer in hemophilia B. N.Engl.J.Med.  2011;365:2357-2365. 
Nathwani AC, Reiss UM, Tuddenham EGD, et al.  Long-Term Safety and Efficacy of Factor IX Gene 
Therapy in Hemophilia B.  N.Engl.J.Med. 2014;371:1994-2004 and Supplemental Appendix, available at:  
http://www.nejm.org/doi/suppl/10.1056/NEJMoa1407309/suppl_file/nejmoa1407309_appendix.pdf. 

 
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Paneda A, Venrell L, Mauleon I, et al.  Effect of Adeno-Associated Virus Serotype and Genomic Structure 
on Liver Transduction and Biodistribution in Mice of Both Genders.  Hum.Gene Ther.  2009;20:908-917. 
Paneda A, Lopez-Franco E, Kaeppel C, et al.  Safety and Liver Transduction Efficacy of rAAV5-
cohPBGD in Nonhuman Primates: A Potential Therapy for Acute Intermittent Porphyria.  Hum.Gene 
Ther.  2013;24:1007-1017. 
Pipe SW. Go long! A touchdown for factor VIII? Blood. 2010;116:153-154. 
Schenk-Braat EA, van Mierlo MM, Wagemaker G et al.  An inventory of shedding data from clinical gene 
therapy trials.  J Gene Med. 2007; 9:910-921. 
Simonelli F, Maguire AM, Testa F et al. Gene therapy for Leber's congenital amaurosis is safe and 
effective through 1.5 years after vector administration. Mol.Ther. 2010;18:643-650. 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.  Guidelines for the management of hemophilia.  
Haemophilia.  2012:1-47. 
Stonebraker JS, Brooker M, Amand RE, et al. A study of reported factor VIII use around the world. 
Haemophilia. 2010;16:33-46. 

 
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22 
INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Patients  
In accordance with FDA Form 1572, the Investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and IRB 
review and approval in 21 CFR Part 56 are met.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312. 

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06 March 2015 
24 PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (See pages 2-3).  Text 
that has been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font. 
Section No./Title 
Text Revisions 
2/Synopsis (Objectives) 
Rationale 
The primary objectives of the study are: 
• 
To assess the safety of a single intravenous administration of a recombinant AAV5 encoding human coagulation FVIII 
(AAV5-SQ-codop-hFVIII-SQ
• 
To determine the dose of AAV5-SQ-codop-hFVIII
) vector.  
-SQ
The secondary objectives of the study are: 
 required to achieve expression of FVIII at or above 5% of 
normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and magnitude of AAV-mediated FVIII 
activity in individuals with haemophilia A will be determined and correlated to an appropriate BMN 270 dose. 
• 
To describe the immune response to the FVIII transgene and AAV capsid proteins following systemic administration of 
rAAV5-SQ-codopAAV5-hFVIII
2 
-SQ 
2/Synopsis (Diagnosis 
and All Criteria for 
Inclusion and 
Exclusion) 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe haemophilia A as evidenced by their medical history.  Patients 
will be considered as severe if their FVIII levels have ever declined tobaseline level is
 
 1 IU/dL or less 
5 
2/Synopsis (Diagnosis 
and All Criteria for 
Inclusion and 
Exclusion) 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
12.  
1 
Receipt of any vector or gene transfer agent 
2/Synopsis (Statistical 
Methods) 
We can only assess the true steady state of FVIII protein produced from BMN 270 after a minimum of 9672
6 
 hours has elapsed 
since the last infusion of FVIII protein concentrates. 
8/Study Objectives 
The primary objectives of the study are: 
• 
To assess the safety of a single intravenous administration of a recombinant AAV5 encoding human coagulation FVIII 
(AAV5-SQ-codop-hFVIII-SQ
• 
To determine the dose of AAV5-SQ-codop-hFVIII
) vector.  
-SQ
2 
 required to achieve expression of hFVIII at or above 5% of 

 
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Section No./Title 
Text Revisions 
normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration and magnitude of AAV-mediated hFVIII 
activity in individuals with haemophilia A will be determined and correlated to an appropriate BMN 270 dose. 
Rationale 
The secondary objectives of the study are: 
• 
To describe the immune response to the hFVIII transgene product and AAV capsid proteins following systemic 
administration of rAAV5-SQ-codopAAV5-hFVIII
9.3.1/Inclusion Criteria 
-SQ 
Individuals eligible to participate in this study must meet all of the following criteria: 
1.  Males that are 18 years or older with established severe Haemophilia A as evidenced by their medical history.  Patients will be 
considered as severe if their FVIII levels have ever declined tobaseline level is 
 
 1 IU/dL or less 
5 
9.3.2/Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
1 
12.  Receipt of any vector or gene transfer agent 
9.4.8.1/FVIII Washout 
Patients will have a washout period of 72 hours 
6 
prior to the BMN 270 infusion. 
9.4.8.2/Glucocorticoid 
Treatment of Elevated 
Hepatic Transaminases 
Reports of abnormal LFTs (defined as 1.5x the patient’s baseline level) should be made to BioMarin within 24 hours of the lab 
value being available.  If the LFTs are abnormal, treatment with prednisolone initiated at a dose of 60mg60 mg per day and then 
gradually tapered (60 mg daily for the first week, then 40 mg the second week, then 30 mg the third week, then 20 mg the fourth 
week, then stop) 
 
will be started immediately. 
6 
9.7.8.5/Viral Shedding 
Viral shedding has been extensively studied in all similar clinical trials performed to date. (; ;(Nathwani, 2014, N.Eng.J.Med 
(Supplemental Appendix); Manno, 2006, Nature Med.(Supplemental Appendix);
3/4/6 
 Schenk-Braat, 2007, J Gene Med; Croteau, 
2004, Ann Occup Hyg). 
 
10.4.1.4/Abnormal 
Laboratory Values 
A clinical laboratory abnormality is considered clinically significant and 
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality
should be documented as AE if any of the following 
conditions is met: 
persists upon repeat 
confirmatory testing.
6 
  

 
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Section No./Title 
Text Revisions 
 
Rationale 
10.4.1.9/Pregnancy 
Although not an AE per se, pregnancy in the partner of a patient taking trial medication should be reported as an 
SAEexpeditiously to the Sponsor
Pregnancy in partner should be reported within 24 hours of the site becoming aware of the pregnancy by faxing the Pregnancy 
Form in the study reference materials to BPV.  In addition, pregnancy in a patient is also reported on the End of Study eCRF. 
 to facilitate outcome monitoring by the Sponsor.  Pregnancy in partner should be reported 
during the period up to 5 years after viral infusion. 
6 
12.2/Screening Visit 
• 
Samples for hFVIII Assays 
o 
Baseline hFVIII activity – chromogenic FXa (plasma) (at least 9672
o 
Baseline hFVIII activity level –one-stage APTT assay (at least 96
 hours off therapy) 
72
• 
FVIII Treatment Washout (refer to Section 
 hours off therapy) 
9.4.8.1) 
6 
12.3/Baseline Visit 
• 
Samples for FVIII Assays 
o 
FVIII activity – chromogenic FXa (plasma) (at least 9672
o 
FVIII activity level –APTT One stage assay (at least 96
 hours off therapy) 
72
• 
 hours off therapy) 
6 
FVIII Treatment Washout (refer to Section 9.4.8.1) 
12.4/Treatment Visit 
• 
o 
Blood sample for AAV5 Assays (must be performed before the BMN 270 infusion) 
o 
AAV5 antibody titer 
6 
AAV5 transduction inhibition assays 
14.2/Primary and 
Secondary Efficacy 
Analysis 
We can only assess the true steady state of hFVIII protein produced from BMN 270 after a minimum of 9672
 
 hours has elapsed 
since the last infusion of FVIII protein concentrates. 
6 
21/References 
Manno CS, Arruda VR, Pierce GF, et al.  Successful transduction of liver in hemophilia by AAV-Factor IX and limitations 
imposed by the host immune response.  Nature Med. 2006;12:342-347 and Supplemental Appendix, available at: 
http://www.nature.com/nm/journal/v12/n3/extref/nm1358-S3.pdf.
3/6 
. 

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BioMarin is a registered trademark of BioMarin Pharmaceutical Inc. 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study 
of BMN 270, an Adenovirus-Associated Virus Vector–Mediated 
Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
Protocol Number: 
270-201 
Active Investigational 
Product: 
AAV5-hFVIII-SQ 
IND/European Union 
Drug Regulating 
Authorities Clinical Trials 
(EudraCT) Number: 
2014-003880-38 
 
Indication: 
Haemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 1/2 
Sponsor's Responsible 
Medical Monitor: 
 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Duration of Patient 
Participation: 
Approximately 264 weeks 
Dose: 
Varied 
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
10 February 2015 
Property of BioMarin 
CONFIDENTIAL 
 
May not be divulged, published, or otherwise disclosed to others without prior written approval from 
BioMarin. 
 
This study will be conducted according to the principles of Good Clinical Practice as described in the 
U.S. Code of Federal Regulations and the International Conference on Harmonisation Guidelines, 
including the archiving of essential documents. 
 
PI
PI

 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
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AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  
A Phase 1/2, Dose-Escalation Safety, Tolerability and Efficacy Study of BMN 270, an Adenovirus-
Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Patients with Severe 
Haemophilia A 
PROTOCOL NUMBER: 
270-201 
STUDY SITES: 
Approximately 6-10 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 1/2 
STUDY RATIONALE: 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 
males.  It is caused by deficiency in the activity of coagulation factor VIII (FVIII), an essential 
cofactor in the intrinsic coagulation cascade. This disorder can be either inherited, due to a new 
mutation or an acquired immunologic process, leading to insufficient quantities of FVIII or a 
dysfunctional FVIII, but all are characterized by a defective coagulation process.  The clinical 
phenotype of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease comprises 1-5% of 
wild type activity and the mild form is 5-40% activity. The clinical manifestations of severe HA 
remain frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a 
substantially increased risk of death from haemorrhage when the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or recombinant 
FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, and at the time of a 
bleed, to prevent or control bleeding episodes, respectively. The half-life for rhFVIII (under 24 hours 
for most approved products) necessitates frequent infusions, and although a major advance in the 
treatment of HA, it remains common for severe HA patients to continue to have multiple bleeding 
events on treatment (mean of 1 to 7 episodes/year with prophylaxis up to 30 to 50 for on demand 
treatment).  The consequence of multiple bleeding events is the development of an underlying 
pathology that contributes to debilitating multiple-joint arthropathy and substantially increased risk of 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
death. Chemical modification (e.g. direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve half-life by approximately 50%, and 
thus, show promise in reduced dosing and maintaining activity levels above 1% trough. However, 
these longer acting FVIIIs remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive treatment 
of HA to give patients a FVIII level compatible with a normal and haemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous production 
of active FVIII following a single intravenous administration of a vector with the appropriate gene 
sequence. Haemophilia A is well suited for a gene replacement approach because clinical 
manifestations are attributable to the lack of a single gene product (FVIII) that circulates in minute 
amounts (200 ng/ml) in the plasma. Tightly regulated control of gene expression is not essential, and 
modest increases in the level of FVIII (any increase of the plasma level by 2 ng/ml induces an increase 
in activity of 1%) can ameliorate the severe form of the disease.  Thus, relatively small changes in 
endogenous FVIII activity results in clinically relevant improvements in disease phenotype. Finally, 
the response to gene transduction can be assessed using validated quantitative rather than qualitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise. They have an excellent and well 
defined safety profile, and can direct long term transgene expression with tropism for specific tissues 
such as the liver (for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical 
trial for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild is achievable following a single peripheral vein administration of AAV-8 vector. 
Several participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous haemorrhages, even when they undertook activities that previously resulted in bleeding. 
Thus, gene therapy treatment has resulted in a substantial improvement in their quality of life.  
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII under the 
control of a liver-selective promoter (Figure 1).  
 
 
 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
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AUTHORITY USE 
ONLY: 
Figure 1. BMN 270 transgene construct, ~5.0 kbp 
 
BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, potentially 
life-long expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
The clinical study BMN 270-201 is a first-in-human study designed to assess the relationship of vector 
dose to the augmentation of residual FVIII activity, and whether these levels are sufficient to alter the 
clinical phenotype. The relationship of dose to safety will be correlated to the activity of hFVIII in 
patients with severe HA. 
OBJECTIVES:  
The primary objectives of the study are: 
• 
To assess the safety of a single intravenous administration of a recombinant AAV5 encoding 
human coagulation FVIII (AAV5-SQ-codop-hFVIII) vector.  
• 
To determine the dose of AAV5-SQ-codop-hFVIII required to achieve expression of FVIII at 
or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The kinetics, duration 
and magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be 
determined and correlated to an appropriate BMN 270 dose. 
The secondary objectives of the study are: 
• 
To describe the immune response to the FVIII transgene and AAV capsid proteins following 
systemic administration of rAAV5-SQ-codop-hFVIII 
• 
To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during the 
study 
• 
To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment 
during the study 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STUDY DESIGN AND PLAN:  
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe haemophilia 
A. Eligible patients will enter the dose escalation part of the study followed by a 16-week 
Post-Infusion Follow-Up period during which safety and efficacy assessments will be taken. After the 
primary endpoint analysis at 16 weeks, safety and efficacy will then be assessed for approximately 
5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe HA, and do 
not have transduction inhibition activity to AAV5 will be eligible to enroll in the study. Participants 
will be enrolled sequentially into one of up to three cohorts according to dose level:  
1. 6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous dose 
(iv) 
2. 2E13 vg per kilogram, iv 
3. 6E13 vg per kilogram, iv 
 
Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose escalation may 
occur after a single patient has been safely dosed if the resulting FVIII activity at Week 3 is < 5 IU/dL. 
Three weeks is expected to be the time the expression will be close to the maximum.  This escalation 
paradigm is intended to minimize the patient numbers exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical studies of 
mice and monkeys.  The starting dose has a significant safety margin (10-fold) from no observed 
adverse effect level (NOAEL) in non-human primates.   
Approximately three weeks after an injection, the decision to escalate to the next dose level will be 
made based on the review of safety parameters and FVIII activity by the Sponsor and a panel of 
investigators participating in the study.  
If the FVIII activity is ≥ 5 IU/dL, then the other patients of the dose group will be enrolled without 
waiting for 3 weeks between patients. 
Patient 1 will be dosed by intravenous perfusion with 6E12 vector genomes [vg] per kilogram of body 
weight. If the activity level does not reach ≥ 5 IU/dL at 21 days, then a higher dose (2E13 vg per 
kilogram) will be used for the next patient.  
If the activity level does not reach ≥ 5 IU/dL after Patient 2, then the highest dose (6E13 vg per 
kilogram) will be used for the next patient.  

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
For each dose, if the activity level reaches 5 IU/dL and no safety issue is found, then up to four 
patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no further dose 
escalation will take place, but additional patients will then be dosed at this dose level for a total of 
6 patients per dose. 
Because patients develop neutralizing immunity upon exposure to the capsid, re-challenge of vector is 
not a treatment option and these patients have effectively a single opportunity for therapy using this 
AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks post dose. Safety will be 
evaluated for approximately 5 years after dose.  Any safety signal will trigger a review of the data and 
possible additional analysis including mononuclear collection. 
NUMBER OF PATIENTS PLANNED:  
Up to 12 patients may enroll into the study; the actual number of patients will depend on the criteria 
for dose escalation. A total of 6 patients may be enrolled at a single dose level. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe haemophilia A as evidenced by their 
medical history.  Patients will be considered as severe if their FVIII levels have ever declined 
to 1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitates for a minimum of 150 exposure 
days (EDs) 
3. Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 12 months 
using a modified Nijmegen Bethesda assay higher than 0.6 Bethesda Unit (BU) 
6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months 
post-treatment 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction 
inhibition and AAV5 total antibodies  
2. Evidence of detectable viral load of HIV  
3. Significant liver dysfunction as defined by abnormal elevation of ALT (alanine transaminase) 
to 3 times the upper limit of normal, bilirubin, alkaline phosphatase, or an INR (international 
normalized ratio) of 1.4. Potential participants who have had a liver biopsy in the past 3 years 
are excluded if they had significant fibrosis of 3 or 4 as rated on a scale of 0-4 
4. Evidence of any bleeding disorder not related to Haemophilia A 
5. Platelet count of < 100 x 109/L 
Creatinine ≥ 1.5 mg/dL 
6. Liver cirrhosis of any etiology as assessed by liver ultrasound  
7. Hepatitis B if surface antigen is positive 
8. Hepatitis C if RNA is positive 
9. Treatment with any IP within 30 days prior to the screening visit 
10. Any disease or condition at the physician’s discretion that would prevent the patient from fully 
complying with the requirements of the study.  The physician may exclude patients unwilling 
or unable to agree on not using alcohol for the 16-week period following the viral infusion. 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each patient will receive a single injection of BMN 270 as an intravenous infusion. The volume of 
infusion will depend on the dose level. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
The study is open label with comparison of FVIII activity to baseline values. No reference therapy will 
be evaluated in this study. 
DURATION OF TREATMENT:  
BMN 270 is given as a single dose by intravenous perfusion. 
CRITERIA FOR EVALUATION: 
The following safety outcome measurements will be assessed: 
Safety: 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
• 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
• 
Change in clinical laboratory tests (serum chemistry and haematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding 
• 
Liver function tests (LFT) 
 
No major toxicity is expected based on preclinical studies in mice and monkeys. An asymptomatic 
transaminitis was observed at week 8-10 after administration with an AAV8-FIX, providing the 
rationale for the following surveillance plan. Each patient will have comprehensive surveillance plan 
monitoring LFTs once a week from dose to completion of Week 6, 3 times per week from Weeks 7 to 
12, and once a week from Weeks 13 to 16.  If a patient’s ALT is found to be greater than 1.5x baseline 
during these periods, then LFTs will be monitored three times per week or until the ALT returns to 
baseline. LFTs will be monitored every other month for the first year and then every three months for 
up to 5 years post-dose in the safety extension. 
There will be a detailed monitoring plan for assessment of cellular and humoral responses to AAV5 
capsid and FVIII protein.   
Efficacy:
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of the study is 
to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post BMN 270 
administration. 
  
Secondary efficacy measures include assessing the impact of BMN 270 on the frequency of FVIII 
replacement therapy and on the number of bleeding episodes during the study.  Patients will be asked 
to keep a patient diary to record the details in these areas.   
The FVIII antigen and activity level as measured by an ELISA (antigen level) and by one-stage APTT 
and/or chromogenic FXa assay (activity level), will be used for plasma profiles; FVIII activity will be 
used to determine PD parameters.  Traditional PK analysis is not applicable. 
Pharmacodynamics: 
If supported by the FVIII activity data, non-compartmental analysis and observation will be used to 
estimate individual values of Cb (baseline concentration), Css (steady state concentration), Tss (time 
to steady state), C(t) and AUC(0-t) where t is 16 weeks.   

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
STATISTICAL METHODS:  
The sample size is based upon clinical considerations and could detect a strong clinical efficacy signal. 
Up to 12 patients may be dosed in the study.  The patients will be followed in a longitudinal manner 
and all the relevant information will be collected. The analysis of the data will be descriptive in nature 
but data collected in a longitudinal manner may be analyzed using longitudinal methods such as mixed 
effect model which takes into account the correlation among the observation taken at various time 
points within a participant. Efficacy is a secondary endpoint, defined as biologically active FVIII at 
≥ 5 IU/dL by chromogenic FXa assay and/or one-stage APTT assay between 1 to 16 weeks following 
study treatment. FVIII activity will be assessed weekly during the study period.  We can only assess 
the true steady state of FVIII protein produced from BMN 270 after a minimum of 96 hours has 
elapsed since the last infusion of FVIII protein concentrates. 
Analysis of neutralizing antibody response and other immunological parameters as well as viral 
shedding will be primarily descriptive and involve both inter-participant and intra-participant 
comparisons across doses. 
 

 
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3 TABLE OF CONTENTS 
1    TITLE PAGE…………………………………………………………………………...…1 
2 SYNOPSIS ...........................................................................................................................2 
3 TABLE OF CONTENTS ...................................................................................................10 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................15 
5 ETHICS..............................................................................................................................17 
5.1 Institutional Review Board or Independent Ethics Committee ................................17 
5.2 Ethical Conduct of Study ..........................................................................................18 
5.3 Patient Information and Informed Consent ...............................................................18 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................19 
7 INTRODUCTION .............................................................................................................20 
7.1 Nonclinical Studies ...................................................................................................21 
7.2 Previous Clinical Studies ..........................................................................................22 
7.3 Study Rationale .........................................................................................................23 
7.4 Summary of Overall Risks and Benefits ...................................................................25 
8 STUDY OBJECTIVES ......................................................................................................27 
9 INVESTIGATIONAL PLAN ............................................................................................28 
9.1 Overall Study Design and Plan .................................................................................28 
9.2 Discussion of Study Design, Including Choice of Control Group ............................34 
9.3 Selection of Study Population ...................................................................................34 
9.3.1 
Inclusion Criteria .........................................................................................34 
9.3.2 
Exclusion Criteria ........................................................................................35 
9.3.3 
Removal of Patients from Treatment or Assessment ..................................35 
9.3.4 
Patient Identification and Replacement of Patients .....................................37 
9.3.5 
Duration of Patient Participation .................................................................37 
9.4 Treatments .................................................................................................................37 
9.4.1 
Treatments Administered ............................................................................37 
9.4.2 
Identity of Investigational Product ..............................................................37 
9.4.3 
Storage .........................................................................................................37 
9.4.4 
Directions for Administration .....................................................................38 

 
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9.4.5 
Method of Assigning Patients to Treatment Groups ...................................38 
9.4.6 
Selection of Doses Used in the Study .........................................................39 
9.4.7 
Blinding .......................................................................................................39 
9.4.8 
Prior and Concomitant Medications ............................................................40 
9.4.9 
Treatment Compliance ................................................................................40 
9.5 Investigational Product Accountability .....................................................................41 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................41 
9.6 Dietary or Other Protocol Restrictions......................................................................41 
9.7 Safety and Efficacy Variables ...................................................................................41 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................41 
9.7.2 
Primary Efficacy Variables .........................................................................42 
9.7.3 
Secondary Efficacy Variables .....................................................................42 
9.7.4 
Immunogenicity ...........................................................................................42 
9.7.5 
Pharmacodynamics ......................................................................................43 
9.7.6 
Exploratory Biomarker Assessments ..........................................................43 
9.7.7 
Quality of Life Assessment .........................................................................43 
9.7.8 
Safety Variables ..........................................................................................43 
10 REPORTING ADVERSE EVENTS .................................................................................48 
10.1 Safety Parameters and Definitions ............................................................................48 
10.1.1 Adverse Events ............................................................................................48 
10.2 Serious Adverse Events ............................................................................................49 
10.2.1 Events of Special Interest (EOSI) ...............................................................49 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................49 
10.3.1 Adverse Event Reporting Period .................................................................49 
10.3.2 Eliciting Adverse Events .............................................................................50 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................50 
10.4 Procedures for Recording Adverse Events ...............................................................52 
10.4.1 Recording Adverse Events on a eCRF ........................................................52 
10.5 Reporting Requirements ...........................................................................................55 
10.5.1 Expedited Reporting Requirements .............................................................55 
10.5.2 Ethics Committee Reporting Requirements ................................................56 

 
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10.6 Follow-up of Patients after Adverse Events .............................................................56 
10.7 Post-Study Adverse Events .......................................................................................56 
10.8 Urgent Safety Measures ............................................................................................57 
10.8 BioMarin Pharmacovigilance Contact Information ..................................................58 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................59 
12 STUDY PROCEDURES ...................................................................................................60 
12.1 Prestudy .....................................................................................................................60 
12.2 Screening Visit ..........................................................................................................60 
12.3 Baseline Visit ............................................................................................................61 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................62 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................62 
12.5.1 Every Visit ...................................................................................................62 
12.5.2 Every 4 Weeks .............................................................................................63 
12.5.3 Weeks 1, 3, and 6 ........................................................................................63 
12.5.4 Weeks 1, 8, and 16 ......................................................................................63 
12.5.5 Weeks 1, 2, 3, 4, and 16 ..............................................................................63 
12.6 Safety Follow-Up – Year 1 .......................................................................................63 
12.6.1 Every Visit ...................................................................................................64 
12.6.2 Weeks 28 and 52 .........................................................................................64 
12.7 Safety Follow-Up – Years 2-5 ..................................................................................64 
12.7.1 Every Visit ...................................................................................................64 
12.7.2 Every Other Visit (Every 6 Months) ...........................................................65 
12.8 Early Termination Visit ............................................................................................65 
12.9 End of Study..............................................................................................................66 
13 DATA QUALITY ASSURANCE .....................................................................................67 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................68 
14.1 Statistical and Analytical Plans .................................................................................68 
14.1.1 Interim Analyses ..........................................................................................68 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........68 
14.2 Primary and Secondary Efficacy Analysis................................................................68 
14.3 Immunogenicity ........................................................................................................68 

 
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14.4 Pharmacodynamic Analyses .....................................................................................69 
14.5 Safety Analysis .........................................................................................................69 
14.6 Determination of Sample Size ..................................................................................69 
14.7 Analysis Populations .................................................................................................70 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................70 
15 DATA MONITORING COMMITTEE .............................................................................71 
16 COMPENSATION, INSURANCE AND INDEMNITY ..................................................72 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................73 
18 STUDY MONITORING AND AUDITING .....................................................................75 
19 RETENTION OF RECORDS ...........................................................................................76 
20 USE OF INFORMATION AND PUBLICATION ...........................................................77 
21 REFERENCES ..................................................................................................................78 
22 INVESTIGATOR RESPONSIBILITIES ..........................................................................80 
22.1 Conduct of Study and Protection of Human Patients ...............................................80 
23 SIGNATURE PAGE .........................................................................................................81 
24 APPENDICES ...................................................................................................................82 
 
LIST OF TABLES 
Table 9.1.1: Schedule of Events – Screening and Infusion .....................................................30 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up .................................................32 
Table 9.1.3:  Schedule of Events – Safety Follow-Up .............................................................33 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................45 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................51 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................51 
 
LIST OF FIGURES 
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp .........................................................24 
Figure 9.1.1:  Flow Chart of Dose Escalation Scheme ............................................................29 
 
 

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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAV 
Abbreviations 
adeno-associated virus 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine transaminase 
APTT 
activated partial thromboplastin time 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
eCRF 
electronic case report form 
DMC 
Data Monitoring Committee 
ED 
exposure days 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FVIII 
coagulation factor VIII 
FXa 
coagulation factor Xa 
GCP 
Good Clinical Practice 
HA 
Haemophilia A 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 

 
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IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LFT 
liver funtion test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
vg 
vector genomes 
 
Investigational Product (IP): 
Definition of Terms:  
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 
 

 
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5 
ETHICS 
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which Investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1 
Institutional Review Board or Independent Ethics Committee 
Investigators are expected to interact with Ethics Committees (ECs) promptly, as required, 
during the course of the study. This includes, but is not limited to, providing appropriate 
documentation to support study initiation and maintaining appropriate flow of safety and 
other information during the course of the study and for study close-out activities. BioMarin 
(or designee) will assist Investigators with access to timely and accurate information and 
with assurance of prompt resolution of any queries. 
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB) or independent ethics committee (IEC) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin Pharmaceutical Inc. (BioMarin) or its designee. The 
Investigator will provide the IRB/IEC/REB with all appropriate material, including the 
protocol, Investigator’s Brochure (IB), the Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the patients, 
including all ICFs translated to a language other than the native language of the clinical site. 
The study will not be initiated and Investigational Product (IP) supplies will not be shipped 
to the site until appropriate documents from the IRB/IEC/REB confirming unconditional 
approval of the protocol, the ICF and all patient recruitment materials are obtained in writing 
by the Investigator and copies are received at BioMarin or its designee. The approval 
document should refer to the study by protocol title and BioMarin protocol number (if 
possible), identify the documents reviewed, and include the date of the review and approval. 
BioMarin will ensure that the appropriate reports on the progress of the study are made to the 
IRB/IEC/REB and BioMarin by the Investigator in accordance with applicable guidance 
documents and governmental regulations. 

 
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5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
eligible patients for study enrollment; adhering to diagnostic or other procedures as specified 
in the protocol; and assuring appropriate compliance with study treatment administration and 
accountability. 
This study will be conducted in accordance with the following: 
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
• US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (ICH 
E6) 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the patients will 
be respected and the investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each patient will provide written, informed consent before any 
study-related tests or evaluations are performed. 
5.3 
Patient Information and Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (Section 4.8), United 
States Code of Federal Regulations (CFR) 21 CFR §50, European Clinical Trial Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and other applicable local 
regulations, will be obtained for each patient prior to entering the patient into the study. The 
Investigator will prepare the ICF and provide the documents to BioMarin for approval prior 
to submission to the IRB/IEC/REB approval. BioMarin and the IRB/IEC/REB must approve 
the documents before they are implemented. A copy of the approved ICF , and if applicable, 
a copy of the approved patient information sheet and all ICFs translated to a language other 
than the native language of the clinical site must also be received by BioMarin or designee 
prior to any study-specific procedures being performed. 
The Investigator will provide copies of the signed ICF to each patient and will maintain the 
original in the record file of the patient. 

 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to patients. Patients who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee, a fully executed and signed US Food and Drug Administration (FDA) Form FDA 
1572 and a Financial Disclosure Form. All sub-Investigators must be listed on Form FDA 
1572. Financial Disclosure Forms must also be completed for all sub-Investigators listed on 
the Form FDA 1572 who will be directly involved in the treatment or evaluation of patients 
in this study. 
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical research associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each patient as well as 
other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required. 
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR. 
Laboratory evaluations will be performed at the local laboratories associated with the study 
sites. Refer to the Laboratory Manual for more details. 

 
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7 
INTRODUCTION 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin.Haematol.). It is caused by mutations in 
the factor VIII (FVIII) gene that codes for FVIII protein, an essential cofactor in the 
coagulation cascade. Clinical manifestations of severe FVIII deficiency are frequent 
unprovoked bleeding episodes in joints and soft tissues causing permanent disability and 
occasionally death mostly after brain haemorrhage. Treatment in Western (Berntorp, 2012, 
Haemophilia.) countries consists of intravenous injection of plasma derived or recombinant 
FVIII protein concentrates at the time of a bleed, or prophylactically, to prevent bleeding 
episodes. The short half-life for FVIII (~8-12 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s haemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from haemorrhage in life (Stonebraker, 2010, Haemophilia.). 
Chemical modification or bioengineering of FVIII may improve half-life to around 20 hours 
(Pipe, 2010, Blood). However, these long acting FVIII variants do not eliminate the need for 
lifelong FVIII protein administration or problems of FVIII inhibitor formation, which occurs 
in 30% of patients on standard FVIII replacement therapy (Nathwani, 1992, Baillieres 
Clin.Haematol.).  
Gene therapy offers the potential of a cure through continuous endogenous production of 
human FVIII following a single administration of vector. Haemophilia A is well suited for 
this approach because its clinical manifestations are attributable to the lack of a single gene 
product (FVIII) that circulates in low amounts (100-200 ng/ml) in the plasma. Tightly 
regulated control of gene expression is not essential and a modest increase in the level of 
FVIII (a plasma level of 2ng/ml protein leads to a 1% expression) can ameliorate the severe 
phenotype (Srivastava, 2012, Haemophilia); thus the therapeutic goal for gene therapy is a 
modest increase in hFVIII. Finally, the consequences of gene transfer can be assessed using 
simple quantitative rather than qualitative endpoints that can be easily assayed in most 
clinical laboratories. 
BMN 270 contains the cDNA for the B-domain deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 

 
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7.1 
Nonclinical Studies 
The nonclinical program supports a single IV administration of BMN 270, the planned 
clinical route of administration, for the treatment of Haemophilia A in male patients.  This 
nonclinical program took into account the guidelines and reflection papers for gene therapy 
medicinal products under EMA Advanced Therapies. The primary pharmacodynamics (PD), 
pharmacokinetics (PK), and toxicity of IV BMN 270 were characterized in a series of single 
dose studies in species that were vector permissive and responsive to the transgene (normal 
CD-1 mouse, B and T cell deficient mouse model of haemophilia A (B6;129S-F8tm1Kaz/J x 
B6.129S6-Rag2tm1Fwa N12; FVIII KO x Rag2, and normal cynomolgus and rhesus monkeys).  
Some PD studies evaluated additional PK, immunogenicity and toxicity endpoints. 
The primary PD of BMN 270 was assessed in a series of non-GLP single dose studies in a 
FVIII KO x Rag2 mouse model of severe Haemophilia A that recapitulates the change in 
coagulation observed in the human severe disease population without interfering cross 
species immunogenicity.  PD activity and expression of hFVIII was assessed for durations up 
to 13-weeks in the FVIII KO x Rag2 mouse given dose range of 2E11 through 2E14 vector 
genomes (vg)/kg.  Low levels of plasma hFVIII were observed in mice given 2E12 vg/kg 
after eight-weeks, post dose.  Plasma hFVIII activity using bleeding time as an endpoint was 
evaluated in the FVIII KO x Rag2 mouse given up to 2E13 and 1E14 vg/kg BMN 270 at 
8 weeks, post dose.  BMN 270 related correction of bleeding times showed a dose 
relationship that was similar to that observed in mice given matched IU levels of Refacto®.   
All cynomolgus monkeys used in this program were screened for neutralizing anti-AAV5 
activity prior to study enrollment.  PD activity and plasma hFVIII concentrations were 
evaluated in the cynomolgus monkey given up to 6E13 vg/kg BMN 270 for eight weeks.  
Peak expression of hFVIII was observed three to six weeks post administration with a 
subsequent decrease in expression presumably due to immunogenicity though not necessarily 
correlated to antibody titer.   
The normal mouse was utilized in the GLP toxicology study to assess the safety profile of 
BMN 270 without the background of disease progression and in sufficient number per 
parameter.  The GLP single dose toxicity study in normal CD-1 mice given 6E12 and 6E13 
vg/kg with a 4 and 13-week follow up period monitored clinical pathology, defined potential 
target organs, immunogenicity, gene expression and activity. No changes in liver function 
were observed.  In a single dose PD study in monkey given BMN 270, formation of 
anti-AAV5 total antibodies was observed at Week 8 with relatively low formation of 
anti-hFVIII total antibodies.  No changes in liver function was observed. 

 
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The overall nonclinical safety profile includes formation of anti-AAV5 total antibodies with 
relatively lower formation of anti-hFVIII total antibodies.  Immunogenicity against the AAV 
capsid and hFVIII is an anticipated finding for BMN 270 treatment and will be monitored in 
the nonclinical and clinical programs.  Though not observed in the nonclinical species, liver 
toxicity utilizing clinical pathology parameters will be monitored in the clinical program 
based on previous literature.  Cellular immune response will also be monitored.  
Additionally, the BMN 270 transgene product has a final sequence matching that of the 
protein replacement treatment, Refacto® and therefore the safety profile of the BMN 270 
transgene product is anticipated to be similar to Refacto® and have no unique FVIII-specific 
target organs of toxicity.  The AAV5 capsid has not been modified and therefore no unique 
capsid-specific safety findings are anticipated.  Because the biodistribution pattern of AAV5 
after IV administration is consistent across species, BioMarin will confirm the nonclinical 
distribution pattern of BMN 270 during clinical development.  Biodistribution of the AAV5 
capsid has been documented to predominately target the liver with relatively lower levels of 
transduction observed in the lung, kidney, spleen, testes and blood compartment depending 
on the species and timing of administration. Liver targeted distribution of a similar AAV5 
Factor IX gene therapy product was observed in the rhesus macaque monkey with low levels 
of vector genomes detected in spleen, kidney and testis (Paneda, 2009, Hum.Gene Ther.). 
Despite distribution to non-liver organs, no expression of Factor IX was detected in these 
tissues.  Additionally, distribution to the testis was observed in another study in monkeys 
given an AAV5-codon-optimized human porphobilinogen deaminase; however, vector 
genomes in the semen were only transiently observed within one week but not thereafter 
(Paneda, 2013, Hum.Gene Ther.).  
Both normal and disease model mice and a limited number of monkeys were utilized to 
establish proof of concept, species scaling and dose response in order to select the 
first-in-human (FIH) dose of 6E12 vg/kg.  This dose represents > 30-fold safety factor from 
the no observed adverse effect level (NOAEL) in enabling nonclinical studies.  
7.2 
Previous Clinical Studies 
This is the first clinical study for BMN 270. 
BioMarin’s program for haemophilia A builds on previous clinical trials of AAV-mediated 
gene transfer for a related condition, haemophilia B, that were conducted with an AAV2 
vector (Manno, 2003, Blood) and an AAV8 vector (Nathwani, 2011, N.Eng.J.Med.; 
Nathwani, 2014, N.Eng.J.Med.). The large size of the FVIII cDNA was shortened and a 
preclinical validation of this approach was performed with an AAV8 vector (McIntosh, 2013, 
Blood). 

 
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AAV serotype 5 is also used in clinical trials and has shown good safety in a recent phase 1 
study for treatment of Acute Intermittent Porphyria (D’Avola. 2014, J Hepatology).  
AAV using other serotypes have been used in 105 clinical studies to date and no safety issue 
specific to the vector was ever reported.   
7.3 
Study Rationale 
Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Nathwani, 1992, Baillieres Clin. Haematol).  It is caused by deficiency in 
the activity of coagulation factor VIII (FVIII), an essential cofactor in the intrinsic 
coagulation cascade. This disorder can be either inherited, due to a new mutation or an 
acquired immunologic process, leading to insufficient quantities of FVIII or a dysfunctional 
FVIII, but all are characterized by a defective coagulation process. . The clinical phenotype 
of HA patients is largely governed by the level of residual expression. Severe HA is 
classified as FVIII activity less than 1% of wild type (< 1 IU/dL), moderate disease 
comprises 1-5% of wild type activity and the mild form is 5-40% activity. The clinical 
manifestations of severe HA remain frequent spontaneous bleeding episodes, predominantly 
in joints and soft tissues, with a substantially increased risk of death from haemorrhage when 
the brain is involved.   
Treatment of severe HA presently consists of intravenous injection of plasma derived or 
recombinant FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per week, 
and at the time of a bleed, to prevent or control bleeding episodes, respectively. The half-life 
for rhFVIII (under 24 hours for most approved products) necessitates frequent infusions, and 
although a major advance in the treatment of HA, it remains common for severe HA patients 
to continue to have multiple bleeding events on treatment (mean of 1 to 7 episodes/year with 
prophylaxis up to 30 to 50 for on demand treatment) (Nagel, 2011, Haemophilia).  The 
consequence of multiple bleeding events is the development of an underlying pathology that 
contributes to debilitating multiple-joint arthropathy and substantially increased risk of death 
(Nagel, 2011, Haemophilia).  Chemical modification (e.g. direct conjugation of polyethylene 
glycol (PEG) polymers) and bioengineering of FVIII (e.g. FVIII-Fc fusion proteins) improve 
half-life by approximately 50%, and thus, show promise in reduced dosing and maintaining 
activity levels above 1% trough (Stonebraker, 2010, Haemophilia), (Mahlangu, 2014, Blood). 
However, these longer acting FVIIIs remain dependent on multiple infusions to maintain 
critical levels of FVIII activity in severe HA patients. There is therefore a strong unmet need 
for a fully preventive treatment of HA to give patients a FVIII level compatible with a 
normal and haemorrhage-free life.  

 
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Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous administration of a vector with the 
appropriate gene sequence. Haemophilia A is well suited for a gene replacement approach 
because clinical manifestations are attributable to the lack of a single gene product (FVIII) 
that circulates in minute amounts (200 ng/ml) in the plasma. Tightly regulated control of 
gene expression is not essential, and modest increases in the level of FVIII (any increase of 
the plasma level by 2 ng/ml induces an increase in activity of 1%) can ameliorate the severe 
form of the disease.  Thus, relatively small changes in endogenous FVIII activity results in 
clinically relevant improvements in disease phenotype. Finally, the response to gene 
transduction can be assessed using validated quantitative rather than qualitative endpoints 
that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, but 
adeno-associated viral (AAV) vectors show the greatest promise (Pipe, 2010, Blood). They 
have an excellent and well defined safety profile, and can direct long term transgene 
expression with tropism for specific tissues such as the liver (Nathwani, 2005, Curr.Hematol 
Rep.) for serotypes 2, 5 and 8 among others).  Indeed, an on-going gene therapy clinical trial 
for a related disorder, haemophilia B, has established that stable (>36 months) expression of 
human factor IX at levels that are sufficient for conversion of their bleeding phenotype from 
severe to moderate or mild is achievable following a single peripheral vein administration of 
AAV-8 vector(Nathwani, 2011, NEJM). Several participants in this trial have been able to 
discontinue factor prophylaxis without suffering spontaneous haemorrhages, even when they 
undertook activities that previously resulted in bleeding. Thus, gene therapy treatment has 
resulted in a substantial improvement in their quality of life (Nathwani, 2011, Mol.Ther.). 
(Bainbridge, 2008, NEJM; Maguire, 2009, Lancet; Simonelli, 2010, Mol.Ther.). 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of rhFVIII 
under the control of a liver-selective promoter (Figure 7.3.1).  
Figure 7.3.1:  BMN 270 Transgene Construct, ~5.0 kbp 
 
 

 
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BMN 270 will be delivered by single intravenous dose and is designed to achieve stable, 
potentially life-long expression of active hFVIII in the plasma, synthesized from 
vector-transduced liver tissue. The clinical study BMN 270-201 is a first-in-human study 
designed to assess the relationship of vector dose to the augmentation of residual FVIII 
activity, and whether these levels are sufficient to alter the clinical phenotype. The 
relationship of dose to safety will be correlated to the activity of hFVIII in patients with 
severe HA. 
7.4 
Summary of Overall Risks and Benefits 
Safety will be assessed by adverse event reporting and clinical laboratory assessment. Based 
on prior human studies with peripheral injections of AAV vectors, there is no known safety 
risk of AAV gene therapy. However, a mild asymptomatic transaminitis was observed at 
week 8-10 after administration with an AAV8-FIX, providing the rationale for the following 
surveillance plan (Manno, 2006, Nature Med.).  Each patient will have comprehensive 
surveillance plan monitoring LFTs once a week from dose to completion of Week 6, 3 times 
per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is 
found to be greater than 1.5x baseline during these periods, then LFTs will be monitored 
three times per week or until the ALT returns to baseline.  LFTs will be monitored every 
other month for the first year and then every three months for up to 5 years post-dose in the 
safety extension.   
Dose selection:  The benefit of this study can only be enhanced by selecting a starting dose 
that potentially could contribute to a better opportunity of observing a therapeutic effect, and 
therefore, reducing the possibility of a sub-therapeutic effect. With this consideration in 
mind, the starting dose 6E12 vg/kg was selected using overall data from the pre-clinical 
studies conducted in mice (normal and disease model, Rag2 -/- x FVIII -/-) and monkey.  
A detectable pharmacological response based on activity was observed at 6E12 vg/kg. 
A 10-fold safety margin based upon the NOAEL was observed in the GLP 13-week study in 
normal mouse at the highest dose administered.  A 30-fold safety margin in an 8-week dose 
response study in disease model mice based on histology was observed at the highest dose 
administered.  No BMN 270-related changes in clinical observations or chemistry was 
observed in the monkey at doses up to 6E13 vg/kg, a 10-fold safety margin after 8-weeks.  
Overall, no BMN 270-related findings, except expected formation of anti-AAV5 antibodies, 
were observed at the highest administered doses of 6E13, 2E14 and vg/kg in the normal 
mouse, disease model mouse and monkey, respectively. 

 
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Based on these key pre-clinical findings it can be suggested that the proposed starting dose of 
6E12 vg/kg should not pose any risk or safety concerns to patients but may potentially 
benefit the patient therapeutically. 

 
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8 
STUDY OBJECTIVES 
The primary objectives of the study are: 
• To assess the safety of a single intravenous administration of a recombinant AAV5 
encoding human coagulation FVIII (AAV5-SQ-codop-hFVIII) vector.  
• To determine the dose of AAV5-SQ-codop-hFVIII required to achieve expression of 
hFVIII at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.  The 
kinetics, duration and magnitude of AAV-mediated hFVIII activity in individuals 
with haemophilia A will be determined and correlated to an appropriate BMN 270 
dose. 
The secondary objectives of the study are: 
• To describe the immune response to the hFVIII transgene product and AAV capsid 
proteins following systemic administration of rAAV5-SQ-codop-hFVIII 
• To assess the impact of BMN 270 on the frequency of FVIII replacement therapy 
during the study 
• To assess the impact of BMN 270 on the number of bleeding episodes requiring 
treatment during the study 
 
 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a first-in-man, phase 1/2 open-label, dose escalation study in patients with severe 
haemophilia A. Eligible patients will enter the dose escalation part of the study followed by a 
16-week Post-Infusion Follow-Up period during which safety and efficacy assessments will 
be taken. After the primary endpoint analysis at 16 weeks, safety and efficacy will then be 
assessed for approximately 5 years. 
Patients who provide written informed consent, meet the entry criteria definition of severe 
HA, and do not have transduction inhibition activity to AAV5 will be eligible to enroll in the 
study. Participants will be enrolled sequentially into one of up to three cohorts according to 
dose level:  
1. 6E12 vector genomes [vg] per kilogram of body weight, given as a single intravenous 
dose (iv) 
2. 2E13 vg per kilogram, iv 
3. 6E13 vg per kilogram, iv 
Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose 
escalation may occur after a single patient has been safely dosed if the resulting FVIII 
activity at Week 3 is < 5 IU/dL. Three weeks is expected to be the time the expression will be 
close to the maximum.  This escalation paradigm is intended to minimize the patient numbers 
exposed to subtherapeutic doses. 
The starting dose was based on the expression and safety of FVIII observed in nonclinical 
studies of mice and monkeys.  The starting dose has a significant safety margin (10-fold) 
from no observed adverse effect level (NOAEL) in non-human primates.   
Approximately three weeks after an injection, the decision to escalate to the next dose level 
will be made based on the review of safety parameters and FVIII activity by the Sponsor and 
a panel of investigators participating in the study.  
If the FVIII activity is ≥5 IU/dL, then the other patients of the dose group will be enrolled 
without waiting for 3 weeks between patients. 
 

 
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Figure 9.1.1:  Flow Chart of Dose Escalation Scheme 
 
Patient 1 will be dosed by intravenous perfusion with 6E12 vector genomes [vg] per 
kilogram of body weight. If the activity level does not reach ≥5 IU/dL (expressed as % in 
Figure 9.1.1) at 21 days, then a higher dose (2E13 vg per kilogram) will be used for the next 
patient.  
If the activity level does not reach ≥5 IU/dL after Patient 2, then the highest dose (6E13 vg 
per kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and if no safety issue is found, then up to 
four patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no 
further dose escalation will take place, but additional patients will then be dosed at this dose 
level for a total of 6 patients per dose. 
Because patients develop neutralizing immunity upon exposure to the capsid, re-challenge of 
vector is not a treatment option and these patients have effectively a single opportunity for 
therapy using this AAV capsid. Efficacy will be determined by FVIII activity at 16 weeks 
post dose. Safety will be evaluated for approximately 5 years after dose.  Any safety signal 
will trigger a review of the data and possible additional analysis including mononuclear 
collection. 
A summary of events and assessments are provided by visit in Table 9.1.1 for Screening, 
Baseline and BMN 270 Infusion, in Table 9.1.2 for Post-Infusion Follow-up, and in 
Table 9.1.3 for Safety Follow-up. 

 
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Table 9.1.1: Schedule of Events – Screening and Infusion 
Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion Visit 
(Day 1) 
Screening (Day 
-28 to  Day -1) 
Baseline (Day -7 to 
Day -1)i 
Informed consent 
X 
 
 
Medical History 
X 
 
 
Physical Exama 
X 
X 
X 
Vital Signs 
X 
 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
Documentation of bleeding episodes and FVIII usage (by either patient or clinical information) 
X 
X 
 
Electrocardiogram 
X 
 
 
Chest X-ray 
X 
 
 
Liver Ultrasound 
X 
 
 
FVIII Treatment Washoutb 
X 
 
 
hFVIII Assaysc 
X 
X 
 
AAV5 Assaysd 
X 
 
 
Screen for Hepatitis B, Hepatitis C, HIVe 
X 
 
 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPf 
X 
X 
 
Mononuclear cell collection for CTL baseline 
 
X 
 
PCR of vector genomes in blood, saliva, urine, semen, and stools 
 
X 
 
Biomarker testingg 
X 
 
 
Exploratory biomarker assessmentsh 
 
X 
 
Quality of Life (QoL) assessment 
 
X 
 
BMN 270 Infusion 
 
 
X 

 
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a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.  Height and 
weight will be recorded at Screening only. 
b Patients will have a washout period of 72 hours. If a bleeding occurs, another washout period of 72 hours will be performed. If another bleeding occurs during this 
second washout period, then the patient may be excluded from the study at the physician’s discretion. 
c Includes baseline hFVIII activity (chromogenic FXa and one-stage APTT assays), hFVIII coagulation activity exploratory assay, hFVIII inhibitor level (Bethesda assay 
with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen (ELISA).  hFVIII assays should be assessed only when the patient has been off FVIII 
therapy for at least the previous 4 days. 
d Screening (done during screening) and confirmation (at baseline) of AAV5 pre-existing immunity may include plasma samples for 3 assays (in vivo transduction 
inhibition, in vitro transduction inhibition and AAV5 total antibody assays). 
e Patients with documented negative results within the last 30 days do not need to be retested. 
f Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
g Includes HLA typing, FVIII mutation status, TNFα and IL10a single nucleotide polymorphisms. 
h Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 
i Should the screening visit occur within 7 days of the drug infusion, physical examination, vital signs, blood chemistry, haematology, urine tests, coagulation screen, and 
CRP do not need to be repeated at Baseline. 
 
 
 

 
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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up 
Assessment 
Follow-Up After BMN 270 Administration - Weeks* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPb   X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII activity assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII antibody titer 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker assessmentse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QoL assessment 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
AAV5 antibody titer 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Testing for reactivation of hepatitis B and hepatitis C 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Mononuclear cell collection  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
* Visit windows are ±48 hours 
a Brief physical examination should be done at all weekly visits except Week 16, where a complete physical examination should be performed.  Refer to Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included.  Each patient will have comprehensive surveillance plan monitoring LFTs once a week from dose to 
completion of Week 6, 3 times per week (every other day excluding weekends) from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is found 
to be greater than 1.5x baseline during these periods, then LFTs will be monitored three times per week or until the ALT returns to baseline. 
c Includes hFVIII activity level (APTT and FXa chromogenic assay), hFVIII activity confirmation (frozen plasma), Bethesda assay (with Nijmegen modification) for 
hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA). 
d Collection to occur on Day 1, 3, 7 following BMN 270 infusion, and then weekly until 3 consecutive negative results are obtained 
e Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to Haemophilia A disease.  The 
genetic/genomic testing on these exploratory samples is optional. 
 

 
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Table 9.1.3:  Schedule of Events – Safety Follow-Up 
Assessment 
Year 1 - Weeks* 
Years 
2-5* 
ETV (early 
termination 
visit) 
20 
28 
36 
44 
52 
Q3M 
Physical exama 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, haematology, urine tests, coagulation screen, and CRPb 
X 
X 
X 
X 
X 
X 
X 
hFVIII activity assaysc 
X 
X 
X 
X 
X 
X 
X 
AAV5 antibody titer 
X 
X 
X 
X 
X 
X 
X 
hFVIII antibody titer 
X 
X 
X 
X 
X 
X 
X 
Mononuclear Cell Collection (for determination of FVIII and Capsid specific CTL activity) 
X 
X 
X 
X 
X 
X 
X 
PCR of vector genomes in blood, saliva, urine, semen, and stoolsd 
X 
X 
X 
X 
X 
X 
X 
QoL assessment 
 
X 
 
 
X 
Xe 
X 
* Visit windows are ±72 hours 
a Complete physical examination should be performed at Weeks 52 and every 52 weeks thereafter; brief physical exam may be performed at other study visits.  Refer to 
Section 9.7.8.4. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included. 
c Includes hFVIII activity level (one-stage APTT and chromogenic FXa assay), hFVIII activity confirmation (frozen plasma), Bethesda assay (with Nijmegen 
modification) for hFVIII inhibitor level, hFVIII coagulation activity exploratory assay, and hFVIII antigen (ELISA). 
d Sample testing during Safety Follow-Up is not required if 3 consecutive samples are cleared during the Post-Infusion Follow-Up period. 
e QoL assessment during Years 2-5 of Safety Follow-up should be performed at every other visit (every 6 months) starting with the Week 78 visit (ie, 26 weeks after the 
Week 52 visit at the end of Year 1 of the Safety Follow-up period). 

 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-201 is designed to be a first-in-man, phase 1/2 open-label, dose escalation study in 
patients with severe haemophilia A.  Three doses of BMN 270 will be evaluated and the dose 
escalation decision tree is summarized in Figure 9.1.1.   
The decision to escalate to the next dose level will be made based on the review of safety 
parameters and FVIII activity by the Sponsor and a panel of investigators participating in the 
study.  
There will be no control group. Parameters for each patient will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
replacement therapy).  
As AAV based treatment always leads to anti-capsid immune response, no true control group 
(for example with an empty AAV) is possible.  
9.3 
Selection of Study Population 
Up to 12 severe haemophilia A patients may enroll into the study; the actual number of 
patients will depend on the criteria for dose escalation. A total of 6 patients may be enrolled 
at a single dose level. 
Additional criteria for participation in the study are provided in Section 9.3.1 and 
Section 9.3.2. 
9.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Males that are 18 years or older with established severe Haemophilia A as evidenced 
by their medical history.  Patients will be considered as severe if their FVIII levels 
have ever declined to 1 IU/dL or less 
2. Treated/exposed to FVIII concentrates or cryoprecipitates for a minimum of 
150 exposure days (EDs) 
3. Greater or equal to 12 bleeding episodes only if on on-demand therapy over the 
previous 12 months.  Does not apply to patients on prophylaxis 
4. Able to sign informed consent and comply with requirements of the trial 
5. No history of inhibitor, or no inhibitor on 2 consecutive occasions within the past 
12 months using a modified Nijmegen Bethesda assay higher than 0.6 Bethesda Unit 
(BU) 

 
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6. Sexually active patients must be willing to use an acceptable method of contraception 
such as double barrier, including hormonal contraception for at least 6 months post-
treatment. 
9.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 
transduction inhibition and AAV5 total antibodies 
2. Evidence of detectable viral load of HIV  
3. Significant liver dysfunction as defined by abnormal elevation of ALT (alanine 
transaminase) to 3 times the upper limit of normal, bilirubin, alkaline phosphatase, or 
an INR (international normalized ratio) of 1.4. Potential participants who have had a 
liver biopsy in the past 3 years are excluded if they had significant fibrosis of 3 or 4 
as rated on a scale of 0-4 
4. Evidence of any bleeding disorder not related to Haemophilia A 
5. Platelet count of < 100 x 109/L 
6. Creatinine ≥ 1.5 mg/dL 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound  
8. Hepatitis B if surface antigen is positive 
9. Hepatitis C if RNA is positive 
10. Treatment with any IP within 30 days prior to the screening visit 
11. Any disease or condition at the physician’s discretion that would prevent the patient 
from fully complying with the requirements of the study.  The physician may exclude 
patients unwilling or unable to agree on not using alcohol for the 16-week period 
following the viral infusion. 
9.3.3 Removal of Patients from Treatment or Assessment 
Patients may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any patient who requests to be withdrawn. 
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment. When possible, the tests and 
evaluations listed for the termination visit should be carried out. 
BioMarin must be notified of all patient withdrawals as soon as possible. BioMarin also 
reserves the right to discontinue the study at any time for either clinical or administrative 

 
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reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or BioMarin may withdraw a patient from the study 
include, but are not limited to, the following: 
• Patient requires medication or medical procedure prohibited by the protocol 
• Patient does not adhere to study requirements specified in the protocol 
• Patient was erroneously admitted into the study or does not meet entry criteria 
• Patient is lost to follow-up 
If a patient fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the patient cannot be reached by telephone, a certified letter should 
be sent to the patient requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each patient, before enrollment into the study, 
that for evaluation of study results, the patient’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each patient. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the patient and the patient will 
be removed from the study. 
9.3.3.1 
Study Safety Evaluation Criteria 
If any of the following events occur (except the persistence of AAV5) in a patient in the 
study who has received BMN 270 infusion, an extensive safety analysis will be performed 
and BioMarin and the Principal Investigator will discuss pursuing the trial or increasing the 
time before the next patient is enrolled. 
• 
A 5-fold increase in ALT after BMN 270 administration 
• The occurrence of other drug-related Grade III-IV toxicity, including liver failure and 
clinical hepatitis 
• Drug-related Grade II toxicity that persists for at least 7 days 
• The occurrence of neutralizing antibodies to hFVIII following BMN 270 infusion 

 
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• The persistent detection of the AAV vector genome in the semen of a participant 
more than 26 weeks after BMN 270 infusion, as discussed in Section 9.7.8.5  
• The occurrence of a malignancy at any point after BMN 270 infusion that is assessed 
as possibly, probably, or definitely related to the study agent 
• Any unexplained serious adverse event ≥ grade 4 assessed as at least possibly related 
to study drug 
9.3.4 Patient Identification and Replacement of Patients 
Each patient will be assigned a unique patient identifier. This unique identifier will be on all 
CRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 
Patients who withdraw from the study after Week 16 will not be replaced. 
9.3.5 Duration of Patient Participation 
The duration of this study will be approximately 264 weeks.  This includes 4 weeks of 
screening, 1 day of BMN 270 infusion, 16 weeks of Post-Infusion Follow-Up, and 244 weeks 
of Safety Follow-Up.  A primary endpoint analysis on safety and efficacy will be performed 
at 16 weeks. 
9.4 
Treatments 
BioMarin or its designee will provide the study site with study drug sufficient for study 
completion. BioMarin is responsible for shipping study drug to clinical sites. 
9.4.1 Treatments Administered 
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study. 
9.4.2 Identity of Investigational Product 
9.4.2.1 
Product Characteristics and Labeling 
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the IB in a secure 
area accessible only to the designated pharmacists and clinical site personnel. All IP must be 

 
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stored and inventoried and the inventories must be carefully and accurately documented 
according to applicable state, federal and local regulations, ICH GCP, and study procedures. 
9.4.4 Directions for Administration 
After a physical exam performed by the PI or designee, participants will be admitted on the 
day of BMN 270 infusion. An IV catheter will be inserted into a suitable peripheral vein 
(e.g. the median cubital vein) and flushed with saline. FVIII protein concentrate will not be 
given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
will be used to infuse through an in-line, low protein binding 0.22 micron filter. BMN 270 
will be infused through the catheter using an appropriate infusion pump while monitoring 
the vital signs (pulse, blood pressure, respiration rate and temperature) at 15 minute 
(± 5 minutes) intervals. The anticipated maximum interval from initiation of thawing of 
BMN 270 to completion of the infusion is 4 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes) for 
6 hours and then every 2 hours (± 15 minutes) for 6 hours and then at 4 hour intervals. If the 
vital signs are stable the catheter will be removed 20-24 hours after the infusion. Hemostasis 
at the puncture site will be established by applying pressure according to standard 
protocol for infusing FVIII concentrates. Patients will remain hospitalized for 24 hours to 
observe for any immediate toxicity of the procedure. After 24 hours of hospitalization, 
participants will be discharged unless toxicity has been observed in which case 
hospitalization may be extended or transfer to an outpatient facility may occur based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
9.4.5 Method of Assigning Patients to Treatment Groups 
Patients who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Sponsor will be required prior to enrollment of each 
study patient. Upon their enrollment into the study, patients will be assigned a unique patient 
number and dose level by the Sponsor. 
Patients are enrolled serially and their dose is defined in Section 9.4.6.2 below. Escalation is 
based on FVIII activity 3 weeks after injection. Patients may receive the next higher dose if 
the previous patient does not meet the activity criteria, or the same dose if the previous 

 
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patient meets the activity criteria. Up to 6 patients can have the same dose, for a total of 12 
patients in this study.  
9.4.6 Selection of Doses Used in the Study 
The starting dose was based on the expression of hFVIII observed in nonclinical studies of 
mice and monkeys. The starting dose has a significant safety margin (10-fold) from NOAEL 
in non-human primates. The dose escalation is half-logs based.    
9.4.6.1 
Selection of Timing of Dose for Each Patient 
A minimum of three weeks are required between patients, to allow for evaluation of safety 
and expression of hFVIII. After three weeks, depending on the activity level, the choice of 
the dose for the next patient will be made as described below.  
9.4.6.2 
Selection of Dose for Each Patient 
The starting dose was determined by expression of hFVIII observed in mice and monkeys 
and a scale up factor based on previous experience, an improved purification process over 
previous trials (thus decreasing the risk of immune response), and a new evaluation of the 
titer (PCR performed after hairpin removal). 
Approximately three weeks after an injection, the decision to escalate to the next dose level 
will be made based on the review of safety parameters and FVIII activity by the Sponsor and 
a panel of investigators participating in the study.  
Patient 1 will be dosed with 6E12 vector genomes [vg] per kilogram of body weight. If the 
activity level does not reach ≥5 IU/dL at 21 days, then a higher dose (2E13 vg per kilogram) 
will be used for the next patient.  
If the activity level does not reach ≥5 IU/dL after Patient 2, then the highest dose (6E13 vg 
per kilogram) will be used for the next patient.  
For each dose, if the activity level reaches 5 IU/dL and if no safety issue is found, then up to 
four patients will receive this dose.  If at any time activity levels reach 10 IU/dL or higher, no 
further dose escalation will take place, but additional patients will then be dosed at this dose 
level for a total of 6 patients per dose. 
Refer to Figure 9.1.1 for a visual representation of the study design. 
9.4.7 Blinding 
This is an open-label study. 

 
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9.4.8 Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a patient for 30 days before 
Screening will be recorded on the designated CRF. The Investigator may prescribe additional 
medications during the study, as long as the prescribed medication is not prohibited by the 
protocol. In the event of an emergency, any needed medications may be prescribed without 
prior approval, but the medical monitor must be notified of the use of any contraindicated 
medications immediately thereafter. Any concomitant medications added or discontinued 
during the study should be recorded on the CRF. 
The following medications are prohibited starting 30 days before Screening: 
• Live vaccines 
• Immunosuppressive agents 
Haemophilia treatments are discussed in the washout section below (Section 9.4.8.1). 
9.4.8.1 
Factor VIII Washout 
Patients will have a washout period of 72 hours. If a bleeding occurs, another washout period 
of 72 hours will be performed. If another bleeding occurs during this second washout period, 
then the patient may be excluded from the study at the physician’s discretion.  
9.4.8.2 
Glucocorticoid Treatment of Elevated Hepatic Transaminases 
During the Post-Infusion Follow-up Period, each patient will have comprehensive 
surveillance plan monitoring LFTs once a week from dose to completion of Week 6, 3 times 
per week from Weeks 7 to 12, and once a week from Weeks 13 to 16.  If a patient’s ALT is 
found to be greater than 1.5x baseline during these periods, then LFTs will be monitored 
three times per week or until the ALT returns to baseline.  
Reports of abnormal LFTs (defined as 1.5x the patient’s baseline level) should be made to 
BioMarin within 24 hours of the lab value being available.  If the LFTs are abnormal, 
treatment with prednisolone initiated at a dose of 60mg per day and then gradually tapered 
will be started immediately.   
9.4.9 Treatment Compliance 
Study drug will be administered to patients at the study site by a qualified professional.  The 
quantity dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided 
for the study.  Sites will be instructed to return all used and unused study drug containers. 

 
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9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, patients to whom IP is dispensed (patient-by-patient dose 
specific accounting), and IP lost or accidentally or deliberately destroyed. The Investigator or 
designee must retain all unused or expired study supplies until the study monitor (on-site 
CRA) has confirmed the accountability data. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials. 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin 
and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 
study drug or study drug materials must be accounted for on a Study Drug Return Form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study. 
9.7 
Safety and Efficacy Variables 
As this is a first-in-man study, the primary endpoint of safety will be assessed as explained in 
Section 9.7.8. 
The primary efficacy measure will be to assess plasma FVIII activity. The efficacy goal of 
the study is to establish the dose relationship to FVIII activity ≥ 5 IU/dL at 16 weeks post 
BMN 270 administration.  
9.7.1 Safety and Efficacy Measurements Assessed 
The Schedule of Events (Table 9.1.1) describes the timing of required evaluations. 

 
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9.7.2 Primary Efficacy Variables 
The primary efficacy measure will be the plasma FVIII activity monitored on a regular basis 
after BMN 270 dose. The efficacy goal of the protocol is to ascertain the dose range of 
BMN 270 required to convert severe HA patients to stable expression of FVIII at 5 IU/dL, 
i.e., a mild severity. This is associated in natural history studies with clinically superior long 
term outcomes (Nathwani, 1992, Baillieres Clin.Haematol.). 
To measure the primary efficacy variable, the following assays will be used: 
• FVIII activity (chromogenic FXa assay) 
• FVIII activity by one-stage APTT (Activated Partial Thromboplastin Time) 
• Exploratory FVIII activity assay  
The FVIII activity level and the number of patients with FVIII activity ≥ 5 IU/dL will be 
summarized. 
Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3.  Details on 
performing the assays are included in the Laboratory Manual. 
9.7.3 Secondary Efficacy Variables 
Secondary efficacy measures will be the reduction in the frequency of factor replacement 
therapy, and reduction in the number of bleeding episodes.  Patients will be asked at each 
study visit to report the use of factor replacement therapy and the number of bleeding 
episodes since the previous visit.  This information will be captured on the patient’s diary or 
other patient records. 
Assessment of viral shedding at one week after BMN 270 infusion will also be considered an 
efficacy variable.  
9.7.4 Immunogenicity 
Immunogenicity assays will be performed on plasma.  The assays will include detection of 
anti-capsid, and anti-FVIII total antibody, and determination of neutralizing antibodies 
against FVIII. Any increase in total antibody level, especially during the time period of 
6-12 weeks, will be compared with FVIII activity measurements. Any abnormality of the 
liver parameters will lead to an immunogenicity assessment to determine anti-FVIII and 
capsid specific CTL.  Anti-FVIII and capsid specific CTL assays will be performed on 
collected PBMCs. 
Timing of assessment by these assays is provided in Table 9.1.2 and Table 9.1.3. 

 
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9.7.5 Pharmacodynamics 
The hFVIII antigen and activity level will be measured by an ELISA (antigen) and by one-
stage APTT and/or chromogenic FXa assay (activity).  Individual antigen and activity plasma 
plots will be prepared to assess changes over 16 weeks.  FVIII activity measurements will be 
used to determine PD parameters. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual values of Cb (baseline concentration), Css (steady state concentration), 
Tss (time to steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may 
be used to describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The PD parameters and dose 
will be used to assess clinical pharmacology. 
Sample collection times are indicated in Table 9.1.2 and Table 9.1.3. 
9.7.6 Exploratory Biomarker Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1 and 
Table 9.1.2 to evaluate biochemical, molecular, cellular, and genetic/genomic aspects 
relevant to Haemophilia A disease.  The genetic/genomic testing on these exploratory 
samples is optional. 
9.7.7 Quality of Life Assessment 
A patient-reported outcome (PRO) questionnaire will be used to assess subject quality of life 
(QoL) during the study.  Assessments will occur at the time points listed in the Schedules of 
Assessments. 
Details regarding the QoL assessment will be included in the Study Reference Manual. 
9.7.8 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
9.7.8.1 
Adverse Events 
The occurrence of AEs will be assessed continuously from the time the patient signs the ICF. 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9.1.1.   

 
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9.7.8.2 
Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in 
Table 9.1.1. The scheduled clinical laboratory tests are listed in Table 9.7.8.2.1. Refer to the 
Study Reference Manual for instructions on obtaining and shipping samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
All abnormal clinical laboratory result pages should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Each 
clinically significant laboratory result should be recorded as an adverse event. 
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF. 

 
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Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Haematology 
Urine Tests 
Other 
Albumin  
Haemoglobin  
Appearance 
CRP 
Alkaline phosphatase  Haematocrit  
Color 
 
ALT (SGPT) 
WBC count 
pH 
Coagulation Screen 
including: 
AST (SGOT) 
RBC count 
Specific gravity 
APTT 
Direct bilirubin 
Platelet count 
Ketones 
PT/INR 
Total bilirubin 
Differential cell count  Protein  
TT 
BUN 
 
Glucose  
 
Calcium 
 
Bilirubin 
 
Chloride 
 
Nitrite 
 
Total cholesterol 
 
Urobilinogen 
 
CO2 
 
Haemoglobin 
 
Creatinine 
 
 
 
Glucose 
 
 
 
GGT 
 
 
 
LDH 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Total protein  
 
 
 
Sodium  
 
 
 
Uric acid  
 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon 
dioxide; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; 
SGPT, serum glutamic-pyruvic transaminase; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating 
hormone; WBC, white blood cell; TT, thrombin time; INR, international normalized ratio. 
9.7.8.3 
Liver function and Hepatitis Testing 
Patients will be screened for evidence of previous hepatitis B or hepatitis C infection at 
Screening. If medical records showing no evidence of Hepatitis B or Hepatitis C infection 
from the previous 30 days are available, then the Screening tests do not need to be done.   

 
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Evidence of ongoing infection (positive surface antigen for hepatitis B or positive RNA 
testing for hepatitis C) will be an exclusion criteria. If these parameters are negative and 
therefore no active infection is detected, then the patients may be included if they were 
vaccinated (for hepatitis B) or cleared the infection (for hepatitis C) and their liver function is 
acceptable.  
A liver ultrasound and liver function testing at Screening will identify any significant hepatic 
dysfunction, which is defined as: 
• More than 3x the normal ALT level 
• More than 3x the normal bilirubin level 
• Alkaline phosphatase above the normal cut off. 
• INR over 1.4.  
• Thrombocytopoenia under 100 x 109/L 
9.7.8.4 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE. 
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Safety Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored hourly for 6 hours and then every 2 hours for 6 hours 
and then at 4 hour intervals.  
A complete physical examination is necessary during Screening/Baseline; thereafter, brief 
physical examinations may be performed at the discretion of the investigator based on the 
patient’s clinical condition. Particular attention should be given to signs of bleeding, as well 
as assessing possible hemarthroses. 
A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems (level of consciousness, speech, language, cranial 
nerves, motor strength, motor tone, abnormal movements, reflexes, upper extremity 
sensation, lower extremity sensations, gait, Romberg, nystagmus, and coordination). 
A brief physical examination will include general appearance, cardiovascular, respiratory, 
neurologic, and gastrointestinal assessments. 

 
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Weight and height will be recorded at Screening only. 
9.7.8.5 
Viral Shedding 
Viral shedding has been extensively studied in all similar clinical trials performed to date. 
(Appendix 1; Appendix 2; Schenk-Braat, 2007, J Gene Med; Croteau, 2004, Ann Occup 
Hyg). It has been constantly shown that the vector was not detectable anymore at 40 days, 
with its persistence in semen for 16 weeks in the seminal fluid but not in motile sperm 
(Manno, 2006, Nature Med.).  In addition, it has always involved only an extremely small 
fraction of the injected dose.  
Viral shedding will also be extensively studied in the present clinical trial, every week up to 
16 weeks, then every 4 weeks to one year, then every three months.  During the Post-Infusion 
Follow-Up period, patients will undergo testing of various bodily fluids to look for evidence 
of viral shedding for possible viral transmission.  Bodily fluids will be tested by PCR at the 
time points indicated in Table 9.1.2 and Table 9.1.3.  Fluids tested will include: 
• Blood 
• Saliva 
• Semen 
• Urine 
• Stool 
Details for sample collection and storage are provided in the Laboratory Manual. 

 
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10 
REPORTING ADVERSE EVENTS 
10.1     Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified haematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, a reportable adverse event (AE) is any untoward medical occurrence 
(e.g., sign, symptom, illness, disease or injury) in a patient administered the study-drug or 
other protocol-imposed intervention, regardless of attribution. This includes the following: 
• AEs not previously observed in the patient that emerge during the course of the study. 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures, medication washout, or no-treatment 
run-in). 
An adverse drug reaction is any AE for which there is a reasonable possibility that the 
study-drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study-drug and the AE. 
Bleeding events that are normal events of haemophilia (ie, bleeding events which occur only 
because the patient is a haemophiliac) should not be recorded as AEs but will instead be 
captured in patient diaries.  Bleeding events that occur where a normal 
(ie, non-haemophiliac) patient would bleed, such as bleeding as a result of trauma, should be 
recorded as adverse events.  All bleeding events which meet criteria for being serious should 
be reported as serious adverse events (SAEs) whether or not they are bleeding events that are 
normal sequelae of haemophilia. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 

 
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10.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening  
Note: Life-threatening refers to an event that places the patient at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
• Requires or prolongs inpatient hospitalization.  Hospitalization for less than 24 hours 
will not be considered to be an SAE. Hospitalization solely for the purpose of 
insertion of an in-dwelling IV catheter (such as a Port-a-Cath or other brand) for 
administration of study drug will not be considered an SAE. 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect in the child or fetus of a patient exposed to IP 
prior to conception or during pregnancy 
• 
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the patient or require intervention to prevent one of  the above 
consequences (e.g. anaphylaxis) 
All adverse events that do not meet any of the criteria for SAEs should be regarded as non-
serious AEs. 
10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• Elevation of liver enzymes triggering a corticosteroid treatment 
10.3 
Methods and Timing for Capturing and Assessing Safety Parameters 
10.3.1 Adverse Event Reporting Period 
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported.  After informed consent is obtained and the first administration of study drug, the 
reporting period for all non-serious AEs and SAEs begins and continues for approximately 
5 years or until study discontinuation/termination, whichever is longer. The criteria for 
determining, and the reporting of SAEs is provided in Section 10.2.  

 
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10.3.2 Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs and EOSI, at each patient contact by 
specific questioning and, as appropriate, by examination.  Information on all AEs and SAEs 
and EOSI, should be recorded in the patient’s medical record and on the AE Case Report 
Form (eCRF). 
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the patient or qualified designee will assess AEs 
for severity, relationship to study drug, and seriousness (refer to Section 10.2 for SAE 
definitions).  These assessments should be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS). 
10.3.3.1 
Seriousness 
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
10.3.3.2 
Severity 
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient’s life or functioning.  The severity of each will be assessed using the 
defined categories in Table 10.3.3.2.1. 
The Investigator will determine the severity of each AE and SAE and EOSI using the NCI 
CTCAE v4. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v4 as stated below. 

 
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Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life threatening or debilitating: consequences; urgent intervention 
indicated 
Grade 4 and 5 AEs 
should always be 
reported as SAEs 
5 
Death related to AE 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden. 
 
10.3.3.3 
Causality 
The Investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF.  To ensure consistency of causality assessments, 
Investigators should apply the guidance in Table 10.3.3.3.1. 
Table 10.3.3.3.1:  Causality Attribution Guidance 
Relationship 
Description 
Not Related 
• 
Exposure to the IP has not occurred 
OR 
• 
The administration of the IP and the occurrence of the AE are not 
reasonably related in time  
OR 
• 
The AE is considered likely to be related to an etiology other than the use 
of the IP; that is, there are no facts, evidence, or arguments to suggest a 
causal relationship to the IP. 
Related 
• 
The administration of the IP and the occurrence of the AE are reasonably 
related in time 
AND 
• 
The AE could possibly be explained  by factors or causes other than 
exposure to the IP 
                                      
 
OR 
• 
The administration of IP and the occurrence of the AE are reasonably 
related in time  
AND 
• 
The AE is more likely explained by exposure to the IP than by other 
factors or causes. 

 
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Factors suggestive of a causal relationship could include (but are not limited to): 
• Plausible temporal relationship 
• Absence of alternative explanations 
• Rarity of event in a given patient or disease state 
• Absence of event prior to study drug exposure 
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.4.1.1 
Diagnosis versus Signs and Symptoms 
Using accepted medical terminology, enter the diagnosis (if known).  If not known, enter 
sign(s) and/or symptom(s).  If a diagnosis subsequently becomes available, then this 
diagnosis should be entered on the AE eCRF, replacing the original entries where 
appropriate. 

 
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10.4.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe haemorrhage leads 
to renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points.  Such an event should be recorded only once on the AE eCRF unless 
its severity increases or decreases (in which case it should be recorded again on the AE 
eCRF). 
A recurrent AE is one that occurs and resolves between patient evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
10.4.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the AE eCRF, or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the AE eCRF. 
A clinical laboratory abnormality should be documented as AE if any of the following 
conditions is met: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation)  
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality  
• The abnormality suggests a disease and/or organ toxicity 

 
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• The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of hFVIII activity 
should not be reported as adverse events unless signs of worsening are observed. 
10.4.1.5 
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.4.1.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
10.4.1.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 

 
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• Perform a protocol-mandated efficacy measurement 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
• Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9 
Pregnancy 
Although not an AE per se, pregnancy in the partner of a patient taking trial medication 
should be reported as an SAE to facilitate outcome monitoring by the Sponsor.  Pregnancy in 
partner should be reported during the period up to 5 years after viral infusion. 
Pregnancy in partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by faxing the Pregnancy Form in the study reference materials to BPV.  In 
addition, pregnancy in a patient is also reported on the End of Study eCRF. The Investigator 
must make every effort to follow the patient through resolution of the pregnancy (delivery or 
termination) and to report the resolution on the Pregnancy Follow-up Form in the study 
reference materials. In the event of pregnancy in the partner of a study patient, the 
Investigator should make every reasonable attempt to obtain the woman’s consent for release 
of protected health information. 
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the AE eCRF, and 
expeditiously reported to the Sponsor as an SAE. 
10.5 
Reporting Requirements 
10.5.1 Expedited Reporting Requirements 
All SAEs and EOSI that occur during the course of the AE Reporting Period (refer to 
Section 10.3.1), whether or not considered related to study drug, must be reported by entering 
the information in the AE eCRF  and submitting  to BioMarin Pharmacovigilance (BPV) 

 
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within 24 hours of the site becoming aware of the event.    Investigators should not wait to 
collect information that fully documents the event before notifying BPV of an SAE.  
BioMarin may be required to report certain SAEs to regulatory authorities within 7 calendar 
days of being notified about the event; therefore, it is important that Investigators submit any 
information requested by BioMarin as soon as it becomes available. 
If the EDC is unavailable, all SAEs should be reported to BPV by completing the SAE 
Report Form and faxing or emailing the completed form to BPV within 24 hours of the site 
becoming aware of the event.  Once the EDC is available, the information should be entered 
in the AE eCRF. 
The reporting period for SAEs begins after informed consent is obtained and the first 
administration of study drug is given.  It continues for approximately 5 years or until study 
discontinuation/termination, whichever is longer.  
10.5.2 Ethics Committee Reporting Requirements 
Reporting of SAEs to the Independent Ethics Committee (IEC) will be done in compliance 
with the standard operating procedures and policies of the IEC and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the IEC 
was properly and promptly notified as required. 
10.6 
Follow-up of Patients after Adverse Events 
The Investigator should follow all unresolved AEs and SAEs until the events are resolved or 
have stabilized, the patient is lost to follow-up, or it has been determined that the study 
treatment or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs 
(with dates) should be documented on the AE eCRF and submitted to BioMarin 
Pharmacovigilance and in the patient’s medical record to facilitate source data verification. 
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, or autopsy report) deemed necessary to appropriately evaluate the SAE report. 
10.7 
Post-Study Adverse Events 
At the last scheduled visit, the Investigator should instruct each patient to report, to the 
Investigator and/or to BPV directly, any subsequent SAEs that the patient’s personal 
physician(s) believes might be related to prior study treatment. 
The Investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a patient has discontinued or terminated study participation, if the Investigator believes 

 
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that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the Investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a patient that participated in this 
study.  
10.8 
Urgent Safety Measures 
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect patients against any immediate hazards 
that may affect the safety of patients, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• 
Immediate need to revise the IP administration (eg, modified dose amount or frequency 
not defined in protocol) 
• 
Lack of study scientific value, or detrimental study conduct or management 
• 
Discovery that the quality or safety of the IP does not meet established safety 
requirements 

 
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10.8 
BioMarin Pharmacovigilance Contact Information 
Contact information for BioMarin Pharmacovigilance is as follows: 
BioMarin Pharmaceutical Inc. 
Address 
105 Digital Drive 
 
 
Novato, CA 94949 
Phone:  
 
Fax: 
 
 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows: 
Name:  
 
Address: 
105 Digital Drive 
 
 
Novato, CA 94949 USA 
Phone:  
 
E-mail: 
 
 
PI
PI
PI
PI
PI

 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
 

 
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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the patient, the Investigator or designee and witness (if 
required) before any study-related procedures are performed. 
12.2 
Screening Visit 
Screening assessments will be performed within 28 days (± 14 days) of BMN 270 infusion 
while baseline assessments will take place a within 7 days of BMN 270 infusion (Day 1). 
Should the screening visit occur within 7 days of the drug infusion, physical examination, 
vital signs, blood chemistry, haematology, urine tests, coagulation screen, and CRP do not 
need to be repeated at Baseline.  
The following procedures will be performed during the Screening Period: 
• Full medical history, including haemophilia A history, Hepatitis B, Hepatitis C, and 
HIV. Patients with documented negative results within the last 30 days do not need to 
be retested. 
• Complete Physical Exam (including height and weight) 
• Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature)  
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either patient or clinical 
information) 
• Electrocardiogram 
• Chest X-ray 
• Liver Ultrasound 
• FVIII Treatment Washout (refer to Section 9.4.8.1) 
• Samples for hFVIII Assays 
o Baseline hFVIII activity – chromogenic FXa (plasma) (at least 96 hours 
off therapy) 
o Baseline hFVIII activity level –one-stage APTT assay (at least 96 hours 
off therapy) 
o hFVIII coagulation activity exploratory assay 
o hFVIII inhibitor level (Bethesda assay with Nijmegen modification) 

 
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o hFVIII total antibody assay 
o hFVIII antigen (ELISA) 
• Blood sample for AAV5 Assays 
o AAV5 antibody titer 
o AAV5 transduction inhibition assays 
• Screen for Hepatitis B, Hepatitis C, and HIV if required  
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• Blood samples for Biomarker testing (HLA typing, FVIII mutation status, TNFα and 
IL10a single nucleotide polymorphisms) 
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Documentation of bleeding episodes and FVIII usage (by either patient or clinical 
information) 
• Samples for FVIII Assays 
o FVIII activity – chromogenic FXa (plasma) (at least 96 hours off therapy) 
o FVIII activity level –APTT One stage assay (at least 96 hours off therapy) 
o FVIII coagulation activity exploratory assay 
o FVIII inhibitor level (Bethesda assay with Nijmegen modification) 
o FVIII antibody assay 
o FVIII antigen (ELISA) 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• Mononuclear cell collection for CTL baseline 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
• Exploratory biomarker assessments 
• QoL assessment 

 
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12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one treatment visit for each patient.  Patients will be hospitalized for 24 hours 
for the BMN 270 Infusion Visit.  The following procedures will be performed during the 
BMN 270 Infusion Visit: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• BMN 270 Infusion 
• Vital Signs 
o Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for the first 
6 hours, every 2 hours (± 15 minutes) for the next 6 hours, and then at 
4 hour (± 15 minutes) intervals for the remainder of the patient’s 
hospitalization. 
12.5 
BMN 270 Infusion Follow-Up Visits 
After BMN 270 has been infused, patients will return to the study site every week 
(± 48 hours) for 16 weeks, when the following procedures will be completed: 
12.5.1 Every Visit 
Every week (Weeks 1 through 16), the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
o Each patient will have comprehensive surveillance plan monitoring LFTs 
once a week from dose to completion of Week 6, 3 times per week (every 
other day excluding weekends) from Weeks 7 to 12, and once a week from 
Weeks 13 to 16.  If a patient’s ALT is found to be greater than 1.5x 
baseline during these periods, then LFTs will be monitored three times per 
week or until the ALT returns to baseline. 
• Samples for FVIII Assays 
o FVIII activity level (APTT) 

 
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o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• FVIII antibody titer 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Collection to occur on Day 1, 3, 7 following BMN 270 infusion, and then 
weekly until 3 consecutive negative results are obtained 
• Exploratory biomarker assessments 
12.5.2 Every 4 Weeks 
Every 4 weeks (Weeks 4, 8, 12, and 16), the following procedure will be performed: 
• Mononuclear cell collection 
12.5.3 Weeks 1, 3, and 6 
At Weeks 1, 3, and 6, the following procedure will be performed: 
• Test for Hepatitis B and Hepatitis C reactivation 
12.5.4 Weeks 1, 8, and 16 
At Weeks 1, 8, and 16, the following procedure will be performed: 
• AAV5 antibody titer 
12.5.5 Weeks 1, 2, 3, 4, and 16 
At Weeks 1, 2, 3, 4, and 16, the following procedure will be performed: 
• QoL assessment 
12.6 
Safety Follow-Up – Year 1 
After the 16 weekly infusion follow-up visits are complete, subjects will return to the study 
site at Weeks 20, 28, 36, 44, and 52 (± 48 hours), when the following procedures will be 
completed: 
 

 
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12.6.1 Every Visit 
At Weeks 20, 28, 36, 44, and 52, the following procedures will be performed: 
• Physical exam 
• Assessment of Adverse Events and Concomitant Medications 
• Vital Signs 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if 3 consecutive 
samples are clear during the Post-Infusion Follow-Up period. 
12.6.2 Weeks 28 and 52 
At Weeks 28 and 52, the following procedure will be performed: 
• QoL assessment 
12.7 
 Safety Follow-Up – Years 2-5 
During Years 2-5 of Safety Follow-up, patients will be assessed every 3 months (± 72 hours). 
At these times, the following procedures will be completed: 
12.7.1 Every Visit 
Every 3 months (± 72 hours), the following procedures will be performed: 
• Physical exam 

 
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o Complete Physical Exam will be performed every 52 weeks; Brief 
Physical Exams may be performed at other visits. 
• Assessment of Adverse Events and Concomitant Medications 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (FXa chromogenic assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing during Safety Follow-Up is not required if 3 consecutive 
samples are clear during the Post-Infusion Follow-Up period. 
• Vital Signs 
12.7.2 Every Other Visit (Every 6 Months) 
Every six months starting at the Week 78 visit (ie, 26 weeks after the Week 52 visit at the 
end of Year 1 of the Safety Follow-up period), the following procedure will be performed: 
• QOL assessment 
12.8 
Early Termination Visit 
The Early Termination visit will occur on the date the patient withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a patient leaves the study prior to the Week 270 visit, the patient will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
• Physical exam 

 
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• Assessment of Adverse Events and Concomitant Medications 
• Blood chemistry, haematology, urine tests, coagulation screen, and CRP (refer to 
Table 9.7.8.2.1) 
• FVIII Assays 
o FVIII activity level (APTT) 
o FVIII activity level (chromogenic FXa assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII activity confirmation (Frozen plasma) 
o FVIII antigen (ELISA) 
• AAV5 antibody titer 
• FVIII antibody titer 
• Mononuclear cell collection 
• PCR of vector genomes in blood, saliva, urine, semen, and stools 
o Sample testing at the ETV is not required if 3 consecutive samples are 
clear during the Post-Infusion Follow-Up period. 
• Vital Signs 
• QOL assessment 
12.9 
End of Study 
The study will end after the last patient completes the last Safety Follow-Up visit 
(Week 270). BioMarin reserves the right to discontinue the study any time for clinical or 
administrative reasons and to discontinue participation of an individual investigator or site 
for clinical or administrative reasons, including, but not limited to, poor enrollment or 
noncompliance with procedures of the protocol or GCP. In addition, the study may be 
terminated if, in the opinion of BioMarin, the safety of the study patients may be 
compromised. 
 

 
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DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
The designated clinical data management group will enter or transfer CRF data into a study 
database. 
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

 
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STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No formal interim analysis is planned.  An analysis of the primary endpoint will be done 
following all patients having completed the study assessments through the end of the 
Post-Infusion Follow-Up Period (Week 16). 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Missing data will not be imputed.  
14.2 
Primary and Secondary Efficacy Analysis 
The patients will be followed in a longitudinal manner and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature. Descriptive statistics 
include the number of patients, mean, median, standard deviation, minimum, and maximum 
for continuous variables and count and percent for categorical variables. Efficacy variables 
will be summarized by dose cohort at each time point. Relationship between dose and 
efficacy results will be examined. 
Data collected in a longitudinal manner may be analyzed using longitudinal methods such as 
mixed effect model which takes into account the correlation among the observation taken at 
various time points within a participant. Efficacy is a secondary endpoint, defined as 
biologically active hFVIII at ≥ 5 IU/dL by chromogenic FXa and/or one-stage APTT assay 
between 1 to 16 weeks following study treatment.  hFVIII activity will be assessed weekly 
during the study period.  We can only assess the true steady state of hFVIII protein produced 
from BMN 270 after a minimum of 96 hours has elapsed since the last infusion of FVIII 
protein concentrates. 
14.3 
Immunogenicity 
Analysis of neutralizing antibody response and other immunological parameters will be 
primarily descriptive and involve both inter-participant and intra-participant comparisons 
across doses. 

 
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14.4 
Pharmacodynamic Analyses 
The FVIII antigen and activity level as measured by an Elisa (antigen level) and by a 
one-stage APTT and/or chromogenic FXa assay (activity level), will be used for plasma 
profiles; FVIII activity will be used to determine PD parameters.  Traditional PK analysis is 
not applicable. 
If supported by FVIII activity data, non-compartmental analysis and observation will be used 
to estimate individual PD parameter values of Cb (baseline), Css (steady state), Tss (time to 
steady state), C(t) and AUC(0-t) where t is 16 weeks.  Other parameters that may be used to 
describe individual FVIII protein and activity plasma profiles are Cmax (maximum 
concentration) and Cavg (average concentration, AUC(0-t)/t).  The parameters will be 
summarized using descriptive statistics.  
14.5 
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the CRF. 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. A by-patient listing will be 
provided for those patients who experience a serious AE (SAE), including death, or experience 
an AE associated with early withdrawal from the study or study drug. Hepatitis is of interest, and 
the percentage of patients who report hepatitis will be presented. 
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent visits. 
Descriptive statistics for physical examination results and vital signs will also be provided.  
Detailed statistical methods will be provided in the SAP. 
14.6 
Determination of Sample Size 
No formal sample size calculations based on statistical power were performed. 
The sample size is determined based upon clinical consideration and could detect a strong 
clinical efficacy signal. Up to 12 patients may be dosed in the study; the actual number of 
patients will depend on the criteria for dose escalation. A total of 6 patients may be enrolled 
at a single dose level. 

 
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14.7 
Analysis Populations 
The Safety analysis population is defined as all enrolled patients who receive any study drug. 
The analysis of safety data will be performed on Safety Set. 
The Full Analysis Set (FAS) is defined as all enrolled patients who receive study drug and 
have at least one Baseline and post-Baseline assessment. The FAS will be used for efficacy 
analysis. 
14.8 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a patient’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on patient risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to patients, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active patients must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 

 
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DATA MONITORING COMMITTEE 
There will be no DMC for this study, however a safety and efficacy evaluation board 
composed of the investigators and sponsor will be established. The primary responsibility of 
the board will be to assess patient’s safety and efficacy data accumulated for a particular dose 
level and to make recommendations regarding dose escalation.  
 
 

 
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COMPENSATION, INSURANCE AND INDEMNITY 
There will be no charge to study patients to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/IEC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study patient’s disease, that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected. 
The Investigator should contact BioMarin immediately upon notification that a study patient 
has been injured by the IP or by procedures performed as part of the study. Any patient who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The patient should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the patient’s health insurance company or other third party 
payer for the cost of this medical treatment. If the patient has followed the Investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law. 

 
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CASE REPORT FORMS AND SOURCE DOCUMENTS 
Electronic case report forms will be provided for each patient. The Investigator must review 
and electronically sign the completed CRF casebook to verify its accuracy. 
CRFs must be completed using a web–based application developed and validated. Study site 
personnel will be trained on the application and will enter the clinical data from source 
documentation. Unless explicitly allowed in the CRF instructions, blank data fields are not 
acceptable.  
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with ICH GCP Guidelines and 21 CFR Part 11, the system will 
require the personnel making the correction to enter a reason for changing the value. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the CRFs must be verifiable to the source data, which 
necessitates access to all original recordings, laboratory reports, and patient records. In 
addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Patients must also allow access to 
their medical records, and patients will be informed of this and will confirm their agreement 
when giving informed consent. If an Investigator or institution refuses to allow access to 
patient records because of confidentiality, arrangements must be made to allow an 
“interview” style of data verification. 
A CRA designated by BioMarin will compare the CRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). If an error is discovered at any time or a clarification is 
needed, the CRA, or designee, will create an electronic query on the associated field. Site 
personnel will then answer the query by either correcting the data or responding to the query. 
The CRA will then review the response and determine either to close the query or re–query 
the site if the response does not fully address the question. This process is repeated until all 
open queries have been answered and closed.  
Before a patient’s CRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Study Monitoring Plan for details on which fields must be 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the CRFs is accurate and complete. The Data Manager, or designee, 

 
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will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 

 
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STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study patients, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 

 
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RETENTION OF RECORDS 
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, patient charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain patient identifiers for at least 15 years after the completion or discontinuation of 
the study. Patient files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
patient files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained. 

 
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USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the Investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  

 
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REFERENCES 
Bainbridge JW, Smith AJ, Barker SS et al. Effect of gene therapy on visual function in 
Leber's congenital amaurosis. N.Engl.J.Med. 2008;358:2231-2239. 
Berntorp E, Halimeh S, Gringeri A, et al.  Management of bleeding disorders in children.  
Haemophilia.  2012; 18 (Suppl. 2):15-23. 
Croteau GA, Martin DB, Camp J et al.  Evaluation of Exposure and Health Care Worker 
Response to Nebulized Administration of tgAAVCF to Patients with Cystic Fibrosis.  Ann. 
Occup. Hyg. 2004; 48[8]:673-681. 
D’Avola D, Lopez-Franco E, Harper P, et al.  Phase 1 Clinical Trial of Liver Directed Gene 
Therapy with rAAV5-PBGD in Acute Intermittent Porphyria: Preliminary Safety Data.  J. 
Hepatology.  2014;60[1]:S58. 
Maguire AM, High KA, Auricchio A et al. Age-dependent effects of RPE65 gene therapy for 
Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009;374:1597-1605. 
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion 
protein in severe hemophilia A. Blood. 2014; 123: 317-325. 
Manno CS, Chew AJ, Hutchison S, et al.  AAV-mediated factor IX gene transfer to skeletal 
muscle in patients with severe hemophilia B.  Blood.  2003;101:2963-2972. 
Manno CS, Arruda VR, Pierce GF, et al.  Successful transduction of liver in hemophilia by 
AAV-Factor IX and limitations imposed by the host immune response.  Nature Med. 
2006;12:342-347. 
McIntosh J, Lenting PJ, Rosales C, et al.  Therapeutic levels of FVIII following a single 
peripheral vein administration of rAAV vector encoding a novel human factor VIII variant.  
Blood.  2013;121:3335-3344. 
Nagel K, Walker I, Decker K, et al. Comparing bleed frequency and factor concentrate use 
bewteen haemophilia A and B patients. Haemophilia. 2011 17: 872-4 
Nathwani AC, Tuddenham EG. Epidemiology of coagulation disorders. Baillieres 
Clin.Haematol. 1992;5:383-439. 
Nathwani AC, McIntosh J, Davidoff AM. An update on gene therapy for hemophilia. 
Curr.Hematol Rep. 2005;4:287-293. 

 
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Nathwani AC, Rosales C, McIntosh J et al. Long-term Safety and Efficacy Following 
Systemic Administration of a Self-complementary AAV Vector Encoding Human FIX 
Pseudotyped With Serotype 5 and 8 Capsid Proteins. Mol.Ther. 2011;19:876-885. 
Nathwani AC, Tuddenham EG, Rangarajan S et al. Adenovirus-associated virus vector-
mediated gene transfer in hemophilia B. N.Engl.J.Med.  2011;365:2357-2365. 
Nathwani AC, Reiss UM, Tuddenham EGD, et al.  Long-Term Safety and Efficacy of Factor 
IX Gene Therapy in Hemophilia B.  N.Engl.J.Med. 2014;371:1994-2004. 
Paneda A, Venrell L, Mauleon I, et al.  Effect of Adeno-Associated Virus Serotype and 
Genomic Structure on Liver Transduction and Biodistribution in Mice of Both Genders.  
Hum.Gene Ther.  2009;20:908-917. 
Paneda A, Lopez-Franco E, Kaeppel C, et al.  Safety and Liver Transduction Efficacy of 
rAAV5-cohPBGD in Nonhuman Primates: A Potential Therapy for Acute Intermittent 
Porphyria.  Hum.Gene Ther.  2013;24:1007-1017. 
Pipe SW. Go long! A touchdown for factor VIII? Blood. 2010;116:153-154. 
Schenk-Braat EA, van Mierlo MM, Wagemaker G et al.  An inventory of shedding data from 
clinical gene therapy trials.  J Gene Med. 2007; 9:910-921. 
Simonelli F, Maguire AM, Testa F et al. Gene therapy for Leber's congenital amaurosis is 
safe and effective through 1.5 years after vector administration. Mol.Ther. 2010;18:643-650. 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.  Guidelines for the management of 
hemophilia.  Haemophilia.  2012:1-47. 
Stonebraker JS, Brooker M, Amand RE, et al. A study of reported factor VIII use around the 
world. Haemophilia. 2010;16:33-46. 

 
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INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Patients  
In accordance with FDA Form 1572, the Investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and IRB 
review and approval in 21 CFR Part 56 are met.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
• He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• He or she will ensure that the IRB/IEC/REB complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312. 

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