A Phase 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII, With Prophylactic Corticosteroids in Hemophilia A Patients
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: BioMarin Pharmaceutical

 
 
 
 
    
 
 
 
 
 
 
Official Title:  A Phase 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and Safety of 
BMN 270, an Adeno-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII, with Prophylactic Corticosteroids in Hemophilia A Patients 
 
NCT Number:  NCT04323098 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 25 May 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
  
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3b, Single Arm, Open-Label Study to Evaluate the 
Efficacy and Safety of BMN 270, an Adeno-Associated 
Virus Vector–Mediated Gene Transfer of Human Factor 
VIII, with Prophylactic Corticosteroids in Hemophilia A 
Patients 
Protocol Number: 
270-303 
Active Investigational Product: 
AAV5-hFVIII-SQ 
IND/European Union Drug Regulating 
Authorities Clinical Trials (EudraCT) 
Number: 
IND #: 017659 
2018-004616-21 
 
Indication: 
Hemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 3b 
Sponsor's Responsible Medical Monitor: 
 MD, MHS 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Duration of Subject Participation: 
Approximately 264 weeks 
Dose: 
6E13 vg/kg  
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
28 February 2020 
 
 
 
 
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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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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Dossier: 
 
Volume:  
 
Page:  
 
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AUTHORITY USE 
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TITLE OF STUDY:  
A Phase 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and Safety of BMN 270, an 
Adeno-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII, with Prophylactic 
Corticosteroids in Hemophilia A Patients 
PROTOCOL NUMBER: 
270-303 
STUDY SITES: 
Approximately 10 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 3b 
STUDY RATIONALE: 
Hemophilia 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 pathway. This disorder can be either inherited, due to 
a genetic aberrancy, 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 generally correlates tightly with the level of residual expression. 
Severe HA is classified as FVIII activity less than 1% of normal (< 1 IU/dL), moderate disease 
comprises 1-5% of normal activity and the mild form is 5-40% activity. The clinical manifestations 
of severe HA are frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, 
with a substantially increased risk of death from hemorrhage when the brain is involved. Subjects 
with moderate disease can exhibit manifestations similar to those seen in patients with severe HA, 
resulting in a comparable bleeding phenotype.  
Treatment of severe HA includes 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 and/or subcutaneous injection of a bi-
specific monoclonal antibody, emicizumab, as prophylaxis 1-4 times per month. 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 prophylactic therapy (median annualized bleeding rate [ABR] of 
1-4 with prophylaxis treatment in a recently published retrospective observational study and 
between 1-2 in 6 prospective FVIII interventional studies) and on-demand-only therapy (median 
ABR of 4.5-18 in a recently published retrospective study and between 20-60 in 6 prospective 

 
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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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FVIII interventional studies). The consequence of multiple bleeding events is the development of 
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 a 1% trough for a greater 
proportion of the dosing interval. However, patients with severe HA who are treated with extended 
half-life FVIII remain dependent on multiple infusions to maintain critical levels of FVIII activity. 
While emicizumab prophylaxis has yielded lower bleed rates compared to prior FVIII prophylaxis, 
it does not physiologically recapitulate the coagulation system, requires chronic, life-long therapy, 
and still necessitates the use of on-demand FVIII concentrates for treatment of breakthrough 
bleeds. 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 hemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous infusion of a vector encoding the 
appropriate gene sequence for long-term episomal expression. HA 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 even 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 hemophilia A. Thus, relatively small changes in endogenous FVIII activity can 
result in clinically relevant improvements in disease phenotype. Finally, the circulating FVIII 
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 and 
promoter specificity for specific tissues, such as the liver (for serotypes 2, 5 and 8 among others). 
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
that stable (median follow-up of 6.7 years) expression of human factor IX (hFIX) at levels that are 
sufficient for conversion of their bleeding phenotype from severe to moderate or mild is achievable 
following a single peripheral vein infusion of AAV8-hFIX vector. Several participants in this trial 
have been able to discontinue factor prophylaxis without suffering spontaneous hemorrhages, 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 hybrid human liver-specific promoter Figure 1). 

 
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Figure 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 a single intravenous dose and is designed to achieve durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.  
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose 
escalation study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 
at various dose levels (6E12 vector genomes [vg]/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. Additional 
studies have been undertaken at the 6E13 vg/kg dose (270-301 in subjects with severe HA, and 
270-203 in subjects with severe HA who are also AAV5-antibody positive). 
Three-year results from 270-201 have demonstrated that following gene transfer, mean and median 
FVIII activity levels above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are 
achievable and sustained following a single infusion of 6E13 vg/kg of BMN 270, with an 
acceptable safety profile. Preliminary results from optional liver biopsies (in subjects receiving 
lower doses of BMN 270 in 270-201) confirm pan-lobular and otherwise healthy liver transduction 
at 2.5 years. In addition, an interim analysis of clinical study 270-301, an ongoing phase 3 study 
designed to assess the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg, demonstrated 
FVIII activity levels that were also well above 15 IU/dL, albeit lower than what was observed for 
the 6E13 vg/kg cohort in 270-201.  
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects 
in 270-301; in 270-201, subjects were started on corticosteroids by Week 3 (either therapeutically, 
in response to an ALT elevation, or prophylactically), whereas in 270-301 subjects received 
corticosteroids only in response to an alanine aminotransferase (ALT) elevation. Possibly as a 
result of this difference, subjects receiving 6E13 vg/kg in 270-201 started corticosteroids at an 
earlier date in reference to the date of BMN 270 infusion, showed later advent of first ALT 
elevations, and were also less likely to experience a significant decline in FVIII activity 
concurrently with an ALT elevation when compared with subjects in 270-301 (20% of subjects in 
270-201 vs. 58% of subjects in 270-301). In 270-301, ALT elevation within the first 26 weeks was 
associated with decreased FVIII activity. Recently published data from 270-201 suggests that 

 
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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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AUTHORITY USE 
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corticosteroids may have assisted in rescue or protection of FVIII levels during elevations of ALT 
and in resolution of elevated ALT levels in some subjects. 
The current study is a Phase 3b, single arm, open-label study designed to assess whether 
BMN 270, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and effectively 
improve the FVIII activity profiles and alter the clinical phenotype of hemophilia A patients with 
residual FVIII activity ≤ 1 IU/dL. 
OBJECTIVES:  
The primary efficacy objective of the study is to: 
• 
Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 
The secondary efficacy objectives of the study are to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the use of exogenous 
FVIII replacement therapy from Week 5 to Week 52 for subjects receiving prior FVIII 
prophylaxis or on use of emicizumab from Week 27 to Week 52 for subjects receiving 
prior emicizumab prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the number of 
bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to Week 
52 for subjects receiving prior FVIII prophylaxis or on use of emicizumab from Week 27 
to Week 52 for subjects receiving prior emicizumab prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on quality of life as 
measured by the Haemo-QoL-A questionnaire at Week 52 of the study compared to 
baseline 
 The tertiary efficacy objective of the study is to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on patient-reported 
outcomes (PROs) (other than Haemo-QoL-A) at Week 52 of the study compared to 
baseline 
 The exploratory efficacy objective of the study is to: 
• 
Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 for subjects with detectable AAV5 total antibodies 
below the minimum required dilution at Screening 

 
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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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The safety objectives of the study are to: 
• 
Evaluate the safety of BMN 270 with prophylactic corticosteroids during the first 52 
weeks following intravenous infusion of BMN 270 
• 
Assess the long-term safety of BMN 270 with prophylactic corticosteroids 
STUDY DESIGN AND PLAN:  
This is a Phase 3b, single arm, open-label study in hemophilia A patients with residual FVIII levels 
≤ 1 IU/dL. Subjects will be enrolled at approximately 10 sites worldwide. Subjects must have 
high-quality, well-documented historical data available concerning previous bleeding episodes and 
exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of BMN 270 as a 
single intravenous infusion in conjunction with receipt of a 19-week prophylactic corticosteroid 
regimen starting on the day of BMN 270 infusion (Figure 2). Therapeutic corticosteroids, as 
needed for ALT elevations and/or FVIII decline, will also be available post-infusion. 
Figure 2:  270-303 Study Schema 
 
 

 
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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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In order to minimize bias in the ongoing study and to assure safe and ethical conduct of the clinical 
trial, an independent Data Monitoring Committee (DMC), consisting of experts in clinical trials, 
statistics, and hemophilia, will be convened. The DMC will have access during the trial to 
amalgamated FVIII activity levels, FVIII usage, and bleeding data and review available safety and 
efficacy (eg, FVIII activity) data during the study on an ongoing basis; they may determine, based 
on emerging data and the risk/benefit profile, that further enrollment should be paused to enable 
modification of the protocol or discontinued.  
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to Week 52). 
After the final analysis, safety and efficacy will then continue to be assessed long-term for a total 
of approximately 5 years for each subject. 
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic FVIII 
replacement therapy 4 weeks following infusion of BMN 270 or if FVIII activity has consistently 
increased above 5 IU/dL, whichever is earlier. Four weeks represents the time by which 
endogenous production of FVIII following gene transfer is expected to be efficacious, based on 
prior study results. Subjects previously receiving emicizumab, given its approximate 1-month half-
life, will remain on emicizumab prophylaxis until BMN 270 infusion, with their final dose 
administered prior to Day 1. 
In subjects who experience recurring 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 or Sponsor-designated Data 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.  
There will be an ongoing review of individual subject safety by the Medical Monitor, and both 
safety and efficacy data by the DMC. Patients will receive prophylactic corticosteroids with 
tapering of the dosage based upon consideration of ALT values, FVIII activity levels, and 
consultation with the Investigator and the Medical Monitor. Therapeutic oral corticosteroids may 
be initiated if a subject’s ALT values increase from baseline levels, after consultation between the 
Investigator and the Medical Monitor. 
In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at 
the Investigator’s discretion) in order to facilitate timely and appropriate clinical management 
decisions; where possible, a matched sample for testing at the central laboratory should be 
collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. 

 
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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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Additionally, any safety signal may trigger a review of the data and possible additional 
immunogenicity studies or other diagnostics deemed necessary that include an assessment of 
cellular immune responses using collected peripheral blood mononuclear cells (PBMCs). 
An optional liver biopsy will be performed (in subjects who consent to do so) at or around Week 
26, Week 52, and/or during Years 2-5 following BMN 270 infusion. Subjects who consent to the 
liver biopsy will have additional assessments, including a liver ultrasound and FibroScan, and will 
receive prophylactic FVIII prior to the procedure, as indicated in the judgment of the Investigator, 
to minimize the risk of bleeding. 
At applicable sites, certain study assessments may be performed by a mobile nursing (MN) 
professional at the patient's home or another suitable location such as their school or office (if the 
subject has given written informed consent to participate in MN visits), or at the site or approved 
lab facility as a shortened lab draw-only visit, to improve access and convenience for patients 
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 patient and the 
patient gives written informed consent to participate in MN visits, the MN network will 
communicate with the patient and the patient’s site. 
NUMBER OF SUBJECTS PLANNED:  
Approximately 20 subjects will be enrolled into the study, with at least 16 AAV5 TAb-negative 
and up to 25% AAV5 total antibodies (TAb) detectable but below the minimum required dilution. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Patients are eligible to be included in the study only if all of the following criteria apply: 
1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as 
evidenced by medical history, at the time of signing the informed consent.  
2. Must have been on prophylactic hemophilia therapy for at least 12 months prior to study 
entry. High-quality, well-documented historical data concerning bleeding episodes and 
hemophilia therapy usage over the previous 12 months must be available. 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs). 
4. Willing and able to provide written, signed informed consent after the nature of the study 
has been explained and prior to any study-related procedures. 

 
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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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5. No previous documented history of a detectable FVIII inhibitor, and results from a 
Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda 
Units (BU) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff 
for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart 
within the past 12 months (at least one of which should be tested at the central laboratory). 
6. Sexually active participants must agree to use an acceptable method of effective 
contraception, either double-barrier contraception (ie, condom + diaphragm; or condom or 
diaphragm + spermicidal gel or foam) or their female partner either using hormonal 
contraceptives or having an intrauterine device. Participants must agree to contraception 
use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception 
use only if they have had 3 consecutive semen samples with viral vector DNA below the 
limit of detection. 
7. Willing to abstain from alcohol consumption for at least the first 52 weeks following 
BMN 270 infusion. 
Patients are excluded from the study if any of the following criteria apply: 
1. Detectable pre-existing antibodies to the AAV5 capsid. Up to 25% of subjects may have 
detectable pre-existing AAV5 capsid antibodies, so long as the detectable titer level is 
below the minimum required dilution (< 20). 
2. Any evidence of active infection or any immunosuppressive disorder, including HIV 
infection.  
3. Significant liver dysfunction with any of the following abnormal laboratory results: 
• 
ALT (alanine aminotransferase) > 1.25x upper limit of normal (ULN); 
• 
AST (aspartate aminotransferase) > 1.25x ULN; 
• 
GGT (gamma-glutamyltransferase) > 1.25x ULN; 
• 
Total bilirubin > 1.25x ULN; 
• 
Alkaline phosphatase > 1.25x ULN; or 
• 
INR (international normalized ratio) ≥ 1.4. 
Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat 
testing of the entire liver test panel within the same Screening window and, if eligibility 
criteria are met on retest, may be enrolled after confirmation by the Medical Monitor.  

 
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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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4. Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated 
on a scale of 0-4 on the Batts-Ludwig or METAVIR scoring systems, or an equivalent 
grade of fibrosis if an alternative scale is used. 
5. Evidence of any bleeding disorder not related to hemophilia 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/FibroScan. 
9. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface 
antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody 
[HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control 
(CDC) table for the interpretation of serological test results in the Laboratory Manual. 
10. Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral therapy.  
11. Active malignancy, except non-melanoma skin cancer.  
12. History of hepatic malignancy. 
13. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), 
with the exception of catheter-associated thrombosis for which anti-thrombotic treatment 
is not currently ongoing.  
14. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
15. Treatment with any investigational product within 30 days or 5 half-lives of the 
investigational product prior to the screening period. For subjects who have received a 
prior investigational product, all ongoing adverse events (AEs) experienced while 
receiving that investigational product must have resolved prior to screening for this study. 
16. Any condition that, in the opinion of the Investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including corticosteroid 
treatment outlined in the protocol) and/or would impact or interfere with evaluation and 
interpretation of subject safety or efficacy result. 
17. Prior treatment with any vector or gene transfer agent. 
18. Major surgery planned in the 52-week period following the infusion with BMN 270. 

 
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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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19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines 
within 30 days before the BMN 270 infusion. 
20. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of efficacy and safety of BMN 270 
and with prior consultation with the Medical Monitor. 
21. Known allergy or hypersensitivity to BMN 270 investigational product formulation. 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a 
bleeding episode. 
Optional Liver Biopsy Inclusion and Exclusion Criteria 
Individuals eligible for the optional liver biopsy must meet the following inclusion criterion: 
8. Able to sign informed consent and comply with requirements for the optional liver biopsy 
9. Documentation of FVIII activity level ≥ 50 IU/dL (or higher, depending on local 
guidelines and/or Investigator discretion) within 24 hours prior to the liver biopsy being 
performed (FVIII activity levels should be assessed at the local laboratory). Subjects may 
be treated with additional exogenous FVIII replacement products in order to increase their 
FVIII activity to an appropriate level, under the supervision/instruction of the Investigator. 
Individuals who meet any of the following exclusion criteria will not be eligible for the optional 
liver biopsy: 
1. Any condition that, in the opinion of the Investigator or a hepatologist or radiologist, 
would make liver biopsy contraindicated. This includes (but is not limited to): 
abnormalities detected on liver ultrasound performed within 28 days of procedure or prior 
liver ultrasound result within 90 days that would preclude safe performance of the biopsy. 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single intravenous infusion of BMN 270 at 6E13 vg/kg. The volume of 
infusion will depend on the subject’s weight 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
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 
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CRITERIA FOR EVALUATION: 
Efficacy:  
Primary efficacy endpoint: 
• 
Change of the hFVIII activity, as measured by chromogenic substrate assay, during 
Weeks 49-52 post-BMN 270 infusion from baseline. Each subject’s hFVIII activity during 
Weeks 49-52 is defined as the median of the values obtained during this 4-week window. 
Values for hFVIII activity will be excluded if obtained within 72 hours since the last 
infusion of exogenous FVIII protein concentrates. 
Secondary efficacy endpoints:  
• 
Change from baseline in the annualized utilization (IU/kg/year) and infusion rate 
(number/year) of exogenous FVIII replacement therapy during Week 5 to Week 52 post-
BMN 270 infusion, for subjects receiving FVIII prophylaxis during the 12 months prior to 
study entry or change from baseline in the annualized utilization (mg/kg/year) of 
emicizumab during Week 27 to Week 52 post-BMN 270 infusion for subjects receiving 
prior emicizumab prophylaxis. 
• 
Change from baseline in the annualized number of bleeding episodes requiring exogenous 
FVIII replacement treatment (annualized bleeding rate, ABR) during Week 5 to Week 52 
post-BMN 270 infusion for subjects receiving prior FVIII prophylaxis, or Week 27 to 
Week 52 post-BMN 270 infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the total score of Haemo-QoL-A at Week 52 post-BMN 270 
infusion 
Tertiary efficacy endpoints:  
 
 
• 
Change from baseline in the EQ-5D-5L score at Week 52 post-BMN 270 infusion. 
• 
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 52 post-
BMN 270 infusion. 
• 
Change from baseline in Patient Reported Outcomes, Burdens, and Experiences (PROBE) 
score at Week 52 post-BMN 270 infusion. 
Safety: 
The following safety outcome measurements will be assessed: 
• 
Incidence of adverse events (AEs) and serious AEs (SAEs) 

 
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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: 
• 
Change in clinical laboratory tests (serum chemistry and hematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding (blood, urine, semen, stool, saliva) 
• 
Liver tests (LTs, including ALT, AST, GGT, lactate dehydrogenase [LDH], total bilirubin, 
and alkaline phosphatase) 
o The frequency and duration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator, review of subject data, 
and/or by independent DMC feedback. 
• 
Immune response to FVIII transgene product and AAV5 capsid proteins 
• 
Immunological assessments, including hFVIII TAb, interferon gamma (IFNg) ELISpot, 
complement, and an exploratory biomarker panel. 
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Pharmacodynamics: 
The FVIII protein concentration and activity level as measured by a validated immunoassay and a 
validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and 
activity will be used to determine PD parameters. 
STATISTICAL METHODS:  
Sample Size 
Approximately 20 subjects may be dosed in the study, including at least 16 subjects who are 
AAV5 antibody-negative and up to 25% of the total number of subjects who have an AAV5 
antibody titer that is detectable but below the minimum required dilution at Screening.   
For the primary endpoint, a sample size of 16 will provide 85% power to demonstrate that the 
change in hFVIII activity during Weeks 49-52 from baseline is greater than 0, assuming an effect 
size of 0.8, using a one-sample t-test at the 1-sided significance level of 0.025 (or equivalently, at 
the 2-sided significance level of 0.05). The effect size of 0.8 is assumed conservatively based on 
the results from 270-201 and the interim results from 270-301. 
 
 
 

 
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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: 
Analysis Population 
The intention-to-treat (ITT) population is defined as all subjects who received BMN 270 infusion. 
The ITT population will be the primary population for safety analyses, as well as being used for 
supportive efficacy analyses. 
The modified intention-to-treat (mITT) population is the primary analysis population for efficacy 
for this study. The mITT population will include all subjects who received BMN 270 infusion and 
who were AAV5 antibody negative at Screening (ie, excludes subjects with an AAV5 antibody 
titer detectable but below the minimum required dilution). 
Subjects with an AAV5 antibody titer detectable but below the minimum required dilution will be 
used for exploratory efficacy analysis on FVIII activity, as measured by chromogenic substrate 
assay, during Weeks 49-52 post-BMN 270 infusion. 
Analysis 
For the primary efficacy endpoint at Week 52 (ie, the change in the hFVIII activity during Weeks 
49-52 post-BMN 270 infusion from baseline, as measured by chromogenic substrate assay), a one-
sample t-test will be used to test the null hypothesis that the change is 0 or less against the 
alternative hypothesis that the change is greater than 0. Baseline value of 1 IU/dL (eligible subjects 
must have residual FVIII levels ≤ 1 IU/dL as evidenced by medical history) will be used in the 
calculation of change from baseline since all the subjects will be on prophylactic hemophilia 
therapy prior to BMN 270 infusion where the FVIII activity level cannot be reliably measured. 
Descriptive summaries of the proportions of subjects whose FVIII activity during Weeks 49-52 is 
greater than or equal to select thresholds, such as 5, 15, 25, 30, and 40 IU/dL, and the confidence 
intervals of the proportions will also be provided.  
The analyses of the secondary and tertiary efficacy endpoints will be descriptive. Mean and 
associated 95% confidence interval will be provided for the following secondary endpoints, where 
the baseline value will be derived from the data in the approximately 12-month period prior to 
BMN 270 infusion: 
• 
Change from baseline in the annualized utilization (IU/kg/year) of exogenous FVIII 
replacement therapy during Weeks 5-52 post-BMN 270 infusion, for subjects receiving 
FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in 
the annualized utilization (mg/kg/year) of emicizumab during Week 27 to Week 52 
post-BMN 270 infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the annualized infusion rate (number/year) of exogenous FVIII 
replacement therapy during Weeks 5-52 post-BMN 270 infusion, for subjects receiving 
FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in 

 
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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 annualized utilization (mg/kg/year) of emicizumab during Week 27 to Week 52 
post-BMN 270 infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the annualized number of bleeding episodes (number/year) 
requiring exogenous FVIII replacement treatment during Weeks 5-52 post-BMN 270 
infusion for subjects receiving prior FVIII prophylaxis, or Weeks 27-52 post-BMN 270 
infusion for subjects receiving prior emicizumab prophylaxis from baseline 
Mean change from baseline and associated 95% confidence interval will be calculated for the total 
score of Haemo-QoL-A at Week 52 post-BMN 270 infusion as well. 
The incidence of AEs will be summarized by system organ class, preferred term, relationship to 
study drug, seriousness, and severity. Clinical laboratory test values, vital signs, vector shedding 
and immune response parameters will be summarized descriptively by visit.  
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to Week 52).  
No formal interim analysis is planned. Informal analyses (ie, no hypothesis testing) may be 
performed at different timepoints to assess efficacy and safety over time. The primary efficacy 
endpoint for such analyses involves hFVIII activity, as measured by chromogenic substrate assay, 
and is defined as median FVIII activity during a specific 4-week time interval post-BMN 270 
infusion. 
Details of the planned analyses will be specified in the SAP. 

 
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3 
TABLE OF CONTENTS 
2 SYNOPSIS ...........................................................................................................................2 
3 TABLE OF CONTENTS ...................................................................................................16 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................21 
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 ..........................................................................................28 
7.3 Study Rationale .........................................................................................................28 
7.3.1 
Optional Liver Biopsy Rationale .................................................................32 
7.4 Summary of Overall Risks and Benefits ...................................................................32 
7.4.1 
Optional Liver Biopsy Risks and Benefits ..................................................34 
8 STUDY OBJECTIVES ......................................................................................................35 
9 INVESTIGATIONAL PLAN ............................................................................................36 
9.1 Overall Study Design and Plan .................................................................................36 
9.2 Discussion of Study Design, Including Choice of Control Group ............................53 
9.3 Selection of Study Population ...................................................................................53 
9.3.1 
Inclusion Criteria .........................................................................................53 
9.3.2 
Exclusion Criteria ........................................................................................54 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................56 
9.3.4 
Subject Identification and Replacement of Subjects ...................................58 
9.3.5 
Duration of Subject Participation ................................................................58 
9.4 Treatments .................................................................................................................58 
9.4.1 
Treatments Administered ............................................................................58 
9.4.2 
Identity of Investigational Product ..............................................................59 
9.4.3 
Storage .........................................................................................................59 

 
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9.4.4 
Directions for Administration .....................................................................59 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................61 
9.4.6 
Selection of Dose Used in the Study ...........................................................61 
9.4.7 
Blinding .......................................................................................................61 
9.4.8 
Prior and Concomitant Medications ............................................................61 
9.4.9 
Treatment Compliance ................................................................................66 
9.5 Investigational Product Accountability .....................................................................66 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................66 
9.6 Dietary or Other Protocol Restrictions ......................................................................67 
9.7 Safety and Efficacy Variables ...................................................................................67 
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 ...........................................................................................69 
9.7.5 
Pharmacodynamics ......................................................................................70 
9.7.6 
Pharmacokinetics .........................................................................................70 
9.7.7 
Exploratory Assessments ............................................................................70 
9.7.8 
Safety Variables ..........................................................................................72 
10 REPORTING ADVERSE EVENTS .................................................................................80 
10.1 Safety Parameters and Definitions ............................................................................80 
10.1.1 Adverse Events ............................................................................................80 
10.2 Serious Adverse Events ............................................................................................81 
10.2.1 Events of Special Interest (EOSI) ...............................................................82 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................82 
10.3.1 Adverse Event Reporting Period .................................................................82 
10.3.2 Eliciting Adverse Events .............................................................................82 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................82 
10.4 Procedures for Recording Adverse Events ...............................................................85 
10.4.1 Recording Adverse Events on a eCRF ........................................................85 
10.5 Reporting Requirements ...........................................................................................88 

 
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10.5.1 Expedited Reporting Requirements .............................................................88 
10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements..............................................................................89 
10.6 Follow-up of Subjects after Adverse Events .............................................................89 
10.7 Post-Study Adverse Events .......................................................................................89 
10.8 Urgent Safety Measures ............................................................................................90 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................91 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................92 
12 STUDY PROCEDURES ...................................................................................................93 
12.1 Prestudy .....................................................................................................................93 
12.2 Screening Visit ..........................................................................................................93 
12.2.1 “Smart Rescreening” Visit ..........................................................................95 
12.3 Baseline Visit ............................................................................................................95 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................96 
12.5 BMN 270 Infusion Follow-Up Visits – Weeks 1-26 ................................................97 
12.5.1 Once per week (Weeks 1 through 26) .........................................................98 
12.5.2 Week 1 - Day 8 ............................................................................................98 
12.5.3 Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26 ................................................99 
12.5.4 Weeks 2, 4, 8, 12, 16, 20, 24, and 26 ..........................................................99 
12.5.5 Weeks 2, 6, 10, 14, 18, 22, 24, and 26 ........................................................99 
12.5.6 Weeks 4, 8, 12, 16, 20, 24, and 26 ..............................................................99 
12.5.7 Weeks 4, 8, 12, 16, 18, 20, 22, 24, and 26 ..................................................99 
12.5.8 Weeks 4, 8, 16, and 26 ................................................................................99 
12.5.9 Weeks 4, 8, 12, 18, 22, and 26 ..................................................................100 
12.5.10 Week 4, 12, and 26 ....................................................................................100 
12.5.11 Weeks 4, 16, and 26 ..................................................................................100 
12.5.12 Weeks 12 and 26 .......................................................................................100 
12.5.13 Weeks  16, 20, and 26 ...............................................................................100 
12.5.14 Weeks 6 and 20 .........................................................................................100 
12.5.15 Week 26 .....................................................................................................100 
12.6 Post-Infusion Follow-Up – Weeks 27-52 ...............................................................101 

 
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12.6.1 Each Visit (Weeks 28, 30, 32, 34, 36, 40, 44, 48, 50, and 52) ..................101 
12.6.2 Weeks 28, 32, 36, 40, 44, 48, and 52 ........................................................101 
12.6.3 Week 28, 36, 44, and 52 ............................................................................102 
12.6.4 Week 32 .....................................................................................................102 
12.6.5 Weeks 32, 36, 40, 44, 48, and 52 ..............................................................102 
12.6.6 Weeks 32, 36, 44, and 52 ..........................................................................102 
12.6.7 Week 36 and 52 .........................................................................................102 
12.6.8 Week 52 .....................................................................................................103 
12.6.9 Week 52 .....................................................................................................103 
12.7 Post-Infusion Follow-Up – Years 2-5 .....................................................................103 
12.7.1 Year 2 (Every 4 Weeks) or Years 3-5 (Every 6 Weeks) ...........................104 
12.7.2 Years 2-5 – Every 12 Weeks and End of Year Visits ...............................104 
12.8 Early Termination Visit ..........................................................................................106 
12.9 Optional Liver Biopsy .............................................................................................107 
12.10 End 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 Efficacy Endpoint ......................................................................................110 
14.3 Secondary Efficacy Endpoints ................................................................................111 
14.4 Tertiary Efficacy Endpoints ....................................................................................112 
14.5 Immunogenicity ......................................................................................................112 
14.6 Pharmacodynamic Analyses ...................................................................................112 
14.7 Safety Analysis .......................................................................................................112 
14.8 Determination of Sample Size ................................................................................112 
14.9 Analysis Populations ...............................................................................................113 
14.10 Changes in the Conduct of the Study or Planned Analyses ....................................113 
15 DATA MONITORING COMMITTEE ...........................................................................114 

 
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16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................115 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................116 
18 STUDY MONITORING AND AUDITING ...................................................................118 
19 RETENTION OF RECORDS..........................................................................................119 
20 USE OF INFORMATION AND PUBLICATION ..........................................................120 
21 REFERENCES ................................................................................................................121 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................123 
22.1 Conduct of Study and Protection of Human Patients .............................................123 
23 SIGNATURE PAGE .......................................................................................................124 
24 APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA .........................................125 
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 1-20) ...............................42 
Table 9.1.3:  Schedule of Events – Post-Infusion Follow-Up (Weeks 21-52) ........................45 
Table 9.1.4:  Schedule of Events-Post-Infusion Follow-Up (Year 2-Year 5) .........................48 
Table 9.1.5:  Schedule of Events-Optional Liver Biopsy ........................................................51 
Table 9.1.6:  Suggested Schedule of Events-Prophylactic Corticosteroids .............................52 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen .......................................................65 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................73 
Table 9.7.8.3.1:  Liver Tests ....................................................................................................75 
Table 9.7.8.3.2: Evaluation of ALT Elevations .......................................................................76 
Table 9.7.8.3.3:  Viral and Autoimmune Hepatitis Testing .....................................................77 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................83 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................84 
 
LIST OF FIGURES 
Figure 1:  hFVIII-SQ Vector Genome and Encoded Protein .....................................................4 
Figure 2:  270-303 Study Schema ..............................................................................................6 
Figure 7.3.1:  hFVIII-SQ Vector Genome and Encoded Protein .............................................30 
Figure 9.1.1:  270-303 Study Schema ......................................................................................36 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAV 
adeno-associated virus 
ABR 
annualized bleeding rate 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CBA 
cytokine bead array 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CL 
clearance 
cNBA 
FVIII chromogenic Nijmegen Bethesda Assay 
CRA 
clinical research associate 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
electronic case report form 
ED 
exposure days 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FVIII 
coagulation factor VIII 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HA 
hemophilia A 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
hFIX 
human coagulation factor IX 

 
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hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
HLP 
hybrid human liver-specific promoter 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 
IFNg 
interferon gamma 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intention-to-treat 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LT 
liver test 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention-to-treat 
MN 
mobile nursing 
NSAID 
non-steroidal anti-inflammatory drug 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
pharmacokinetics 
PRO 
patient-reported outcome 
PROBE 
Patient Reported Outcomes, Burdens, and Experiences 
rhFVIII 
recombinant human FVIII 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
SOI 
Statement of Investigator 
SOP 
standard operating procedure 
SQ 
SFSQNPPVLKRHQR 

 
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SUSAR 
serious unexpected suspected adverse reactions 
TAb 
total antibody 
TGA 
thrombin generation assay 
TI 
transduction inhibitor 
ULN 
upper limit of normal 
vg 
vector genomes 
WPAI+CIQ:HS 
Work Productivity and Activity Impairment plus Classroom Impairment 
Questions: Hemophilia Specific 
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 (R2)]).  
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) 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 will be provided to BioMarin or its designee. The 
Investigator will provide the IRB/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 for patients who do not speak the local language at 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 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 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 adverse event reporting, 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) or E6(R2) (ICH E6R2) if adopted 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation and human Phase 1 study testing. The study will be conducted under a 
protocol reviewed and approved by an IRB/IEC and will be conducted by scientifically and 
medically qualified persons. The potential benefits of the study are in proportion to the 
potential 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), 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. BioMarin and the 
IRB/IEC 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 Statement of Investigator (SOI) form. A US Food and 
Drug Administration (FDA) Form FDA 1572 serves as an acceptable SOI form. If Form 
FDA 1572 may not be used in a particular region, the Investigator must provide a fully 
executed SOI on the form provided by the Sponsor. All Investigators and Sub-Investigators 
must be listed on Form FDA 1572 or its equivalent SOI. Financial Disclosure Forms must 
also be completed for all Investigators and Sub-Investigators listed on the Form FDA 1572 
or SOI 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. 
Clinical Laboratory assessments will be performed at a nominated central laboratory. 
Bioanalytical samples will be sent to the appropriate specialty laboratories for testing. Refer 
to laboratory manual for more details.  

 
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7 
INTRODUCTION 
Hemophilia 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 pathway. 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 
hemorrhage. Treatment in Western countries (Berntorp, 2012) consists of intravenous 
injection of plasma-derived or recombinant FVIII protein concentrates at the time of a bleed 
to control it 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 hemophilia A patients. These individuals develop 
debilitating arthropathy and have a substantially increased risk of death from hemorrhage in 
life (Stonebraker, 2010). Chemical modification or bioengineering of FVIII may improve 
half-life to 18-19 hours (Kaufman, 2013). However, these extended half-life 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 (hFVIII) following a single administration of vector. Hemophilia 
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); 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 hybrid human liver-
specific transcription promoter (HLP). 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 intravenous (IV) infusion of BMN 270, the 
planned clinical route of administration, for the treatment of hemophilia A in male patients. 
This nonclinical program took into account the guidelines and reflection papers for gene 

 
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therapy medicinal products under European Medicines Agency (EMA) Advanced Therapies 
as well as FDA guidance. 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 including normal CD-1 mice, a B-and 
T-cell deficient mouse model of hemophilia 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. 
Results of the nonclinical program to date are detailed in the IB supplied by BioMarin. 
Investigators are to review this document prior to initiating this study. 
7.2 
Previous Clinical Studies 
Ongoing clinical studies for BMN 270 include: 
• 270-201, a phase 1/2, dose-escalation study in patients with severe HA 
• 270-203, a phase 2 study in patients with severe HA who have anti-AAV5 antibody 
titers 
• 270-301, a phase 3 study in patients with severe HA who receive BMN 270 at the 
6E13 vector genomes [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 
A comprehensive review of safety, efficacy, and immunogenicity results from these studies is 
contained in the IB supplied by BioMarin. Investigators are to review this document prior to 
initiating this study. 
7.3 
Study Rationale 
Hemophilia 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 pathway. This disorder can be either 
inherited, due to a genetic aberrancy, 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 generally correlates 
tightly with the level of residual expression. Severe HA is classified as FVIII activity less 
than 1% of normal (< 1 IU/dL), moderate disease comprises 1-5% of normal activity and the 
mild form is 5-40% activity. The clinical manifestations of severe HA are frequent 
spontaneous bleeding episodes, predominantly in joints and soft tissues, with a substantially 
increased risk of death from hemorrhage when the brain is involved. Subjects with moderate 

 
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disease can exhibit manifestations similar to those seen in patients with severe HA, resulting 
in a comparable bleeding phenotype.  
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 prophylactic therapy 
(median ABR of 1-4 with prophylaxis treatment in a recently published retrospective 
observational study (Berntorp, 2017) and between 1-2 in 6 prospective FVIII interventional 
studies) and on-demand-only therapy (median ABR of 4.5-18 in a recently published 
retrospective study (Berntorp, 2017) and between 20-60 in 6 prospective FVIII interventional 
studies). The consequence of multiple bleeding events is the development of 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 a 1% trough for a greater 
proportion of the dosing interval. However, patients with severe HA who are treated with 
extended half-life FVIII remain dependent on multiple infusions to maintain critical levels of 
FVIII activity. 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 hemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous infusion of a vector encoding the 
appropriate gene sequence for long-term episomal expression. Hemophilia 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 even 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 hemophilia A. Thus, relatively small changes in 
endogenous FVIII activity can result in clinically relevant improvements in disease 
phenotype. Finally, the circulating FVIII 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 

 
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well-defined safety profile, and can direct long-term transgene expression with tropism and 
promoter specificity for specific tissues, such as the liver (for serotypes 2, 5 and 8 among 
others). Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, 
has established that stable (median follow-up of 6.7years; Nathwani, 2018) expression of 
human factor IX (hFIX) at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
infusion of AAV8-hFIX vector. Several participants in this trial have been able to 
discontinue factor prophylaxis without suffering spontaneous hemorrhages, 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 hybrid human liver-specific promoter (Figure 7.3.1). 
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 a single intravenous dose and is designed to achieve durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.  
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 
dose escalation study in subjects with severe HA designed to assess the safety and efficacy of 
BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. 
Additional studies have been undertaken at the 6E13 vg/kg dose (270-301 in subjects with 

 
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severe HA, and 270-203 in subjects with severe HA who are also AAV5-antibody positive). 
With the exception of 270-203, subjects in other BMN 270 studies who are AAV5-antibody 
positive have been excluded. In 270-303, up to 25% of subjects may have detectable pre-
existing AAV5 capsid antibodies, so long as the detectable titer level is below the minimum 
required dilution (< 20). It is expected that subjects with such a low detectable titer level will 
respond in a similar manner to subjects who are AAV5 capsid antibody negative. 
Three-year results from 270-201 have demonstrated that following gene transfer, mean and 
median FVIII activity levels above 15% (15 IU/dL), as measured by a chromogenic substrate 
assay, are achievable and sustained following a single infusion of 6E13 vg/kg of BMN 270, 
with an acceptable safety profile (Pasi, 2020). Preliminary results from optional liver biopsies 
(in subjects receiving lower doses of BMN 270 in 270-201) confirm pan-lobular and 
otherwise healthy liver transduction at 2.5 years. In addition, an interim analysis of clinical 
study 270-301, an ongoing phase 3 study designed to assess the efficacy and safety of 
BMN 270 at a dose of 6E13 vg/kg, demonstrated FVIII activity levels that were also well 
above 15 IU/dL, albeit lower than what was observed for the 6E13 vg/kg cohort in 270-201 
(Pasi, 2020).  
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than 
subjects in 270-301; in 270-201, subjects were started on corticosteroids by Week 3 (either 
therapeutically, in response to an alanine aminotransferase [ALT] elevation, or 
prophylactically), whereas in 270-301 subjects received corticosteroids only in response to an 
ALT elevation. Possibly as a result of this difference, subjects receiving 6E13 vg/kg in 
270-201 started corticosteroids at an earlier date in reference to the date of BMN 270 
infusion, showed later advent of first ALT elevations, and were also less likely to experience 
a significant decline in FVIII activity concurrently with an ALT elevation when compared 
with subjects in 270-301 (20% of subjects in 270-201 vs. 58% of subjects in 270-301). In 
270-301, ALT elevation within the first 26 weeks was associated with decreased FVIII 
activity. Recently published data from 270-201 suggests that corticosteroids may have 
assisted in rescue or protection of FVIII levels during elevations of ALT and in resolution of 
elevated ALT levels in some subjects (Pasi, 2020). 
The current study is a Phase 3b, single arm, open-label study designed to assess whether 
BMN 270, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and 
effectively improve the FVIII activity profiles and alter the clinical phenotype of hemophilia 
A patients with residual FVIII activity ≤ 1 IU/dL. 

 
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7.3.1 Optional Liver Biopsy Rationale 
The usual 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 thereafter. 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 270-303 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 the majority of subjects, as well as 
inter-subject variability in post-therapy FVIII activity 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 sub-studies 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 sub-study is to provide a better understanding of the long-
term gene expression related to genome circularization, health of the liver, and variation in 
FVIII activity levels observed after gene therapy with BMN 270. With use of prophylactic 
corticosteroids, it is believed that there will be stable hepatic function and FVIII activity 
expression, with tolerance of prophylactic corticosteroid therapy and no change to the risk of 
thromboembolism. This sub-study aims to evaluate the effect on the liver by performing liver 
biopsies at approximately Week 26, Week 52, and/or during Years 2-5.  
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 

 
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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. In almost all 
subjects, ALT elevations decreased quickly following corticosteroid treatment. There were 
differences in the use of corticosteroids across studies. Subjects in 270-201 received 
corticosteroids an average of 8 weeks earlier following BMN 270 infusion than the mITT 
population in 270-301, were more likely to avoid a significant decline in FVIII activity 
concurrently with an ALT elevation, and saw a more robust recovery of FVIII activity upon 
the first use of corticosteroids, than did the subjects in the mITT population in 270-301. 
Despite the clinical response to steroids, no associations between safety parameters 
(transient ALT rises), or efficacy as measured by FVIII activity levels were found to be 
temporally associated with anti-AAV5 antibody or cellular immune responses. 
In this study, corticosteroids will be initiated prophylactically (ie, prior to any increase in 
ALT) on Day 1, prior to the BMN 270 infusion. Close monitoring of ALT and FVIII activity 
is recommended to enable early and timely initiation of therapeutic corticosteroid treatment 
(ie, in response to an increase in ALT). During prophylactic and therapeutic corticosteroid 
treatment, emphasis will be placed on a slow taper of the dose, with the aim of achieving 
ALT levels near the subject’s baseline to limit hepatocellular toxicity and possibly ameliorate 
reduction of transgene expression over the period when ALT elevations have been observed. 
At the highest dose tested in 270-201 (6E13 vg/kg), the majority of subjects achieved FVIII 
activity 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 

 
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infusions. All subjects who will be included in the final 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, although the impact of prophylactic corticosteroids 
requires further investigation. 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 
270-303 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 the risks and benefits of treatment with BMN 270, refer to the 
current version of the Investigator’s Brochure. 
7.4.1 Optional Liver Biopsy 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 sub-study will have a comprehensive pre-/post-
biopsy surveillance plan according to the standard procedures at the institution. Timing of the 
liver biopsies will occur at Weeks 26, 52, and/or during Years 2-5. 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 sub-study 
is optional and will not have any effect on the subject’s continued participation in 270-303. 

 
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8 
STUDY OBJECTIVES 
The primary efficacy objective of the study is to: 
• Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52 following 
intravenous infusion of BMN 270  
The secondary efficacy objectives of the study are to: 
• Assess the impact of BMN 270 with prophylactic corticosteroids on the use of 
exogenous FVIII replacement therapy from Week 5 to Week 52 for subjects receiving 
prior FVIII prophylaxis or on use of emicizumab from Week 27 to Week 52 for 
subjects receiving prior emicizumab prophylaxis 
• Assess the impact of BMN 270 with prophylactic corticosteroids on the number of 
bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to 
Week 52 for subjects receiving prior FVIII prophylaxis or on use of emicizumab from 
Week 27 to Week 52 for subjects receiving prior emicizumab prophylaxis 
• Assess the impact of BMN 270 with prophylactic corticosteroids on quality of life as 
measured by the Haemo-QoL-A questionnaire at Week 52 of the study compared to 
baseline 
The tertiary efficacy objective of the study is to: 
• Assess the impact of BMN 270 with prophylactic corticosteroids on patient-reported 
outcomes (PROs) (other than Haemo-QoL-A) at Week 52 of the study compared to 
baseline  
The exploratory efficacy objective of the study is to: 
• Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 for subjects with detectable AAV5 total antibodies 
below the minimum required dilution at Screening 
The safety objectives of the study are to: 
• Evaluate the safety of BMN 270 with prophylactic corticosteroids during the first 
52 weeks following intravenous infusion  
• Assess the long-term safety of BMN 270 with prophylactic corticosteroids 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 3b, single arm, open-label study in hemophilia A patients with residual FVIII 
levels  ≤  1 IU/dL. Subjects will be enrolled at approximately 10 sites worldwide. Subjects 
must have high-quality, well-documented historical data available concerning previous 
bleeding episodes and exogenous FVIII usage over the previous 12 months in order to be 
eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of 
BMN 270 as a single intravenous infusion in conjunction with receipt of a 19-week 
prophylactic corticosteroid regimen starting on the day of the BMN 270 infusion. 
Post-infusion, subjects will be eligible to receive on-demand corticosteroids, as indicated. 
(Figure 9.1.1). 
Figure 9.1.1:  270-303 Study Schema 
 
 
In order to minimize bias in the ongoing study and to assure safe and ethical conduct of the 
clinical trial, an independent Data Monitoring Committee (DMC), consisting of experts in 
clinical trials, statistics, and hemophilia, will be convened. The DMC will have access during 
the trial to amalgamated FVIII activity levels, FVIII usage, and bleeding data and review 
available safety and efficacy (eg, FVIII activity) data during the study on an ongoing basis; 
they may determine, based on emerging data and the risk/benefit profile, that further 
enrollment should be paused to enable modification of the protocol or discontinued.  

 
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The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to Week 
52). After the final analysis, safety and efficacy will then continue to be assessed long-term 
for a total of approximately 5 years for each subject. 
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic 
FVIII replacement therapy 4 weeks following infusion of BMN 270 or if FVIII activity has 
consistently increased above 5 IU/dL, whichever is earlier. Four weeks represents the time by 
which endogenous production of FVIII following gene transfer is expected to be efficacious, 
based on prior study results. Subjects previously receiving emicizumab, given its 
approximate 1-month half-life, will remain on emicizumab prophylaxis until BMN 270 
infusion, with their final dose administered prior to Day 1. 
In subjects who experience recurring 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 or Sponsor-designated Data 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.  
There will be an ongoing review of individual subject safety by the Medical Monitor, and 
both safety and efficacy data by the DMC. Patients will receive prophylactic corticosteroids 
with tapering of the dosage based upon consideration of ALT values, FVIII activity levels, 
and consultation with the Investigator and the Medical Monitor. Therapeutic oral 
corticosteroids may be initiated if a subject’s ALT values increase from baseline levels, after 
consultation between the Investigator and the Medical Monitor. 
In case of a safety concern, additional unscheduled laboratory tests may be performed locally 
(at the Investigator’s discretion) in order to facilitate timely and appropriate clinical 
management decisions; where possible, a matched sample for testing at the central laboratory 
should be collected (using the Unscheduled Visit lab kit) at the same time as the local 
unscheduled sample. 
Any safety signal may trigger a review of the data and possible additional immunogenicity 
studies or other diagnostics deemed necessary that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMCs). 

 
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An optional liver biopsy will be performed (in subjects who consent to do so) at or around 
Week 26, Week 52, and/or during Years 2-5 following BMN 270 infusion. Subjects who 
consent to the liver biopsy will have additional assessments, including a liver ultrasound and 
FibroScan, and will receive prophylactic FVIII prior to the procedure, as indicated in the 
judgment of the Investigator, to minimize the risk of bleeding. 
At applicable sites, certain study assessments may be performed by a mobile nursing (MN) 
professional at the patient's home or another suitable location such as their school or office 
(if the subject has given written informed consent to participate in MN visits), or at the site or 
approved lab facility as a shortened lab draw-only visit, to improve access and convenience 
for patients 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 patient and the patient gives written informed consent to participate in MN 
visits, the MN network will communicate with the patient and the patient’s site. 
Schedules of assessments for the Screening and Infusion period (Table 9.1.1), Post-Infusion 
follow-up periods (Table 9.1.2, Table 9.1.3, Table 9.1.4), and the optional liver biopsy 
(Table 9.1.5) are presented below. 
 
 

 
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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)l 
Screening 
Smart 
Rescreeningi 
(Day -28 to 
Day -1) 
Baseline 
(Day -7 to 
Day -1)k 
Screening 
Day -42 to 
Day -29 
Screening* 
(Day -28 to 
Day -1) 
Informed consent 
X 
Xo 
 
 
 
Demographics (age, sex, race, ethnicity) 
 
X 
 
 
 
Medical History 
 
X 
 
 
 
Physical Examinationa 
 
X 
 
X 
X 
Height and Weight 
 
X 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
 
X 
X 
X 
X 
Documentation of bleeding episodes and hemophilia therapy usage for previous 
12 months (by either subject or clinical information) 
 
X 
X 
X 
 
Distribution of subject diaries and training in their useb 
 
X 
 
 
 
Electrocardiogram 
 
X 
 
 
 
Liver Ultrasound/FibroScan 
 
X 
 
 
 
hFVIII Assaysc 
 
X 
Xj 
X 
 
hFVIII TAb 
 
X 
 
X 
 
Screen for Hepatitis B, Hepatitis C, HIVd 
 
X 
 
 
 
Blood chemistry, hematology, and coagulation testse 
 
X 
X 
X 
 
Fasting lipid panel (blood triglycerides, total cholesterol, HDL cholesterol, and LDL 
cholesterol) 
 
 
 
 
X 
Fasting FibroTest 
 
 
 
 
X 
Urine Testse 
 
X 
X 
X 
 
Liver Testse  
 
X 
X 
X 
 
AAV5 TAb Assay (CDx)f 
X 
X 
X 
 
X 
Immunogenicity AAV5 TAb Assay 
 
 
 
X 
X 
AAV5 TI Assay 
 
 
 
X 
X 
IFNg ELISpot 
 
 
 
X 
 
Plasma, PBMC, and RBC collection for exploratory biomarkersh 
 
 
 
X 
 
Complement Panel 
 
 
 
X 
 

 
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Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion 
Visit 
(Day 1)l 
Screening 
Smart 
Rescreeningi 
(Day -28 to 
Day -1) 
Baseline 
(Day -7 to 
Day -1)k 
Screening 
Day -42 to 
Day -29 
Screening* 
(Day -28 to 
Day -1) 
Biomarker testingg  
 
X 
 
 
 
Serum for exploratory biomarkersh 
 
X 
 
 
X 
Exploratory CK18 and Grp78 assessment 
 
X 
 
X 
 
TGA Assayh 
 
 
 
X 
 
Haemo-QoL-A assessment 
 
 
 
X 
 
EQ-5D-5L  
 
 
 
X 
 
WPAI+CIQ:HS 
 
 
 
X 
 
PROBE 
 
 
 
X 
 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
 
 
 
X 
X 
Pharmacokinetics 
 
 
 
Xn 
 
BMN 270 Infusion 
 
 
 
 
X 
Hypersensitivity blood assessmentsm 
 
 
 
 
X 
* Screening assessments should be performed within 28 days of BMN 270 infusion (and must be performed within 42 days prior to BMN 270 infusion). 
a Complete physical examination should be done at Screening. Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit. 
b Diaries should be distributed to subjects who have consented to participate in the study and who have been determined to meet all study eligibility criteria. 
c Includes baseline FVIII activity (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), coagulation exploratory assay, chromogenic Nijmegen-Bethesda Assay for hFVIII 
inhibitor level, and hFVIII protein assay. Baseline activity should be assessed at trough (at least >72 hours after last dose of replacement FVIII therapy, or 5x the known half-life of the 
FVIII concentrates administered). 
d Patients with documented negative results within the last 30 days do not need to be retested. Hepatitis B screening should include hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), and hepatitis B core antibody (HBcAb). 
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. ABO blood typing assessment should be performed at Screening. 
f Screening, Smart Re-screening, and Infusion Day samples will be tested using the CDx AAV5 total antibody (TAb) assay. During Screening, the CDx AAV5 TAb assay test may be done 
first, under a standalone informed consent form, before the main ICF for the study is signed and further screening procedures are performed. If performed during the early Screening 
period, the CDx AAV5 TAb assessment does not need to be repeated as part of general Screening. Sample collection on the day of the infusion visit must be performed before the 
BMN 270 infusion is given.  
g Includes HLA genotyping and FVIII genotyping. 
 
h Blood samples will be collected to evaluate biochemical, molecular, cellular, immunological, 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 

 
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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, as well as testing of the 
thrombin generation assay (TGA) sample, will be performed only as deemed necessary by the Sponsor. 
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 Should the screening visit occur within 30 days of infusion, physical examination, blood chemistry, LTs, hematology, and urine and coagulation tests do not need to be repeated at 
Baseline. 
l With the exception of the collection of samples for polymerase chain reaction (PCR) vector DNA analysis, assessments on the day of infusion must be performed prior to the infusion. 
Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. 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), and following the infusion hourly (± 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Shedding 
samples for PCR of vector DNA analysis (blood, saliva, urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been completed. 
m In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital signs will be performed and additional blood samples 
will be collected within 1 hour, and 8-24 hours following the hypersensitivity reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. Additional samples will 
be collected at the 1 hour and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory cytokine bead array (CBA) to assess inflammatory biomarkers and 
plasma cytokine levels. Inpatient observation can be extended and additional blood samples can be collected if deemed necessary at the discretion of the Investigator and Medical Monitor. 
n Samples will be drawn immediately prior to recombinant FVIII concentrate infusion (between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours 
post-FVIII infusion. For subjects receiving emicizumab, pharmacokinetics assessment is optional. 
o If the subject underwent early AAV5 TAb testing and was consented using the full study ICF, the ICF does not need to be re-administered and re-signed as part of regular Screening. If the 
subject underwent early AAV5 TAb testing and was consented using the dedicated stand-alone ICF for that purpose, the full ICF will need to be signed if the subject proceeds to regular 
Screening. 
 

 
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Table 9.1.2:  Schedule of Events-Post-Infusion Follow-Up (Week 1-20) 
Assessment 
Follow-Up After BMN 270 Infusion – Weeks 
1 
2f 
3f 
4 
5f 
6f 
7f 
8 
9f 
10f 
11f 
12 
13f 
14f 
15f 
16 
17f 
18 
19f 
20 
Study Day* 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
Physical examinationa 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Weighta 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Assessment of Adverse Events and 
Concomitant Medications (including 
review of bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Blood chemistry, hematology, and 
coagulation testsb  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Urine Testsb 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Liver Testsb  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PCR of vector DNA in blood, saliva, 
urine, semen, and stoolsd 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Immunogenicity AAV5 TAb Assay 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
AAV5 TI Assay 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
hFVIII TAb 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
IFNg ELISpot  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Plasma, PBMC, and RBC collection for 
exploratory biomarkerse 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Complement Panel 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum for exploratory biomarkerse 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Exploratory CK18 and Grp78 assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
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Assessment 
Follow-Up After BMN 270 Infusion – Weeks 
1 
2f 
3f 
4 
5f 
6f 
7f 
8 
9f 
10f 
11f 
12 
13f 
14f 
15f 
16 
17f 
18 
19f 
20 
Study Day* 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
TGA Assaye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Haemo-QOL-A assessment 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
WPAI+CIQ:HS 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PROBE 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Testing for reactivation of hepatitis B and 
hepatitis C 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
* Visit windows are ± 48 hours.  
a Brief physical examination should be done at scheduled visits. Additional physical exams may be done at the discretion of the PI. 
b Refer to Table 9.7.8.2.1for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests (LTs). LTs may be monitored more or less frequently (and in particular when ALT 
values are > upper limit of normal (ULN) or ≥ 1.5x baseline value) 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. Subjects with ALT > ULN or ≥ 1.5x baseline value during the study and either an alternative etiology 
considered or for further evaluation of the lab abnormality 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 ≥ 1.5x baseline value; (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. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to 
facilitate timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab 
kit) at the same time as the local unscheduled sample. 
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level, coagulation 
exploratory assay, and hFVIII protein 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 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. 

 
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d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained; longer collection and testing may be performed based on batch testing 
schedules, result turnaround times, or discussions between Medical Monitor and Investigator. Collection and testing of semen samples must continue at least through Week 12, even if 
3 consecutive results below the limit of detection in that compartment have already been recorded.  
e 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 TGA assay and any other 
exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
f Visits between scheduled clinic visits may be performed by a mobile nursing (MN) professional at the subject’s home or another suitable location (if the subject has given written informed 
consent to participate in MN visits), or at the site or approved lab facility as a shortened lab draw-only visit. The MN service or site will collect blood samples at these visits. For site lab 
draw-only visits, sites will contact the subject via phone call or e-mail to collect information regarding adverse events, changes to concomitant medications, bleeding episodes, and FVIII 
use. For MN visits, the service will collect this information. Unscheduled visits may also be conducted by MN as appropriate. 
g Testing for reactivation of hepatitis B and hepatitis C only for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry. 
 

 
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Table 9.1.3:  Schedule of Events – Post-Infusion Follow-Up (Weeks 21-52) 
Assessment 
Follow-Up After BMN 270 Infusion-Weeks 
21f 
22 
23f 
24 
25f 
26 
28 
30f 
32 
34f 
36 
40 
44 
48 
50f 
52 
Study Day* 
148 
155 
162 
169 
176 
183 
197 
211 
225 
239 
253 
281 
309 
337 
351 
365 
Physical examinationa 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Weighta 
 
 
 
 
 
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 
Blood chemistry, hematology, and coagulation testsb  
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Urine Testsb 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Liver Testsb 
X  
X 
X  
X 
X  
X 
X 
X  
X 
X  
X 
X 
X 
X 
X 
X 
hFVIII assaysc 
X  
X 
X  
X 
X  
X 
X 
X  
X 
X  
X 
X 
X 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and 
stoolsd 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Immunogenicity AAV5 TAb Assay 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
AAV5 TI Assay 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
hFVIII TAb 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
IFNg ELISpot 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Plasma, PBMC, and RBC collection for exploratory 
biomarkerse 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
 
 
X 
Complement Panel 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Serum for exploratory biomarkerse 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Exploratory CK18 and Grp78 assessment 
X  
X 
X  
X 
X  
X 
X 
X  
X 
X  
X 
X 
X 
X 
X 
X 
TGA Assaye 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 

 
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Assessment 
Follow-Up After BMN 270 Infusion-Weeks 
21f 
22 
23f 
24 
25f 
26 
28 
30f 
32 
34f 
36 
40 
44 
48 
50f 
52 
Study Day* 
148 
155 
162 
169 
176 
183 
197 
211 
225 
239 
253 
281 
309 
337 
351 
365 
Haemo-QOL-A assessment 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
EQ-5D-5L  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
WPAI+CIQ:HS 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
PROBE 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Testing for reactivation of hepatitis B and hepatitis C 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
Optional liver biopsyh 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
* Visit windows are ± 48 hours.  
a Physical examination should be done at all visits. Weight should be recorded at all visits. 
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). LTs may be monitored more or less frequently (and in particular when ALT 
values are > ULN or ≥ 1.5x baseline value) 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. Subjects with > ULN or ≥ 1.5x baseline value during the study and either an alternative etiology considered or for further 
evaluation of the lab abnormality 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 ≥ 1.5x baseline value; (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. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate 
clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local 
unscheduled sample 
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level, coagulation 
exploratory assay, and hFVIII protein. 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 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 Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained; longer collection and testing may be performed based on batch testing 
schedules, result turnaround times, or discussions between Medical Monitor and Investigator. 

 
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e 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 TGA assay and any other 
exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
f Visits between scheduled clinic visits may be performed by a mobile nursing (MN) professional at the subject’s home or another suitable location (if the subject has given written informed 
consent to participate in MN visits), or at the site or approved lab facility as a shortened lab draw-only visit. The MN service or site will collect blood samples at these visits. For site lab 
draw-only visits, sites will contact the subject via phone call or e-mail to collect information regarding adverse events, changes to concomitant medications, bleeding episodes, and FVIII 
use. For MN visits, the service will collect this information. Unscheduled visits may also be conducted by MN as appropriate. 
g Testing for reactivation of hepatitis B and hepatitis C only for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry. 
h Optional liver biopsy should be obtained within two weeks of Week 26. Additional follow-up liver biopsy will be obtained at Week 52. Subjects should fast for at least 8 hours prior to 
liver ultrasound and optional liver biopsies. 
 

 
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Table 9.1.4:  Schedule of Events-Post-Infusion Follow-Up (Year 2-Year 5) 
Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Years 2-5 
Year 2 
Year 3-5 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
Q12W 
Q4Wg 
Q6Wg 
W104 
W156 
W208 
W260 
Physical examinationb 
X 
 
 
X 
X 
Weightb 
Xa 
 
 
Xa 
X 
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and hemophilia therapy 
use) 
X 
X  
X  
X 
X 
Vital Signs 
X 
 
 
X 
X 
Blood chemistry, hematology, and coagulation testsc 
Xa 
 
 
Xc 
X 
Urine Testsc 
Xa 
 
 
Xc 
X 
Liver Testsc 
X 
X 
X 
X 
X 
hFVIII assaysd 
X 
X 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
(X)e 
 
 
(X)e 
(X)e 
Immunogenicity AAV5 TAb Assay 
 
 
 
X 
X 
AAV5 TI Assay  
 
 
 
X 
X 
hFVIII TAb 
X 
 
 
X 
X 
IFNg ELISpota  
Xa 
 
 
X 
X 
Plasma, PBMC, and RBC collection for exploratory biomarkersf 
X 
 
 
X 
X 
Serum for exploratory biomarkersf 
X 
 
 
X 
X 
Exploratory CK18 and Grp78 assessment 
X 
X 
X 
X 
X 
TGA Assayf 
 
 
 
X 
X 
Haemo-QoL-A assessment 
Xa 
 
 
Xa 
X 
EQ-5D-5L  
Xa 
 
 
Xa 
X 
WPAI+CIQ:HS 
Xa 
 
 
Xa 
X 

 
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Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Years 2-5 
Year 2 
Year 3-5 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
Q12W 
Q4Wg 
Q6Wg 
W104 
W156 
W208 
W260 
PROBE 
Xa 
 
 
Xa 
X 
Optional liver biopsyh 
 
 
 
X 
 
* Visit windows are ± 2 weeks for visits in Years 2-5. 
a These assessments need to be performed only at every other Q12W and every End of Year visit (ie, Weeks 76, 104, 128, 156, 180, 208, 232, and 260). 
b Complete physical examination should be performed at the End of Year visits; brief physical exam 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. 
c 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 > ULN or ≥ 1.5x baseline value) 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. Subjects with ALT > ULN or ≥ 1.5x baseline value during the study and either an alternative etiology considered or for further 
evaluation of the lab abnormality 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 ≥ 1.5x baseline value; (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. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and 
appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time 
as the local unscheduled sample 
d Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level, coagulation 
exploratory assay, and hFVIII protein 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 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. 
e Sample testing during Years 2-5 is not required if at least 3 consecutive samples were below the limit of detection during Year 1; additional collection and testing may be performed based 
on batch testing schedules, result turnaround times, or discussions between Medical Monitor and Investigator. Subjects who have not had 3 consecutive semen samples below the limit of 
detection 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). 

 
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f Blood samples will be collected to evaluate biochemical, molecular, cellular, immunological, 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, as well as testing of the TGA 
assay sample, will be performed only as deemed necessary by the Sponsor. 
g 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) or Q6W (during 
Years 3-5) until vector shedding has been cleared, either by reporting to the site to provide samples or by providing those samples to a MN professional. Unscheduled visits may also be 
conducted by MN as appropriate. 
h An optional liver biopsy may be performed at any time between Years 2-5 of the study. The optional biopsy would be triggered by a FVIII activity decline by > 50% from steady-state, 
over 2 consecutive measurements, or by a sustained ALT rise > ULN. If neither triggered is observed, the optional biopsy should be performed at the end of Year 5. 
 

 
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Table 9.1.5:  Schedule of Events-Optional Liver Biopsy  
 
Within 28 Days Before 
Biopsy Day 
Within 7 Days Before 
Biopsy Day 
Biopsy Day (BD) 
Informed Consent for Liver Biopsy Procedure 
X 
 
 
Liver Ultrasounda 
X 
 
 
Physical examination 
X 
 
X 
Hematology, Coagulation, Chemistry Assessmentsb 
X 
 
X 
Liver Testsb 
X 
 
X 
FibroScan 
X 
 
 
FVIII Activity Level Assessment (central and local) 
 
X 
X* 
Exploratory CK18 and Grp78 assessment 
 
X 
X* 
Pre-Biopsy Consultationc 
 
X 
 
Liver Biopsyd 
 
 
X 
PBMC Collection (whole blood draw) 
 
 
Xe 
* If the Day -7 and biopsy day visits occur on the same day, these tests do not need to be duplicated. 
a Liver ultrasound must be performed within 28 days prior to the scheduled biopsy. Subjects should fast for at least 8 hours prior to liver ultrasound. 
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) and hepatologist and/or radiologist. 
d Subjects should fast for at least 8 hours prior to optional liver biopsy. 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. 
e Blood draw for PBMC collection should be performed on the biopsy day or ± 1 week from the biopsy day. 
 

 
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Table 9.1.6:  Suggested Schedule of Events-Prophylactic Corticosteroids 
Assessment 
Corticosteroid Treatment Periodb 
Post-Corticosteroid 
Periodc 
D1 
Week 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
32 
Prophylactic 
corticosteroid 
dose 
(mg/day) 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
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 
 
 
 
 
 
FVIII activity 
testing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hepatitis B 
testingd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HCV Viral 
Loadd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
a This table provides an example of a prophylactic corticosteroid course. Clinical judgment, weighing the potential risks and benefits of corticosteroid treatment, should always be exercised 
when considering adjustment of corticosteroid doses, and discussions between the Investigator and Medical Monitor are advised for any questions or concerns. Dosages are for prednisone 
or an equivalent dose of another corticosteroid. FVIII and liver tests are also reflected in the Schedule of Events for the study. 
b Following initiation or completion of corticosteroid regimen, if a recurrence of ALT values > ULN or ≥ 1.5x baseline value is reported, corticosteroid management decisions will be based 
on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation, 
relationship between increases in ALT and FVIII activity, ALT levels/FVIII activity post-corticosteroid initiation, and adverse events related to corticosteroid dosing. Guidance for tapering 
oral corticosteroid dosing can be found in Section 9.4.8.2, although a discussion between the PI and Medical Monitor should take place prior to tapering the corticosteroid dose. 
c After discontinuation of oral corticosteroids, weekly labs for ALT levels and FVIII activity will be measured once a week for 4 weeks to ensure stability in values. 
d Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry. Tests are also reflected in the Schedule of Events for the study. 
 

 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-303 is a Phase 3b, single arm, open-label study designed to assess whether 
BMN 270, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and 
effectively improve the FVIII activity profiles and alter the clinical phenotype of hemophilia 
A patients with residual FVIII activity ≤ 1 IU/dL. Subjects must have high-quality, well-
documented historical data available concerning previous bleeding episodes and exogenous 
FVIII usage over the previous 12 months in order to be eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of 
BMN 270 as a single intravenous infusion in conjunction with receipt of a prophylactic 
corticosteroid regimen. Post-infusion, subjects will be eligible to receive on-demand 
corticosteroids, as indicated.  
9.3 
Selection of Study Population 
Approximately 20 adult hemophilia A patients with residual FVIII levels ≤ 1 IU/dL may 
enroll into the study.  
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 inclusion 
criteria: 
1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as 
evidenced by medical history, at the time of signing the informed consent.  
2. Must have been on prophylactic hemophilia therapy for at least 12 months prior to 
study entry. High-quality, well-documented historical data concerning bleeding 
episodes and hemophilia therapy usage over the previous 12 months must be 
available. 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs). 
4. Willing and able to provide written, signed informed consent after the nature of the 
study has been explained and prior to any study-related procedures. 
5. No previous documented history of a detectable FVIII inhibitor, and results from 
a Bethesda assay or Bethesda assay with Nijmegen modification of less than 
0.6 Bethesda Units (BU) (or less than 1.0 BU for laboratories with a historical lower 
sensitivity cutoff for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least 
one week apart within the past 12 months (at least one of which should be tested at 
the central laboratory). 

 
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6. Sexually active participants must agree to use an acceptable method of effective 
contraception, either double-barrier contraception (ie, condom + diaphragm; or 
condom or diaphragm + spermicidal gel or foam) or their female partner either using 
hormonal contraceptives or having an intrauterine device. Participants must agree to 
contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may 
stop contraception use only if they have had 3 consecutive semen samples with viral 
vector DNA below the limit of detection. 
7. Willing to abstain from alcohol consumption for at least the first 52 weeks following 
BMN 270 infusion. 
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 antibodies to the AAV5 capsid. Up to 25% of subjects may 
have detectable pre-existing AAV5 capsid antibodies, so long as the titer level is 
below the minimum required dilution (< 20). 
2. Any evidence of active infection or any immunosuppressive disorder, including HIV 
infection.  
3. Significant liver dysfunction with any of the following abnormal laboratory results: 
• ALT (alanine aminotransferase) > 1.25x ULN; 
• AST (aspartate aminotransferase) > 1.25x ULN; 
• GGT (gamma-glutamyltransferase) > 1.25x ULN; 
• Total bilirubin > 1.25x ULN; 
• Alkaline phosphatase > 1.25x ULN; or 
• INR (international normalized ratio) ≥ 1.4. 
Subjects whose liver laboratory assessments fall outside of these ranges may undergo 
repeat testing of the entire liver test panel within the same Screening window and, if 
eligibility criteria are met on retest, may be enrolled after confirmation by the Medical 
Monitor.  
4. FibroScan or prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a 
scale of 0-4 on the Batts-Ludwig (Batts, 1995) or METAVIR (Bedossa, 1996) scoring 
systems, or an equivalent grade of fibrosis if an alternative scale is used. 
5. Evidence of any bleeding disorder not related to hemophilia A. 
6. Platelet count of < 100 x 109/L. 
7. Creatinine ≥ 1.5 mg/dL. 
8. Liver cirrhosis of any etiology as assessed by FibroScan or liver ultrasound. 

 
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9. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B 
surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core 
antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for 
Disease Control (CDC) table for the interpretation of serological test results in the 
Laboratory Manual. 
10. Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral 
therapy.  
11. Active malignancy, except non-melanoma skin cancer.  
12. History of hepatic malignancy. 
13. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial 
embolus), with the exception of catheter-associated thrombosis for which anti-
thrombotic treatment is not currently ongoing.  
14. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
15. Treatment with any investigational product within 30 days or 5 half-lives of the 
investigational product prior to the screening period. For subjects who have received 
a prior investigational product, all ongoing adverse events (AEs) experienced while 
receiving that investigational product must have resolved prior to screening for this 
study. 
16. Any condition that, in the opinion of the Investigator or Sponsor would prevent the 
patient from fully complying with the requirements of the study (including possible 
corticosteroid treatment outlined in the protocol) and/or would impact or interfere 
with evaluation and interpretation of subject safety or efficacy result. 
17. Prior treatment with any vector or gene transfer agent. 
18. Major surgery planned in the 52-week period following the infusion with BMN 270. 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion. 
20. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study that does not interfere with the requirements of the 
current protocol or have the potential to impact the evaluation of efficacy and safety 
of BMN 270 and with prior consultation with the Medical Monitor. 
21. Known allergy or hypersensitivity to BMN 270 investigational product formulation. 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or 
a bleeding episode. 
9.3.2.1 
Optional Liver Biopsy Inclusion and Exclusion Criteria 
Individuals eligible for the optional liver biopsy must meet the following inclusion criterion: 

 
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1. Able to sign informed consent and comply with requirements for the optional liver 
biopsy 
2. Documentation of FVIII activity ≥ 50 IU/dL (or higher, depending on local guidelines 
and/or Investigator discretion) within 24 hours prior to the liver biopsy being 
performed (FVIII activity 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 activity to an appropriate level, under the 
supervision/instruction of the Investigator. 
Individuals who meet any of the following exclusion criteria will not be eligible for the 
optional liver biopsy: 
1. Any condition that, in the opinion of the Investigator or a hepatologist/radiologist 
would make liver biopsy contraindicated. This includes (but is not limited to) 
abnormalities detected on liver ultrasound performed within 28 days of procedure, or 
prior liver ultrasound result within 90 days that would preclude safe performance of 
the biopsy. 
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. 
Such subjects will always be asked about the reason(s) for withdrawal. The Investigator will 
discuss with the subject appropriate procedures for withdrawal from the study. The 
Investigator should ask the subject’s consent to perform the procedures listed under the early 
termination visit. Should a subject withdraw from the study, all efforts will be made to 
complete and report the observations as thoroughly as possible up to the date of the 
withdrawal.  
A subject’s participation in the study may be discontinued at any time at the discretion of 
BioMarin or 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 and 
every effort will be made to gather follow-up safety data if possible. 
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 

 
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• Subject does not adhere to study requirements specified in the protocol 
• Subject was erroneously enrolled into the study or does not meet entry criteria and not 
yet been dosed with BMN 270; subjects who do not meet entry criteria but who 
erroneously receive BMN 270 should remain in the study for safety monitoring 
• 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. 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, an urgent evaluation by the DMC will be required and further enrollment into the 
trial will be temporarily put on hold if recommended by the DMC per Section 9.1.  

 
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1. Liver dysfunction (criteria do not apply to ALT elevations with an extra-hepatic 
etiology): 
• 
ALT > 5x ULN, for more than 2 weeks 
• 
ALT > 3x ULN and (total bilirubin > 2x ULN or INR >1.5) 
• 
ALT > 3x ULN with signs and symptoms of liver dysfunction  
2. The occurrence of Grade 4 or Grade 5 adverse events assessed as related to study 
drug (events of liver dysfunction are defined above).  
3. The occurrence of an AE of hepatic failure. 
4 The detection of high-titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in two subjects. 
5 The occurrence of any cancer (except non-melanoma skin cancer) at any point after 
BMN 270 infusion. 
6 The occurrence of a thromboembolic event with FVIII activity > 150 IU/dL in one 
subject. 
If any of the following events occurs in a subject in the study who has received BMN 270 
infusion, an urgent evaluation by the DMC will be required. Further enrollment into the trial 
will continue while DMC evaluation is ongoing, unless deemed otherwise by the DMC: 
1. The detection of high-titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in one subject. 
2. Occurrence of a thromboembolic event in one subject. 
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 
electronic case report form (eCRF) pages. In legal jurisdictions where use of initials is not 
permitted, a substitute identifier will be used. 
Subjects who withdraw from the study after receiving BMN 270 will not be replaced. 
9.3.5 Duration of Subject Participation 
The duration of participation for each subject will be approximately 264 weeks. This includes 
4 weeks of screening, 1 day of BMN 270 infusion, and 260 weeks of post-infusion follow-up. 
9.4 
Treatments 
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. BioMarin is responsible for shipping study drug to clinical sites. 

 
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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 10 mL Crystal Zenith® (CZ) vial. Each vial contains 8.5 mL (extractable volume 8 mL) 
of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 
7.4 phosphate buffer. 
The IP is labelled according to the particulars approved by the relevant regulatory agencies.  
9.4.3 Storage 
At the study site, all IP must be stored under the conditions specified in the Pharmacy 
Manual 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 
On the day of infusion, the subject will come to the infusion site, where a physical 
examination will be performed by the Investigator or designee. If the subject is found to have 
an active acute illness at the time of planned infusion, then the infusion should be deferred 
until the illness has resolved; screening procedures may require repetition if outside the 
specified window. 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. Refer to the 
Pharmacy Manual for IP administration instructions.  
BMN 270 will be infused through the catheter using an appropriate infusion pump at an 
initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min 
up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an 
increase. Of note, the IP has been shown to be stable at room temperature for 10 hours 
following completion of product thaw. Vital signs (pulse, blood pressure, respiration rate and 
temperature) should be monitored at 15 minute (±5 minutes) intervals throughout the time 
period of the infusion.  

 
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As with any infused biological product, there is a potential risk of acute, systemic 
hypersensitivity reactions (including anaphylaxis) with BMN 270. Dosing will be 
administered at a qualified infusion site, with appropriate resuscitation equipment and 
medication available and easily accessible. 
Clinical staff administering BMN 270 should be trained appropriately in recognizing and 
managing the signs and symptoms associated with potential hypersensitivity, anaphylactic, 
and anaphylactoid reactions. Additionally, the Investigator should be familiar with 
Sampson’s criteria for defining anaphylaxis (Sampson, 2006; Appendix 1).  
Should symptoms of potential hypersensitivity occur, the infusion may be slowed or halted at 
the Investigator’s discretion, with consideration of the subject’s clinical condition. If the 
infusion is halted, it should only be restarted if the Investigator considers it safe and 
appropriate to do so. Antihistamines, anti-pyretic, and/or corticosteroid administration is 
permitted prior to restarting an interrupted infusion after an infusion-related reaction. At the 
restart, the infusion rate may be adjusted (ie, to a slower rate [minimum of 1 mL/min], with 
the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the 
subject’s clinical condition permits such an increase) with careful monitoring of the subject. 
In the event of an infusion rate reaction with more than one dosing interruption, the infusion 
rate would not go beyond 1mL/min. 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment 
including physical examination and vital signs will be performed and additional blood 
samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. 
Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 
1 week after the event for an optional, exploratory cytokine bead array (CBA) to assess 
inflammatory biomarkers and plasma cytokine levels. Inpatient observation can be extended 
and additional blood samples can be collected if deemed necessary at the discretion of the 
Investigator and Medical Monitor. Exploratory biomarker samples at baseline and at post-
infusion study visits may also be used to assess changes in these biomarkers to better 
elucidate the mechanisms of infusion-related hypersensitivity reactions. Inpatient observation 
can be extended and additional blood samples can be collected if deemed necessary at the 
discretion of the Investigator and Medical Monitor. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes). 
If the vital signs are stable the catheter will be removed 8 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 at 

 
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least 8 hours to observe for any immediate toxicity of the procedure; inpatient observation 
can be extended beyond 8 hours if needed per Investigator discretion. After the observation 
period, subjects 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. 
Prior to discharging subjects from the clinic, the Investigator or designee should instruct 
subjects how to recognize signs and symptoms of potential (delayed) hypersensitivity 
reactions and anaphylaxis, and to contact a medical practitioner or seek emergency care in 
case of such an event. 
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 Medical Monitor will be required prior to enrollment 
of each study subject. Upon their enrollment into the study, subjects will be assigned a 
unique subject number. 
Approximately 20 subjects will be enrolled into the single arm study of 6E13 vg/kg with 
prophylactic corticosteroids. Up to 25% of the total number of patients dosed should have an 
AAV5 antibody titer that is detectable but below the minimum required dilution at Screening. 
9.4.6 Selection of Dose Used in the Study 
Data from previous human studies (270-201, 270-301) indicated that dosing at 6E13 vg/kg 
showed improvement in FVIII activity, bleeding episodes, and exogenous FVIII utilization 
and infusion rate. Dosing was well tolerated, with mild increases in ALT as the most 
common adverse event. Please refer to the IB for detailed efficacy and safety data. 
This dose is expected to be safe and effective based on clinical experience to date in 270-201 
and 270-301, as well as non-clinical data. 
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 eCRF. 
The Investigator may prescribe additional medications, deemed necessary to provide 
adequate prophylactic or supportive care, during the study, as long as the prescribed 

 
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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 
eCRF. Medications should, whenever possible, not be recorded in the electronic database 
with a frequency of as needed (PRN).  
The following medications are prohibited starting 30 days before Screening and through the 
end of the study, and the Sponsor must be notified if a subject receives any of these during 
the study: 
• Any investigational therapy 
• Fitusiran 
• Concizumab 
• Efavirenz 
• Lamivudine 
The following medications and agents should be avoided, starting 30 days prior to and for at 
least 52 weeks after BMN 270 infusion and minimized throughout the remaining duration of 
the study. 
• Alcohol  
• Herbal and natural remedies and dietary supplements 
• Medications which may be hepatotoxic, including isotretinoin and 
dextroamphetamine/amphetamine 
• Medications which may reduce or increase the plasma concentration of 
corticosteroids 
Subjects should be counseled to avoid starting potentially hepatotoxic therapies and to inform 
the Investigator of any new medications prescribed by other physicians. Investigators should 
carefully consider both the mechanism of action and potential hepatotoxicity of any new 
medication prior to initiation. If a potentially concerning new medication is started, 
Investigators should closely monitor both FVIII activity and ALT levels (eg, weekly to every 
2 weeks for the first month) in order to determine if any detrimental effects on the efficacy 
or safety of BMN 270 have occurred. If co-medications are required during the course of the 
study, where possible, please check the National Center for Biotechnology Information 
LiverTox website for potential hepatotoxicity issues prior to prescribing (NCBI, 2020). 

 
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Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated. 
The following medications should be avoided during oral corticosteroid therapy: 
• Vaccines 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 
9.4.8.1 
Concomitant Hemophilia Treatments 
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic 
FVIII replacement therapy 4 weeks following infusion of BMN 270 or if FVIII activity has 
consistently increased above 5 IU/dL, whichever is earlier. Subjects previously receiving 
emicizumab, given its approximate 1-month half-life, will remain on emicizumab 
prophylaxis until BMN 270 infusion, with their final dose administered prior to Day 1. 
FVIII replacement therapy can always be taken as needed by the subject for treatment of an 
acute bleeding episode; the subject must carefully record his treatment and bleeding episodes 
in his diary. Prophylactic FVIII use can be used on a case-by-case basis and in consultation 
with the Medical Monitor to prevent bleeding in extenuating circumstances 
(eg peri-operative).  
In addition, information on FVIII usage and bleeding episodes by medical history must be 
well-documented and available and will be collected from subjects for the 12-month period 
immediately preceding study enrollment. Further information on the details that should be 
provided as part of the subject’s well-documented medical and FVIII usage history are 
provided in the Investigator Site File Binder. 
In order to enable rigorous comparisons of pre-study versus on-study FVIII usage and 
bleeding episodes, the Medical Monitor will review each screened patient’s prior bleed and 
hemophilia medication logs to determine if they are of "high-quality". Elements that will be 
assessed to judge the quality of such historical data may include, but are not limited to, the 
following: 
• Date, type (eg, joint, muscle, other), location of bleeds 
• Date, name, dose (calculated in IU/kg), and reason for use (eg, usual prophylaxis, 
one-time prophylaxis, treatment for bleed, surgery) of hemophilia medications. 
9.4.8.2 
Therapeutic Corticosteroid Treatment and/or Alternative 
Immunosuppressive Agent Treatment of Elevated Hepatic Transaminases 
Refer to steroid prescription guidelines to determine eligibility, monitoring and managing of 
side effects during steroid treatment. Prior to dosing, all subjects must be screened per steroid 

 
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prescription guidelines to ensure the subject is eligible to receive corticosteroid treatment as 
outlined in the protocol. Refer to corticosteroid prescription guidelines for recommended 
monitoring for, and management of, potential side effects of corticosteroids, including 
guidance on medications that should be avoided during corticosteroid treatment.  
All subjects will be started on prophylactic corticosteroids starting on the day of infusion 
(Day 1). The first dose of prophylactic corticosteroids (40 mg of prednisone or prednisolone, 
or an equivalent dose of another corticosteroid) should be taken at least 3 hours prior to the 
start of the BMN 270 infusion and continued on a daily basis. Table 9.1.6: provides an 
example of a possible prophylactic corticosteroid course, including taper and post-
corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C 
reactivation. Clinical judgment, weighting the potential risks and benefits of corticosteroid 
treatment, should always be exercised when considering adjustment of corticosteroid doses. 
Discussions between the Investigator and Medical Monitor are advised for any questions or 
concerns. 
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels 
become increased (eg, ≥ 1.5x baseline value or > ULN) and alternative etiologies have been 
ruled out, prompt institution of newly administered or an increased dose of therapeutic or 
on-demand oral corticosteroids (prednisone or an equivalent dose of another corticosteroid) 
should be considered after consultation with the Medical Monitor (refer to Table 9.7.8.3.2). 
• Whenever possible, a confirmatory lab draw for ALT should be performed within 
72 hours, along with FVIII activity, prior to initiating oral corticosteroids. 
• Newly administered corticosteroids or dose increases are not indicated if elevations in 
ALT are clearly not related to BMN 270 (eg, elevated ALT with concurrent increase 
in CPK due to intensive exercise) although this should be discussed with the Medical 
Monitor. 
• Alternative immunosuppressive agents may also be considered for use on a case-by-
case basis and following consultation with the Medical Monitor (eg, if prolonged 
corticosteroid use is contraindicated). 
Unless otherwise indicated, therapeutic corticosteroid treatment should be initiated at a dose 
of 60 mg/day. If the ALT level immediately returns to ≤ 1.5x baseline and FVIII activity 
levels continue to rise and/or remain within or above the normal range in the 2 weeks 
following corticosteroid initiation, on-demand corticosteroids can be discontinued. However, 
if this is not the case, therapeutic corticosteroids should be tapered over a longer period of 
time. At minimum, the recommended duration of on-demand corticosteroids is 60 mg/day for 
3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper 
thereafter. Should a scenario arise in which a deviation from the minimum recommended 

 
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dose and/or duration of therapeutic corticosteroids may be clinically indicated, a discussion 
should take place between the Investigator and Medical Monitor regarding corticosteroid 
dose adjustments. Tapering of corticosteroid dosages should be guided by the following 
(Table 9.4.8.2.1:): 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen 
Corticosteroids should be tapered 
on an individual subject basis with 
the following guiding principles: 
 
Corticosteroids may be tapered if: 
• 
ALT ≤ 1.5x baseline value; and 
• 
FVIII activity levels > 90% of the pre-decline FVIII activity 
levels; and 
• 
There is no concern for adrenal insufficiency post-withdrawal 
Increasing Corticosteroid Dose 
If ALT level is increasing or FVIII activity level is decreasing while on 
oral corticosteroids, any increases in oral corticosteroid dosing should 
be made only upon consultation 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. 
 
After discontinuation of on-demand oral corticosteroids, labs for ALT and FVIII levels will 
be measured once a week for 4 weeks to ensure stability in values. 
Following initiation or completion of therapeutic oral corticosteroids, if increased ALT levels 
(eg, > ULN or ≥ 1.5x baseline value) are reported, corticosteroid management decisions will 
be based on discussions between the Investigator and Medical Monitor. Modification of the 
corticosteroid regimen may take into consideration possible confounders for the ALT 
elevation and impact on FVIII expression.  
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 SoA. 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.). Alternative, non-steroidal systemic immunosuppressive agents may be 
used, following a discussion between the Investigator and the Medical Monitor, should 
corticosteroid use be deemed by an Investigator to be clinically ineffective, not tolerated, 
and/or contraindicated. Hepatitis B status and HCV viral load will be rechecked 6 weeks 
after the start of oral corticosteroid/immunosuppressive agent treatment and then 1 week and 
13 weeks after the completion of oral corticosteroid/immunosuppressive agent treatment in 

 
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subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse 
events suspected to be caused by or related to corticosteroid/immunosuppressive agent use) 
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. The above guidance should also be followed in the event that an alternative 
immunosuppressive agent is used, as applicable. 
9.4.9 Treatment Compliance 
IP will be administered to subjects at the study site and/or the dosing facility by a qualified 
health care 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 IP 
containers. 
9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP 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 standard 
operating procedures (SOPs). 
9.5.1 Return and Disposition of Clinical Supplies 
Unused IP 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 IP or study materials (or must be referenced in their institution SOPs). 
Unused IP may be destroyed on site, per the site’s standard operating procedures, but only 
after BioMarin has granted approval for drug destruction. The study monitor must account 
for all IP in a formal reconciliation process prior to IP destruction. All IP destroyed on site 
must be documented. Documentation must be provided to BioMarin or designee and retained 
in the Investigator study files. If a site is unable to destroy IP appropriately, the site can 
return unused IP to BioMarin upon request. The return of IP or IP materials must be 
accounted for on a IP return form provided by BioMarin. 

 
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All IP and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable state and federal regulations and study procedures. 
For additional information, please refer to the Pharmacy Manual. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study. Alcohol should be avoided 
starting at the time of informed consent for study participation and for the first 52 weeks of 
the study, and particularly within 48 hours prior to lab work. Alcohol use should be 
minimized throughout the remaining duration of the 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 blood 
and semen samples, respectively. Subjects should also abstain from organ donation. 
9.7 
Safety and Efficacy Variables 
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 
9.7.2.1 
FVIII Activity 
The primary efficacy variable is change of the hFVIII activity, as measured by chromogenic 
substrate assay during Weeks 49-52 post-BMN 270 infusion from baseline. 
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 the end of 16 weeks after BMN 270 infusion and who have not resumed 
FVIII replacement therapy. 
In the event of an FVIII activity level decline during the study: 
• If FVIII activity has declined at least 20% from the peak but less than 35% and has 
declined for at least 2 consecutive assessments, FVIII activity and LTs should be 
repeated every 7 days until FVIII activity is stable or increasing 
• If FVIII activity has declined ≥ 35% from the peak and has declined for at least 
2 consecutive assessments, FVIII activity and LTs should be repeated every 72 hours 
until FVIII activity is stable or increasing 

 
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Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline 
in FVIII activity is observed, then this additional testing may be deferred (upon consultation 
between the Investigator and the Medical Monitor) until either a more clear trend of decline 
has been demonstrated or until the FVIII activity levels stabilize or increase. 
Details on collecting FVIII activity samples are included in the Laboratory Manual.  
9.7.3 Secondary Efficacy Variables 
9.7.3.1 
Factor VIII Replacement Therapy/Bleeding Episodes 
Secondary efficacy variables include: 
• Change in the annualized utilization (IU/kg/year) and infusion (number/year) rates 
of exogenous FVIII replacement therapy during Week 5 to Week 52 post-BMN 270 
infusion from the baseline number and utilization of exogenous FVIII replacement 
therapy, for subjects receiving FVIII prophylaxis during the 12 months prior to study 
entry, or change in administration of exogenous FVIII replacement therapy Week 27 
to Week 52 post-BMN 270 infusion for subjects receiving prior emicizumab 
prophylaxis.  
• Change in the annualized number of bleeding episodes requiring exogenous FVIII 
replacement treatment (annualized bleeding rate, ABR) during Week 5 to Week 52 
post-BMN 270 infusion for subjects receiving prior FVIII prophylaxis, or Week 27 to 
Week 52 post-BMN 270 infusion for subjects receiving prior emicizumab 
prophylaxis, from the baseline ABR during the 12 months prior to study entry. 
Subjects must have high quality documented historical data available concerning previous 
bleeding episodes and hemophilia treatment over the previous 12 months in order to be 
eligible to enroll in the study. During the study, 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.  
Subjects are strongly encouraged to immediately consult Investigator for guidance regarding 
exogenous FVIII administration for suspected bleeds or bleeding episodes within the first 
30 days post-BMN 270 infusion. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis or use of emicizumab. 
9.7.3.2 
Patient-Reported Outcomes (PRO) 
The Haemo-QoL-A questionnaire is a validated hemophilia-specific health-related quality 
of life questionnaire for adults (Rentz, 2008). It consists of 41 questions covering six 

 
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domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, 
Emotional Impact and Treatment Concerns). Items are answered on a 6-point Likert-type 
scale, ranging from 0 (None of the time) to 5 (All of the time). Higher scores mean better 
health-related quality of life or less impairment for a particular subscale 
(Haemo-QoL Study Group, 2017). 
The EQ-5D-5L instrument is a self-reported questionnaire designed to measure general 
health status (The EuroQol Group, 1990) (Brooks, 1996). The EQ-5D-5L is composed of 
2-parts: a descriptive system that assesses 5 levels of perceived problems (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) in 5 dimensions and the EQ visual 
analogue scale (EQ VAS) assessment for overall health. 
The Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) instrument is designed to measure the effect of 
disease symptom severity on work productivity and classroom productivity (if applicable) 
(Recht, 2014). The WPAI+CIQ:HS questionnaire yields scores related to work/classroom 
absenteeism, reduced on-the-job effectiveness, overall work/classroom impairment, and 
activity impairment. WPAI+CIQ:HS outcomes are expressed as impairment percentages, 
with higher numbers indicating greater impairment and less productivity (Reilly, 2002). 
The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is 
designed to investigate and directly probe patient perspectives on outcomes they deem 
relevant to their life and care. PROBE aims to develop a new global tool to enhance the 
direct patient-voice in health care decision-making (Chai-Adisaksopha, 2017). 
Details (including sample copies where applicable) for each of the PRO instruments are 
provided in the Investigator Site File Binder. 
9.7.4 Immunogenicity 
Immunogenicity assays will be performed on plasma and PBMCs. The assays will include 
detection of anti-AAV5 capsid and anti-FVIII total antibodies, as well as determination of 
neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid 
(transduction inhibitors, TI). FVIII inhibitors will be assessed using the chromogenic 
Bethesda assay with Nijmegen modification. Any abnormality of the liver parameters will 
lead to a retrospective immunogenicity assessment to evaluate FVIII- and capsid-specific 
cellular immunogenicity. FVIII- and capsid-specific cellular immunity will be assessed by 
stimulated cytokine secretion using an ELISpot assay performed on collected PBMCs. 

 
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9.7.5 Pharmacodynamics 
The FVIII protein concentration and activity level as measured by a validated immunoassay 
and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII 
protein and activity will be used to determine PD parameters. 
9.7.6 Pharmacokinetics 
Sparse FVIII activity assessments, prior to BMN 270 administration, will be collected to 
estimate each subject’s half-life of replacement FVIII concentrate used for prophylaxis. 
Samples will be drawn immediately prior to recombinant FVIII concentrate infusion 
(between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours 
post-FVIII infusion. If supported by the data, sparse samples together with established 
population pharmacokinetic models will be used to estimate an individual subject’s FVIII 
activity clearance (CL) value. Individual subject CL estimates may then be evaluated against 
post-BMN 270 FVIII activity levels to determine if an association exists between an 
individual’s FVIII activity CL value and FVIII activity levels achieved with BMN 270. 
For subjects receiving emicizumab, pharmacokinetics assessment is optional.    
9.7.7 Exploratory Assessments 
Blood samples will be collected from subjects at the time points indicated in the Schedules of 
Events 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 in this study may be used for exploratory 
research once testing for the primary purpose has been completed.  
9.7.7.1 
Optional Liver Biopsy 
Subjects electing to undergo an optional liver biopsy are required to consent to the procedure 
and collection of tissue in the study ICF. The analysis of the optional liver biopsy is 
considered exploratory. Patients who elect to proceed will have a liver biopsy performed 
around Week 26, Week 52, and/or during Years 2-5. Additional liver biopsies at times 
deemed to be clinically relevant (eg, decreasing FVIII at a time of increased ALT) may be 

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pursued. Subjects will be asked to consent to the procedure for each liver biopsy performed 
during the study. 
Subjects who consent to the procedure will have a liver biopsy via either transjugular or 
percutaneous (ultrasound-guided) route, according to the standard procedures of the 
institution. Two tissue cores will be harvested in the context of the optional liver biopsy. 
Subjects will be required to observe an 8-hour fasting period before the procedure. 
Within 24 hours prior to the biopsy being performed, subjects must have a documented FVIII 
activity level of ≥ 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 on the day the biopsy, prior to the procedure. 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”. 
Details on required procedures for the optional liver biopsy are outlined in Table 9.1.5. 
Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 28 days before the procedure, as follows: 
•
Physical examination
•
Hematology, coagulation, chemistry assessments
•
Liver tests
•
Liver ultrasound (subject should fast at least 8 hours prior to ultrasound)
•
FibroScan
Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 7 days before the procedure, as follows: 
•
Local FVIII activity level assessment
•
Pre-biopsy consultation (with hepatologist and/or radiologist)
On the day of the biopsy, brief physical examination and liver and blood tests should be 
performed before the procedure (including hematology, coagulation, and chemistry). FVIII 
activity assessment should also be performed to ensure the subject has sufficient FVIII 
activity to protect against procedure-related bleeding (as discussed above). LT assessment 
and a whole blood draw for PBMC collection should be performed on the biopsy day or ± 1 
week from the biopsy day. 

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The optional liver biopsy should be performed in the morning if feasible, 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 Study Reference 
Manual. 
Following completion of the biopsy, the subject should remain under observation in the clinic 
for at least 4-6 hours. Overnight post-procedure observation may be done at the investigator’s 
discretion and/or according to local guidelines. 
Clinically significant findings reported from the histopathological analysis of the biopsy 
sample are subject to AE reporting (Section 10). Such findings should be further assessed 
and followed as clinically appropriate to manage the subject’s medical care. A hepatologist 
and/or other specialist clinicians should be consulted if required. In the event that fibrotic 
changes are observed on the biopsy sample, additional liver ultrasound, FibroScan and/or 
Enhanced Liver Fibrosis (ELF) testing (as regionally available and/or approved by HA) may 
be considered 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. In case of a safety concern, additional unscheduled 
laboratory tests may be performed locally (at the Investigator’s discretion) in order to 
facilitate timely and appropriate clinical management decisions; where possible, a matched 
sample for testing at the central laboratory should be collected (using the Unscheduled Visit 
lab kit) at the same time as the local unscheduled sample 
9.7.8.1 
Adverse Events 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. 
9.7.8.2 
Clinical Laboratory Assessments 
The scheduled clinical laboratory tests are listed in Table 9.7.8.2.1. Refer to the On Site File 
Binder 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: (1) the cause of the abnormality is 
determined; (2) the value returns to baseline or to within normal limits; or (3) 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 eCRF. 
In case of a safety concern, additional unscheduled laboratory tests may be performed locally 
(at the Investigator’s discretion) in order to facilitate timely and appropriate clinical 
management decisions; where possible, a matched sample for testing at the central laboratory 
should be collected (using the Unscheduled Visit lab kit) at the same time as the local 
unscheduled sample. 
Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urine Tests 
Coagulation Screen 
including: 
Albumin 
Hemoglobin 
Appearance 
APTT 
BUN 
Hematocrit 
Color 
PT/INR 
Calcium 
WBC count 
pH 
TT 
Chloride 
RBC count 
Specific gravity 
 
Total cholesterol 
Platelet count 
Ketones 
 
CPK 
Differential cell count 
Protein 
 
Creatinine 
RBC indices (MCV and 
MCH) 
Glucose 
Other Tests: 
CRP 
 
Bilirubin 
ABO blood typing*  
Glucose 
 
Nitrite 
 
Phosphorus 
 
Urobilinogen 
 
Potassium 
 
Hemoglobin 
 
Total protein 
 
 
 
Sodium 
 
 
 
Uric Acid 
 
 
 
BUN, blood urea nitrogen; CPK, creatinine phosphokinase; 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; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin. 
 *ABO blood typing assessment should be performed at Screening. 
 
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel 
(including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) and 

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FibroTest will be assessed at the BMN 270 infusion visit. Subjects will fast for at least 
8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment 
including physical examination and vital signs will be performed and additional blood 
samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. 
Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 1 
week after the event for an optional, exploratory CBA to assess inflammatory biomarkers and 
plasma cytokine levels. Inpatient observation can be extended and additional blood samples 
can be collected if deemed necessary at the discretion of the Investigator and Medical 
Monitor. 
At applicable sites, certain study assessments may be performed by an MN professional at the 
patient's home or another suitable location, such as their school or office, to improve access 
and convenience for patients 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 patient and the patient gives written informed consent to 
participate in MN visits, the MN network will communicate with the patient and the patient’s 
site. MN visits will be allowed at the visits indicated in the Schedules of Events. Unscheduled 
visits may also be conducted by MN as appropriate. 
9.7.8.3 
Liver and Hepatitis Testing 
Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C infection 
at Screening; hepatitis B screening should include HBsAg, HBsAb, and HBcAb. Subjects with 
documented results showing an absence of active hepatitis B or hepatitis C infection (as 
measured by negative surface antigen or DNA for hepatitis B or negative RNA testing for 
hepatitis C) 30 days prior to providing signed informed consent do not need to repeat those 
tests during the screening period.  
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. 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 the timepoints listed in Table 9.1.6. Subjects with a history of 

 
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hepatitis B or hepatitis C will be asked for information about the treatments received as part 
of their medical history assessment at Screening. 
A liver ultrasound/FibroScan and liver tests (LTs) during Screening will identify any 
significant hepatic dysfunction.  
LTs will be monitored on a regular basis; 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 
 

 
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Elevated ALT levels (above the upper limit of normal range) should be evaluated according 
to the following plan: 
Table 9.7.8.3.2: Evaluation of ALT Elevations 
ALT Level 
Work-Up 
≥1.5x Baseline 
- <2x Baseline 
 
Continue to monitor LTs and FVIII per protocol (repeat within 24-72 hours if next 
protocol scheduled visit is >24-72 hours from the time of the reported ALT elevation) 
 
Consider evaluation to rule out alternative etiology (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.) (refer to Table 9.7.8.3.3:) 
 
If ALT is > ULN or > 2x baseline in 2 consecutive assessments within 24-72 hours 
and alternative etiologies have been ruled out, start oral corticosteroids upon 
consultation with the Medical Monitor (refer to Section 9.4.8.2) 
 
Consider liver biopsy at the discretion of the Investigator or Medical Monitor 
 ≥2x Baseline 
or > ULN - 
<3x ULN  
 
Repeat LTs and FVIII within 24-72 hours 
 
Continue to monitor LTs weekly until ALT is stable or improving 
 
Evaluate and rule out alternative etiologies (as above) 
 
Consult with Medical Monitor 
 
If ALT is ≥ 2x baseline or > ULN - < 3x ULN in 2 consecutive assessments within 
72 hours and alternative etiologies have been ruled out, start oral corticosteroids upon 
consultation with the Medical Monitor (refer to Section 9.4.8.2) 
 
Obtain other possibly relevant laboratory evaluations (albumin, PT/INR, CRP, etc.) 
 
Obtain complete blood count with differential to assess for eosinophilia 
 
Obtain PBMC to evaluate potential immune response (prior to starting oral 
corticosteroids) 
 
If no improvement in 14 days, consider gastroenterology and/or hepatology consult, 
abdominal workup, imaging (including MRI or ultrasound), and/or liver biopsy as 
appropriate 
≥3x ULN 
 
Consult with Medical Monitor 
 
Evaluate and rule out alternative etiologies (as above) 
 
Repeat LTs and FVIII within 24-48 hours, and continue with monitoring of LTs at 
least twice weekly for as long as the subject’s ALT remains ≥ 3x ULN 
 
If ≥3x ULN in 2 consecutive assessments within 48 hours, start oral corticosteroids 
(refer to Section 9.4.8.2) 
 
Obtain other possibly relevant laboratory evaluations (albumin, PT/INR, CRP, etc.) 
 
Obtain complete blood count with differential to assess for eosinophilia 
 
Obtain PBMC to evaluate potential immune response (prior to starting oral 
corticosteroids) 
 
If no improvement in 14 days, consider gastroenterology and/or hepatology consult, 
abdominal workup, imaging (including MRI or ultrasound), and/or liver biopsy as 
appropriate 
 

 
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When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT 
workup, the following tests should be performed: 
Table 9.7.8.3.3:  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 
 
 
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 the timepoints indicated in the schedules of events. 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 at least 8 hours 
during the subject’s stay in the clinic. Any abnormal vital sign assessments should be 
repeated, and both values should be recorded in the eCRF. 
A complete physical examination should be performed during Screening/Baseline, at 
Week 26 (± 2 weeks) 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. 

 
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A brief physical examination will include general appearance, cardiovascular, dermatologic, 
respiratory, gastrointestinal, musculoskeletal, and neurologic assessments. 
Height will be recorded at Screening only. Weight will be recorded at Screening and then at 
the timepoints indicated in the Schedules of Assessments. 
9.7.8.6 
Vector Shedding 
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 polymerase chain reaction (PCR). Fluids tested will include: 
• Blood 
• Saliva 
• Semen 
• Urine 
• Stool 
Vector shedding will also be extensively studied in the present clinical trial. Testing will 
continue until at least 3 consecutive results below the limit of detection are obtained; 
additional collection and testing may be performed based on batch testing schedules, result 
turnaround times, or discussions between Medical Monitor and Investigator. Testing of 
semen will continue at least through Week 12, even if 3 consecutive results below the limit 
of detection have been recorded in that compartment prior to that time point. Subjects who 
have not had 3 consecutive semen samples below the limit of detection by Week 52 should 
continue to have PCR testing in 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).  
Samples may be fractionated prior to shedding analysis in order to better characterize the 
presence, structure, and location of vector DNA and/or vector capsid within each matrix. 
If needed, the fractionation may be performed with samples collected specifically for 
shedding analysis (saliva, blood, semen, urine, stool). Alternatively, the vector DNA 
characterization during shedding analysis may utilize already fractionated exploratory 
samples obtained from the above biofluids, such as exploratory plasma samples, exploratory 
PBMC samples, and red blood cells recovered during PBMC/plasma isolations.  
Fractionation of semen to collect purified sperm separately from non-sperm cells may be 
performed, after consultation between the Medical Monitor and the Investigator, in parallel at 
any visit where semen samples are collected. The shedding analysis of a fractionated semen 

 
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sample will only be performed if vector DNA was detected in the whole semen sample for 
the same visit. Fractionation of semen during shedding analysis may be stopped if purified 
sperm tested positive for vector DNA on at least three visits, or if purified sperm tested 
below the limit of detection for vector DNA on at least three consecutive visits. 
Contraception use may need to be extended beyond 12 weeks in individual subjects based on 
observed vector shedding in semen. After 12 weeks, 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 hematology, 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, an adverse event (AE) is any untoward medical occurrence in a subject, 
temporally associated with the use of study intervention, whether or not considered related to 
the study intervention.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention.  
Events meeting the AE definition include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Events not meeting the AE definition include: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

 
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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: 
• 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: 
• Results in death 
• Is life-threatening  
Note: Life-threatening refers to an event in which the subject was at risk of death at 
the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. If the investigational product preparation, infusion, and 
post-infusion observation period require transfer to an inpatient setting for 
completion, in the absence of an AE, this will not be considered an SAE. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.  
• 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 medical/surgical intervention to prevent one of the 
other outcomes listed above (eg, anaphylaxis)  

 
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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 > ULN or > 1.5x baseline value, regardless of whether that 
elevation triggers an initiation or modification of oral corticosteroid treatment 
• Thromboembolic event 
• Immediate reactions: infusion-related reactions, hypersensitivity adverse events, or 
anaphylaxis 
• Development of anti-FVIII inhibitory antibodies (inhibitors) 
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 drug, only SAEs associated 
with any protocol-imposed interventions will be collected. AEs occurring during this 
time period should be recorded on the Medical History eCRF. 
• After informed consent is obtained and following infusion 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 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. The Investigator will record all relevant AE/SAE/EOSI information in the 
subject’s medical record and 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). 

 
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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 Investigator will determine the severity of each 
AE, SAE and EOSI using the Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v5. Adverse events that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE v5as stated in 
Table 10.3.3.2.1 
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 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/or 
corticosteroids and/or other immunosuppressant agents and will record it on the source 
documents and AE eCRF. 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 and/or corticosteroids has not occurred 
OR 
• 
The administration of the IP and/or corticosteroids 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 and/or corticosteroids; that is, there are no facts, evidence, or 
arguments to suggest a causal relationship to the IP and/or corticosteroids. 
Related 
• 
The administration of the IP and/or corticosteroids 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 and/or corticosteroids 
OR 
 
• 
The administration of IP and/or corticosteroids and the occurrence of the AE 
are reasonably related in time  
AND 
• 
The AE is more likely explained by exposure to the IP and/or corticosteroids 
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 and/or corticosteroid exposure 
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug and/or corticosteroid 
action 
• Similarity to adverse reactions seen with related drug products 
• Abatement of AE with discontinuation of study drug and/or corticosteroids, and/or 
recurrence of AE with reintroduction of study drug and/or corticosteroids 
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 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 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 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 hemorrhage 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. For 

 
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example, if a subject has an adverse event of ALT increased that subsequently resolves, but 
the subject’s ALT increases again, that should be reported as two adverse events – the initial 
ALT increase, and the second ALT increase.  
10.4.1.4 
Abnormal Laboratory Values 
Laboratory test results will be recorded on the laboratory results pages of the 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.  

 
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For purposes of this study, laboratory tests showing a decreased level of FVIII 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. 
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 documented 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 worsened 
• Insert an in-dwelling IV catheter (such as a Port-a-Cath or other brand, if applicable) 
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. 

 
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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 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 BioMarin 
Pharmacovigilance (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. IND safety reports will be submitted within 7 calendar days for fatal or 
life-threatening unexpected suspected adverse reactions (SUSARs) and within 15 calendar 
days for other non-life-threatening SUSARs 

 
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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 electronic data capture (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 Institutional Review Board or Independent Ethics Committee Reporting 
Requirements 
Reporting of SAEs to the Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB) will be done in compliance with the standard operating procedures and policies of the 
IEC/IRB and with applicable regulatory requirements. Adequate documentation must be 
obtained by BioMarin showing that the IEC/IRB was properly and promptly notified as 
required. 
10.6 
Follow-up of Subjects after Adverse Events 
After the initial AE/SAE/EOSI report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All AEs/SAEs/EOSI will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up. Resolution 
of AEs/SAEs/EOSI (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 and EOSI, 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 or 
EOSI 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 drug. 
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 drug. The Sponsor should also be 
notified if the Investigator should become aware of the development of cancer or of a 

 
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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 
IRB/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 
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: 
• 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, MHS 
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 substrate FVIII assay and the one-stage clotting FVIII 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 should be performed within 28 days of BMN 270 infusion (and must 
be performed within 42 days prior to BMN 270 infusion), while baseline assessments will 
take place within 7 days prior to BMN 270 infusion (Day 1). Should the screening visit occur 
within 30 days of the drug infusion, physical examination, vital signs, blood chemistry, LTs, 
hematology, urine tests, and coagulation tests do not need to be repeated at Baseline.  
During the first part of the Screening Period (Day -42 to Day -29), testing for AAV5 TAb 
titers using the CDx screening assay may be performed, so that subjects can verify their 
AAV5 TAb status. Subjects who agree to participate in this activity may be asked to sign a 
separate ICF documenting this decision. Subjects who do not have testing during this period 
will have CDx AAV5 TAb testing along with the rest of the Screening assessments. 
If the subject underwent early AAV5 TAb testing and was consented using the full study 
ICF, the ICF does not need to be re-administered and re-signed as part of regular Screening. 
If the subject underwent early AAV5 TAb testing and was consented using the dedicated 
stand-alone ICF for that purpose, the full ICF will need to be signed if the subject proceeds to 
regular Screening. 
The following procedures will be performed during the Screening Period: 
• Demographics (age, sex, race, ethnicity) 
• Full medical history, including hemophilia 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 hemophilia 
therapy prior to the study should also be collected. 
• 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 

 
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• Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) for the previous 12 months 
o Further information on details to be included in documentation of previous 
bleeding episodes and FVIII usage, refer to the Investigator Site File 
Binder. 
• Distribution of subject diaries and training in diary completion 
• Electrocardiogram 
• Liver ultrasound/FibroScan 
• Samples for hFVIII Assays 
o Baseline FVIII activity – chromogenic substrate FVIII assay 
o Baseline FVIII activity level – one-stage clotting FVIII assay 
o hFVIII coagulation activity exploratory assay (collected but not tested 
prior to enrollment) 
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level  
o hFVIII protein assay (collected but not tested prior to enrollment) 
• hFVIII total antibody (TAb) assay (collected but not tested prior to enrollment) 
• 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) 
o Hepatitis B screening should include HBsAg, HBsAb, and HBcAb. 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
o ABO blood typing assessment should be performed at Screening 
• Urine tests (refer to Table 9.7.8.2.1) 
• Liver tests (refer to Table 9.7.8.3.1) 
• AAV5 TAb Assessment (CDx) 
o If performed during the early Screening period, the CDx AAV5 TAb 
assessment does not need to be repeated as part of general Screening 
• Biomarker testing (including HLA genotyping and FVIII genotyping status) 
• Serum for exploratory biomarkers 
• Exploratory CK18 and Grp78 assessment 

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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 chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)
•
Urine tests (refer to Table 9.7.8.2.1)
•
Liver tests (refer to Table 9.7.8.3.1)
•
AAV5 TAb Assessment (CDx)
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit. Subjects are 
considered enrolled into the study once the Baseline visit has occurred. The following 
procedures will be performed during the Baseline Period: 
•
Brief physical examination
•
Vital signs
•
Assessment of adverse events and concomitant medications
•
Documentation of bleeding episodes and FVIII usage (by either subject or clinical
information)
•
Samples for hFVIII Assays
o
Baseline FVIII activity – chromogenic substrate FVIII assay
o
Baseline FVIII activity level – one-stage clotting FVIII assay

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o
hFVIII coagulation activity exploratory assay
o
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level
o
hFVIII protein assay
•
hFVIII TAb
•
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)
•
Urine tests (refer to Table 9.7.8.2.1)
•
Liver tests (refer to Table 9.7.8.3.1 )
•
Immunogenicity AAV5 TAb assay
•
AAV5 TI assay
•
IFNg ELISpot
•
Plasma, PBMC, and RBC collection for exploratory biomarkers
•
Complement Panel
•
Exploratory CK18 and Grp78 assessment
•
TGA Assay
•
Haemo-QoL-A assessment
•
EQ-5D-5L
•
WPAI+CIQ:HS
•
PROBE
•
PCR of vector DNA in blood, saliva, urine, semen, and stools
•
Pharmacokinetics
o
Samples will be drawn immediately prior to recombinant FVIII concentrate 
infusion (between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII 
infusion, and 24-52 hours post-FVIII infusion. For subjects receiving 
emicizumab, pharmacokinetics assessment is optional
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 at 
least 8 hours for the BMN 270 Infusion Visit. The following procedures will be performed 
during the BMN 270 Infusion Visit: 
•
Initiation of prophylactic corticosteroids (at least 3 hours prior to BMN 270 infusion)
•
Brief physical examination

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•
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 at least
8 hours during the subject’s stay in the clinic.
•
Assessment of adverse events and concomitant medications
•
Fasting lipid panel (blood triglycerides, total cholesterol, HDL cholesterol, and LDL
cholesterol) (sample collected pre-infusion)
o
Subjects will fast for at least 8 hours prior to pre-infusion laboratory
sampling on the day of the infusion visit.
•
Fasting FibroTest
•
AAV5 TAb Assay (CDx) (sample collected pre-infusion for analysis)
•
Immunogenicity AAV5 TAb Assay
•
AAV5 TI Assay
•
Serum for exploratory biomarkers
•
BMN 270 Infusion
•
Hypersensitivity blood assessments (if required, see below)
•
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Collection of samples for PCR testing should occur between 2 and
24 hours after the BMN 270 infusion has been completed
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment 
including physical examination and vital signs will be performed and additional blood 
samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. 
Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 
1 week after the event for an optional, exploratory CBA to assess inflammatory biomarkers 
and plasma cytokine levels. Inpatient observation can be extended and additional blood 
samples can be collected if deemed necessary at the discretion of the Investigator and 
Medical Monitor. 
12.5 
BMN 270 Infusion Follow-Up Visits – Weeks 1-26 
After BMN 270 has been infused, subjects will have weekly assessments during Weeks 1-26. 
Visits between scheduled clinic visits may be performed by a mobile nursing (MN) 
professional at the subject’s home or another suitable location (if the subject has given 

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written informed consent to participate in MN visits), or at the site or approved lab facility as 
a shortened lab draw-only visit. The MN service or site will collect blood samples at these 
visits. For site lab draw-only visits, sites will contact the subject via phone call or e-mail to 
collect information regarding adverse events, changes to concomitant medications, bleeding 
episodes, and hemophilia therapy use. For MN visits, the service will collect this 
information. Unscheduled visits may also be conducted by MN as appropriate. 
At the Week 1-26 visits, the following procedures will be completed. 
12.5.1 Once per week (Weeks 1 through 26)  
The following procedures will be performed at one visit per week from Weeks 1 through 26: 
•
Assessment of adverse events and concomitant medications (including review of 
subject diary for bleeding and FVIII use)
•
Liver Tests (refer to Table 9.7.8.3.1)
o
LTs may be monitored more or less frequently (and in particular when ALT 
values are > ULN or ≥ 1.5x baseline value) 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.
•
Samples for FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level
o
FVIII protein assay
•
Exploratory CK18 and Grp78 assessment
12.5.2 Week 1 - Day 8 
On Day 8, the following procedures will be performed, in addition to the weekly assessments 
required in Section 0: 
•
PCR of vector DNA in blood, saliva, urine, semen, and stools
•
Plasma, PBMC, and RBC collection for exploratory biomarkers
•
Serum for exploratory biomarkers
•
Complement Panel

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12.5.3 Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26 
At Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26, the following procedure will be performed: 
•
Serum for exploratory biomarkers
12.5.4 Weeks 2, 4, 8, 12, 16, 20, 24, and 26 
At Weeks 2, 4, 8, 12, 16, 20, 24, and 26, the following procedure will be performed: 
•
Complement Panel
12.5.5 Weeks 2, 6, 10, 14, 18, 22, 24, and 26 
At Weeks 2, 6, 10, 14, 18, 22, 24, and 26, the following procedure will be performed: 
•
IFNg ELISpot
12.5.6 Weeks 4, 8, 12, 16, 20, 24, and 26 
At Weeks 4, 8, 12, 16, 20, 24, and 26, the following procedures will be performed: 
•
Vital Signs
•
Weight (not done at Week 24)
•
hFVIII TAb
•
PCR of vector DNA in blood, saliva, urine, semen, and stools (not done at Week 24)
o
Sample testing to occur until at least 3 consecutive sample results below the
limit of detection have been obtained. Testing of semen will continue at least
through Week 12, even if 3 consecutive results below the limit of detection
have been recorded in that compartment prior to that time point.
12.5.7 Weeks 4, 8, 12, 16, 18, 20, 22, 24, and 26 
At Weeks 4, 8, 12, 16, 18, 20, 22, 24, and 26, the following procedures will be performed: 
•
Brief physical examination
o
A complete physical examination should be done at Week 26.
12.5.8 Weeks 4, 8, 16, and 26 
At Weeks 4, 8, 16, and 26, the following procedures will be performed: 
•
Immunogenicity AAV5 TAb Assay
•
AAV5 TI Assay

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12.5.9 Weeks 4, 8, 12, 18, 22, and 26 
At Weeks 4, 8, 12, 18, 22, and 26, the following procedure will be performed: 
•
Plasma, PBMC, and RBC collection for exploratory biomarkers
12.5.10Week 4, 12, and 26 
At Weeks 4, 12, and 26, the following procedure will be performed: 
•
Haemo-QoL-A assessment
•
EQ-5D-5L
•
WPAI+CIQ:HS
•
PROBE
12.5.11  Weeks 4, 16, and 26 
At Weeks 4, 16, and 26, the following procedure will be performed: 
•
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)
12.5.12  Weeks 12 and 26 
At Weeks 12 and 26, the following procedure will be performed: 
•
Urine Tests (refer to Table 9.7.8.2.1)
12.5.13 Weeks  16, 20, and 26 
At Weeks 16, 20, and 26, the following procedure will be performed: 
•
TGA Assay
12.5.14  Weeks 6 and 20 
At Weeks 6 and 20, the following procedure will be performed: 
•
Testing for reactivation of hepatitis B and hepatitis C
o
Testing for reactivation of hepatitis B and hepatitis C only for subjects
with a past medical history of hepatitis B or hepatitis C prior to study
entry.
12.5.15  Week 26  
At Week 26, the following optional procedure will be performed: 
•
Optional liver biopsy (refer to Section 12.9 for assessments related to liver biopsy)

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12.6 
Post-Infusion Follow-Up – Weeks 27-52 
After Week 27, subjects will have assessments at Weeks 28, 30, 32, 34, 36, 40, 44, 48, 50, 
and 52. Visits between scheduled clinic visits may be performed by a mobile nursing (MN) 
professional at the subject’s home or another suitable location (if the subject has given 
written informed consent to participate in MN visits), or at the site or approved lab facility as 
a shortened lab draw-only visit. The MN service or site will collect blood samples at these 
visits. For site lab draw-only visits, sites will contact the subject via phone call or e-mail to 
collect information regarding adverse events, changes to concomitant medications, bleeding 
episodes, and hemophilia therapy use. For MN visits, the service will collect this 
information. Unscheduled visits may also be conducted by MN as appropriate. 
At these visits, the following assessments will be performed. 
12.6.1 Each Visit (Weeks 28, 30, 32, 34, 36, 40, 44, 48, 50, and 52) 
The following procedures will be performed at every visit (Week 26, 28, 30, 32, 34, 36, 40, 
44, 48, 50, and 52): 
•
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
•
Liver Tests (refer to Table 9.7.8.3.1)
o
LTs may be monitored more or less frequently (and in particular when ALT
values are > ULN or ≥ 1.5x baseline value) 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.
•
Samples for FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level
o
FVIII protein assay
•
Exploratory CK18 and Grp78 assessment
12.6.2 Weeks 28, 32, 36, 40, 44, 48, and 52 
At Weeks 28, 32, 36, 40, 44, 48, and 52, the following procedure will be performed: 
•
Brief physical examination (complete physical examination at Week 52)

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12.6.3 Week 28, 36, 44, and 52 
At Weeks 28, 36, 44, and 52, the following procedure will be performed: 
•
Plasma, PBMC, and RBC collection for exploratory biomarkers
12.6.4 Week 32 
At Week 32, the following procedure will be performed: 
•
Testing for reactivation of hepatitis B and hepatitis C
o
Testing for reactivation of hepatitis B and hepatitis C only for subjects
with a past medical history of hepatitis B or hepatitis C prior to study
entry.
12.6.5 Weeks 32, 36, 40, 44, 48, and 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedure will be performed: 
•
Vital Signs
12.6.6 Weeks 32, 36, 44, and 52 
At Weeks 32, 36, 44, and 52, the following procedures will be performed: 
•
Weight
•
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)
•
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing to occur until at least 3 consecutive sample results below the
limit of detection have been obtained.
•
TGA assay
12.6.7 Week 36 and 52 
At Weeks 36 and 52, the following procedures will be performed: 
•
Urine Tests (refer to Table 9.7.8.2.1)
•
Immunogenicity AAV5 TAb Assay
•
AAV5 TI Assay
•
hFVIII TAb
•
IFNg ELISpot
•
Complement Panel
•
Serum for exploratory biomarkers

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12.6.8 Week 52 
At Week 52, the following procedure will be performed: 
•
Haemo-QoL-A assessment
•
EQ-5D-5L
•
WPAI+CIQ:HS
•
PROBE
12.6.9 Week 52 
At Week 52, the following optional procedure will be performed: 
•
Optional liver biopsy (refer to Section12.9 for assessments related to liver biopsy)
12.7 
Post-Infusion Follow-Up – Years 2-5 
During Years 2-5, at applicable sites, certain study assessments may be performed by a 
mobile nursing (MN) professional at the patient's home or another suitable location, such as 
their school or office, to improve access and convenience for patients 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 patient 
and the patient gives written informed consent to participate in MN visits, the MN network 
will communicate with the patient and the patient’s site. MN visits will be allowed for the 
Q4W and Q6W visits during Years 2-5; the Q12W visits and End of Year visits during 
Years 2-5 will not be performed by an MN professional but will be done at the study site. 
Unscheduled visits may also be conducted by MN as appropriate. 
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) or Q6W 
(during Years 3-5) until vector shedding has been cleared, either by reporting to the site to 
provide samples or by providing those samples to a MN professional.  
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed: 

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12.7.1 Year 2 (Every 4 Weeks) or Years 3-5 (Every 6 Weeks) 
During Years 2 (every 4 weeks  ± 2 weeks) or 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 9.7.8.3.1)
o
LTs may be monitored more or less frequently (and in particular when
ALT values are > ULN or ≥ 1.5x baseline value) 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.
•
FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level

If a subject tests positive in the cNBA during Years 3-5, a fresh
sample should be collected within 4 weeks of the initial visit that
had a positive result.
o
FVIII protein assay
•
Exploratory CK18 and Grp78 assessment
12.7.2 Years 2-5 – Every 12 Weeks and End of Year Visits 
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 104
•
Year 3 – Week 116, Week 128, Week 140, Week 156
•
Year 4 – Week 168, Week 180, Week 192, Week 208
•
Year 5 – Week 220, Week 232, Week 244, Week 260 (final study visit)
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: 

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•
Physical examination
o
Complete physical examination will be performed at the End of Year
visits; brief physical examination may be performed at other visits.
•
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)
•
Vital Signs
•
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)
(at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
•
Urine Tests (refer to Table 9.7.8.2.1) (at Week 76, Week 128, Week 180, Week 232,
and End of Year visits only)
•
Liver Tests (refer to Table 9.7.8.3.1)
o
LTs may be monitored more or less frequently (and in particular when
ALT values are > ULN or ≥ 1.5x baseline value) 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.
•
FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level

If a subject tests positive in the cNBA during Years 3-5, a fresh
sample should be collected within 4 weeks of the initial visit that
had a positive result.
o
FVIII protein assay
•
Immunogenicity AAV5 TAb Assay (at End of Year visits only)
•
AAV5 TI Assay (at End of Year visits only)
•
hFVIII TAb
•
Interferon gamma (IFNg) ELISpot (at Week 76, Week 128, Week 180, Week 232,
and End of Year visits only)
•
Plasma, PBMC, and RBC collection for exploratory biomarkers
•
Serum for exploratory biomarkers

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•
Exploratory CK18 and Grp78 assessment
•
TGA Assay (at End of Year visits only)
•
Haemo-QoL-A assessment (at Week 76, Week 128, Week 180, Week 232, and End of 
Year visits only)
•
EQ-5D-5L (at Week 76, Week 128, Week 180, Week 232, and End of Year visits 
only)
•
WPAI+CIQ:HS (at Week 76, Week 128, Week 180, Week 232, and End of Year 
visits only)
•
PROBE (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
•
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 below the limit of detection during the Post-Infusion Follow-Up 
period in Weeks 1-52. Subjects who have not had 3 consecutive semen 
samples below the limit of detection 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).
•
Optional liver biopsy (Years 2-5) (refer to Section 12.9 for assessments related to 
liver biopsy)
12.8 
Early Termination 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 ETV. The Early Termination Visit (ETV) will occur on the 
date the subject withdraws from the study, even if the date does not correspond to a protocol-
specific visit. At the ETV, as many of the following assessments as possible should be done: 
•
Complete physical examination
•
Weight
•
Assessment of Adverse Events and Concomitant Medications (including review of
subject diary for bleeding and FVIII use)
•
Vital Signs
•
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)
•
Urine Tests (refer to Table 9.7.8.2.1)
•
Liver Tests (refer to Table 9.7.8.3.1)

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•
FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level
o
FVIII protein assay
•
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
•
Immunogenicity AAV5 TAb Assay
•
AAV5 TI Assay
•
hFVIII TAb
•
IFNg ELISpot
•
Plasma, PBMC, and RBC collection for exploratory biomarkers
•
Serum for exploratory biomarkers
•
Exploratory CK18 and Grp78 assessment
•
TGA Assay
•
Haemo-QoL-A assessment
•
EQ-5D-5L
•
WPAI+CIQ:HS
•
PROBE
12.9 
Optional Liver Biopsy 
Details on required procedures for the optional liver biopsy are outlined in Table 9.1.5. 
Subjects may be asked to provide a liver biopsy around Week 26, Week 52, and during the 
Years 2-5 period post-BMN 270 infusion. 
Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 28 days before the procedure, as follows: 
•
Liver ultrasound (subject should fast at least 8 hours prior to ultrasound)
•
Physical examination
•
Hematology, coagulation, chemistry assessments
•
Liver tests
•
FibroScan

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Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 7 days before the procedure, as follows: 
•
FVIII activity level assessment (central and local)
•
Exploratory CK18 and Grp78 assessment
•
Pre-biopsy consultation (with hepatologist and/or radiologist)
On the day of the biopsy, brief physical examination and liver and blood tests should be 
performed before the procedure (including hematology, coagulation, and chemistry). FVIII 
activity assessment should also be performed to ensure the subject has sufficient FVIII 
activity to protect against procedure-related bleeding (as discussed above). LT assessment 
and a whole blood draw for PBMC collection should be performed on the biopsy day or ± 1 
week from the biopsy day. 
The optional liver biopsy should be performed in the morning if feasible, 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 Study Reference 
Manual. 
Following completion of the biopsy, the subject should remain under observation in the clinic 
for at least 4-6 hours. Overnight post-procedure observation may be done at the investigator’s 
discretion and/or according to local guidelines. 
12.10 End of Study 
The study will end after the last subject yet to complete the Week 260 visit does so, has 
transferred to another BMN 270 study, is withdrawn from the study, or discontinues from the 
study. 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, 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.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications.  

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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 
analyses. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No formal interim analysis is planned. Informal analyses (ie, no hypothesis testing) may be 
performed at different timepoints to assess efficacy and safety over time. The primary 
efficacy endpoint for such analyses involves hFVIII activity, as measured by chromogenic 
substrate assay, and is defined as median FVIII activity during a specific 4-week time 
interval post-BMN 270 infusion. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data. 
Missing data imputation and sensitivity analyses to assess the impact of missing data on the 
primary and secondary efficacy endpoints analyses are described in the following sections. 
Additional details regarding the handling of missing data will be provided in the SAP. 
14.2 
Primary Efficacy Endpoint 
For the primary efficacy endpoint at Week 52 (ie, the change in the hFVIII activity during 
Weeks 49-52 post-BMN 270 infusion from baseline, as measured by chromogenic substrate 
assay), a one-sample t-test will be used to test the null hypothesis that the change is 0 or less 
against the alternative hypothesis that the change is greater than 0 at the 1-sided significance 
level of 0.025 (or equivalently, at the 2-sided significance level of 0.05). Baseline value of 
1 IU/dL (eligible subjects must have residual FVIII levels ≤ 1 IU/dL as evidenced by medical 
history) will be used in the calculation of change from baseline since all the subjects will be 
on prophylactic hemophilia therapy prior to BMN 270 infusion where the FVIII activity level 
cannot be reliably measured. Descriptive summaries of the proportions of subjects whose 
hFVIII activity during Weeks 49-52 is greater than or equal to select thresholds, such as 
5, 15, 25, 30, and 40 IU/dL, and the confidence intervals of the proportions will also be 
provided.  
For a subject with a missing value of the primary endpoint, the median value in the subject’s 
last 4-week window containing a valid observation will be used. Additional analyses will be 

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conducted to examine the sensitivity of the results to the handling of missing data, including 
analysis using observed cases, and a mixed model for repeated measures (MMRM) approach. 
Further detail will be provided in the SAP. 
The analyses for the primary endpoint will be performed using the analysis populations as 
defined in Section 14.9. 
14.3 
Secondary Efficacy Endpoints 
The analyses of the secondary efficacy endpoints will be descriptive. Mean and associated 
95% confidence interval will be provided for the following secondary endpoints, where the 
baseline value will be derived from the data in the approximately 12-month period prior to 
BMN 270 infusion: 
•
Change from baseline in the annualized utilization (IU/kg/year) of exogenous FVIII
replacement therapy during Weeks 5-52 post-BMN 270 infusion, for subjects
receiving FVIII prophylaxis during the 12 months prior to study entry, or change
from baseline in the annualized utilization (mg/kg/year) of emicizumab during
Week 27 to Week 52 post-BMN 270 infusion for subjects receiving prior emicizumab
prophylaxis
•
Change from baseline in the annualized infusion rate (number/year) of exogenous
FVIII replacement therapy during Weeks 5-52 post-BMN 270 infusion, for subjects
receiving FVIII prophylaxis during the 12 months prior to study entry, or change
from baseline in the annualized utilization (mg/kg/year) of emicizumab during Week
27 to Week 52 post-BMN 270 infusion for subjects receiving prior emicizumab
prophylaxis
•
Change from baseline in the annualized number of bleeding episodes (number/year)
requiring exogenous FVIII replacement treatment during Weeks 5-52 post-BMN 270
infusion for subjects receiving prior FVIII prophylaxis, or Weeks 27-52
post-BMN 270 infusion for subjects receiving prior emicizumab prophylaxis
Mean change from baseline and associated 95% confidence interval will be calculated for the 
total score of Haemo-QoL-A at Week 52 post-BMN 270 infusion as well. 
The missing value of the change for annualized utilization and annualized infusion rate will 
be imputed as 0. The missing value of the change for annualized number of bleeding 
episodes will be imputed using the median value of the changes of all observed cases. 
A sensitivity analysis is planned to analyze ABR using a generalized linear mixed model 
assuming negative binomial as the underlying distribution. The model will include period 
(pre- to post-BMN 270 infusion) as the only factor, repeated within subject. The actual 
number of bleeding episodes will be used as the dependent variable with the time period 
adjustment (annualization) being implemented as the offset.  

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To assess the impact of missing data, analyses using observed case are planned as sensitivity 
analyses for the secondary endpoints. Multiple imputation methods may also be performed. 
14.4 
Tertiary Efficacy Endpoints 
The analyses of the tertiary efficacy endpoints will be descriptive. Mean change from 
baseline and associated 95% confidence interval will be provided for EQ-5D-5L, 
WPAI+CIQ: HS and PROBE scores at Week 52 post-BMN 270 infusion. 
14.5 
Immunogenicity 
Analysis of total and neutralizing antibody response and other immunological parameters 
will be primarily descriptive and involve both inter-subject and intra-subject comparisons. 
14.6 
Pharmacodynamic Analyses 
Plasma FVIII protein concentrations and FVIII activities determined over the course of the 
study will primarily be evaluated and summarized with descriptive statistical measures 
(eg, mean, standard deviation, CV%, min, median, max).  
14.7 
Safety Analysis 
All AEs will be coded to system organ class and preferred term using the current version of 
MedDRA. The incidence of AEs will be summarized by system organ class, preferred term, 
relationship to study drug, seriousness, and severity. A by-subject listing will be provided for 
those subjects who experience an SAE, including death, EOSI, or an AE resulting in early 
withdrawal from the study.  
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. 
14.8 
Determination of Sample Size 
Approximately 20 subjects may be dosed in the study, including at least 16 subjects who are 
AAV5 antibody-negative and up to 25% of the total number of subjects who have an AAV5 
antibody titer that is detectable but below the minimum required dilution at Screening. 
For the primary endpoint, a sample size of 16 will provide 85% power to demonstrate that 
the change in hFVIII activity during Weeks 49-52 from baseline is greater than 0, assuming 
an effect size of 0.8, using a one-sample t-test at the 1-sided significance level of 0.025 (or 

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equivalently, at the 2-sided significance level of 0.05). The effect size of 0.8 is assumed 
conservatively based on the results from 270-201 and the interim results from 270-301. 
14.9 
Analysis Populations 
The intention-to-treat (ITT) population is defined as all subjects who received BMN 270 
infusion. The ITT population will be the primary population for safety analyses, as well as 
being used for supportive efficacy analyses. 
The modified intention-to-treat (mITT) population is the primary analysis population for 
efficacy for this study. The mITT population will include all subjects who received 
BMN 270 infusion and who were AAV5 antibody negative at Screening (ie, excludes 
subjects with an AAV5 antibody titer detectable but below the minimum required dilution). 
Subjects with an AAV5 antibody titer detectable but below the minimum required dilution 
will be used for exploratory efficacy analysis on FVIII activity, as measured by chromogenic 
substrate assay, during Weeks 49-52 post BMN 270 infusion. 
14.10 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 must be sought, 
and the Investigator should inform BioMarin and the full IRB/IEC within 2 working days 
after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/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 IRB/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 IRB/IEC, 
and all active subjects must again provide informed consent. 

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15 
DATA MONITORING COMMITTEE 
An independent DMC will be convened for this study. The duties of the DMC will include: 
•
Conducting an ongoing review of individual subject safety and efficacy data during
the study.
•
Recommending whether to continue enrolling subjects based on emerging data and
the overall risk/benefit analysis of BMN 270.
•
Making other recommendations on the conduct and reporting of the trial based on
their evaluation of clinical data.
Details on the composition of the committee, frequency of meetings, and other committee 
functions and parameters are included in the DMC Charter and in the SAP. 

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16 
COSTS, COMPENSATION, AND SUBJECT INJURY 
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 
approval, BioMarin may reimburse the reasonable cost of travel for study-related visits in 
accordance with BioMarin’s travel and reimbursement policy. BioMarin will not pay for any 
hospitalizations, tests, or treatments for medical problems of any sort related solely to the 
study subject’s disease. Costs associated with such hospitalizations, tests, and treatments 
should be billed and collected in the way that such costs are usually billed and collected 
outside the study. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the study drug 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 immediate 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 cost of the 
medical treatment is not covered by health insurance or another third party that usually pays 
these costs, then either BioMarin or the institution may pay for reasonable and necessary 
medical services to treat the injuries caused by the study drug or study procedures. In some 
jurisdictions, BioMarin is obligated by law to pay for study-related injuries without prior 
recourse to third party payer billing and/or regardless of fault. 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 eCRF casebook to verify its accuracy. 
eCRFs 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 eCRF 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 date and time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the eCRFs 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 direct source document verification of study data by the 
site monitor is prohibited by institutional policy or local law, then the Investigator must make 
available facilities and/or personnel to allow GCP-compliant source verification to occur. 
Examples of such methods include certified copies of records which have study data visible 
but sensitive information redacted, or other GCP-compliant means agreed between the 
Investigator and the Sponsor. 
A site monitor designated by BioMarin will compare the eCRFs 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 site monitor, 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 site monitor 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 eCRF 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 

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source data verified. The Investigator will then electronically sign the casebook, specifying 
that the information on the eCRFs 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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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, peer-reviewed 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 
Batts KP & Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg 
Pathol. 1995;19:1409-1417. 
Bedossa P, Pynard T, French METAVIR Cooperative Study Group. An algorithm for 
grading activity in chronic hepatitis C. Hepatology. 1996;24:289-293. 
Berntorp E, Dolan G, Hay C, Linari S et al. European retrospective study of real-life 
haemophilia treatment. Haemophilia. 2017;23(1):105-114. 
Berntorp E, Peake I, Budde U, Laffan M et al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia. 2012;18(Suppl.6):1-13. 
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37:53-72. 
Chai-Adisaksopha C, Skinner M, Curtis R, et al. Psychometric Properties of the Patient 
Reported Outcomes, Burdens and Experiences (PROBE) Questionnaire. Blood. 
2017;130:5645. 
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16:199-208. 
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 20 January 2020). 
Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: 
a randomized dose comparison. Blood. 2012;119(6): 1335-1344. 
Haemo-QoL Study Group. Scoring Manual. Available at: http://haemoqol.de/scoring/ 
manual. Last accessed 28 July 2017.  
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. 2013;122(22):3568-3574. 
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. 2014;371(21):1994-2004. 

 
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National Center for Biotechnology Information (NCBI). LiverTox: Clinical and Research 
Information on Drug-Induced Liver Injury. Available at: https://livertox.nih.gov (last 
accessed 14 January 2020). 
National Hemophilia Foundation. MASAC recommendation for liver biopsies in gene 
therapy trials for hemophilia. Available at https://www.hemophilia.org/sites/default/files/ 
document/files/256.pdf. 2019. MASAC Recommendation #256. Last accessed 18 December 
2019. 
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. 
Reilly M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ 
WPAI_Scoring.html. Last accessed 28 July 2017.  
Recht M, Neufeld EJ, Sharma VR, Solem CT et al. Impact of Acute Bleeding on Daily 
Activities of Patients with Congenital Hemophilia with Inhibitors and Their Caregivers and 
Families: Observations from the Dosing Observational Study in Hemophilia (DOSE). Value 
in Health. 2014;17:744-748. 
Rentz A, Flood E, Altisent C, Bullinger M et al. Cross-cultural development and 
psychometric evaluation of a patient-reported health-related quality of life questionnaire for 
adults with haemophilia. Haemophilia. 2008;14(5):1023-34. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: summary report—second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol. 2006;117:391-397. 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS et. al. Guidelines for the 
management of hemophilia 128. Haemophilia. 2013;19(1):e1-47. 
Stonebraker JS, Brooker M, Amand RE, Farrugia A et. al. A study of reported factor VIII use 
around the world. Haemophilia. 2010;16(1):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 and/or principles of ICH E6 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 subjects. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential subjects, 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 
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 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 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 
section 4.9 are kept, and those records are available for inspection in accordance with 
21 CFR 312.68 and/or ICH E6 section 4.9.7. 
• The IRB/EC complies with the requirements of 21 CFR Part 56, ICH E6 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 subjects or others are reported to the 
IRB/EC. Additionally, he or she will not make any changes in the research without 
IRB/EC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects. 
• 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. 

 
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23 
SIGNATURE PAGE 
Protocol Title: A Phase 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and 
Safety of BMN 270, an Adeno-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII, with Prophylactic Corticosteroids in Hemophilia A Patients 
Protocol Number: 270-303 
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, as stated in the protocol, and other information supplied to me. 
 
 
 
 
Investigator Signature 
 
 
 
 
 
Date 
 
 
Printed name:  
 
 
 
 
Accepted for the Sponsor: 
 
Printed name:  
 MD, MHS, 
, Clinical Sciences 
 
PI
PI
PI
PI
PI

 
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24 
APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA 
According to the National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network (NIAID/FAAN) Second Symposium on the definition and 
management of anaphylaxis, anaphylaxis is highly likely when any one of the following 
3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, 
swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (eg, hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a. Infants and children: low systolic blood pressure (age specific) or greater than 
30% decrease is systolic BP 
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from 
that person’s baseline. 
Source: Sampson, 2006. 

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270-303 Amendment 1 
Page 6 
 
Proprietary and Confidential 
15 September 2020 
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 prospective FVIII interventional studies). The consequence of multiple bleeding events is the 
development of 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 a 1% trough for a 
greater proportion of the dosing interval. However, patients with severe HA who are treated with 
extended half-life FVIII remain dependent on multiple infusions to maintain critical levels of FVIII 
activity. While emicizumab prophylaxis has yielded lower bleed rates compared to prior FVIII 
prophylaxis, it does not physiologically recapitulate the coagulation system, requires chronic, life-
long therapy, and still necessitates the use of on-demand FVIII concentrates for treatment of 
breakthrough bleeds. 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 hemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous infusion of a vector encoding the 
appropriate gene sequence for long-term episomal expression. HA 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 even 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 hemophilia A. Thus, relatively small changes in endogenous FVIII activity can 
result in clinically relevant improvements in disease phenotype. Finally, the circulating FVIII 
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 and 
promoter specificity for specific tissues, such as the liver (for serotypes 2, 5 and 8 among others). 
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
that stable (median follow-up of 6.7 years) expression of human factor IX (hFIX) at levels that are 
sufficient for conversion of their bleeding phenotype from severe to moderate or mild is achievable 
following a single peripheral vein infusion of AAV8-hFIX vector. Several participants in this trial 
have been able to discontinue factor prophylaxis without suffering spontaneous hemorrhages, 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 hybrid human liver-specific promoter (Figure 1). 
 
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270-303 Amendment 1
Page 7
Proprietary and Confidential
15 September 2020
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 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 a single intravenous dose and is designed to achieve durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose 
escalation study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 
at various dose levels (6E12 vector genomes [vg]/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. Additional 
studies have been undertaken at the 6E13 vg/kg dose (270-301 in subjects with severe HA, and 
270-203 in subjects with severe HA who are also AAV5-antibody positive).
Three-year results from 270-201 have demonstrated that following gene transfer, mean and median 
FVIII activity levels above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are 
achievable and sustained following a single infusion of 6E13 vg/kg of BMN 270, with an 
acceptable safety profile. Preliminary results from optional liver biopsies (in subjects receiving 
lower doses of BMN 270 in 270-201) confirm pan-lobular and otherwise healthy liver transduction 
at 2.5 years. In addition, an interim analysis of clinical study 270-301, an ongoing phase 3 study 
designed to assess the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg, demonstrated
FVIII activity levels that were also well above 15 IU/dL, albeit lower than what was observed for 
the 6E13 vg/kg cohort in 270-201. 
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	

 
270-303 Amendment 1 
Page 8 
 
Proprietary and Confidential 
15 September 2020 
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: 
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects 
in 270-301; in 270-201, subjects were started on corticosteroids by Week 3 (either therapeutically, 
in response to an ALT elevation, or prophylactically), whereas in 270-301 subjects received 
corticosteroids only in response to an alanine aminotransferase (ALT) elevation. Possibly as a 
result of this difference, subjects receiving 6E13 vg/kg in 270-201 started corticosteroids at an 
earlier date in reference to the date of BMN 270 infusion, showed later advent of first ALT 
elevations, and were also less likely to experience a significant decline in FVIII activity 
concurrently with an ALT elevation when compared with subjects in 270-301 (20% of subjects in 
270-201 vs. 58% of subjects in 270-301). In 270-301, ALT elevation within the first 26 weeks was 
associated with decreased FVIII activity. Recently published data from 270-201 suggests that 
corticosteroids may have assisted in rescue or protection of FVIII levels during elevations of ALT 
and in resolution of elevated ALT levels in some subjects. 
The current study is a Phase 3b, single arm, open-label study designed to assess whether 
BMN 270, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and effectively 
improve the FVIII activity profiles and alter the clinical phenotype of hemophilia A patients with 
residual FVIII activity ≤ 1 IU/dL. 
OBJECTIVES:  
The primary efficacy objective of the study is to: 
• 
Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 
The secondary efficacy objectives of the study are to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the use of exogenous 
FVIII replacement therapy from Week 5 to Week 52 for subjects receiving prior FVIII 
prophylaxis or on use of emicizumab from Week 27 to Week 52 for subjects receiving 
prior emicizumab prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the number of 
bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to Week 
52 for subjects receiving prior FVIII prophylaxis or on use of emicizumab from Week 27 
to Week 52 for subjects receiving prior emicizumab prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on quality of life as 
measured by the Haemo-QoL-A questionnaire at Week 52 of the study compared to 
baseline 
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270-303 Amendment 1 
Page 9 
 
Proprietary and Confidential 
15 September 2020 
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 tertiary efficacy objective of the study is to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on patient-reported 
outcomes (PROs) (other than Haemo-QoL-A) at Week 52 of the study compared to 
baseline 
 The exploratory efficacy objective of the study is to: 
• 
Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 for subjects with detectable AAV5 total antibodies 
below the minimum required dilution at Screening 
The safety objectives of the study are to: 
• 
Evaluate the safety of BMN 270 with prophylactic corticosteroids during the first 52 
weeks following intravenous infusion of BMN 270 
• 
Assess the long-term safety of BMN 270 with prophylactic corticosteroids 
STUDY DESIGN AND PLAN:  
This is a Phase 3b, single arm, open-label study in hemophilia A patients with residual FVIII levels 
≤ 1 IU/dL. Subjects will be enrolled at approximately 10 sites worldwide. Subjects must have 
high-quality, well-documented historical data available concerning previous bleeding episodes and 
exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of BMN 270 as a 
single intravenous infusion in conjunction with receipt of a 19-week prophylactic corticosteroid 
regimen starting on the day of BMN 270 infusion (Figure 2). Therapeutic corticosteroids, as 
needed for ALT elevations and/or FVIII decline, will also be available post-infusion. 
 
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270-303 Amendment 1
Page 10 
Proprietary and Confidential 
15 September 2020
Figure 2:  270-303 Study Schema
In order to minimize bias in the ongoing study and to assure safe and ethical conduct of the clinical 
trial, an independent Data Monitoring Committee (DMC), consisting of experts in clinical trials, 
statistics, and hemophilia, will be convened. The DMC will have access during the trial to 
amalgamated FVIII activity levels, FVIII usage, and bleeding data and review available safety and 
efficacy (eg, FVIII activity) data during the study on an ongoing basis; they may determine, based 
on emerging data and the risk/benefit profile, that further enrollment should be paused to enable 
modification of the protocol or discontinued.  
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to Week 52). 
After the final analysis, safety and efficacy will then continue to be assessed long-term for a total 
of approximately 5 years for each subject.
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic FVIII 
replacement therapy 4 weeks following infusion of BMN 270 or if FVIII activity has consistently 
increased above 5 IU/dL, whichever is earlier. Four weeks represents the time by which 
endogenous production of FVIII following gene transfer is expected to be efficacious, based on 
prior study results. Subjects previously receiving emicizumab, given its approximate 1-month half-
life, will remain on emicizumab prophylaxis until BMN 270 infusion, with their final dose 
administered prior to Day 1. 
In subjects who experience recurring 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 or Sponsor-designated Data 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 are not attending the Q4W/Q6W visits during Years 2-5 may 
receive a scheduled monthly follow-up telephone call from the site to ask about adverse events, 
concomitant medications, and bleeding events/FVIII replacement usage.
There will be an ongoing review of individual subject safety by the Medical Monitor, and both 
safety and efficacy data by the DMC. Patients will receive prophylactic corticosteroids with 
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270-303 Amendment 1 
Page 11 
 
Proprietary and Confidential 
15 September 2020 
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: 
tapering of the dosage based upon consideration of ALT values, FVIII activity levels, and 
consultation with the Investigator and the Medical Monitor. Therapeutic oral corticosteroids may 
be initiated if a subject’s ALT values increase from baseline levels, after consultation between the 
Investigator and the Medical Monitor. 
In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at 
the Investigator’s discretion) in order to facilitate timely and appropriate clinical management 
decisions; where possible, a matched sample for testing at the central laboratory should be 
collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. 
Additionally, any safety signal may trigger a review of the data and possible additional 
immunogenicity studies or other diagnostics deemed necessary that include an assessment of 
cellular immune responses using collected peripheral blood mononuclear cells (PBMCs). 
An optional liver biopsy will be performed (in subjects who consent to do so) at or around Week 
26, Week 52, and/or during Years 2-5 following BMN 270 infusion. Subjects who consent to the 
liver biopsy will have additional assessments, including a liver ultrasound and FibroScan, and will 
receive prophylactic FVIII prior to the procedure, as indicated in the judgment of the Investigator, 
to minimize the risk of bleeding. 
At applicable sites, certain study assessments may be performed by a mobile nursing (MN) 
professional at the patient's home or another suitable location such as their school or office (if the 
subject has given written informed consent to participate in MN visits), or at the site or approved 
lab facility as a shortened lab draw-only visit, to improve access and convenience for patients 
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 patient and the 
patient gives written informed consent to participate in MN visits, the MN network will 
communicate with the patient and the patient’s site. 
NUMBER OF SUBJECTS PLANNED:  
Approximately 20 subjects will be enrolled into the study, with at least 16 AAV5 TAb-negative 
and up to 25% AAV5 total antibodies (TAb) detectable but below the minimum required dilution. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Patients are eligible to be included in the study only if all of the following criteria apply: 
1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as 
evidenced by medical history, at the time of signing the informed consent.  
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270-303 Amendment 1 
Page 12 
 
Proprietary and Confidential 
15 September 2020 
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: 
2. Must have been on prophylactic hemophilia therapy for at least 12 months prior to study 
entry. High-quality, well-documented historical data concerning bleeding episodes and 
hemophilia therapy usage over the previous 12 months must be available. 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs). 
4. Willing and able to provide written, signed informed consent after the nature of the study 
has been explained and prior to any study-related procedures. 
5. No previous documented history of a detectable FVIII inhibitor, and results from a 
Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda 
Units (BU) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff 
for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart 
within the past 12 months (at least one of which should be tested at the central laboratory). 
6. Sexually active participants must agree to use an acceptable method of effective 
contraception, either double-barrier contraception (ie, condom + diaphragm; or condom or 
diaphragm + spermicidal gel or foam) or their female partner either using hormonal 
contraceptives or having an intrauterine device. Participants must agree to contraception 
use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception 
use only if they have had 3 consecutive semen samples with viral vector DNA below the 
limit of detection. 
7. Willing to abstain from alcohol consumption for at least the first 52 weeks following 
BMN 270 infusion. 
Patients are excluded from the study if any of the following criteria apply: 
1. Detectable pre-existing antibodies to the AAV5 capsid. Up to 25% of subjects may have 
detectable pre-existing AAV5 capsid antibodies, so long as the detectable titer level is 
below the minimum required dilution (< 20). 
2. Any evidence of active infection, including COVID-19, or any immunosuppressive 
disorder, including HIV infection.  
3. Significant liver dysfunction with any of the following abnormal laboratory results: 
• 
ALT (alanine aminotransferase) > 1.25x upper limit of normal (ULN); 
• 
AST (aspartate aminotransferase) > 1.25x ULN; 
• 
GGT (gamma-glutamyltransferase) > 1.25x ULN; 
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270-303 Amendment 1 
Page 13 
 
Proprietary and Confidential 
15 September 2020 
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: 
• 
Total bilirubin > 1.25x ULN; 
• 
Alkaline phosphatase > 1.25x ULN; or 
• 
INR (international normalized ratio) ≥ 1.4. 
Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat 
testing of the entire liver test panel within the same Screening window and, if eligibility 
criteria are met on retest, may be enrolled after confirmation by the Medical Monitor.  
4. Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated 
on a scale of 0-4 on the Batts-Ludwig or METAVIR scoring systems, or an equivalent 
grade of fibrosis if an alternative scale is used. 
5. Evidence of any bleeding disorder not related to hemophilia 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/FibroScan. 
9. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface 
antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody 
[HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control 
(CDC) table for the interpretation of serological test results in the Laboratory Manual. 
10. Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral therapy.  
11. Active malignancy, except non-melanoma skin cancer.  
12. History of hepatic malignancy. 
13. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), 
with the exception of catheter-associated thrombosis for which anti-thrombotic treatment 
is not currently ongoing.  
14. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
15. Treatment with any investigational product within 30 days or 5 half-lives of the 
investigational product prior to the screening period. For subjects who have received a 
prior investigational product, all ongoing adverse events (AEs) experienced while 
receiving that investigational product must have resolved prior to screening for this study. 
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270-303 Amendment 1 
Page 14 
 
Proprietary and Confidential 
15 September 2020 
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: 
16. Any condition that, in the opinion of the Investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including corticosteroid 
treatment and/or the use of alternative immunosuppressive agents outlined in the protocol) 
and/or would impact or interfere with evaluation and interpretation of subject safety or 
efficacy result. 
17. Prior treatment with any vector or gene transfer agent. 
18. Major surgery planned in the 52-week period following the infusion with BMN 270. 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines 
within 30 days before the BMN 270 infusion. 
20. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of efficacy and safety of BMN 270 
and with prior consultation with the Medical Monitor. 
21. Known allergy or hypersensitivity to BMN 270 investigational product formulation. 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a 
bleeding episode. 
Optional Liver Biopsy Inclusion and Exclusion Criteria 
Individuals eligible for the optional liver biopsy must meet the following inclusion criterion: 
1. Able to sign informed consent and comply with requirements for the optional liver biopsy 
2. Documentation of FVIII activity level ≥ 50 IU/dL (or higher, depending on local 
guidelines and/or Investigator discretion) within 24 hours prior to the liver biopsy being 
performed (FVIII activity levels should be assessed at the local laboratory). Subjects may 
be treated with additional exogenous FVIII replacement products in order to increase their 
FVIII activity to an appropriate level, under the supervision/instruction of the Investigator. 
Individuals who meet any of the following exclusion criteria will not be eligible for the optional 
liver biopsy: 
1. Any condition that, in the opinion of the Investigator or a hepatologist or radiologist, 
would make liver biopsy contraindicated. This includes (but is not limited to): 
abnormalities detected on liver ultrasound performed within 28 days of procedure or prior 
liver ultrasound result within 90 days that would preclude safe performance of the biopsy. 
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270-303 Amendment 1 
Page 15 
 
Proprietary and Confidential 
15 September 2020 
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: 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single intravenous infusion of BMN 270 at 6E13 vg/kg. The volume of 
infusion will depend on the subject’s weight 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
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: 
Efficacy:  
Primary efficacy endpoint: 
• 
Change of the hFVIII activity, as measured by chromogenic substrate assay, during 
Weeks 49-52 post-BMN 270 infusion from baseline. Each subject’s hFVIII activity during 
Weeks 49-52 is defined as the median of the values obtained during this 4-week window. 
Values for hFVIII activity will be excluded if obtained within 72 hours since the last 
infusion of exogenous FVIII protein concentrates. 
Secondary efficacy endpoints:  
• 
Change from baseline in the annualized utilization (IU/kg/year) and infusion rate 
(number/year) of exogenous FVIII replacement therapy during Week 5 to Week 52 post-
BMN 270 infusion, for subjects receiving FVIII prophylaxis during the 12 months prior to 
study entry or change from baseline in the annualized utilization (mg/kg/year) of 
emicizumab during Week 27 to Week 52 post-BMN 270 infusion for subjects receiving 
prior emicizumab prophylaxis. 
• 
Change from baseline in the annualized number of bleeding episodes requiring exogenous 
FVIII replacement treatment (annualized bleeding rate, ABR) during Week 5 to Week 52 
post-BMN 270 infusion for subjects receiving prior FVIII prophylaxis, or Week 27 to 
Week 52 post-BMN 270 infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the total score of Haemo-QoL-A at Week 52 post-BMN 270 
infusion 
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270-303 Amendment 1 
Page 16 
 
Proprietary and Confidential 
15 September 2020 
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: 
Tertiary efficacy endpoints:  
• 
Change from baseline in the EQ-5D-5L score at Week 52 post-BMN 270 infusion. 
• 
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 52 post-
BMN 270 infusion. 
• 
Change from baseline in Patient Reported Outcomes, Burdens, and Experiences (PROBE) 
score at Week 52 post-BMN 270 infusion. 
Safety: 
The following safety outcome measurements will be assessed: 
• 
Incidence of adverse events (AEs) and serious AEs (SAEs) 
• 
Change in clinical laboratory tests (serum chemistry and hematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding (blood, urine, semen, stool, saliva) 
• 
Liver tests (LTs, including ALT, AST, GGT, lactate dehydrogenase [LDH], total bilirubin, 
and alkaline phosphatase) 
o 
The frequency and duration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator, review of subject data, 
and/or by independent DMC feedback. 
• 
Immune response to FVIII transgene product and AAV5 capsid proteins 
• 
Immunological assessments, including hFVIII TAb, interferon gamma (IFNg) ELISpot, 
complement, and an exploratory biomarker panel. 
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Pharmacodynamics: 
The FVIII protein concentration and activity level as measured by a validated immunoassay and a 
validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and 
activity will be used to determine PD parameters. 
 
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270-303 Amendment 1 
Page 17 
 
Proprietary and Confidential 
15 September 2020 
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:  
Sample Size 
Approximately 20 subjects may be dosed in the study, including at least 16 subjects who are 
AAV5 antibody-negative and up to 25% of the total number of subjects who have an AAV5 
antibody titer that is detectable but below the minimum required dilution at Screening.   
For the primary endpoint, a sample size of 16 will provide 85% power to demonstrate that the 
change in hFVIII activity during Weeks 49-52 from baseline is greater than 0, assuming an effect 
size of 0.8, using a one-sample t-test at the 1-sided significance level of 0.025 (or equivalently, at 
the 2-sided significance level of 0.05). The effect size of 0.8 is assumed conservatively based on 
the results from 270-201 and the interim results from 270-301. 
Analysis Population 
The intention-to-treat (ITT) population is defined as all subjects who received BMN 270 infusion. 
The ITT population will be the primary population for safety analyses, as well as being used for 
supportive efficacy analyses. 
The modified intention-to-treat (mITT) population is the primary analysis population for efficacy 
for this study. The mITT population will include all subjects who received BMN 270 infusion and 
who were AAV5 antibody negative at Screening (ie, excludes subjects with an AAV5 antibody 
titer detectable but below the minimum required dilution). 
Subjects with an AAV5 antibody titer detectable but below the minimum required dilution will be 
used for exploratory efficacy analysis on FVIII activity, as measured by chromogenic substrate 
assay, during Weeks 49-52 post-BMN 270 infusion. 
Analysis 
For the primary efficacy endpoint at Week 52 (ie, the change in the hFVIII activity during Weeks 
49-52 post-BMN 270 infusion from baseline, as measured by chromogenic substrate assay), a one-
sample t-test will be used to test the null hypothesis that the change is 0 or less against the 
alternative hypothesis that the change is greater than 0. Baseline value of 1 IU/dL (eligible subjects 
must have residual FVIII levels ≤ 1 IU/dL as evidenced by medical history) will be used in the 
calculation of change from baseline since all the subjects will be on prophylactic hemophilia 
therapy prior to BMN 270 infusion where the FVIII activity level cannot be reliably measured. 
Descriptive summaries of the proportions of subjects whose FVIII activity during Weeks 49-52 is 
greater than or equal to select thresholds, such as 5, 15, 25, 30, and 40 IU/dL, and the confidence 
intervals of the proportions will also be provided.  
The analyses of the secondary and tertiary efficacy endpoints will be descriptive. Mean and 
associated 95% confidence interval will be provided for the following secondary endpoints, where 
the baseline value will be derived from the data in the approximately 12-month period prior to 
BMN 270 infusion: 
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270-303 Amendment 1 
Page 18 
 
Proprietary and Confidential 
15 September 2020 
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: 
• 
Change from baseline in the annualized utilization (IU/kg/year) of exogenous FVIII 
replacement therapy during Weeks 5-52 post-BMN 270 infusion, for subjects receiving 
FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in 
the annualized utilization (mg/kg/year) of emicizumab during Week 27 to Week 52 
post-BMN 270 infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the annualized infusion rate (number/year) of exogenous FVIII 
replacement therapy during Weeks 5-52 post-BMN 270 infusion, for subjects receiving 
FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in 
the annualized utilization (mg/kg/year) of emicizumab during Week 27 to Week 52 
post-BMN 270 infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the annualized number of bleeding episodes (number/year) 
requiring exogenous FVIII replacement treatment during Weeks 5-52 post-BMN 270 
infusion for subjects receiving prior FVIII prophylaxis, or Weeks 27-52 post-BMN 270 
infusion for subjects receiving prior emicizumab prophylaxis from baseline 
Mean change from baseline and associated 95% confidence interval will be calculated for the total 
score of Haemo-QoL-A at Week 52 post-BMN 270 infusion as well. 
The incidence of AEs will be summarized by system organ class, preferred term, relationship to 
study drug, seriousness, and severity. Clinical laboratory test values, vital signs, vector shedding 
and immune response parameters will be summarized descriptively by visit.  
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to Week 52).  
No formal interim analysis is planned. Informal analyses (ie, no hypothesis testing) may be 
performed at different timepoints to assess efficacy and safety over time. The primary efficacy 
endpoint for such analyses involves hFVIII activity, as measured by chromogenic substrate assay, 
and is defined as median FVIII activity during a specific 4-week time interval post-BMN 270 
infusion. 
Details of the planned analyses will be specified in the SAP. 
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LIST OF TABLES 
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LIST OF FIGURES 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
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INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
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Table 9.1.1:  Schedule of Events-Screening and Infusion 
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Assessment 
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Table 9.1.2:  Schedule of Events-Post-Infusion Follow-Up (Week 1-20) 
Assessment 
Follow-Up After BMN 270 Infusion – Weeks 
1 
2f 
3f 
4 
5f 
6f 
7f 
8 
9f 
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13f 
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Assessment 
Follow-Up After BMN 270 Infusion – Weeks 
1 
2f 
3f 
4 
5f 
6f 
7f 
8 
9f 
10f 
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13f 
14f 
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21f 
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Table 9.1.5:  Schedule of Events-Optional Liver Biopsy  
 
Within 28 Days Before 
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Table 9.1.6:  Suggested Schedule of Events-Prophylactic Corticosteroids 
Assessment 
Corticosteroid Treatment Periodb 
Post-Corticosteroid 
Periodc 
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Treatments 
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Product Characteristics and Labeling 
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Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen 
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Investigational Product Accountability 
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Safety and Efficacy Variables 
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9.7.2 Primary Efficacy Variables 
9.7.2.1 
FVIII Activity 
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9.7.3.1 
Factor VIII Replacement Therapy/Bleeding Episodes 
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Table 9.7.8.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urine Tests 
Coagulation Screen 
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9.7.8.3 
Liver and Hepatitis Testing 
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Table 9.7.8.3.1:  Liver Tests 
Liver Tests (LTs) 
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Table 9.7.8.3.2: Evaluation of ALT Elevations 
ALT Level 
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Table 9.7.8.3.3:  Viral and Autoimmune Hepatitis Testing 
Viral Hepatitis Workup Testing 
Autoimmune Hepatitis Workup Testing 
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9.7.8.4 
HIV Testing 
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9.7.8.5 
Vital Signs, Physical Examinations and Other Observations Related to Safety 
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9.7.8.6 
Vector Shedding 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
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10.1.1 Adverse Events 
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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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Note: Life-threatening refers to an event in which the subject was at risk of death at
the time of the event. It does not refer to an event, which hypothetically might have
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10.2.1 Events of Special Interest (EOSI) 
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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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10.3.3.1 
Seriousness 
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Severity 
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Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale 
Grade 
Description 
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10.3.3.3 
Causality 
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Table 10.3.3.3.1:  Causality Attribution Guidance 
Relationship 
Description 
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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 
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10.4.1.3 
Abnormal Laboratory Values 
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10.4.1.4 
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10.4.1.5 
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10.4.1.6 
Hospitalization, Prolonged Hospitalization, or Surgery 
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Deaths 
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10.4.1.8 
Pregnancy 
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Reporting Requirements 
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10.7 
Post-Study Adverse Events 
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Urgent Safety Measures 
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APPROPRIATENESS OF MEASUREMENTS 
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STUDY PROCEDURES 
12.1 
Prestudy 
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12.3 
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12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
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12.5 
BMN 270 Infusion Follow-Up Visits – Weeks 1-26 
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12.8 
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12.9 
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13 
DATA QUALITY ASSURANCE 
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
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14.1.1 Interim Analyses 
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14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
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14.2 
Primary Efficacy Endpoint 
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14.3 
Secondary Efficacy Endpoints 
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14.4 
Tertiary Efficacy Endpoints 
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14.5 
Immunogenicity 
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14.6 
Pharmacodynamic Analyses 
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14.7 
Safety Analysis 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3b, Single Arm, Open-Label Study to Evaluate the 
Efficacy and Safety of BMN 270, an Adeno-Associated 
Virus Vector–Mediated Gene Transfer of Human Factor 
VIII, with Prophylactic Corticosteroids in Hemophilia A 
Patients 
Protocol Number: 
270-303 
Active Investigational Product: 
AAV5-hFVIII-SQ 
IND/European Union Drug Regulating 
Authorities Clinical Trials (EudraCT) 
Number: 
IND #: 017659 
2018-004616-21 
 
Indication: 
Hemophilia A 
Sponsor: 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Development Phase: 
Phase 3b 
Sponsor's Responsible Medical Monitor: 
 MD, MHS 
 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
Duration of Subject Participation: 
Approximately 264 weeks 
Dose: 
6E13 vg/kg  
Study Population: 
Males aged 18 or older 
Date of Original Protocol: 
28 February 2020 
Date of Amendment 1: 
15 September 2020 
Date of Amendment 2: 
25 May 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

 
270-303 Amendment 2 
Page 2 
 
Proprietary and Confidential 
25 May 2021 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY  
Amendment 2 
25 May 2021 
RATIONALE AND SUMMARY OF CHANGES 
A summary of major changes covered by Amendment 2 to the 270-303 protocol is provided 
below: 
1. Changes have been made to enhance screening for potential malignancies (including 
hepatic cancers) and establishing baseline liver health during the Screening Period. 
Rationale: The changes made include: 
• Clarifying that all patients should undergo a liver ultrasound at Screening to screen 
for clinically significant liver disease and hepatocellular carcinoma (HCC), and that a 
FibroScan can also be performed at the discretion of the Investigator; 
• Moving the fasting FibroTest from Day 1 to Screening for assessment of liver 
fibrosis. 
As no current guidelines regarding HCC screening exist for AAV gene therapy recipients, the 
Sponsor engaged experts regarding current and recommended screening for HCC prior to 
administration of gene therapy. Protocol amendments contained herein were made based 
upon expert opinion, literature review, and evaluation of best practices. 
2. 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 for Year 1 through 
Year 5 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. 
3. Malignancy (except non-melanoma skin cancer) has been added as an Event of Special 
Interest (EOSI). 

 
270-303 Amendment 2 
Page 3 
 
Proprietary and Confidential 
25 May 2021 
Rationale: The occurrence of malignancy (as above) was added as an EOSI for purposes of 
expedited safety reporting and additional safety monitoring. 
4. HIV-positive patients (serological evidence of HIV-1 or HIV-2 infection)  may now 
enroll in the study, provided their HIV infection is stable and well-controlled with an 
adequate CD4 count (>200/mm3) and an undetectable viral load, respectively, at 
Screening and they are on an antiretroviral therapy (ART) regimen that does not contain 
efavirenz or another potentially hepatotoxic ART. 
Rationale: HIV-positive subjects were initially included in prior BMN 270 studies.  
However, after an HIV-positive subject in 270-302 developed markedly elevated liver 
enzyme levels after receiving 4E13 vg/kg of BMN 270, out of an abundance of caution for 
the long-term liver health of HIV-positive patients, further enrollment of HIV-positive 
subjects was suspended in 270-301 (Protocol Amendment 3) and 270-302 (Protocol 
Amendment 3). The subject in 270-302 referenced above was receiving efavirenz and 
lamivudine as part of his ART regimen. Following discussion with a liver advisory board and 
review of the accumulated 270-301 data, efavirenz and not lamivudine has been implicated 
as the most likely medication that interacted with BMN 270 and contributed to the 270-302 
subject's elevated liver enzyme levels. Due to its hepatotoxicity, efavirenz is considered a 
prohibited medication in all BMN 270 studies. 
The two HIV-positive subjects on stable, non-efavirenz-containing ART regimens who were 
enrolled in and dosed in 270-301 study prior to Amendment 3 have been monitored closely. 
Following BMN 270 infusion, these subjects continued their ART as prescribed and followed 
routine monitoring of CD4 count and viral load. Results from 270-301 show similar safety 
results for the two HIV-positive subjects compared to those who are HIV-negative. The 
Sponsor believes that HIV infection, in and of itself, is not a contraindication to receive 
BMN 270 and has therefore removed the exclusion of HIV-positive subjects, as long as they 
are not receiving efavirenz or other potentially hepatotoxic ART in their HIV treatment 
regimen. 
5. Language has been added concerning the use of the SARS-CoV-2 vaccines. 
Rationale: Due to the 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.  
6. The reactive corticosteroid regimen for ALT elevation has been updated. 

 
270-303 Amendment 2 
Page 4 
 
Proprietary and Confidential 
25 May 2021 
Rationale: The guidance for the reactive corticosteroid regimen, including management of 
ALT elevations and corticosteroid taper, reflects the data gathered from previous BMN 270 
studies. This change attempts to promote the safe and effective use of reactive 
corticosteroids. 
7. Thrombin generation assay (TGA) assessment has been removed. 
Rationale: Assessment of TGA in other studies in the BMN 270 development program has 
provided sufficient data; additional assessments are not expected to be needed. Removing 
this assessment helps to alleviate patient and site burden. If TGA assessments from 270-303 
are needed in the future, backup aliquots from other platelet-poor plasma samples can be 
utilized. 
8. Frequency of testing of FVIII antigen BDD Assay (hFVIII protein assay) has been 
decreased. 
Rationale: Assessment of the hFVIII protein assay in other studies in the BMN 270 
development program will provide robust characterization of transgene specific activity (ie, 
ratio of FVIII coagulation activity to FVIII protein expression). As subjects enrolled in this 
study are not expected to have different hFVIII specific activity findings, reducing the 
number of these assessments is acceptable and helps alleviate patient and site burden. 
9. AAV5 transduction inhibition (TI) assessment after Year 1 has been modified. AAV5 TI 
will be assessed through Year 1, then again at the end of the study (either the End of Year 
visit for Year 5, or the Early Termination Visit as applicable). 
Rationale: The most significant information from this assessment is obtained from baseline 
and samples collected shortly after dosing. As the TI remains high after dosing, there is no 
need to continue to track frequently more than a year after infusion. 
10. Timepoints for exploratory assessment of Grp78 have been limited to Screening, 
Baseline, and at the time of a liver biopsy. 
Rationale: Longitudinal measurement of Grp78 from an exploratory study testing whether 
levels of plasma Grp78 correlate with FVIII activity or ALT rise in plasma have not revealed 
significant correlations. 
11. The timeframe for assessment of secondary efficacy endpoints concerning annualized 
bleeding rate (ABR) and exogenous FVIII utilization has been changed from Week 5-52 
post-infusion to Week 5 to last visit by data cutoff, to align with a similar change made 
for Study 270-301. 
12. Additional minor changes have been made for consistency and clarity. 
Refer to Section 25 for a summary of revisions to Amendment 1 (dated 15 September 2020). 

 
270-303 Amendment 2 
Page 5 
 
Proprietary and Confidential 
25 May 2021 
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 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and Safety of BMN 270, an 
Adeno-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII, with Prophylactic 
Corticosteroids in Hemophilia A Patients 
PROTOCOL NUMBER: 
270-303 
STUDY SITES: 
Approximately 15 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 3b 
STUDY RATIONALE: 
Hemophilia 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 pathway. This disorder can be either inherited, due to 
a genetic aberrancy, 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 generally correlates tightly with the level of residual expression. 
Severe HA is classified as FVIII activity less than 1% of normal (< 1 IU/dL), moderate disease 
comprises 1-5% of normal activity and the mild form is 5-40% activity. The clinical manifestations 
of severe HA are frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, 
with a substantially increased risk of death from hemorrhage when the brain is involved. Subjects 
with moderate disease can exhibit manifestations similar to those seen in patients with severe HA, 
resulting in a comparable bleeding phenotype.  
Treatment of severe HA includes 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 and/or subcutaneous injection of a 
bi-specific monoclonal antibody, emicizumab, as prophylaxis 1-4 times per month. 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 prophylactic therapy (median annualized bleeding rate [ABR] of 
1-4 with prophylaxis treatment in a recently published retrospective observational study and 
between 1-2 in 6 prospective FVIII interventional studies) and on-demand-only therapy (median 
ABR of 4.5-18 in a recently published retrospective study and between 20-60 in 6 prospective 

 
270-303 Amendment 2 
Page 6 
 
Proprietary and Confidential 
25 May 2021 
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 interventional studies). The consequence of multiple bleeding events is the development of 
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 a 1% trough for a greater 
proportion of the dosing interval. However, patients with severe HA who are treated with extended 
half-life FVIII remain dependent on multiple infusions to maintain critical levels of FVIII activity. 
While emicizumab prophylaxis has yielded lower bleed rates compared to prior FVIII prophylaxis, 
it does not physiologically recapitulate the coagulation system, requires chronic, life-long therapy, 
and still necessitates the use of episodic FVIII concentrates for treatment of breakthrough bleeds. 
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 hemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous infusion of a vector encoding the 
appropriate gene sequence for long-term episomal expression. HA 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 even 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 hemophilia A. Thus, relatively small changes in endogenous FVIII activity can 
result in clinically relevant improvements in disease phenotype. Finally, the circulating FVIII 
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 and 
promoter specificity for specific tissues, such as the liver (for serotypes 2, 5 and 8 among others). 
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
that stable (median follow-up of 6.7 years) expression of human factor IX (hFIX) at levels that are 
sufficient for conversion of their bleeding phenotype from severe to moderate or mild is achievable 
following a single peripheral vein infusion of AAV8-hFIX vector. Several participants in this trial 
have been able to discontinue factor prophylaxis without suffering spontaneous hemorrhages, 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 hybrid human liver-specific promoter (Figure 1). 
 

 
270-303 Amendment 2 
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Proprietary and Confidential 
25 May 2021 
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 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 a single intravenous dose and is designed to achieve durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.  
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose 
escalation study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 
at various dose levels (6E12 vector genomes [vg]/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. Additional 
studies have been undertaken at the 6E13 vg/kg dose (270-301 in subjects with severe HA, and 
270-203 in subjects with severe HA who are also AAV5-antibody positive). 
Four-year results from 270-201 and one-year results from 270-301 have demonstrated that 
following gene transfer, mean and median FVIII activity levels above 15% (15 IU/dL), as 
measured by a chromogenic substrate assay, are achievable and sustained following a single 
infusion of 6E13 vg/kg of BMN 270, with an acceptable safety profile. Preliminary results from 
optional liver biopsies (in subjects receiving lower doses of BMN 270 in 270-201) confirm dose-
dependent pan-lobular and otherwise healthy liver transduction at 2.7-4.1 years.  
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects 
in 270-301; in 270-201, subjects were scheduled to start corticosteroids by Week 3 (either before 
Week 3, in response to an alanine aminotransferase (ALT) elevation, or at Week 3 otherwise, per 

 
270-303 Amendment 2 
Page 8 
 
Proprietary and Confidential 
25 May 2021 
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: 
protocol), whereas in 270-301 subjects received corticosteroids only in response to an ALT 
elevation. Possibly as a result of this difference, subjects receiving 6E13 vg/kg in 270-201 started 
corticosteroids at an earlier date in reference to the date of BMN 270 infusion and showed later 
onset of first ALT elevations when compared with subjects in 270-301. Recently published data 
from 270-201 and recent analysis of 270-301 data suggest that corticosteroids may have assisted in 
rescue or protection of FVIII activity levels during elevations of ALT and in resolution of elevated 
ALT levels in some subjects. 
The current study is a Phase 3b, single arm, open-label study designed to assess whether 
BMN 270, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and effectively 
improve the FVIII activity profiles and alter the clinical phenotype of hemophilia A patients with 
residual FVIII activity ≤ 1 IU/dL. 
OBJECTIVES:  
The primary efficacy objective of the study is to: 
• 
Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 
The secondary efficacy objectives of the study are to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the use of exogenous 
FVIII replacement therapy from Week 5 to last visit by data cutoff (for Week 52 analysis) 
for subjects receiving prior FVIII prophylaxis or on use of emicizumab from Week 27 to 
last visit by data cutoff (for Week 52 analysis) for subjects receiving prior emicizumab 
prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the number of 
bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to last 
visit by data cutoff (for Week 52 analysis) for subjects receiving prior FVIII prophylaxis or 
on use of emicizumab from Week 27 to last visit by data cutoff (for Week 52 analysis) for 
subjects receiving prior emicizumab prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on quality of life as 
measured by the Haemo-QoL-A questionnaire at Week 52 of the study compared to 
baseline 
The tertiary efficacy objective of the study is to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on patient-reported 
outcomes (PROs) (other than Haemo-QoL-A) at Week 52 of the study compared to 
baseline 

 
270-303 Amendment 2 
Page 9 
 
Proprietary and Confidential 
25 May 2021 
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 exploratory efficacy objective of the study is to: 
• 
Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 for subjects with detectable AAV5 total antibodies 
below the minimum required dilution at Screening 
The safety objectives of the study are to: 
• 
Evaluate the short-term safety of BMN 270 with prophylactic corticosteroids following 
intravenous infusion of BMN 270 
• 
Assess the long-term safety of BMN 270 with prophylactic corticosteroids 
STUDY DESIGN AND PLAN:  
This is a Phase 3b, single arm, open-label study in hemophilia A patients with residual FVIII levels 
≤ 1 IU/dL. Subjects will be enrolled at approximately 15 sites worldwide. Subjects must have high-
quality, well-documented historical data available concerning previous bleeding episodes and 
exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of BMN 270 as a 
single intravenous infusion in conjunction with receipt of a 19-week prophylactic corticosteroid 
regimen starting on the day of BMN 270 infusion (Figure 2). Reactive corticosteroids, as needed 
for ALT elevations, will also be utilized post-infusion. 
Figure 2:  270-303 Study Schema  
 

 
270-303 Amendment 2 
Page 10 
 
Proprietary and Confidential 
25 May 2021 
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: 
 
In order to minimize bias in the ongoing study and to assure safe and ethical conduct of the clinical 
trial, an independent Data Monitoring Committee (DMC), consisting of experts in clinical trials, 
statistics, and hemophilia, will be convened. The DMC will have access during the trial to 
amalgamated FVIII activity levels, FVIII usage, and bleeding data and review available safety and 
efficacy (eg, FVIII activity) data during the study on an ongoing basis; they may determine, based 
on emerging data and the risk/benefit profile, that further enrollment should be paused to enable 
modification of the protocol or discontinued.  
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to Week 52). 
After the final analysis, safety and efficacy will then continue to be assessed long-term for a total 
of approximately 5 years for each subject. 
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic FVIII 
replacement therapy 4 weeks following infusion of BMN 270 or if FVIII activity has consistently 
increased above 5 IU/dL, whichever is earlier. Four weeks represents the time by which 
endogenous production of FVIII following gene transfer is expected to be efficacious, based on 
prior study results. Subjects previously receiving emicizumab, given its approximate 1-month half-
life, will remain on emicizumab prophylaxis until BMN 270 infusion, with their final dose 
administered prior to Day 1. 
In subjects who experience recurring 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 ≥ 5 IU/dL 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 or Sponsor-designated Data 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 are not attending the Q4W/Q6W visits during Years 2-5 may 
receive a scheduled monthly follow-up telephone call from the site to ask about adverse events, 
concomitant medications, and bleeding events/FVIII replacement usage. 
There will be an ongoing review of individual subject safety by the Medical Monitor, and both 
safety and efficacy data by the DMC. Patients will receive prophylactic corticosteroids with 
tapering of the dosage based upon consideration of ALT values and if needed, consultation with 
the Investigator and the Medical Monitor. Reactive oral corticosteroids may be initiated if a 
subject’s ALT values increase from baseline levels, after consultation between the Investigator and 
the Medical Monitor. 
In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at 
the Investigator’s discretion) in order to facilitate timely and appropriate clinical management 

 
270-303 Amendment 2 
Page 11 
 
Proprietary and Confidential 
25 May 2021 
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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decisions; where possible, a matched sample for testing at the central laboratory should be 
collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. 
Additionally, any safety signal may trigger a review of the data and possible additional 
immunogenicity studies or other diagnostics deemed necessary that include an assessment of 
cellular immune responses using collected peripheral blood mononuclear cells (PBMCs). 
An optional liver biopsy will be performed (in subjects who consent to do so) at or around Week 
26, Week 52, and/or during Years 2-5 following BMN 270 infusion. Subjects who consent to the 
liver biopsy will have additional assessments, including a liver ultrasound and FibroScan, and will 
receive prophylactic FVIII prior to the procedure, as indicated in the judgment of the Investigator, 
to minimize the risk of bleeding. 
At applicable sites, certain study assessments may be performed by a mobile nursing (MN) 
professional at the patient's home or another suitable location such as their school or office (if the 
subject has given written informed consent to participate in MN visits), or at the site or approved 
lab facility as a shortened lab draw-only visit, to improve access and convenience for patients 
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 patient and the 
patient gives written informed consent to participate in MN visits, the MN network will 
communicate with the patient and the patient’s site. 
NUMBER OF SUBJECTS PLANNED:  
Approximately 20 subjects will be enrolled into the study, with at least 16 AAV5 TAb-negative 
and up to 25% AAV5 total antibodies (TAb) detectable but below the minimum required dilution. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Patients are eligible to be included in the study only if all of the following criteria apply: 
1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as 
evidenced by medical history, at the time of signing the informed consent.  
2. Must have been on prophylactic hemophilia therapy for at least 12 months prior to study 
entry. High-quality, well-documented historical data concerning bleeding episodes and 
hemophilia therapy usage over the previous 12 months must be available. 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure 
days (EDs). 

 
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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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4. Willing and able to provide written, signed informed consent after the nature of the study 
has been explained and prior to any study-related procedures. 
5. No previous documented history of a detectable FVIII inhibitor, and results from a 
Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda 
Units (BU) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff 
for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart 
within the past 12 months (at least one of which should be tested at the central laboratory). 
6. Sexually active participants must agree to use an acceptable method of effective 
contraception, either double-barrier contraception (ie, condom + diaphragm; or condom or 
diaphragm + spermicidal gel or foam) or their female partner either using hormonal 
contraceptives or having an intrauterine device. Participants must agree to contraception 
use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception 
use only if they have had 3 consecutive semen samples with viral vector DNA below the 
limit of detection. 
7. Willing to abstain from alcohol consumption for at least the first 52 weeks following 
BMN 270 infusion. 
Patients are excluded from the study if any of the following criteria apply: 
1. Subjects with detectable pre-existing antibodies to the AAV5 capsid are excluded with the 
following exception: up to 25% of subjects may have detectable pre-existing AAV5 capsid 
antibodies with titer level below the minimum required dilution (< 20).  
2. Any evidence of active infection, including COVID-19, or any immunosuppressive 
disorder, except for HIV infection. HIV-positive patients who meet all other eligibility 
criteria may be included if they have a CD4 count > 200/mm3 and an undetectable viral 
load (unquantifiable viral load as defined as less than the limit of quantification by the 
testing laboratory’s assay is permitted) while receiving an antiretroviral therapy (ART) 
regimen that does not contain efavirenz or another potentially hepatotoxic ART.  
3. Significant liver dysfunction with any of the following abnormal laboratory results: 
• 
ALT (alanine aminotransferase) > 1.25x upper limit of normal (ULN); 
• 
AST (aspartate aminotransferase) > 1.25x ULN; 
• 
GGT (gamma-glutamyltransferase) > 1.25x ULN; 
• 
Total bilirubin > 1.25x ULN; 

 
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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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• 
Alkaline phosphatase > 1.25x ULN; or 
• 
INR (international normalized ratio) ≥ 1.4. 
Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat 
testing of the entire liver test panel within the same Screening window and, if eligibility 
criteria are met on retest, may be enrolled after confirmation by the Medical Monitor.  
4. Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated 
on a scale of 0-4 on the Batts-Ludwig or METAVIR scoring systems, or an equivalent 
grade of fibrosis if an alternative scale is used. 
5. Evidence of any bleeding disorder not related to hemophilia A. 
6. Platelet count of < 100 x 109/L. 
7. Creatinine ≥ 1.5 mg/dL. 
8. Liver cirrhosis or other clinically significant liver disease of any etiology as assessed by 
liver ultrasound/FibroScan. 
9. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface 
antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody 
[HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control 
(CDC) table for the interpretation of serological test results in the Laboratory Manual. 
10. Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral therapy.  
11. Active malignancy, except non-melanoma skin cancer.  
12. History of hepatic malignancy. 
13. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), 
with the exception of catheter-associated thrombosis for which anti-thrombotic treatment is 
not currently ongoing.  
14. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
15. Treatment with any investigational product within 30 days or 5 half-lives of the 
investigational product prior to the screening period. For subjects who have received a 
prior investigational product, all ongoing adverse events (AEs) experienced while 
receiving that investigational product must have resolved prior to screening for this 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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16. Any condition that, in the opinion of the Investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including corticosteroid 
treatment and/or the use of alternative immunosuppressive agents outlined in the protocol) 
and/or would impact or interfere with evaluation and interpretation of subject safety or 
efficacy result. 
17. Prior treatment with any vector or gene transfer agent. 
18. Major surgery planned in the 52-week period following the infusion with BMN 270. 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines 
within 30 days before the BMN 270 infusion. 
20. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of efficacy and safety of BMN 270 
and with prior consultation with the Medical Monitor. 
21. Known allergy or hypersensitivity to BMN 270 investigational product formulation. 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a 
bleeding episode. 
Optional Liver Biopsy Inclusion and Exclusion Criteria 
Individuals eligible for the optional liver biopsy must meet the following inclusion criterion: 
1. Able to sign informed consent and comply with requirements for the optional liver biopsy 
2. Documentation of FVIII activity level ≥ 50 IU/dL (or higher, depending on local 
guidelines and/or Investigator discretion) within 24 hours prior to the liver biopsy being 
performed (FVIII activity levels should be assessed at the local laboratory). Subjects may 
be treated with additional exogenous FVIII replacement products in order to increase their 
FVIII activity to an appropriate level, under the supervision/instruction of the Investigator. 
Individuals who meet any of the following exclusion criteria will not be eligible for the optional 
liver biopsy: 
1. Any condition that, in the opinion of the Investigator or a hepatologist or radiologist, 
would make liver biopsy contraindicated. This includes (but is not limited to): 
abnormalities detected on liver ultrasound performed within 28 days of procedure or prior 
liver ultrasound result within 90 days that would preclude safe performance of the biopsy. 

 
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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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INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single intravenous infusion of BMN 270 at 6E13 vg/kg. The volume of 
infusion will depend on the subject’s weight 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
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: 
Efficacy:  
Primary efficacy endpoint: 
• 
Change of the hFVIII activity, as measured by chromogenic substrate assay, during 
Weeks 49-52 post-BMN 270 infusion from baseline. Each subject’s hFVIII activity during 
Weeks 49-52 is defined as the median of the values obtained during this 4-week window. 
Values for hFVIII activity will be excluded if obtained within 72 hours since the last 
infusion of exogenous FVIII protein concentrates. 
Secondary efficacy endpoints:  
• 
Change from baseline in the annualized utilization (IU/kg/year) and infusion rate 
(number/year) of exogenous FVIII replacement therapy from Week 5 post-BMN 270 
infusion to last visit by data cutoff (for Week 52 analysis) for subjects receiving FVIII 
prophylaxis during the 12 months prior to study entry, or change from baseline in the 
annualized utilization (mg/kg/year) of emicizumab from Week 27 post-BMN 270 infusion 
to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior emicizumab 
prophylaxis. 
• 
Change from baseline in the annualized number of bleeding episodes requiring exogenous 
FVIII replacement treatment (annualized bleeding rate, ABR) from Week 5 post-BMN 270 
infusion to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior 
FVIII prophylaxis, or from Week 27 post-BMN 270 infusion to last visit by data cutoff 
(for Week 52 analysis) for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the total score of Haemo-QoL-A at Week 52 post-BMN 270 
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 
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Tertiary efficacy endpoints:  
• 
Change from baseline in the EQ-5D-5L score at Week 52 post-BMN 270 infusion. 
• 
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 52 post-
BMN 270 infusion. 
• 
Change from baseline in Patient Reported Outcomes, Burdens, and Experiences (PROBE) 
score at Week 52 post-BMN 270 infusion. 
Safety: 
The following safety outcome measurements will be assessed: 
• 
Incidence of adverse events (AEs) and serious AEs (SAEs) 
• 
Change in clinical laboratory tests (serum chemistry and hematology) 
• 
Change in vital signs 
• 
Change in physical examination  
• 
Vector shedding (blood, urine, semen, stool, saliva) 
• 
Liver tests (LTs, including ALT, AST, GGT, lactate dehydrogenase [LDH], total bilirubin, 
and alkaline phosphatase) 
o The frequency and duration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator, review of subject data, 
and/or by independent DMC feedback. 
• 
Immune response to FVIII transgene product and AAV5 capsid proteins 
• 
Immunological assessments, including hFVIII TAb, interferon gamma (IFNg) ELISpot, 
complement, and an exploratory biomarker panel. 
There will be a detailed assessment of cellular and humoral responses to AAV5 capsid and FVIII 
protein.  
Pharmacodynamics: 
The FVIII protein concentration and activity level as measured by a validated immunoassay and a 
validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and 
activity will be used to determine PD parameters. 
 

 
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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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STATISTICAL METHODS:  
Sample Size 
Approximately 20 subjects may be dosed in the study, including at least 16 subjects who are 
AAV5 antibody-negative and up to 25% of the total number of subjects with an AAV5 antibody 
titer that is detectable but below the minimum required dilution (<20) at Screening.   
For the primary endpoint, a sample size of 16 will provide 85% power to demonstrate that the 
change in hFVIII activity during Weeks 49-52 from baseline is greater than 0, assuming an effect 
size of 0.8, using a one-sample t-test at the 1-sided significance level of 0.025 (or equivalently, at 
the 2-sided significance level of 0.05). The effect size of 0.8 is assumed conservatively based on 
the results from 270-201 and the interim results from 270-301. 
Analysis Population 
The intention-to-treat (ITT) population is defined as all subjects who received BMN 270 infusion. 
The ITT population will be the primary population for safety analyses, as well as being used for 
supportive efficacy analyses. 
The modified intention-to-treat (mITT) population is the primary analysis population for efficacy 
for this study. The mITT population will include all subjects who received BMN 270 infusion and 
who were AAV5 antibody negative at Screening (ie, excludes subjects with an AAV5 antibody 
titer detectable but below the minimum required dilution). 
Subjects with an AAV5 antibody titer detectable but below the minimum required dilution will be 
used for exploratory efficacy analysis on FVIII activity, as measured by chromogenic substrate 
assay, during Weeks 49-52 post-BMN 270 infusion. 
Analysis 
For the primary efficacy endpoint at Week 52 (ie, the change in the hFVIII activity during Weeks 
49-52 post-BMN 270 infusion from baseline, as measured by chromogenic substrate assay), a one-
sample t-test will be used to test the null hypothesis that the change is 0 or less against the 
alternative hypothesis that the change is greater than 0. Baseline value of 1 IU/dL (eligible subjects 
must have residual FVIII levels ≤ 1 IU/dL as evidenced by medical history) will be used in the 
calculation of change from baseline since all the subjects will be on prophylactic hemophilia 
therapy prior to BMN 270 infusion where the FVIII activity level cannot be reliably measured. 
Descriptive summaries of the proportions of subjects whose FVIII activity during Weeks 49-52 is 
greater than or equal to select thresholds, such as 5, 15, 25, 30, and 40 IU/dL, and the confidence 
intervals of the proportions will also be provided.  
The analyses of the secondary and tertiary efficacy endpoints will be descriptive. Mean and 
associated 95% confidence interval will be provided for the following secondary endpoints, where 
the baseline value will be derived from the data in the approximately 12-month period prior to 
BMN 270 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 
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Volume:  
 
Page:  
 
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• 
For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in the 
annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy from Week 5 
post BMN 270 infusion to last visit by data cutoff (for Week 52 analysis); and separately, 
for subjects receiving prior emicizumab prophylaxis, change from baseline in the 
annualized utilization (mg/kg/year) of emicizumab from Week 27 post BMN 270 infusion 
to last visit by data cutoff (for Week 52 analysis)  
• 
For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in the 
annualized infusion rate (number/year) of exogenous FVIII replacement therapy from 
Week 5 post BMN 270 infusion to last visit by data cutoff (for Week 52 analysis); and 
separately for subjects receiving prior emicizumab prophylaxis, change from baseline in 
the annualized utilization (mg/kg/year) of emicizumab from Week 27 post BMN 270 to 
last visit by data cutoff (for Week 52 analysis) infusion 
• 
Change from baseline in the annualized number of bleeding episodes (number/year) 
requiring exogenous FVIII replacement treatment from Week 5 post-BMN 270 infusion to 
last visit by data cutoff (for Week 52 analysis) for subjects receiving prior FVIII 
prophylaxis, or from Week 27 post-BMN 270 infusion to last visit by data cutoff (for 
Week 52 analysis) for subjects receiving prior emicizumab prophylaxis from baseline 
Mean change from baseline and associated 95% confidence interval will be calculated for the total 
score of Haemo-QoL-A at Week 52 post-BMN 270 infusion as well. 
The incidence of AEs will be summarized by system organ class, preferred term, relationship to 
study drug, seriousness, and severity. Clinical laboratory test values, vital signs, vector shedding 
and immune response parameters will be summarized descriptively by visit.  
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to Week 52).  
No formal interim analysis is planned. Informal analyses (ie, no hypothesis testing) may be 
performed at different timepoints to assess efficacy and safety over time. The primary efficacy 
endpoint for such analyses involves hFVIII activity, as measured by chromogenic substrate assay, 
and is defined as median FVIII activity during a specific 4-week time interval post-BMN 270 
infusion. 
Details of the planned analyses will be specified in the SAP. 

 
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3 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2 
2 SYNOPSIS ...........................................................................................................................5 
3 TABLE OF CONTENTS ...................................................................................................19 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................25 
5 ETHICS..............................................................................................................................28 
5.1 Institutional Review Board or Independent Ethics Committee ................................28 
5.2 Ethical Conduct of Study ..........................................................................................28 
5.3 Subject Information and Informed Consent ..............................................................29 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................30 
7 INTRODUCTION .............................................................................................................31 
7.1 Nonclinical Studies ...................................................................................................31 
7.2 Previous Clinical Studies ..........................................................................................32 
7.3 Study Rationale .........................................................................................................32 
7.3.1 
Optional Liver Biopsy Rationale .................................................................35 
7.4 Summary of Overall Risks and Benefits ...................................................................36 
7.4.1 
Optional Liver Biopsy Risks and Benefits ..................................................38 
8 STUDY OBJECTIVES ......................................................................................................40 
9 INVESTIGATIONAL PLAN ............................................................................................41 
9.1 Overall Study Design and Plan .................................................................................41 
9.2 Discussion of Study Design ......................................................................................59 
9.3 Selection of Study Population ...................................................................................59 
9.3.1 
Inclusion Criteria .........................................................................................59 
9.3.2 
Exclusion Criteria ........................................................................................60 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................62 
9.3.4 
Subject Identification and Replacement of Subjects ...................................65 
9.3.5 
Duration of Subject Participation ................................................................65 
9.4 Treatments .................................................................................................................65 
9.4.1 
Treatments Administered ............................................................................65 
9.4.2 
Identity of Investigational Product ..............................................................65 

 
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9.4.3 
Storage .........................................................................................................65 
9.4.4 
Directions for Administration .....................................................................65 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................67 
9.4.6 
Selection of Dose Used in the Study ...........................................................68 
9.4.7 
Blinding .......................................................................................................68 
9.4.8 
Prior and Concomitant Medications ............................................................68 
9.4.9 
Treatment Compliance ................................................................................75 
9.5 Investigational Product Accountability .....................................................................75 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................75 
9.6 Dietary or Other Protocol Restrictions......................................................................75 
9.7 Safety and Efficacy Variables ...................................................................................76 
9.7.1 
Safety and Efficacy Measurements Assessed .............................................76 
9.7.2 
Primary Efficacy Variables .........................................................................76 
9.7.3 
Secondary Efficacy Variables .....................................................................76 
9.7.4 
Immunogenicity ...........................................................................................78 
9.7.5 
Pharmacodynamics ......................................................................................78 
9.7.6 
Pharmacokinetics .........................................................................................78 
9.7.7 
Exploratory Assessments ............................................................................78 
9.7.8 
Safety Variables ..........................................................................................80 
10 REPORTING ADVERSE EVENTS .................................................................................87 
10.1 Safety Parameters and Definitions ............................................................................87 
10.1.1 Adverse Events ............................................................................................87 
10.2 Serious Adverse Events ............................................................................................88 
10.2.1 Events of Special Interest (EOSI) ...............................................................89 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................89 
10.3.1 Adverse Event Reporting Period .................................................................89 
10.3.2 Eliciting Adverse Events .............................................................................89 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................89 
10.4 Procedures for Recording Adverse Events ...............................................................92 
10.4.1 Recording Adverse Events on a eCRF ........................................................92 

 
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10.5 Reporting Requirements ...........................................................................................95 
10.5.1 Expedited Reporting Requirements .............................................................95 
10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements..............................................................................96 
10.6 Follow-up of Subjects after Adverse Events .............................................................96 
10.7 Post-Study Adverse Events .......................................................................................96 
10.8 Urgent Safety Measures ............................................................................................97 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................98 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................99 
12 STUDY PROCEDURES .................................................................................................100 
12.1 Prestudy ...................................................................................................................100 
12.2 Screening Visit ........................................................................................................100 
12.2.1 “Smart Rescreening” Visit ........................................................................102 
12.3 Baseline Visit ..........................................................................................................103 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ..................................................104 
12.5 BMN 270 Infusion Follow-Up Visits – Weeks 1-26 ..............................................105 
12.5.1 Once per week (Weeks 1 through 26) .......................................................105 
12.5.2 Week 1 - Day 8 ..........................................................................................106 
12.5.3 Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26 ..............................................106 
12.5.4 Weeks 2, 4, 8, 12, 16, 20, 24, and 26 ........................................................106 
12.5.5 Weeks 2, 6, 10, 14, 18, 22, 24, and 26 ......................................................106 
12.5.6 Weeks 4, 8, 12, 16, 20, 24, and 26 ............................................................106 
12.5.7 Weeks 4, 8, 12, 16, 18, 20, 22, 24, and 26 ................................................107 
12.5.8 Weeks 4, 8, 16, and 26 ..............................................................................107 
12.5.9 Weeks 4, 8, 12, 18, 22, and 26 ..................................................................107 
12.5.10 Week 4, 12, and 26 ....................................................................................107 
12.5.11 Weeks 4, 16, and 26 ..................................................................................107 
12.5.12 Weeks 12 and 26 .......................................................................................108 
12.5.13 Weeks 6 and 20 .........................................................................................108 
12.5.14 Week 26 .....................................................................................................108 
12.6 Post-Infusion Follow-Up – Weeks 27-52 ...............................................................108 

 
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12.6.1 Each Visit (Weeks 28, 30, 32, 34, 36, 40, 44, 48, 50, and 52) ..................108 
12.6.2 Weeks 28, 32, 36, 40, 44, 48, and 52 ........................................................109 
12.6.3 Week 28, 36, 44, and 52 ............................................................................109 
12.6.4 Week 32 .....................................................................................................109 
12.6.5 Weeks 32, 36, 40, 44, 48, and 52 ..............................................................109 
12.6.6 Weeks 32, 36, 44, and 52 ..........................................................................109 
12.6.7 Week 36 and 52 .........................................................................................110 
12.6.8 Week 52 .....................................................................................................110 
12.6.9 Week 52 .....................................................................................................110 
12.7 Post-Infusion Follow-Up – Years 2-5 .....................................................................110 
12.7.1 Year 2 (Every 4 Weeks) or Years 3-5 (Every 6 Weeks) (not 
required for treatment failure subjects) .....................................................111 
12.7.2 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)................................................................................................112 
12.8 Early Termination Visit ..........................................................................................114 
12.9 Optional Liver Biopsy .............................................................................................115 
12.10 End of Study ...........................................................................................................116 
13 DATA QUALITY ASSURANCE ...................................................................................117 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................118 
14.1 Statistical and Analytical Plans ...............................................................................118 
14.1.1 Interim Analyses ........................................................................................118 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........118 
14.2 Primary Efficacy Endpoint......................................................................................118 
14.3 Secondary Efficacy Endpoints ................................................................................119 
14.4 Tertiary Efficacy Endpoints ....................................................................................120 
14.5 Immunogenicity ......................................................................................................120 
14.6 Pharmacodynamic Analyses ...................................................................................120 
14.7 Safety Analysis .......................................................................................................120 
14.8 Determination of Sample Size ................................................................................120 
14.9 Analysis Populations ...............................................................................................121 
14.10 Changes in the Conduct of the Study or Planned Analyses ....................................121 

 
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15 DATA MONITORING COMMITTEE ...........................................................................122 
16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................123 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................124 
18 STUDY MONITORING AND AUDITING ...................................................................126 
19 RETENTION OF RECORDS .........................................................................................127 
20 USE OF INFORMATION AND PUBLICATION .........................................................128 
21 REFERENCES ................................................................................................................129 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................132 
22.1 Conduct of Study and Protection of Human Patients .............................................132 
23 SIGNATURE PAGE .......................................................................................................133 
24 APPENDICES .................................................................................................................134 
25 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................136 
 
LIST OF TABLES  
Table 9.1.1:  Schedule of Events-Screening and Infusion .......................................................44 
Table 9.1.2:  Schedule of Events-Post-Infusion Follow-Up (Week 1-20) ...............................48 
Table 9.1.3:  Schedule of Events – Post-Infusion Follow-Up (Weeks 21-52) ........................51 
Table 9.1.4:  Schedule of Events-Post-Infusion Follow-Up (Year 2-Year 5) .........................54 
Table 9.1.5:  Schedule of Events-Optional Liver Biopsy ........................................................57 
Table 9.1.6:  Suggested Schedule of Events-Prophylactic Corticosteroids .............................58 
Table 9.4.8.2.2.1:  Management of ALT Elevations with Reactive Corticosteroids ...............72 
Table 9.4.8.2.2.2:  Viral and Autoimmune Hepatitis Testing ..................................................73 
Table 9.7.8.2.1:  Clinical Laboratory Tests .............................................................................82 
Table 9.7.8.4.1:  Liver Tests ....................................................................................................84 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................90 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................91 
 

 
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LIST OF FIGURES  
Figure 1:  hFVIII-SQ Vector Genome and Encoded Protein .....................................................7 
Figure 2:  270-303 Study Schema ..............................................................................................9 
Figure 7.3.1:  hFVIII-SQ Vector Genome and Encoded Protein .............................................34 
Figure 9.1.1:  270-303 Study Schema ......................................................................................41 
 
LIST OF APPENDICES  
Appendix 1:  Sampson’s Anaphylaxis Criteria ......................................................................135 
 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviations 
Terms 
AAV 
adeno-associated virus 
ABR 
annualized bleeding rate 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CL 
clearance 
cNBA 
FVIII chromogenic Nijmegen Bethesda Assay 
CRA 
clinical research associate 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
electronic case report form 
ED 
exposure days 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FVIII 
coagulation factor VIII 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HA 
hemophilia A 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
hFIX 
human coagulation factor IX 
hFVIII 
human coagulation factor VIII 

 
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Abbreviations 
Terms 
HIPAA 
Health Insurance Portability and Accountability Act 
HLP 
hybrid human liver-specific promoter 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 
IFNg 
interferon gamma 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intention-to-treat 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LT 
liver test 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention-to-treat 
MN 
mobile nursing 
NSAID 
non-steroidal anti-inflammatory drug 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
pharmacokinetics 
PRO 
patient-reported outcome 
PROBE 
Patient Reported Outcomes, Burdens, and Experiences 
rhFVIII 
recombinant human FVIII 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
SOI 
Statement of Investigator 
SOP 
standard operating procedure 
SQ 
SFSQNPPVLKRHQR 
SUSAR 
serious unexpected suspected adverse reactions 
TAb 
total antibody 

 
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Abbreviations 
Terms 
TI 
transduction inhibitor 
ULN 
upper limit of normal 
vg 
vector genomes 
WPAI+CIQ:HS 
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific 
 
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 (R2)]).  
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) 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 will be provided to BioMarin or its designee. The 
Investigator will provide the IRB/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 for patients who do not speak the local language at 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 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 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 adverse event reporting, 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) or E6(R2) (ICH E6R2) if adopted 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation and human Phase 1 study testing. The study will be conducted under a 
protocol reviewed and approved by an IRB/IEC and will be conducted by scientifically and 
medically qualified persons. The potential benefits of the study are in proportion to the 
potential 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), 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. BioMarin and the 
IRB/IEC 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 Statement of Investigator (SOI) form. A US Food and 
Drug Administration (FDA) Form FDA 1572 serves as an acceptable SOI form. If Form 
FDA 1572 may not be used in a particular region, the Investigator must provide a fully 
executed SOI on the form provided by the Sponsor. All Investigators and Sub-Investigators 
must be listed on Form FDA 1572 or its equivalent SOI. Financial Disclosure Forms must 
also be completed for all Investigators and Sub-Investigators listed on the Form FDA 1572 
or SOI 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. 
Clinical Laboratory assessments will be performed at a nominated central laboratory. 
Bioanalytical samples will be sent to the appropriate specialty laboratories for testing. Refer 
to laboratory manual for more details.  

 
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7 
INTRODUCTION  
Hemophilia 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 pathway. 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 
hemorrhage. Treatment in Western countries (Berntorp 2012) consists of intravenous 
injection of plasma-derived or recombinant FVIII protein concentrates at the time of a bleed 
to control it 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 hemophilia A patients. These individuals develop 
debilitating arthropathy and have a substantially increased risk of death from hemorrhage in 
life (Stonebraker 2010). Chemical modification or bioengineering of FVIII may improve 
half-life to 18-19 hours (Kaufman 2013). However, these extended half-life 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 (hFVIII) following a single administration of vector. Hemophilia 
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 hybrid human liver-
specific transcription promoter (HLP). 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 intravenous (IV) infusion of BMN 270, the 
planned clinical route of administration, for the treatment of hemophilia A in male patients. 
This nonclinical program took into account the guidelines and reflection papers for gene 

 
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therapy medicinal products under European Medicines Agency (EMA) Advanced Therapies 
as well as FDA guidance. 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 including normal CD-1 mice, a B-and 
T-cell deficient mouse model of hemophilia 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. 
Results of the nonclinical program to date are detailed in the IB supplied by BioMarin. 
Investigators are to review this document prior to initiating this study. 
7.2 
Previous Clinical Studies  
Ongoing clinical studies for BMN 270 include: 
• 270-201, a phase 1/2, dose-escalation study in patients with severe HA 
• 270-203, a phase 2 study in patients with severe HA who have anti-AAV5 antibody 
titers 
• 270-301, a phase 3 study in patients with severe HA who receive BMN 270 at the 
6E13 vector genomes [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 
A comprehensive review of safety, efficacy, and immunogenicity results from these studies is 
contained in the IB supplied by BioMarin. Investigators are to review this document prior to 
initiating this study. 
7.3 
Study Rationale  
Hemophilia 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 pathway. This disorder can be either 
inherited, due to a genetic aberrancy, 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 generally correlates 
tightly with the level of residual expression. Severe HA is classified as FVIII activity less 
than 1% of normal (< 1 IU/dL), moderate disease comprises 1-5% of normal activity and the 
mild form is 5-40% activity. The clinical manifestations of severe HA are frequent 
spontaneous bleeding episodes, predominantly in joints and soft tissues, with a substantially 
increased risk of death from hemorrhage when the brain is involved. Subjects with moderate 

 
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disease can exhibit manifestations similar to those seen in patients with severe HA, resulting 
in a comparable bleeding phenotype.  
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 prophylactic therapy 
(median ABR of 1-4 with prophylaxis treatment in a recently published retrospective 
observational study (Berntorp 2017) and between 1-2 in 6 prospective FVIII interventional 
studies) and on-demand-only therapy (median ABR of 4.5-18 in a recently published 
retrospective study (Berntorp, 2017) and between 20-60 in 6 prospective FVIII interventional 
studies). The consequence of multiple bleeding events is the development of 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 a 1% trough for a greater 
proportion of the dosing interval. However, patients with severe HA who are treated with 
extended half-life FVIII remain dependent on multiple infusions to maintain critical levels of 
FVIII activity. 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 hemorrhage-free life.  
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of active FVIII following a single intravenous infusion of a vector encoding the 
appropriate gene sequence for long-term episomal expression. Hemophilia 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 even 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 hemophilia A. Thus, relatively small changes in 
endogenous FVIII activity can result in clinically relevant improvements in disease 
phenotype. Finally, the circulating FVIII 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 

 
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well-defined safety profile, and can direct long-term transgene expression with tropism and 
promoter specificity for specific tissues, such as the liver (for serotypes 2, 5 and 8 among 
others). Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, 
has established that stable (median follow-up of 6.7years; Nathwani, 2018) expression of 
human factor IX (hFIX) at levels that are sufficient for conversion of their bleeding 
phenotype from severe to moderate or mild is achievable following a single peripheral vein 
infusion of AAV8-hFIX vector. Several participants in this trial have been able to 
discontinue factor prophylaxis without suffering spontaneous hemorrhages, 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 hybrid human liver-specific promoter (Figure 7.3.1). 
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 a single intravenous dose and is designed to achieve durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.  
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 
dose escalation study in subjects with severe HA designed to assess the safety and efficacy of 
BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. 
Additional studies have been undertaken at the 6E13 vg/kg dose (270-301 in subjects with 

 
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severe HA, and 270-203 in subjects with severe HA who are also AAV5-antibody positive). 
With the exception of 270-203, subjects in other BMN 270 studies who are AAV5-antibody 
positive have been excluded. In 270-303, up to 25% of subjects may have detectable 
pre-existing AAV5 capsid antibodies, so long as the detectable titer level is below the 
minimum required dilution (< 20). It is expected that subjects with such a low detectable titer 
level will respond in a similar manner to subjects who are AAV5 capsid antibody negative. 
Four-year results from 270-201 and one-year results from 270-301 have demonstrated that 
following gene transfer, mean and median FVIII activity levels above 15% (15 IU/dL), as 
measured by a chromogenic substrate assay, are achievable and sustained following a single 
infusion of 6E13 vg/kg of BMN 270, with an acceptable safety profile. Preliminary results 
from optional liver biopsies (in subjects receiving lower doses of BMN 270 in 270-201) 
confirm dose-dependent pan-lobular and otherwise healthy liver transduction at 2.7-4.1 
years.  
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than 
subjects in 270-301; in 270-201, subjects were scheduled to start corticosteroids by Week 3 
(either before Week 3, in response to an alanine aminotransferase (ALT) elevation, or at 
Week 3 otherwise, per protocol), whereas in 270-301 subjects received corticosteroids only 
in response to an ALT elevation. Possibly as a result of this difference, subjects receiving 
6E13 vg/kg in 270-201 started corticosteroids at an earlier date in reference to the date of 
BMN 270 infusion and showed later onset of first ALT elevations when compared with 
subjects in 270-301. Recently published data from 270-201 and recent analysis of 270-301 
data suggest that corticosteroids may have assisted in rescue or protection of FVIII activity 
levels during elevations of ALT and in resolution of elevated ALT levels in some subjects 
(Pasi 2020). 
The current study is a Phase 3b, single arm, open-label study designed to assess whether 
BMN 270, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and 
effectively improve the FVIII activity profiles and alter the clinical phenotype of hemophilia 
A patients with residual FVIII activity ≤ 1 IU/dL. 
7.3.1 Optional Liver Biopsy Rationale  
The usual 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 thereafter. 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 

 
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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 270-303 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 the majority of subjects, as well as 
inter-subject variability in post-therapy FVIII activity 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 sub-studies 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 sub-study is to provide a better understanding of the long-
term gene expression related to genome circularization, health of the liver, and variation in 
FVIII activity levels observed after gene therapy with BMN 270. With use of prophylactic 
corticosteroids, it is believed that there will be stable hepatic function and FVIII activity 
expression, with tolerance of prophylactic corticosteroid therapy and no change to the risk of 
thromboembolism. This sub-study aims to evaluate the effect on the liver by performing liver 
biopsies at approximately Week 26, Week 52, and/or during Years 2-5.  
7.4 
Summary of Overall Risks and Benefits  
Overall, 151 subjects have received a BMN 270 infusion at one of 4 dose levels (6E12 vg/kg, 
2E13 vg/kg, 4E13 vg/kg, or 6E13 vg/kg) in one of the four ongoing BMN 270 clinical 
studies (270-201, 270-301, 270-302, 270-203). 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.  
Transient, asymptomatic ALT elevation (grade 1 to 3 in severity) has been observed in most 
subjects administered BMN 270 shortly after dosing, with no evidence for major impacts 
upon liver function; no events meeting the Hy’s Law criteria have been identified. Liver 
function remained stable over time. Across the 6E13 vg/kg cohort of 270-201 and 270-301, 

 
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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, 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). 
Short-lived infusion reactions associated with one-time BMN 270 administration have 
included symptoms such as nausea, maculopapular rash, urticaria, diarrhea, watery eyes, 
rigors, chills, myalgia, fever, tachycardia and hypotension emerging within 24 hours of 
receiving BMN 270. Most infusion-related reactions were Grade 1 or Grade 2 in severity, 
and all events resolved, typically within 48 hours following medical management. While 
some cases required temporary interruption of the infusion, followed by re-initiation at a 
slower rate, all subjects completed their infusions. The reactions with onset during or within 
approximately 5 hours after the end of infusion responded to treatment with systemic 
antihistamines and/or corticosteroids, where administered. Infusion-related reactions were 
effectively mitigated by managing infusion rate and medications.  
No subjects have experienced thromboembolic events or developed inhibitors to FVIII 
following BMN 270 infusion. 
In this study, corticosteroids will be initiated prophylactically (ie, prior to any increase in 
ALT) on Day 1, prior to the BMN 270 infusion. Close monitoring of ALT and FVIII activity 
is recommended to enable early and timely initiation of reactive corticosteroid treatment (ie, 
in response to an increase in ALT). During reactive corticosteroid treatment, emphasis will 
be placed on a timely taper of the dose to limit sequelae associated with prolonged 
corticosteroid use. 

 
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Subjects given the 6E13 vg/kg dose in 270-201 and 270-301 have achieved mean FVIII 
activity above 40 IU/dL at 49-52 weeks post-infusion, with 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.  
The current data available has shown an established positive benefit:risk profile for 
BMN 270 at the 6E13 vg/kg dosing level, although the impact of prophylactic corticosteroids 
requires further investigation. 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 
270-303 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 the risks and benefits of treatment with BMN 270, refer to the 
current version of the Investigator’s Brochure. 
7.4.1 Optional Liver Biopsy 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 sub-study will have a comprehensive pre-/post-
biopsy surveillance plan according to the standard procedures at the institution. Timing of the 
liver biopsies will occur at Weeks 26, 52, and/or during Years 2-5. 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 10.4.1.6).  

 
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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 sub-study 
is optional and will not have any effect on the subject’s continued participation in 270-303. 

 
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8 
STUDY OBJECTIVES  
The primary efficacy objective of the study is to: 
• Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52 following 
intravenous infusion of BMN 270  
The secondary efficacy objectives of the study are to: 
• Assess the impact of BMN 270 with prophylactic corticosteroids on the use of 
exogenous FVIII replacement therapy from Week 5 to last visit by data cutoff (for 
Week 52 analysis) for subjects receiving prior FVIII prophylaxis or on use of 
emicizumab from Week 27 to last visit by data cutoff (for Week 52 analysis) for 
subjects receiving prior emicizumab prophylaxis 
• Assess the impact of BMN 270 with prophylactic corticosteroids on the number of 
bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to 
last visit by data cutoff (for Week 52 analysis) for subjects receiving prior FVIII 
prophylaxis or on use of emicizumab from Week 27 to last visit by data cutoff (for 
Week 52 analysis) for subjects receiving prior emicizumab prophylaxis 
• Assess the impact of BMN 270 with prophylactic corticosteroids on quality of life as 
measured by the Haemo-QoL-A questionnaire at Week 52 of the study compared to 
baseline 
The tertiary efficacy objective of the study is to: 
• Assess the impact of BMN 270 with prophylactic corticosteroids on patient-reported 
outcomes (PROs) (other than Haemo-QoL-A) at Week 52 of the study compared to 
baseline  
The exploratory efficacy objective of the study is to: 
• Assess the efficacy of BMN 270 with prophylactic corticosteroids defined as FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52, following 
intravenous infusion of BMN 270 for subjects with detectable AAV5 total antibodies 
below the minimum required dilution at Screening 
The safety objectives of the study are to: 
• Evaluate the short-term safety of BMN 270 with prophylactic corticosteroids 
following intravenous infusion  
• Assess the long-term safety of BMN 270 with prophylactic corticosteroids 

 
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9 
INVESTIGATIONAL PLAN  
9.1 
Overall Study Design and Plan  
This is a Phase 3b, single arm, open-label study in hemophilia A patients with residual FVIII 
levels  ≤  1 IU/dL. Subjects will be enrolled at approximately 15 sites worldwide. Subjects 
must have high-quality, well-documented historical data available concerning previous 
bleeding episodes and exogenous FVIII usage over the previous 12 months in order to be 
eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of 
BMN 270 as a single intravenous infusion in conjunction with receipt of a 19-week 
prophylactic corticosteroid regimen starting on the day of the BMN 270 infusion. 
Post-infusion, subjects will be eligible to receive reactive corticosteroids, as indicated 
(Figure 9.1.1). 
Figure 9.1.1:  270-303 Study Schema  
 
 
In order to minimize bias in the ongoing study and to assure safe and ethical conduct of the 
clinical trial, an independent Data Monitoring Committee (DMC), consisting of experts in 
clinical trials, statistics, and hemophilia, will be convened. The DMC will have access during 
the trial to amalgamated FVIII activity levels, FVIII usage, and bleeding data and review 
available safety and efficacy (eg, FVIII activity) data during the study on an ongoing basis; 
they may determine, based on emerging data and the risk/benefit profile, that further 
enrollment should be paused to enable modification of the protocol or discontinued.  

 
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The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion (or have discontinued study participation prior to 
Week 52). After the final analysis, safety and efficacy will then continue to be assessed long-
term for a total of approximately 5 years for each subject. 
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic 
FVIII replacement therapy 4 weeks following infusion of BMN 270 or if FVIII activity has 
consistently increased above 5 IU/dL, whichever is earlier. Four weeks represents the time by 
which endogenous production of FVIII following gene transfer is expected to be efficacious, 
based on prior study results. Subjects previously receiving emicizumab, given its 
approximate 1-month half-life, will remain on emicizumab prophylaxis until BMN 270 
infusion, with their final dose administered prior to Day 1. 
In subjects who experience recurring 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 ≥ 5 IU/dL 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 or Sponsor-designated Data 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 are not attending the Q4W/Q6W visits during Years 2-5 may receive a 
scheduled monthly follow-up telephone call from the site to ask about adverse events, 
concomitant medications, and bleeding events/FVIII replacement usage. 
There will be an ongoing review of individual subject safety by the Medical Monitor, and 
both safety and efficacy data by the DMC. Patients will receive prophylactic corticosteroids 
with tapering of the dosage based upon consideration of ALT values, FVIII activity levels, 
and as indicated, consultation with the Investigator and the Medical Monitor. Reactive oral 
corticosteroids may be initiated if a subject’s ALT values increase from baseline levels, after 
consultation between the Investigator and the Medical Monitor (refer to Section 9.4.8.2). 
In case of a safety concern, additional unscheduled laboratory tests may be performed locally 
(at the Investigator’s discretion) in order to facilitate timely and appropriate clinical 
management decisions; where possible, a matched sample for testing at the central laboratory 
should be collected (using the Unscheduled Visit lab kit) at the same time as the local 
unscheduled sample. 

 
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Any safety signal may trigger a review of the data and possible additional immunogenicity 
studies or other diagnostics deemed necessary that include an assessment of cellular immune 
responses using collected peripheral blood mononuclear cells (PBMCs). 
An optional liver biopsy will be performed (in subjects who consent to do so) at or around 
Week 26, Week 52, and/or during Years 2-5 following BMN 270 infusion. Subjects who 
consent to the liver biopsy will have additional assessments, including a liver ultrasound and 
FibroScan, and will receive prophylactic FVIII prior to the procedure, as indicated in the 
judgment of the Investigator, to minimize the risk of bleeding. 
At applicable sites, certain study assessments may be performed by a mobile nursing (MN) 
professional at the patient's home or another suitable location such as their school or office 
(if the subject has given written informed consent to participate in MN visits), or at the site or 
approved lab facility as a shortened lab draw-only visit, to improve access and convenience 
for patients 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 patient and the patient gives written informed consent to participate in 
MN visits, the MN network will communicate with the patient and the patient’s site. 
Schedules of events for the Screening and Infusion period (Table 9.1.1), Post-Infusion 
follow-up periods (Table 9.1.2, Table 9.1.3, Table 9.1.4), and the optional liver biopsy 
(Table 9.1.5) are presented below. 
 
 

 
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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)o 
Screening 
Smart 
Rescreeningm 
(Day -28 to 
Day -1) 
Baseline 
(Day -7 to 
Day -1)n 
Screening 
Day -42 to 
Day -29 
Screening* 
(Day -28 to 
Day -1) 
Informed consent 
X 
Xp 
 
 
 
Demographics (age, sex, race, ethnicity) 
 
X 
 
 
 
Medical History 
 
X 
 
 
 
Physical Examinationa 
 
X 
 
X 
X 
Height and Weight 
 
X 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
Assessment of Adverse Events and Concomitant Medications 
 
X 
X 
X 
X 
Documentation of bleeding episodes and hemophilia therapy usage for previous 
12 months (by either subject or clinical information) 
 
X 
X 
X 
 
Distribution of subject diaries and training in their useb 
 
X 
 
 
 
Electrocardiogram 
 
X 
 
 
 
Liver Ultrasound (and FibroScan at discretion of Investigator)c 
 
X 
 
 
 
hFVIII Assaysd 
 
X 
Xq 
X 
 
hFVIII TAb 
 
X 
 
X 
 
Screen for Hepatitis B, Hepatitis C, HIVe 
 
X 
 
 
 
SARS-CoV-2 screening (local or central)f 
 
X 
X 
 
 
Blood chemistry, hematology, and coagulation testsg 
 
X 
X 
X 
 
Fasting lipid panel (blood triglycerides, total cholesterol, HDL cholesterol, and LDL 
cholesterol) 
 
 
 
 
X 
Fasting FibroTest 
 
X 
 
 
 

 
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Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion 
Visit 
(Day 1)o 
Screening 
Smart 
Rescreeningm 
(Day -28 to 
Day -1) 
Baseline 
(Day -7 to 
Day -1)n 
Screening 
Day -42 to 
Day -29 
Screening* 
(Day -28 to 
Day -1) 
Urine Testsg 
 
X 
X 
X 
 
Liver Testsg 
 
X 
X 
X 
 
AAV5 TAb Assay (CDx)h 
X 
X 
X 
 
X 
Immunogenicity AAV5 TAb Assay 
 
 
 
X 
X 
AAV5 TI Assay 
 
 
 
X 
X 
IFNg ELISpot 
 
 
 
X 
 
Plasma, PBMC, and RBC collection for exploratory biomarkersi 
 
 
 
X 
 
Biomarker testingi 
 
X 
 
 
 
Serum for exploratory biomarkersj 
 
X 
 
 
X 
Exploratory CK18 and Grp78 assessment 
 
X 
 
X 
 
Haemo-QoL-A assessment 
 
 
 
X 
 
EQ-5D-5L  
 
 
 
X 
 
WPAI+CIQ:HS 
 
 
 
X 
 
PROBE 
 
 
 
X 
 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
 
 
 
X 
X 
Pharmacokinetics 
 
 
 
Xr 
 
BMN 270 Infusion 
 
 
 
 
X 
Complement Panel and Exploratory Cytokine Profilingk  
 
 
 
X 
Xk 
Hypersensitivity blood assessmentsl 
 
 
 
 
Xl 
* Screening assessments should be performed within 28 days of BMN 270 infusion (and must be performed within 42 days prior to BMN 270 infusion). 
a Complete physical examination should be done at Screening. Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit. 
b Diaries should be distributed to subjects who have consented to participate in the study and who have been determined to meet all study eligibility criteria. 

 
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c All patients must have a liver ultrasound performed during the Screening period to screen for significant liver disease and hepatocellular carcinoma. A FibroScan may also be performed at 
the discretion of the Investigator. 
d Includes baseline FVIII activity (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), coagulation exploratory assay, chromogenic Nijmegen-Bethesda Assay for hFVIII 
inhibitor level, and hFVIII protein assay. Baseline activity should be assessed at trough (at least >72 hours after last dose of replacement FVIII therapy, or 5x the known half-life of the 
FVIII concentrates administered). 
e Patients with documented negative results within the last 30 days do not need to be retested. Hepatitis B screening should include hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), and hepatitis B core antibody (HBcAb). 
f SARS-CoV-2 RT-PCR testing is required during Screening, and all subjects must have at least one negative test result prior to dosing. If the test is performed locally an additional 2nd test is 
recommended, but if performed negative results from the 2nd test must be received prior to dosing. A SARS-CoV-2 vaccine is recommended for subjects if indicated and if available. If a 
two-step SARS-CoV-2 vaccine is being used, sites should consider using the flexible re-screen option to allow subjects to receive both doses at least 14 days prior to treatment with BMN 
270 (or at least 30 days prior to treatment with BMN 270 for any live-virus vaccines). It is preferable for SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. Investigators 
should use clinical judgment, taking into consideration local factors, individual risk factors, and benefit/risk related to timing of vaccine administration.  
g Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.4.1 for liver tests. ABO blood typing assessment should be performed at Screening. 
h Screening, Smart Re-screening, and Infusion Day samples will be tested using the CDx AAV5 total antibody (TAb) assay. During Screening, the CDx AAV5 TAb assay test may be done 
first, under a standalone informed consent form, before the main ICF for the study is signed and further screening procedures are performed. If performed during the early Screening 
period, the CDx AAV5 TAb assessment does not need to be repeated as part of general Screening. Sample collection on the day of the infusion visit must be performed before the 
BMN 270 infusion is given.  
i Includes HLA genotyping and FVIII genotyping. 
j Blood samples will be collected to evaluate biochemical, molecular, cellular, immunological, 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. 
k Complement panel should include C3, C3a, C4, Bb, and sC5b-9 (refer to Table 9.7.8.2.1) and should be collected 2 hours after completion of the infusion. While exploratory samples for 
cytokine profiling will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the Sponsor. 
l In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital signs will be performed and additional blood samples 
will be collected within 1 hour, and 8-24 hours following the hypersensitivity reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. Additional samples will 
be collected at the 1 hour and 8-24 hour time points and, if possible, 1 week after the event for optional exploratory cytokine profiling to assess inflammatory biomarkers and plasma 
cytokine levels. Inpatient observation can be extended and additional blood samples can be collected if deemed necessary at the discretion of the Investigator and Medical Monitor. 
m 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. SARS-CoV-2 RT-PCR testing is required during Screening, and all subjects must have at least one negative test result prior to dosing. If the test 
is performed locally an additional 2nd test is recommended, but if performed negative results from the 2nd test must be received prior to dosing. Subjects who undergo smart rescreening 

 
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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. 
n Should the screening visit occur within 30 days of infusion, physical examination, blood chemistry, LTs, hematology, and urine and coagulation tests do not need to be repeated at 
Baseline. 
o With the exception of the collection of samples for polymerase chain reaction (PCR) vector DNA analysis and the collection of the complement panel/exploratory cytokine profiling 
sample, assessments on the day of infusion must be performed prior to the infusion. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the 
infusion visit. 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), and following the infusion 
hourly (± 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Shedding samples for PCR of vector DNA analysis (blood, saliva, urine, semen, stool) should be collected 
between 2 and 24 hours after the infusion has been completed. 
p If the subject underwent early AAV5 TAb testing and was consented using the full study ICF, the ICF does not need to be re-administered and re-signed as part of regular Screening. If the 
subject underwent early AAV5 TAb testing and was consented using the dedicated stand-alone ICF for that purpose, the full ICF will need to be signed if the subject proceeds to regular 
Screening. 
q Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening. 
r Samples will be drawn immediately prior to recombinant FVIII concentrate infusion (between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours 
post-FVIII infusion. For subjects receiving emicizumab, pharmacokinetics assessment is optional. 
 

 
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Table 9.1.2:  Schedule of Events-Post-Infusion Follow-Up (Week 1-20)  
Assessment 
Follow-Up After BMN 270 Infusion – Weeks 
1 
2f 
3f 
4 
5f 
6f 
7f 
8 
9f 
10f 
11f 
12 
13f 
14f 
15f 
16 
17f 
18 
19f 
20 
Study Day* 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
Physical examinationa 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Weight 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Assessment of Adverse Events and 
Concomitant Medications (including 
review of bleeding and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Blood chemistry, hematology, and 
coagulation testsb  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Urine Testsb 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Liver Testsb  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hFVIII protein assay 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PCR of vector DNA in blood, saliva, 
urine, semen, and stoolsd 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Immunogenicity AAV5 TAb Assay 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
AAV5 TI Assay 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
hFVIII TAb 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
IFNg ELISpot  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Plasma, PBMC, and RBC collection for 
exploratory biomarkerse 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Complement Panel and Exploratory 
Cytokine Profilingb 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 

 
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Assessment 
Follow-Up After BMN 270 Infusion – Weeks 
1 
2f 
3f 
4 
5f 
6f 
7f 
8 
9f 
10f 
11f 
12 
13f 
14f 
15f 
16 
17f 
18 
19f 
20 
Study Day* 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
Serum for exploratory biomarkerse 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Exploratory CK18 assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haemo-QOL-A assessment 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
WPAI+CIQ:HS 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PROBE 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Testing for reactivation of hepatitis B and 
hepatitis C 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
* Visit windows are ± 48 hours.  
a Brief physical examination should be done at scheduled visits. Additional physical exams may be done at the discretion of the PI. 
b Refer to Table 9.7.8.2.1for laboratory assessments to be included and for complement panel tests, and to Table 9.7.8.4.1 for liver tests (LTs). LT assessment is weekly, but may be checked 
more frequently when ALT values are > ULN or ≥ 1.5x baseline value or based upon  discussion between the Medical Monitor and the Investigator. Subjects with ALT > ULN or ≥ 1.5x 
baseline value during the study and either an alternative etiology considered or for further evaluation of the lab abnormality 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: the ALT has increased to ≥ 1.5x baseline value or >ULN or 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. In case of a 
safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management 
decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. 
While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the Sponsor. 
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level, and coagulation 
exploratory assay. Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. 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 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. 

 
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d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained; longer collection and testing may be performed based on batch testing 
schedules, result turnaround times, or discussions between Medical Monitor and Investigator. Collection and testing of semen samples must continue at least through Week 12, even if 
3 consecutive results below the limit of detection in that compartment have already been recorded.  
e 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 any other exploratory 
assessments) will be performed only as deemed necessary by the Sponsor. 
f Visits between scheduled clinic visits may be performed by a mobile nursing (MN) professional at the subject’s home or another suitable location (if the subject has given written informed 
consent to participate in MN visits), or at the site or approved lab facility as a shortened lab draw-only visit. The MN service or site will collect blood samples at these visits. For site lab 
draw-only visits, sites will contact the subject via phone call or e-mail to collect information regarding adverse events, changes to concomitant medications, bleeding episodes, and FVIII 
use. For MN visits, the service will collect this information. Unscheduled visits may also be conducted by MN as appropriate. 
g Testing for reactivation of hepatitis B and hepatitis C only for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry. 
 

 
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Table 9.1.3:  Schedule of Events – Post-Infusion Follow-Up (Weeks 21-52)  
Assessment 
Follow-Up After BMN 270 Infusion-Weeks 
21f 
22 
23f 
24 
25f 
26 
28 
30f 
32 
34f 
36 
40 
44 
48 
50f 
52 
Study Day* 
148 
155 
162 
169 
176 
183 
197 
211 
225 
239 
253 
281 
309 
337 
351 
365 
Physical examinationa 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Weight 
 
 
 
 
 
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 
Blood chemistry, hematology, and coagulation testsb  
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Urine Testsb 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Liver Testsb 
X  
X 
X  
X 
X  
X 
X 
X  
X 
X  
X 
X 
X 
X 
X 
X 
hFVIII assaysc 
X  
X 
X  
X 
X  
X 
X 
X  
X 
X  
X 
X 
X 
X 
X 
X 
hFVIII protein assay 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
PCR of vector DNA in blood, saliva, urine, semen, and 
stoolsd 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Immunogenicity AAV5 TAb Assay 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
AAV5 TI Assay 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
hFVIII TAb 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
IFNg ELISpot 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Plasma, PBMC, and RBC collection for exploratory 
biomarkerse 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
 
 
X 
Complement Panel and Exploratory Cytokine Profilingb 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Serum for exploratory biomarkerse 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Exploratory CK18 assessment 
X  
X 
X  
X 
X  
X 
X 
X  
X 
X  
X 
X 
X 
X 
X 
X 

 
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Assessment 
Follow-Up After BMN 270 Infusion-Weeks 
21f 
22 
23f 
24 
25f 
26 
28 
30f 
32 
34f 
36 
40 
44 
48 
50f 
52 
Study Day* 
148 
155 
162 
169 
176 
183 
197 
211 
225 
239 
253 
281 
309 
337 
351 
365 
Haemo-QOL-A assessment 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
EQ-5D-5L  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
WPAI+CIQ:HS 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
PROBE 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Testing for reactivation of hepatitis B and hepatitis C 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
Optional liver biopsyh 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Liver ultrasoundi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
* Visit windows are ± 48 hours.  
a Brief physical examination should be done at all visits where a physical examination is indicated except Week 26 and Week 52, where a complete physical examination should be 
performed Additional physical exams may be done at the discretion of the PI. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included and for complement panel tests, and to Table 9.7.8.4.1 for liver tests (LTs). LT assessment may be checked more 
frequently when ALT values are > ULN or ≥ 1.5x baseline value or based upon  discussion between the Medical Monitor and the Investigator. Subjects with > ULN or ≥ 1.5x baseline 
value during the study and either an alternative etiology considered or for further evaluation of the lab abnormality 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:  the ALT 
has increased to ≥ 1.5x baseline value or >ULN 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. In case of 
a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management 
decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. 
While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the Sponsor. 
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level, and coagulation 
exploratory assay. Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. 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 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 Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained; longer collection and testing may be performed based on batch testing 
schedules, result turnaround times, or discussions between Medical Monitor and Investigator. 

 
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e 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 any other exploratory 
assessments) will be performed only as deemed necessary by the Sponsor. 
f Visits between scheduled clinic visits may be performed by a mobile nursing (MN) professional at the subject’s home or another suitable location (if the subject has given written informed 
consent to participate in MN visits), or at the site or approved lab facility as a shortened lab draw-only visit. The MN service or site will collect blood samples at these visits. For site lab 
draw-only visits, sites will contact the subject via phone call or e-mail to collect information regarding adverse events, changes to concomitant medications, bleeding episodes, and FVIII 
use. For MN visits, the service will collect this information. Unscheduled visits may also be conducted by MN as appropriate. 
g Testing for reactivation of hepatitis B and hepatitis C only for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry. 
h Optional liver biopsy should be obtained within two weeks of Week 26. Additional follow-up liver biopsy will be obtained within two weeks of Week 52. Subjects should fast for at least 
8 hours prior to liver ultrasound and optional liver biopsies. 
i Additional liver ultrasounds may be performed prior to Week 52 at the discretion of the Investigator. 
 

 
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Table 9.1.4:  Schedule of Events-Post-Infusion Follow-Up (Year 2-Year 5)  
Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Years 2-5 
Year 2 
Year 3-5 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
Q12W 
Q4Wg 
Q6Wg 
W104 
W156 
W208 
W260 
Physical examinationb 
X 
 
 
X 
X 
Weightb 
Xa 
 
 
Xa 
X 
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and hemophilia therapy 
use) 
X 
X  
X  
X 
X 
Vital Signs 
X 
 
 
X 
X 
Blood chemistry, hematology, and coagulation testsc 
Xa 
 
 
Xc 
X 
Urine Testsc 
Xa 
 
 
Xc 
X 
Liver Testsc 
X 
X 
X 
X 
X 
hFVIII assaysd 
X 
X 
X 
X 
X 
hFVIII protein assay 
X 
 
 
X 
X 
PCR of vector DNA in blood, saliva, urine, and stools 
(X)e 
 
 
(X)e 
(X)e 
PCR of vector DNA in semen 
(X)e 
(X)e 
(X)e 
(X)e 
(X)e 
Immunogenicity AAV5 TAb Assay 
 
 
 
X 
X 
AAV5 TI Assay  
 
 
 
Xj 
Xj 
hFVIII TAb 
X 
 
 
X 
X 
IFNg ELISpota  
Xa 
 
 
X 
X 
Plasma, PBMC, and RBC collection for exploratory biomarkersf 
X 
 
 
X 
X 
Serum for exploratory biomarkersf 
X 
 
 
X 
X 
Exploratory CK18 assessment 
X 
X 
X 
X 
X 
Haemo-QoL-A assessment 
Xa 
 
 
Xa 
X 
EQ-5D-5L  
Xa 
 
 
Xa 
X 

 
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Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Years 2-5 
Year 2 
Year 3-5 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
Q12W 
Q4Wg 
Q6Wg 
W104 
W156 
W208 
W260 
WPAI+CIQ:HS 
Xa 
 
 
Xa 
X 
PROBE 
Xa 
 
 
Xa 
X 
Optional liver biopsyh 
 
 
 
X 
 
Liver ultrasoundi 
 
 
 
X 
 
* Visit windows are ± 2 weeks for visits in Years 2-5. 
a These assessments need to be performed only at every other Q12W and every End of Year visit (ie, Weeks 76, 104, 128, 156, 180, 208, 232, and 260). 
b Complete physical examination should be performed at the End of Year visits (genitourinary examination may be deferred); brief physical exam 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. 
c Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.4.1 for liver tests. LT assessment may be checked more frequently when ALT values are > ULN or ≥ 
1.5x baseline value or based upon  discussion between the Medical Monitor and the Investigator. Subjects with ALT > ULN or ≥ 1.5x baseline value during the study and either an 
alternative etiology considered or for further evaluation of the lab abnormality 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: the ALT has increased to ≥ 1.5x baseline value or 
>ULN 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. In case of a safety concern, 
additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where 
possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample 
d Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level, coagulation 
exploratory assay. Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. 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 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. 
e Sample testing during Years 2-5 is not required if at least 3 consecutive samples were below the limit of detection during Year 1; additional collection and testing may be performed based 
on batch testing schedules, result turnaround times, or discussions between Medical Monitor and Investigator. Subjects who have not had 3 consecutive semen samples below the limit of 
detection 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). 

 
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f Blood samples will be collected to evaluate biochemical, molecular, cellular, immunological, 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 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. Subjects who are not attending the Q4W/Q6W visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the site to ask about adverse events, 
concomitant medications, and bleeding events/FVIII replacement usage. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in semen must still 
provide samples Q4W (during Year 2) or Q6W (during Years 3-5) until vector shedding has been cleared, either by reporting to the site to provide samples or by providing those samples 
to a MN professional. Unscheduled visits may also be conducted by MN as appropriate. 
h An optional liver biopsy may be performed at any time between Years 2-5 of the study. The optional biopsy would be triggered by a FVIII activity decline by > 50% from steady-state, 
over 2 consecutive measurements, or by a sustained ALT rise > ULN. If neither trigger is observed, the optional biopsy should be performed at the end of Year 5. 
i Additional liver ultrasounds may be performed at interim timepoints (ie, between the End of Year visits) at the discretion of the Investigator. 
j AAV5 TI Assay should be performed only at the end of the study (either the Year 5 End of Year Visit, or at the ETV for subjects who withdraw prior to the end of Year 5). 
 

 
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Table 9.1.5:  Schedule of Events-Optional Liver Biopsy   
 
Within 28 Days Before 
Biopsy Day 
Within 7 Days Before 
Biopsy Day 
Biopsy Day (BD) 
Informed Consent for Liver Biopsy Procedure 
X 
 
 
Liver Ultrasounda 
X 
 
 
Physical examination 
X 
 
X 
Hematology, Coagulation, Chemistry Assessmentsb 
X 
 
X 
Liver Testsb 
X 
 
X 
FibroScan 
X 
 
 
FVIII Activity Level Assessment (central and local) 
 
X 
X* 
Exploratory CK18 and Grp78 assessment 
 
X 
X* 
Pre-Biopsy Consultationc 
 
X 
 
Liver Biopsyd 
 
 
X 
PBMC Collection (whole blood draw) 
 
 
Xe 
* If the Day -7 and biopsy day visits occur on the same day, these tests do not need to be duplicated. 
a Liver ultrasound must be performed within 28 days prior to the scheduled biopsy. Subjects should fast for at least 8 hours prior to liver ultrasound. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.4.1 for liver tests.  
c Subjects will undergo a pre-biopsy consultation with the Investigator (treating hematologist) and hepatologist and/or radiologist. 
d Subjects should fast for at least 8 hours prior to optional liver biopsy. 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. 
e Blood draw for PBMC collection should be performed on the biopsy day or ± 1 week from the biopsy day. 
 

 
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Table 9.1.6:  Suggested Schedule of Events-Prophylactic Corticosteroids  
Assessment 
Corticosteroid Treatment Periodb 
Post-Corticosteroid 
Periodc 
D1 
Week 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
32 
Prophylactic 
corticosteroid 
dose 
(mg/day) 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
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 
 
 
 
 
 
FVIII activity 
testing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hepatitis B 
testingd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HCV Viral 
Loadd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
a This table provides an example of a prophylactic corticosteroid course. Clinical judgment, weighing the potential risks and benefits of corticosteroid treatment, should always be exercised 
when considering adjustment of corticosteroid doses, and discussions between the Investigator and Medical Monitor are advised for any questions or concerns. Dosages are for prednisone 
or an equivalent dose of another corticosteroid. FVIII and liver tests are also reflected in the Schedule of Events for the study. 
b Following initiation or completion of corticosteroid regimen, if a recurrence of ALT values > ULN or ≥ 1.5x baseline value is reported, corticosteroid management decisions will be based 
on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration timing of ALT elevation (prior to or after Week 52), 
as well as possible confounders for the ALT elevation and adverse events related to corticosteroid dosing.  Guidance for tapering oral corticosteroid dosing can be found in Section 9.4.8.2, 
although a discussion between the PI and Medical Monitor should take place prior to tapering the corticosteroid dose. 
c After discontinuation of oral corticosteroids, weekly labs for ALT levels and FVIII activity will be measured once a week for 4 weeks to ensure stability in values. 
d Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry. Tests are also reflected in the Schedule of Events for the study. 
 

 
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9.2 
Discussion of Study Design  
Study 270-303 is a Phase 3b, single arm, open-label study designed to assess whether 
BMN 270, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and 
effectively improve the FVIII activity profiles and alter the clinical phenotype of hemophilia 
A patients with residual FVIII activity ≤ 1 IU/dL. Subjects must have high-quality, well-
documented historical data available concerning previous bleeding episodes and exogenous 
FVIII usage over the previous 12 months in order to be eligible to enroll in the study. 
Given that BMN 270 is likely a one-time treatment, due to antibody formation against the 
AAV5 capsid post-infusion, and the well-characterized clinical experience of patients with 
severe hemophilia A on currently available chronic therapies, having a separate control group 
in this study was deemed to be inappropriate and unnecessary, as has been the case with all 
AAV gene therapy trials to date. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of 
BMN 270 as a single intravenous infusion in conjunction with receipt of a prophylactic 
corticosteroid regimen. Post-infusion, subjects will be eligible to receive reactive 
corticosteroids, as indicated.  
9.3 
Selection of Study Population  
Approximately 20 adult hemophilia A patients with residual FVIII levels ≤ 1 IU/dL may 
enroll into the study.  
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 inclusion 
criteria: 
1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as 
evidenced by medical history, at the time of signing the informed consent.  
2. Must have been on prophylactic hemophilia therapy for at least 12 months prior to 
study entry. High-quality, well-documented historical data concerning bleeding 
episodes and hemophilia therapy usage over the previous 12 months must be 
available. 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs). 

 
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4. Willing and able to provide written, signed informed consent after the nature of the 
study has been explained and prior to any study-related procedures. 
5. No previous documented history of a detectable FVIII inhibitor, and results from 
a Bethesda assay or Bethesda assay with Nijmegen modification of less than 
0.6 Bethesda Units (BU) (or less than 1.0 BU for laboratories with a historical lower 
sensitivity cutoff for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least 
one week apart within the past 12 months (at least one of which should be tested at 
the central laboratory). 
6. Sexually active participants must agree to use an acceptable method of effective 
contraception, either double-barrier contraception (ie, condom + diaphragm; or 
condom or diaphragm + spermicidal gel or foam) or their female partner either using 
hormonal contraceptives or having an intrauterine device. Participants must agree to 
contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may 
stop contraception use only if they have had 3 consecutive semen samples with viral 
vector DNA below the limit of detection. 
7. Willing to abstain from alcohol consumption for at least the first 52 weeks following 
BMN 270 infusion. 
9.3.2 Exclusion Criteria  
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Subjects with detectable pre-existing antibodies to the AAV5 capsid are excluded 
with the following exception: up to 25% of subjects may have detectable pre-existing 
AAV5 capsid antibodies with titer level below the minimum required dilution (< 20). 
2. Any evidence of active infection, including COVID-19, or any immunosuppressive 
disorder, except for HIV infection. HIV-positive patients who meet all other 
eligibility criteria may be included if they have a CD4 count > 200/mm3 and an 
undetectable viral load (unquantifiable viral load as defined as less than the limit of 
quantification by the testing laboratory’s assay is permitted) while receiving an 
antiretroviral therapy (ART) regimen that does not contain efavirenz or another 
potentially hepatotoxic ART. 
3. Significant liver dysfunction with any of the following abnormal laboratory results: 
• ALT (alanine aminotransferase) > 1.25x ULN; 
• AST (aspartate aminotransferase) > 1.25x ULN; 
• GGT (gamma-glutamyltransferase) > 1.25x ULN; 
• Total bilirubin > 1.25x ULN; 
• Alkaline phosphatase > 1.25x ULN; or 

 
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• INR (international normalized ratio) ≥ 1.4. 
Subjects whose liver laboratory assessments fall outside of these ranges may undergo 
repeat testing of the entire liver test panel within the same Screening window and, if 
eligibility criteria are met on retest, may be enrolled after confirmation by the 
Medical Monitor.  
4. FibroScan or prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a 
scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring 
systems, or an equivalent grade of fibrosis if an alternative scale is used. 
5. Evidence of any bleeding disorder not related to hemophilia A. 
6. Platelet count of < 100 x 109/L. 
7. Creatinine ≥ 1.5 mg/dL. 
8. Liver cirrhosis or other clinically significant liver disease of any etiology as assessed 
by FibroScan or liver ultrasound. 
9. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B 
surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core 
antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for 
Disease Control (CDC) table for the interpretation of serological test results in the 
Laboratory Manual. 
10. Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral 
therapy.  
11. Active malignancy, except non-melanoma skin cancer.  
12. History of hepatic malignancy. 
13. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial 
embolus), with the exception of catheter-associated thrombosis for which anti-
thrombotic treatment is not currently ongoing.  
14. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
15. Treatment with any investigational product within 30 days or 5 half-lives of the 
investigational product prior to the screening period. For subjects who have received 
a prior investigational product, all ongoing adverse events (AEs) experienced while 
receiving that investigational product must have resolved prior to screening for this 
study. 

 
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16. Any condition that, in the opinion of the Investigator or Sponsor would prevent the 
patient from fully complying with the requirements of the study (including possible 
corticosteroid treatment and/or use of alternative immunosuppressive agents outlined 
in the protocol) and/or would impact or interfere with evaluation and interpretation of 
subject safety or efficacy result. 
17. Prior treatment with any vector or gene transfer agent. 
18. Major surgery planned in the 52-week period following the infusion with BMN 270. 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion. 
20. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study that does not interfere with the requirements of the 
current protocol or have the potential to impact the evaluation of efficacy and safety 
of BMN 270 and with prior consultation with the Medical Monitor. 
21. Known allergy or hypersensitivity to BMN 270 investigational product formulation. 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or 
a bleeding episode. 
9.3.2.1 
Optional Liver Biopsy Inclusion and Exclusion Criteria  
Individuals eligible for the optional liver biopsy must meet the following inclusion criterion: 
1. Able to sign informed consent and comply with requirements for the optional liver 
biopsy 
2. Documentation of FVIII activity ≥ 50 IU/dL (or higher, depending on local guidelines 
and/or Investigator discretion) within 24 hours prior to the liver biopsy being 
performed (FVIII activity 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 activity to an appropriate level, under the 
supervision/instruction of the Investigator. 
Individuals who meet any of the following exclusion criteria will not be eligible for the 
optional liver biopsy: 
1. Any condition that, in the opinion of the Investigator or a hepatologist/radiologist 
would make liver biopsy contraindicated. This includes (but is not limited to) 
abnormalities detected on liver ultrasound performed within 28 days of procedure, or 
prior liver ultrasound result within 90 days that would preclude safe performance of 
the biopsy. 
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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Such subjects will always be asked about the reason(s) for withdrawal. The Investigator will 
discuss with the subject appropriate procedures for withdrawal from the study. The 
Investigator should ask the subject’s consent to perform the procedures listed under the early 
termination visit. Should a subject withdraw from the study, all efforts will be made to 
complete and report the observations as thoroughly as possible up to the date of the 
withdrawal.  
A subject’s participation in the study may be discontinued at any time at the discretion of 
BioMarin or 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 and 
every effort will be made to gather follow-up safety data if possible. 
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 enrolled into the study or does not meet entry criteria and not 
yet been dosed with BMN 270; subjects who do not meet entry criteria but who 
erroneously receive BMN 270 should remain in the study for safety monitoring 
• 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 subject has missed 3 consecutive visits in 
the study and has failed to communicate a reason for this to the site. In addition, 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. 

 
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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 IRB/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. 
9.3.3.1 
Study Safety Evaluation Criteria  
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, an urgent evaluation by the DMC will be required and further enrollment into the 
trial will be temporarily put on hold if recommended by the DMC per Section 9.1.  
1. Liver dysfunction (criteria do not apply to ALT elevations with an extra-hepatic 
etiology): 
o ALT > 5x ULN, for more than 2 weeks 
o ALT > 3x ULN and (total bilirubin > 2x ULN or INR >1.5) 
o ALT > 3x ULN with signs and symptoms of liver dysfunction  
2. The occurrence of Grade 4 or Grade 5 adverse events assessed as related to study 
drug (events of liver dysfunction are defined above).  
3. The occurrence of an AE of hepatic failure. 
4. The detection of high-titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in two subjects. 
5. The occurrence of any cancer (except non-melanoma skin cancer) at any point after 
BMN 270 infusion. 
6. The occurrence of a thromboembolic event with FVIII activity > 150 IU/dL in one 
subject. 
If any of the following events occurs in a subject in the study who has received BMN 270 
infusion, an urgent evaluation by the DMC will be required. Further enrollment into the trial 
will continue while DMC evaluation is ongoing, unless deemed otherwise by the DMC: 
1. The detection of high-titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in one subject. 

 
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2. Occurrence of a thromboembolic event in one subject. 
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 
electronic case report form (eCRF) pages. In legal jurisdictions where use of initials is not 
permitted, a substitute identifier will be used. 
Subjects who withdraw from the study after receiving BMN 270 will not be replaced. 
9.3.5 Duration of Subject Participation  
The duration of participation for each subject will be approximately 264 weeks. This includes 
4 weeks of screening, 1 day of BMN 270 infusion, and 260 weeks of post-infusion follow-up. 
9.4 
Treatments  
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. BioMarin is responsible for shipping study drug to clinical sites. 
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 10 mL Crystal Zenith® (CZ) vial. Each vial contains 8.5 mL (extractable volume 8 mL) 
of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 
7.4 phosphate buffer. 
The IP is labelled according to the particulars approved by the relevant regulatory agencies.  
9.4.3 Storage  
At the study site, all IP must be stored under the conditions specified in the Pharmacy 
Manual 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  
On the day of infusion, the subject will come to the infusion site, where a physical 
examination will be performed by the Investigator or designee. If the subject is found to have 
an active acute illness at the time of planned infusion, then the infusion should be deferred 
until the illness has resolved; screening procedures may require repetition if outside the 

 
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specified window. 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. Refer to the 
Pharmacy Manual for IP administration instructions.  
BMN 270 will be infused through the catheter using an appropriate infusion pump at an 
initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min 
up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an 
increase. Of note, the IP has been shown to be stable at room temperature for 10 hours 
following completion of product thaw. Vital signs (pulse, blood pressure, respiration rate and 
temperature) should be monitored at 15 minute (±5 minutes) intervals throughout the time 
period of the infusion.  
As with any infused biological product, there is a potential risk of acute, systemic 
hypersensitivity reactions (including anaphylaxis) with BMN 270. Dosing will be 
administered at a qualified infusion site, with appropriate resuscitation equipment and 
medication available and easily accessible. 
Clinical staff administering BMN 270 should be trained appropriately in recognizing and 
managing the signs and symptoms associated with potential hypersensitivity, anaphylactic, 
and anaphylactoid reactions. Additionally, the Investigator should be familiar with 
Sampson’s criteria for defining anaphylaxis (Sampson 2006; Appendix 1).  
Should symptoms of potential hypersensitivity occur, the infusion may be slowed or halted at 
the Investigator’s discretion, with consideration of the subject’s clinical condition. If the 
infusion is halted, it should only be restarted if the Investigator considers it safe and 
appropriate to do so. Antihistamines, anti-pyretic, and/or corticosteroid administration is 
permitted prior to restarting an interrupted infusion after an infusion-related reaction. At the 
restart, the infusion rate may be adjusted (ie, to a slower rate [minimum of 1 mL/min], with 
the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the 
subject’s clinical condition permits such an increase) with careful monitoring of the subject. 
In the event of an infusion rate reaction with more than one dosing interruption, the infusion 
rate would not go beyond 1mL/min. 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment 
including physical examination and vital signs will be performed and additional blood 

 
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samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. 
Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 
1 week after the event for optional exploratory cytokine profiling to assess inflammatory 
biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional 
blood samples can be collected if deemed necessary at the discretion of the Investigator and 
Medical Monitor. Exploratory biomarker samples at baseline and at post-infusion study visits 
may also be used to assess changes in these biomarkers to better elucidate the mechanisms of 
infusion-related hypersensitivity reactions. Inpatient observation can be extended and 
additional blood samples can be collected if deemed necessary at the discretion of the 
Investigator and Medical Monitor. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes). 
If the vital signs are stable the catheter will be removed 8 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 at 
least 8 hours to observe for any immediate toxicity of the procedure; inpatient observation 
can be extended beyond 8 hours if needed per Investigator discretion. After the observation 
period, subjects 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. 
Prior to discharging subjects from the clinic, the Investigator or designee should instruct 
subjects how to recognize signs and symptoms of potential (delayed) hypersensitivity 
reactions and anaphylaxis, and to contact a medical practitioner or seek emergency care in 
case of such an event. 
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 Medical Monitor will be required prior to enrollment 
of each study subject. Upon their enrollment into the study, subjects will be assigned a 
unique subject number. 
Approximately 20 subjects will be enrolled into the single arm study of 6E13 vg/kg with 
prophylactic corticosteroids. Up to 25% of the total number of patients dosed should have an 
AAV5 antibody titer that is detectable but below the minimum required dilution (<20) at 
Screening. 

 
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9.4.6 Selection of Dose Used in the Study  
Data from previous human studies (270-201, 270-301) indicated that dosing at 6E13 vg/kg 
showed improvement in FVIII activity, bleeding episodes, and exogenous FVIII utilization 
and infusion rate. Dosing was well tolerated, with mild increases in ALT as the most 
common adverse event. Please refer to the IB for detailed efficacy and safety data. 
This dose is expected to be safe and effective based on clinical experience to date in 270-201 
and 270-301, as well as non-clinical data. 
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 eCRF. For 
HIV-positive patients, prior to enrollment, the Medical Monitor will review the patient’s 
ART regimen to assess that it does not contain efavirenz or another potentially hepatotoxic 
ART. The Investigator may prescribe additional medications, deemed necessary to provide 
adequate prophylactic or supportive care, 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 
eCRF. Medications should, whenever possible, not be recorded in the electronic database 
with a frequency of as needed (PRN).  
The following medications are prohibited starting 30 days before Screening and through the 
end of the study, and the Sponsor must be notified if a subject receives any of these during 
the study: 
• Any investigational therapy other than BMN 270 
• Fitusiran 
• Concizumab 
• Efavirenz 

 
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The following medications and agents should be avoided, starting 30 days prior to and for at 
least 52 weeks after BMN 270 infusion and minimized throughout the remaining duration of 
the study. 
• Alcohol  
• Herbal and natural remedies and dietary supplements 
• Medications which may be hepatotoxic, including isotretinoin and 
dextroamphetamine/amphetamine 
• Medications which may reduce or increase the plasma concentration of 
corticosteroids 
Subjects should be counseled to avoid starting potentially hepatotoxic therapies and to inform 
the Investigator of any new medications prescribed by other physicians. Investigators should 
carefully consider both the mechanism of action and potential hepatotoxicity of any new 
medication prior to initiation. If a potentially concerning new medication is started, 
Investigators should closely monitor both FVIII activity and ALT levels (eg, weekly to every 
2 weeks for the first month) in order to determine if any detrimental effects on the efficacy 
or safety of BMN 270 have occurred. If co-medications are required during the course of the 
study, where possible, please check the National Center for Biotechnology Information 
LiverTox website for potential hepatotoxicity issues prior to prescribing (NCBI 2020). 
Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated.  
It is preferable for SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. If a two-
step SARS-CoV-2 vaccine is being used, sites should consider using the flexible re-screen 
option to allow subjects to receive both doses at least 14 days prior to treatment with BMN 
270. If a live-virus SARS-CoV-2 vaccine is being used, subjects should wait at least 30 days 
after vaccination to receive a BMN 270 infusion. Investigators should use clinical judgment, 
taking into consideration local factors, individual risk factors, and the benefit/risk related to 
timing of vaccine administration. Administration of SARS-CoV-2 vaccine after BMN 270 
infusion may occur after consultation between Investigator and Medical Monitor. 
The following medications should be avoided during oral corticosteroid therapy: 
• Vaccines 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 

 
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9.4.8.1 
Concomitant Hemophilia Treatments  
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic 
FVIII replacement therapy 4 weeks following infusion of BMN 270 or if FVIII activity has 
consistently increased above 5 IU/dL, whichever is earlier. Subjects previously receiving 
emicizumab, given its approximate 1-month half-life, will remain on emicizumab 
prophylaxis until BMN 270 infusion, with their final dose administered prior to Day 1. 
FVIII replacement therapy can always be taken as needed by the subject for treatment of an 
acute bleeding episode; the subject must carefully record his treatment and bleeding episodes 
in his diary. Prophylactic FVIII use can be used on a case-by-case basis and in consultation 
with the Medical Monitor to prevent bleeding in extenuating circumstances 
(eg peri-operative).  
In addition, information on FVIII usage and bleeding episodes by medical history must be 
well-documented and available and will be collected from subjects for the 12-month period 
immediately preceding study enrollment. Further information on the details that should be 
provided as part of the subject’s well-documented medical and FVIII usage history are 
provided in the Investigator Site File Binder. 
In order to enable rigorous comparisons of pre-study versus on-study FVIII usage and 
bleeding episodes, the Medical Monitor will review each screened patient’s prior bleed and 
hemophilia medication logs to determine if they are of "high-quality". Elements that will be 
assessed to judge the quality of such historical data may include, but are not limited to, the 
following: 
• Date, type (eg, joint, muscle, other), location of bleeds 
• Date, name, dose (calculated in IU/kg), and reason for use (eg, usual prophylaxis, 
one-time prophylaxis, treatment for bleed, surgery) of hemophilia medications. 
9.4.8.2 
Corticosteroid Treatment and/or Alternative Immunosuppressive Agent 
Treatment of Elevated Hepatic Transaminases  
Prior to dosing, all subjects must be screened per steroid prescription guidelines to ensure the 
subject is eligible to receive corticosteroid treatment as outlined in the protocol. Refer to 
corticosteroid prescription guidelines for recommended monitoring for, and management of, 
potential side effects of corticosteroids, including guidance on medications that should be 
avoided during corticosteroid treatment.  

 
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9.4.8.2.1 Prophylactic Corticosteroids  
All subjects will be started on prophylactic corticosteroids starting on the day of infusion 
(Day 1). The first dose of prophylactic corticosteroids (40 mg of prednisone or prednisolone, 
or an equivalent dose of another corticosteroid) should be taken at least 3 hours prior to the 
start of the BMN 270 infusion and continued on a daily basis. Table 9.1.6 provides the 
recommended prophylactic corticosteroid course, including taper and post-corticosteroid 
additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical 
judgment, weighing the potential risks and benefits of corticosteroid treatment, should 
always be exercised when considering adjustment of corticosteroid doses. Discussions 
between the Investigator and Medical Monitor are advised for any questions or concerns. 
9.4.8.2.2 Reactive Corticosteroids  
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels 
become increased (eg, ≥ 1.5x baseline value or > ULN) and alternative etiologies have been 
ruled out, prompt institution of newly administered or an increased dose of reactive (ie, 
started in response to an ALT elevation) oral corticosteroids (prednisone or an equivalent 
dose of another corticosteroid) should be considered after consultation with the Medical 
Monitor (refer to Error! Reference source not found.). 
• Whenever possible, a confirmatory lab draw for ALT should be performed within 
72 hours, along with FVIII activity, prior to initiating reactive oral corticosteroids. 
• Newly administered corticosteroids or dose increases are not indicated if elevations in 
ALT are clearly not related to BMN 270 (eg, elevated ALT with concurrent increase 
in CPK due to intensive exercise) although this should be discussed with the Medical 
Monitor. 
• Alternative immunosuppressive agents may also be considered for use on a case-by-
case basis and following consultation with the Medical Monitor (eg, if prolonged 
corticosteroid use is contraindicated). 
Unless otherwise indicated, reactive corticosteroid treatment should be initiated at a dose of 
60 mg/day. If the ALT level remains stable or declines after 2 weeks, consider gradual taper 
of corticosteroids: 40 mg/day for 3 weeks, 30 mg/day for 1 week, 20 mg/day for 1 week and 
10 mg/day for 1 week. 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 9.4.8.2.2.1): 

 
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Table 9.4.8.2.2.1:  Management of ALT Elevations with Reactive Corticosteroids  
ALT ≥ 1.5x 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, initiate 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 
If the subject has recurrent ALT elevations (≥ 1.5x Baseline or > ULN) and there 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. 
 

 
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When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT 
workup, the following tests should be performed (Table 9.4.8.2.2.2): 
Table 9.4.8.2.2.2:  Viral and Autoimmune Hepatitis Testing  
Viral Hepatitis Workup PCR 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 oral corticosteroids, labs for ALT and FVIII levels will be 
measured once a week for 4 weeks to ensure stability in values. 
Following completion of prophylactic oral corticosteroids, if increased ALT levels (eg, 
> ULN or ≥ 1.5x baseline value) are reported, corticosteroid management decisions will be 
based on discussions between the Investigator and Medical Monitor. Modification of the 
corticosteroid regimen may take into consideration possible confounders for the ALT 
elevation and impact on FVIII expression.  
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 SoA. 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). Alternative, non-steroidal systemic immunosuppressive agents may be used, 
following a discussion between the Investigator and the Medical Monitor, should 
corticosteroid use be deemed by an Investigator to be clinically ineffective, not tolerated, 
and/or contraindicated. Hepatitis B status and HCV viral load will be rechecked 6 weeks 
after the start of oral corticosteroid/immunosuppressive agent treatment and then 1 week and 
13 weeks after the completion of oral corticosteroid/immunosuppressive agent treatment in 
subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse 
events suspected to be caused by or related to corticosteroid/immunosuppressive agent use) 
should be reported as outlined in Section 10 of the protocol.  

 
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Subjects on corticosteroids should receive appropriate counseling 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. The above guidance should also be followed in the event that an alternative 
immunosuppressive agent is used, as applicable. 
9.4.8.3 
Monitoring of HIV-Positive Subjects  
HIV-positive subjects may be enrolled in 270-303 if the subject is well controlled on an ART 
regimen that does not contain efavirenz or another potentially hepatotoxic ART, has a CD4 
count > 200/mm3, and has an undetectable viral load (unquantifiable viral load as defined as 
less than the limit of quantification by the testing laboratory’s assay is permitted). 
HIV-positive subjects were initially included in prior BMN 270 studies.  However, after an 
HIV-positive subject in 270-302 developed markedly elevated liver enzyme levels after 
receiving 4E13 vg/kg of BMN 270, out of an abundance of caution for the long-term liver 
health of HIV-positive patients, further enrollment of HIV-positive subjects was suspended 
in 270-301 (Protocol Amendment 3) and 270-302 (Protocol Amendment 3). The subject in 
270-302 referenced above was receiving efavirenz and lamivudine as part of his ART 
regimen. Following discussion with a liver advisory board and review of the accumulated 
270-301 data, efavirenz and not lamivudine has been implicated as the most likely 
medication that interacted with BMN 270 and contributed to the 270-302 subject's elevated 
liver enzyme levels. Due to its hepatotoxicity, efavirenz is a prohibited medication in all 
BMN 270 studies. 
The two HIV-positive subjects on stable, non-efavirenz-containing ART regimens who were 
enrolled in and dosed in 270-301 study prior to Amendment 3 have been monitored closely. 
Following BMN 270 infusion, these subjects continued their ART as prescribed and followed 
routine monitoring of CD4 count and viral load. Results from 270-301 show similar safety 
results for the two HIV-positive subjects compared to those who are HIV-negative. The 
Sponsor believes that HIV infection, in and of itself, is not a contraindication to receive 
BMN 270 and has therefore removed the exclusion of HIV-positive subjects. 
Subjects should continue ART as prescribed and follow routine monitoring of CD4 count and 
viral load (US Dept Health Human Services 2019). Investigators will continue to monitor 
HIV-positive subjects per routine standard of care. 

 
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9.4.9 Treatment Compliance  
IP will be administered to subjects at the study site and/or the dosing facility by a qualified 
health care 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 IP 
containers. 
9.5 
Investigational Product Accountability  
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP 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 standard 
operating procedures (SOPs). 
9.5.1 Return and Disposition of Clinical Supplies  
Unused IP 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 IP or study materials (or must be referenced in their institution SOPs). 
Unused IP may be destroyed on site, per the site’s standard operating procedures, but only 
after BioMarin has granted approval for drug destruction. The study monitor must account 
for all IP in a formal reconciliation process prior to IP destruction. All IP destroyed on site 
must be documented. Documentation must be provided to BioMarin or designee and retained 
in the Investigator study files. If a site is unable to destroy IP appropriately, the site can 
return unused IP to BioMarin upon request. The return of IP or IP materials must be 
accounted for on a IP return form provided by BioMarin. 
All IP and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable state and federal regulations and study procedures. 
For additional information, please refer to the Pharmacy Manual. 
9.6 
Dietary or Other Protocol Restrictions  
There are no dietary or other protocol restrictions for this study. Alcohol should be avoided 
starting at the time of informed consent for study participation and for the first 52 weeks of 
the study, and particularly within 48 hours prior to lab work. Alcohol use should be 
minimized throughout the remaining duration of the 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 blood 
and semen samples, respectively. Subjects should also abstain from organ donation. 

 
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9.7 
Safety and Efficacy Variables  
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  
9.7.2.1 
FVIII Activity  
The primary efficacy variable is change of the hFVIII activity, as measured by chromogenic 
substrate assay during Weeks 49-52 post-BMN 270 infusion from baseline. 
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 the end of 16 weeks after BMN 270 infusion and who have not resumed 
FVIII replacement therapy. 
Note that fluctuations in FVIII activity after gene therapy are common, and more frequent 
monitoring of FVIII activity levels is not needed in the absence of a concurrent or recent 
ALT elevation or upon consultation between the Investigator and the Medical Monitor. 
Details on collecting FVIII activity samples are included in the Laboratory Manual.  
9.7.3 Secondary Efficacy Variables  
9.7.3.1 
Factor VIII Replacement Therapy/Bleeding Episodes  
Secondary efficacy variables include: 
• Change in the annualized utilization (IU/kg/year) and infusion (number/year) rates 
of exogenous FVIII replacement therapy from Week 5 post-BMN 270 infusion to last 
visit by data cutoff (for Week 52 analysis) from the baseline number and utilization 
of exogenous FVIII replacement therapy for subjects receiving FVIII prophylaxis 
during the 12 months prior to study entry, or change in administration of exogenous 
FVIII replacement therapy from Week 27 post-BMN 270 infusion to last visit by data 
cutoff (for Week 52 analysis) for subjects receiving prior emicizumab prophylaxis.  
• Change in the annualized number of bleeding episodes requiring exogenous FVIII 
replacement treatment (annualized bleeding rate, ABR) from Week 5 post-BMN 270 
infusion to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior 
FVIII prophylaxis, or from Week 27 post-BMN 270 infusion to last visit by data 
cutoff (for Week 52 analysis) for subjects receiving prior emicizumab prophylaxis, 
compared to the baseline ABR during the 12 months prior to study entry. 

 
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Subjects must have high quality documented historical data available concerning previous 
bleeding episodes and hemophilia treatment over the previous 12 months in order to be 
eligible to enroll in the study. During the study, 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. Subjects will be encouraged to discuss any bleeding episodes with the Investigator 
and attempt to objectively assess any reported bleeds through use of ultrasound or non-
invasive imaging.   
Subjects are strongly encouraged to immediately consult Investigator for guidance regarding 
exogenous FVIII administration for suspected bleeds or bleeding episodes within the first 
30 days post-BMN 270 infusion. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis or use of emicizumab. 
9.7.3.2 
Patient-Reported Outcome (PRO) Measures  
The Haemo-QoL-A questionnaire is a validated hemophilia-specific health-related quality 
of life questionnaire for adults (Rentz 2008). It consists of 41 questions covering six domains 
(Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional 
Impact and Treatment Concerns). Items are answered on a 6-point Likert-type scale, ranging 
from 0 (None of the time) to 5 (All of the time). Higher scores mean better health-related 
quality of life or less impairment for a particular subscale (Haemo-QoL Study Group 2017). 
The EQ-5D-5L instrument is a self-reported questionnaire designed to measure general 
health status (The EuroQol Group 1990; Brooks 1996). The EQ-5D-5L is composed of 
2-parts: a descriptive system that assesses 5 levels of perceived problems (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) in 5 dimensions and the EQ visual 
analogue scale (EQ VAS) assessment for overall health. 
The Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) instrument is designed to measure the effect of 
disease symptom severity on work productivity and classroom productivity (if applicable) 
(Recht 2014). The WPAI+CIQ:HS questionnaire yields scores related to work/classroom 
absenteeism, reduced on-the-job effectiveness, overall work/classroom impairment, and 
activity impairment. WPAI+CIQ:HS outcomes are expressed as impairment percentages, 
with higher numbers indicating greater impairment and less productivity (Reilly 2002). 
The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is 
designed to investigate and directly probe patient perspectives on outcomes they deem 

 
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relevant to their life and care. PROBE aims to develop a new global tool to enhance the 
direct patient-voice in health care decision-making (Chai-Adisaksopha 2017). 
Details (including sample copies where applicable) for each of the PRO instruments are 
provided in the Investigator Site File Binder. 
9.7.4 Immunogenicity  
Immunogenicity assays will be performed on plasma and PBMCs. The assays will include 
detection of anti-AAV5 capsid and anti-FVIII total antibodies, as well as determination of 
neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid 
(transduction inhibitors, TI). FVIII inhibitors will be assessed using the chromogenic 
Bethesda assay with Nijmegen modification. Any abnormality of the liver parameters will 
lead to a retrospective immunogenicity assessment to evaluate FVIII- and capsid-specific 
cellular immunogenicity. FVIII- and capsid-specific cellular immunity will be assessed by 
stimulated cytokine secretion using an ELISpot assay performed on collected PBMCs. 
9.7.5 Pharmacodynamics  
The FVIII protein concentration and activity level as measured by a validated immunoassay 
and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII 
protein and activity will be used to determine PD parameters. 
9.7.6 Pharmacokinetics  
Sparse FVIII activity assessments, prior to BMN 270 administration, will be collected to 
estimate each subject’s half-life of replacement FVIII concentrate used for prophylaxis. 
Samples will be drawn immediately prior to recombinant FVIII concentrate infusion 
(between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours 
post-FVIII infusion. If supported by the data, sparse samples together with established 
population pharmacokinetic models will be used to estimate an individual subject’s FVIII 
activity clearance (CL) value. Individual subject CL estimates may then be evaluated against 
post-BMN 270 FVIII activity levels to determine if an association exists between an 
individual’s FVIII activity CL value and FVIII activity levels achieved with BMN 270. 
For subjects receiving emicizumab, pharmacokinetics assessment is optional.    
9.7.7 Exploratory Assessments  
Blood samples will be collected from subjects at the time points indicated in the Schedules of 
Events 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 

 
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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 in this study may be used for exploratory 
research once testing for the primary purpose has been completed.  
9.7.7.1 
Optional Liver Biopsy  
Subjects electing to undergo an optional liver biopsy are required to consent to the procedure 
and collection of tissue in the study ICF. The analysis of the optional liver biopsy is 
considered exploratory. Patients who elect to proceed will have a liver biopsy performed 
around Week 26, Week 52, and/or during Years 2-5. Additional liver biopsies at times 
deemed to be clinically relevant (eg, decreasing FVIII at a time of increased ALT) may be 
pursued. Subjects will be asked to consent to the procedure for each liver biopsy performed 
during the study. 
Subjects who consent to the procedure will have a liver biopsy via either transjugular or 
percutaneous (ultrasound-guided) route, according to the standard procedures of the 
institution. Two tissue cores will be harvested in the context of the optional liver biopsy. 
Subjects will be required to observe an 8-hour fasting period before the procedure. 
Within 24 hours prior to the biopsy being performed, subjects must have a documented FVIII 
activity level of ≥ 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 on the day the biopsy, prior to the procedure. 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”. 
Details on required procedures for the optional liver biopsy are outlined in Table 9.1.5 
Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 28 days before the procedure, as follows: 
• Physical examination 
• Hematology, coagulation, chemistry assessments 
• Liver tests 

 
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• Liver ultrasound (subject should fast at least 8 hours prior to ultrasound) 
• FibroScan 
Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 7 days before the procedure, as follows: 
• Local FVIII activity level assessment 
• Pre-biopsy consultation (with hepatologist and/or radiologist) 
On the day of the biopsy, brief physical examination and liver and blood tests should be 
performed before the procedure (including hematology, coagulation, and chemistry). FVIII 
activity assessment should also be performed to ensure the subject has sufficient FVIII 
activity to protect against procedure-related bleeding (as discussed above). LT assessment 
and a whole blood draw for PBMC collection should be performed on the biopsy day or ± 1 
week from the biopsy day. 
The optional liver biopsy should be performed in the morning if feasible, 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 Study Reference 
Manual. 
Following completion of the biopsy, the subject should remain under observation in the clinic 
for at least 4-6 hours. Overnight post-procedure observation may be done at the 
Investigator’s discretion and/or according to local guidelines. 
Clinically significant findings reported from the histopathological analysis of the biopsy 
sample are subject to AE reporting (Section 10). Such findings should be further assessed 
and followed as clinically appropriate to manage the subject’s medical care. A hepatologist 
and/or other specialist clinicians should be consulted if required. In the event that fibrotic 
changes are observed on the biopsy sample, additional liver ultrasound, FibroScan and/or 
Enhanced Liver Fibrosis (ELF) testing (as regionally available and/or approved by HA) may 
be considered 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. In case of a safety concern, additional unscheduled 
laboratory tests may be performed locally (at the Investigator’s discretion) in order to 
facilitate timely and appropriate clinical management decisions; where possible, a matched 

 
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sample for testing at the central laboratory should be collected (using the Unscheduled Visit 
lab kit) at the same time as the local unscheduled sample 
9.7.8.1 
Adverse Events  
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. 
9.7.8.2 
Clinical Laboratory Assessments  
The scheduled clinical laboratory tests are listed in Table 9.7.8.2.1. Refer to the On Site File 
Binder 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: (1) the cause of the abnormality is 
determined; (2) the value returns to baseline or to within normal limits; or (3) 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 eCRF. 
In case of a safety concern, additional unscheduled laboratory tests may be performed locally 
(at the Investigator’s discretion) in order to facilitate timely and appropriate clinical 
management decisions; where possible, a matched sample for testing at the central laboratory 
should be collected (using the Unscheduled Visit lab kit) at the same time as the local 
unscheduled sample. 

 
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Table 9.7.8.2.1:  Clinical Laboratory Tests  
Blood Chemistry 
Hematology 
Urine Tests 
Coagulation Screen 
including: 
Albumin 
Hemoglobin 
Appearance 
APTT 
BUN 
Hematocrit 
Color 
PT/INR 
Calcium 
WBC count 
pH 
TT 
Chloride 
RBC count 
Specific gravity 
 
Total cholesterol 
Platelet count 
Ketones 
Complement Panel 
CPK 
Differential cell count 
Protein 
C3 
Creatinine 
RBC indices (MCV and MCH) 
Glucose 
C3a 
CRP 
 
Bilirubin 
C4 
Glucose 
 
Nitrite 
Bb 
Phosphorus 
 
Urobilinogen 
sC5b-9 
Potassium 
 
Hemoglobin 
 
Total protein 
 
 
Other Tests: 
Sodium 
 
 
ABO blood typing*  
Uric Acid 
 
 
 
BUN, blood urea nitrogen; CPK, creatinine phosphokinase; 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; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin. 
 *ABO blood typing assessment should be performed at Screening. 
 
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel 
(including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) will be 
assessed at the BMN 270 infusion visit. Subjects will fast for at least 8 hours prior to 
pre-infusion laboratory sampling on the day of the infusion visit. 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment 
including physical examination and vital signs will be performed and additional blood 
samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. 
Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 
1 week after the event for  optional exploratory cytokine profiling to assess inflammatory 
biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional 
blood samples can be collected if deemed necessary at the discretion of the Investigator and 
Medical Monitor. 
At applicable sites, certain study assessments may be performed by an MN professional at 
the patient's home or another suitable location, such as their school or office, to improve 

 
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access and convenience for patients 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 patient and the patient gives written informed consent 
to participate in MN visits, the MN network will communicate with the patient and the 
patient’s site. MN visits will be allowed at the visits indicated in the Schedules of Events. 
Unscheduled visits may also be conducted by MN as appropriate. 
9.7.8.3 
Malignancies  
A liver ultrasound (and FibroScan, at the discretion of the Investigator) will be performed at 
Screening to screen for hepatocellular carcinoma (HCC). Thereafter, liver ultrasounds will be 
performed annually at each End of Year visit starting at Year 1 (Week 52) through the end of 
the study to screen for HCC, or at interim timepoints 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. 
9.7.8.4 
Liver and Hepatitis Testing  
Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C 
infection at Screening; hepatitis B screening should include HBsAg, HBsAb, and HBcAb. 
Subjects with documented results showing an absence of active hepatitis B or hepatitis C 
infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to 
repeat those tests during the screening period.  
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. 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 the timepoints listed in Table 9.1.6. 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. 
A liver ultrasound, fasting FibroTest, and liver tests (LTs) during Screening will be 
performed to assess for clinically significant liver disease and HCC. A FibroScan may also 

 
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be performed during Screening at the discretion of the Investigator. Fasting FibroTest results 
must be available prior to BMN 270 infusion. 
Where a biopsy has been taken for safety-related reasons or was available from a past 
procedure, the Sponsor may request the biopsy information to help evaluate the impact of 
BMN 270 on the liver. The Sponsor may request that slides from a liver biopsy be made 
available for additional histopathological review. 
LTs will be monitored on a regular basis; at each time point, the following LTs should be 
assessed: 
Table 9.7.8.4.1:  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 
 
Elevated ALT levels (above the upper limit of normal range) should be evaluated according 
to the plan outlined in Table 9.4.8.2.2.1 (note that these evaluations may indicate additional 
testing of LTs and FVIII levels at unscheduled visits; these unscheduled laboratory tests may 
be completed by a mobile nursing professional at sites where the use of MN services has 
been approved). 
9.7.8.5 
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. Refer to Section 9.4.8.3 
for guidance on monitoring of HIV-positive subjects. 
9.7.8.6 
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 the timepoints indicated in the schedules of events. 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 at least 8 hours 
during the subject’s stay in the clinic. Any abnormal vital sign assessments should be 
repeated, and both values should be recorded in the eCRF. 

 
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A complete physical examination should be performed during Screening/Baseline, at 
Week 26 (± 2 weeks) 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. The genitourinary examination may be deferred for 
visits after Year 1 unless the subject has genitourinary-related complaints. 
A brief physical examination will include general appearance, cardiovascular, dermatologic, 
respiratory, gastrointestinal, musculoskeletal, and neurologic assessments. 
Height will be recorded at Screening only. Weight will be recorded at Screening and then at 
the timepoints indicated in the Schedules of Events. 
9.7.8.7 
Vector Shedding  
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 polymerase chain reaction (PCR). Fluids tested will include: 
• Blood 
• Saliva 
• Semen 
• Urine 
• Stool 
Vector shedding will also be extensively studied in the present clinical trial. Testing will 
continue until at least 3 consecutive results below the limit of detection are obtained; 
additional collection and testing may be performed based on batch testing schedules, result 
turnaround times, or discussions between Medical Monitor and Investigator. If a positive 
result is obtained in a matrix after 3 consecutive results below the limit of detection have 
already been recorded, testing in that matrix should restart and continue until an additional 3 
consecutive results below the limit of detection have been obtained in order to confirm 
clearance. 
Testing of semen will continue at least through Week 12, even if 3 consecutive results below 
the limit of detection have been recorded in that compartment prior to that time point. 

 
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Subjects who have not had 3 consecutive semen samples below the limit of detection by 
Week 52 should continue to have PCR testing in 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).  
Samples may be fractionated prior to shedding analysis in order to better characterize the 
presence, structure, and location of vector DNA and/or vector capsid within each matrix. 
If needed, the fractionation may be performed with samples collected specifically for 
shedding analysis (saliva, blood, semen, urine, stool). Alternatively, the vector DNA 
characterization during shedding analysis may utilize already fractionated exploratory 
samples obtained from the above biofluids, such as exploratory plasma samples, exploratory 
PBMC samples, and red blood cells recovered during PBMC/plasma isolations.  
Fractionation of semen to collect purified sperm separately from non-sperm cells may be 
performed, after consultation between the Medical Monitor and the Investigator, in parallel at 
any visit where semen samples are collected. The shedding analysis of a fractionated semen 
sample will only be performed if vector DNA was detected in the whole semen sample for 
the same visit. Fractionation of semen during shedding analysis may be stopped if purified 
sperm tested positive for vector DNA on at least three visits, or if purified sperm tested 
below the limit of detection for vector DNA on at least three consecutive visits. 
Contraception use may need to be extended beyond 12 weeks in individual subjects based on 
observed vector shedding in semen. After 12 weeks, 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 hematology, 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, an adverse event (AE) is any untoward medical occurrence in a subject, 
temporally associated with the use of study intervention, whether or not considered related to 
the study intervention.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention.  
Events meeting the AE definition include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Events not meeting the AE definition include: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

 
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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: 
• 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: 
• Results in death 
• Is life-threatening  
Note: Life-threatening refers to an event in which the subject was at risk of death at 
the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. If the investigational product preparation, infusion, and 
post-infusion observation period require transfer to an inpatient setting for 
completion, in the absence of an AE, this will not be considered an SAE. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.  
• 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 medical/surgical intervention to prevent one of the 
other outcomes listed above (eg, anaphylaxis)  

 
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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 > ULN or ≥ 1.5x baseline value, regardless of whether that 
elevation triggers an initiation or modification of oral corticosteroid treatment 
• Events potentially meeting the criteria for Hy’s law (ALT or AST elevation ≥ 3x 
ULN plus total bilirubin ≥ 2x ULN) 
• Thromboembolic event 
• Immediate reactions: infusion-related reactions, hypersensitivity adverse events, or 
anaphylaxis 
• 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 drug, only SAEs associated 
with any protocol-imposed interventions will be collected. AEs occurring during this 
time period should be recorded on the Medical History eCRF. 
• After informed consent is obtained and following infusion 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  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. The Investigator will record all relevant AE/SAE/EOSI information in the 
subject’s medical record and 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/or concomitantly administered 
corticosteroids and/or other immunosuppressive agents, and seriousness (refer to 
Section 10.2 for SAE definitions). These assessments must be made by a study clinician with 

 
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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 Investigator will determine the severity of each 
AE, SAE and EOSI using the Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v4.03. Adverse events that do not have a corresponding CTCAE term will be 
assessed according to the general guidelines for grading used in the CTCAE v4.03 as stated 
in Table 10.3.3.2.1. 
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 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/or 
corticosteroids and/or other immunosuppressant agents and will record it on the source 
documents and AE eCRF. 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 and/or corticosteroids and/or other immunosuppressive 
agents has not occurred 
OR 
• 
The administration of the IP and/or corticosteroids and/or other 
immunosuppressive agents 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 and/or corticosteroids and/or other immunosuppressive agents; that is, 
there are no facts, evidence, or arguments to suggest a causal relationship to 
the IP and/or corticosteroids and/or other immunosuppressive agents. 
Related 
• 
The administration of the IP and/or corticosteroids and/or other 
immunosuppressive agents and the occurrence of the AE are reasonably 
related in time 
AND 
• 
The AE could not possibly be explained by factors or causes other than 
exposure to the IP and/or corticosteroids and/or other immunosuppressive 
agents 
OR 
 
• 
The administration of IP and/or corticosteroids and/or other 
immunosuppressive agents and the occurrence of the AE are reasonably 
related in time  
AND 
• 
The AE is more likely explained by exposure to the IP and/or corticosteroids 
and/or other immunosuppressive agents 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 and/or corticosteroid and/or other 
immunosuppressive agent exposure  
• Consistency with study product pharmacology 
• Known relationship to underlying mechanism of study drug and/or corticosteroid 
and/or other immunosuppressive agent action 
• Similarity to adverse reactions seen with related drug products 

 
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• Abatement of AE with discontinuation of study drug and/or corticosteroids and/or 
other immunosuppressive agents, and/or recurrence of AE with reintroduction of 
study drug and/or corticosteroids and/or other immunosuppressive agents 
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  
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 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 
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. For 
example, if a subject has an adverse event of ALT increased that subsequently resolves, but 

 
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the subject’s ALT increases again, that should be reported as two adverse events – the initial 
ALT increase, and the second ALT increase.  
10.4.1.3 
Abnormal Laboratory Values  
Laboratory test results (including any local FVIII activity or liver test results) will be 
recorded on the laboratory results pages of the 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 unless associated with an AE that has already been 
reported. 
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 AE that has already been reported. 
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.  

 
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For purposes of this study, laboratory tests showing a decreased level of FVIII 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). 
10.4.1.4 
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). 
10.4.1.5 
General Physical Examination Findings  
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.4). 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 documented as an AE or SAE on the AE eCRF. 
10.4.1.6 
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 worsened 
• Insert an in-dwelling IV catheter (such as a Port-a-Cath or other brand, if applicable) 
for administration of study drug or FVIII replacement therapy 
• Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.7 
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. 

 
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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. 
10.4.1.8 
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 BioMarin 
Pharmacovigilance (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. IND safety reports will be submitted within 7 calendar days for fatal or 
life-threatening unexpected suspected adverse reactions (SUSARs) and within 15 calendar 
days for other non-life-threatening SUSARs 

 
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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 electronic data capture (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 Institutional Review Board or Independent Ethics Committee Reporting 
Requirements  
Reporting of SAEs to the Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB) will be done in compliance with the standard operating procedures and policies of the 
IEC/IRB and with applicable regulatory requirements. Adequate documentation must be 
obtained by BioMarin showing that the IEC/IRB was properly and promptly notified as 
required. 
10.6 
Follow-up of Subjects after Adverse Events  
After the initial AE/SAE/EOSI report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All AEs/SAEs/EOSI will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up. Resolution 
of AEs/SAEs/EOSI (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 and EOSI, 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 or 
EOSI 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 drug. 
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 drug. The Sponsor should also be 
notified if the Investigator should become aware of the development of cancer or of a 

 
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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 
IRB/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 
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: 
• 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, MHS 
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 substrate FVIII assay and the one-stage clotting FVIII 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 should be performed within 28 days of BMN 270 infusion (and must 
be performed within 42 days prior to BMN 270 infusion), while baseline assessments will 
take place within 7 days prior to BMN 270 infusion (Day 1). Should the screening visit occur 
within 30 days of the drug infusion, physical examination, vital signs, blood chemistry, LTs, 
hematology, urine tests, and coagulation tests do not need to be repeated at Baseline.  
During the first part of the Screening Period (Day -42 to Day -29), testing for AAV5 TAb 
titers using the CDx screening assay may be performed, so that subjects can verify their 
AAV5 TAb status. Subjects who agree to participate in this activity may be asked to sign a 
separate ICF documenting this decision. Subjects who do not have testing during this period 
will have CDx AAV5 TAb testing along with the rest of the Screening assessments. 
If the subject underwent early AAV5 TAb testing and was consented using the full study 
ICF, the ICF does not need to be re-administered and re-signed as part of regular Screening. 
If the subject underwent early AAV5 TAb testing and was consented using the dedicated 
stand-alone ICF for that purpose, the full ICF will need to be signed if the subject proceeds to 
regular Screening. 
The following procedures will be performed during the Screening Period: 
• Demographics (age, sex, race, ethnicity) 
• Full medical history, including hemophilia A history, hepatitis B, hepatitis C, and 
HIV. Subjects with a history of hepatitis B, hepatitis C, or HIV will be asked for 
information about the treatments received. Any prior pharmacokinetics information 
obtained while the subject was receiving prophylactic or episodic hemophilia therapy 
prior to the study should also be collected. 
• 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 

 
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• Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) for the previous 12 months 
o Further information on details to be included in documentation of previous 
bleeding episodes and FVIII usage, refer to the Investigator Site File 
Binder. 
• Distribution of subject diaries and training in diary completion 
• Electrocardiogram 
• Liver ultrasound to screen for HCC and clinically significant liver disease (FibroScan 
can be performed additionally at the discretion of the Investigator) 
• Samples for hFVIII Assays 
o Baseline FVIII activity – chromogenic substrate FVIII assay 
o Baseline FVIII activity level – one-stage clotting FVIII assay 
o hFVIII coagulation activity exploratory assay (collected but not tested 
prior to enrollment) 
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level  
o hFVIII protein assay (collected but not tested prior to enrollment) 
• hFVIII total antibody (TAb) assay (collected but not tested prior to enrollment) 
• 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) 
o Hepatitis B screening should include HBsAg, HBsAb, and HBcAb. 
• SARS-CoV-2 screening (local or central testing) 
o SARS-CoV-2 RT-PCR testing is required during Screening, and all 
subjects must have at least one negative test result prior to dosing. If the 
test is performed locally an additional 2nd test is recommended, but if 
performed negative results from the 2nd test must be received prior to 
dosing. A SARS-CoV-2 vaccine is recommended for subjects if indicated 
and if available (refer to Section 9.4.8). 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
o ABO blood typing assessment should be performed at Screening 
• Urine tests (refer to Table 9.7.8.2.1) 
• Liver tests (refer to Table 9.7.8.4.1) 
• AAV5 TAb Assessment (CDx) 

 
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o If performed during the early Screening period, the CDx AAV5 TAb 
assessment does not need to be repeated as part of general Screening 
• Fasting FibroTest 
o Subjects will fast for at least 8 hours prior to sampling on the day of the 
FibroTest Screening visit. Fasting FibroTest results must be available prior 
to BMN 270 infusion. 
• Biomarker testing (including HLA genotyping and FVIII genotyping status) 
• Serum for exploratory biomarkers 
• Exploratory CK18 and Grp78 assessment 
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 chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
• Urine tests (refer to Table 9.7.8.2.1) 
• Liver tests (refer to Table 9.7.8.4.1) 

 
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• SARS-CoV-2 screening (local or central testing) 
o SARS-CoV-2 RT-PCR testing is required during smart rescreening, and 
all subjects must have at least one negative test result prior to dosing. If 
the test is performed locally an additional 2nd test is recommended, but if 
performed negative results from the 2nd test must be received prior to 
dosing. A SARS-CoV-2 vaccine is recommended for subjects if indicated 
and if available (refer to Section 9.4.8). 
• AAV5 TAb Assessment (CDx) 
12.3 
Baseline Visit  
Baseline values will be recorded from 1 to 7 days prior to the treatment visit. Subjects are 
considered enrolled into the study once the Baseline visit has occurred. The following 
procedures will be performed during the Baseline Period: 
• Brief physical examination 
• Vital signs 
• Assessment of adverse events and concomitant medications 
• Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
• Samples for hFVIII Assays 
o Baseline FVIII activity – chromogenic substrate FVIII assay 
o Baseline FVIII activity level – one-stage clotting FVIII assay 
o hFVIII coagulation activity exploratory assay 
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level  
o hFVIII protein assay 
• hFVIII TAb  
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
• Urine tests (refer to Table 9.7.8.2.1) 
• Liver tests (refer to Table 9.7.8.4.1) 
• Immunogenicity AAV5 TAb assay 
• AAV5 TI assay 
• IFNg ELISpot  
• Plasma, PBMC, and RBC collection for exploratory biomarkers  
• Complement Panel and Exploratory Cytokine Profiling 

 
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• Exploratory CK18 and Grp78 assessment 
• Haemo-QoL-A assessment 
• EQ-5D-5L 
• WPAI+CIQ:HS 
• PROBE 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
• Pharmacokinetics 
o Samples will be drawn immediately prior to recombinant FVIII 
concentrate infusion (between Day -2 and Day -7), 3 hours (+/- 30 
minutes) post-FVIII infusion, and 24-52 hours post-FVIII infusion. For 
subjects receiving emicizumab, pharmacokinetics assessment is optional. 
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 at 
least 8 hours for the BMN 270 Infusion Visit. The following procedures will be performed 
during the BMN 270 Infusion Visit: 
• Initiation of prophylactic corticosteroids (at least 3 hours prior to BMN 270 infusion) 
• Brief physical examination (prior to 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 at least 
8 hours during the subject’s stay in the clinic. 
• Assessment of adverse events and concomitant medications (prior to infusion) 
• Fasting lipid panel (blood triglycerides, total cholesterol, HDL cholesterol, and LDL 
cholesterol) (sample collected pre-infusion) 
o Subjects will fast for at least 8 hours prior to pre-infusion laboratory 
sampling on the day of the infusion visit. 
• AAV5 TAb Assay (CDx) (sample collected pre-infusion for analysis) 
• Immunogenicity AAV5 TAb Assay (sample collected pre-infusion) 
• AAV5 TI Assay (sample collected pre-infusion) 
• Serum for exploratory biomarkers (sample collected pre-infusion) 
• BMN 270 Infusion 

 
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• Complement Panel and Exploratory Cytokine Profiling (should be collected 2 hours 
after completion of the infusion) 
• Hypersensitivity blood assessments (if required, see below) 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Collection of samples for PCR testing should occur between 2 and 
24 hours after the BMN 270 infusion has been completed 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment 
including physical examination and vital signs will be performed and additional blood 
samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. 
Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 
1 week after the event for optional exploratory cytokine profiling to assess inflammatory 
biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional 
blood samples can be collected if deemed necessary at the discretion of the Investigator and 
Medical Monitor. 
12.5 
BMN 270 Infusion Follow-Up Visits – Weeks 1-26  
After BMN 270 has been infused, subjects will have weekly assessments during Weeks 1-26. 
Visits between scheduled clinic visits may be performed by a mobile nursing (MN) 
professional at the subject’s home or another suitable location (if the subject has given 
written informed consent to participate in MN visits), or at the site or approved lab facility as 
a shortened lab draw-only visit. The MN service or site will collect blood samples at these 
visits. For site lab draw-only visits, sites will contact the subject via phone call or e-mail to 
collect information regarding adverse events, changes to concomitant medications, bleeding 
episodes, and hemophilia therapy use. For MN visits, the service will collect this 
information. Unscheduled visits may also be conducted by MN as appropriate. 
At the Week 1-26 visits, the following procedures will be completed. 
12.5.1 Once per week (Weeks 1 through 26)  
The following procedures will be performed at one visit per week from Weeks 1 through 26: 
• Assessment of adverse events and concomitant medications (including review of 
subject diary for bleeding and FVIII use) 

 
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• Liver Tests (refer to Table 9.7.8.4.1) 
o LT assessment may be checked more frequently when ALT values are > ULN 
or ≥ 1.5x baseline value or based upon  discussion between the Medical 
Monitor and the Investigator.  
• Samples for FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay  
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will 
be tested as deemed necessary by the Sponsor) 
• Exploratory CK18 assessment 
12.5.2 Week 1 - Day 8  
On Day 8, the following procedures will be performed, in addition to the weekly assessments 
required in Section 12.5.1: 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
• Plasma, PBMC, and RBC collection for exploratory biomarkers  
• Serum for exploratory biomarkers 
• Complement Panel and Exploratory Cytokine Profiling 
12.5.3 Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26  
At Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26, the following procedure will be performed: 
• Serum for exploratory biomarkers 
12.5.4 Weeks 2, 4, 8, 12, 16, 20, 24, and 26  
At Weeks 2, 4, 8, 12, 16, 20, 24, and 26, the following procedure will be performed: 
• Complement Panel and Exploratory Cytokine Profiling 
12.5.5 Weeks 2, 6, 10, 14, 18, 22, 24, and 26  
At Weeks 2, 6, 10, 14, 18, 22, 24, and 26, the following procedure will be performed: 
• IFNg ELISpot  
12.5.6 Weeks 4, 8, 12, 16, 20, 24, and 26  
At Weeks 4, 8, 12, 16, 20, 24, and 26, the following procedures will be performed: 
• Vital Signs 

 
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• Weight (not done at Week 24) 
• hFVIII TAb 
• hFVIII protein assay 
• PCR of vector DNA in blood, saliva, urine, semen, and stools (not done at Week 24) 
o Sample testing to occur until at least 3 consecutive sample results below 
the limit of detection have been obtained. Testing of semen will continue 
at least through Week 12, even if 3 consecutive results below the limit of 
detection have been recorded in that compartment prior to that time point. 
12.5.7 Weeks 4, 8, 12, 16, 18, 20, 22, 24, and 26  
At Weeks 4, 8, 12, 16, 18, 20, 22, 24, and 26, the following procedures will be performed: 
• Brief physical examination 
o A complete physical examination should be done at Week 26. 
12.5.8 Weeks 4, 8, 16, and 26  
At Weeks 4, 8, 16, and 26, the following procedures will be performed: 
• Immunogenicity AAV5 TAb Assay 
• AAV5 TI Assay 
12.5.9 Weeks 4, 8, 12, 18, 22, and 26  
At Weeks 4, 8, 12, 18, 22, and 26, the following procedure will be performed: 
• Plasma, PBMC, and RBC collection for exploratory biomarkers 
12.5.10Week 4, 12, and 26  
At Weeks 4, 12, and 26, the following procedure will be performed: 
• Haemo-QoL-A assessment 
• EQ-5D-5L 
• WPAI+CIQ:HS 
• PROBE 
12.5.11  Weeks 4, 16, and 26   
At Weeks 4, 16, and 26, the following procedure will be performed: 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 

 
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12.5.12  Weeks 12 and 26   
At Weeks 12 and 26, the following procedure will be performed: 
• Urine Tests (refer to Table 9.7.8.4.1) 
12.5.13  Weeks 6 and 20   
At Weeks 6 and 20, the following procedure will be performed: 
• Testing for reactivation of hepatitis B and hepatitis C 
o Testing for reactivation of hepatitis B and hepatitis C only for subjects 
with a past medical history of hepatitis B or hepatitis C prior to study 
entry. 
12.5.14  Week 26   
At Week 26 (± 2 weeks), the following optional procedure will be performed: 
• Optional liver biopsy (refer to Section 12.9 for assessments related to liver biopsy) 
12.6 
Post-Infusion Follow-Up – Weeks 27-52  
After Week 27, subjects will have assessments at Weeks 28, 30, 32, 34, 36, 40, 44, 48, 50, 
and 52. Visits between scheduled clinic visits may be performed by a mobile nursing (MN) 
professional at the subject’s home or another suitable location (if the subject has given 
written informed consent to participate in MN visits), or at the site or approved lab facility as 
a shortened lab draw-only visit. The MN service or site will collect blood samples at these 
visits. For site lab draw-only visits, sites will contact the subject via phone call or e-mail to 
collect information regarding adverse events, changes to concomitant medications, bleeding 
episodes, and hemophilia therapy use. For MN visits, the service will collect this 
information. Unscheduled visits may also be conducted by MN as appropriate. 
At these visits, the following assessments will be performed. 
12.6.1 Each Visit (Weeks 28, 30, 32, 34, 36, 40, 44, 48, 50, and 52)  
The following procedures will be performed at every visit (Week 26, 28, 30, 32, 34, 36, 40, 
44, 48, 50, and 52): 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Liver Tests (refer to Table 9.7.8.4.1) 
o LT assessment may be checked more frequently when ALT values are > ULN 
or ≥ 1.5x baseline value or based upon  discussion between the Medical 
Monitor and the Investigator.  

 
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• Samples for FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will 
be tested as deemed necessary by the Sponsor) 
• Exploratory CK18 assessment 
12.6.2 Weeks 28, 32, 36, 40, 44, 48, and 52  
At Weeks 28, 32, 36, 40, 44, 48, and 52, the following procedure will be performed: 
• Brief physical examination (complete physical examination at Week 52) 
12.6.3 Week 28, 36, 44, and 52  
At Weeks 28, 36, 44, and 52, the following procedure will be performed: 
• Plasma, PBMC, and RBC collection for exploratory biomarkers  
12.6.4 Week 32  
At Week 32, the following procedure will be performed: 
• Testing for reactivation of hepatitis B and hepatitis C 
o Testing for reactivation of hepatitis B and hepatitis C only for subjects 
with a past medical history of hepatitis B or hepatitis C prior to study 
entry. 
12.6.5 Weeks 32, 36, 40, 44, 48, and 52  
At Weeks 32, 36, 40, 44, 48, and 52, the following procedure will be performed: 
• Vital Signs 
• hFVIII protein assay 
12.6.6 Weeks 32, 36, 44, and 52  
At Weeks 32, 36, 44, and 52, the following procedures will be performed: 
• Weight 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)  
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing to occur until at least 3 consecutive sample results below 
the limit of detection have been obtained. 

 
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12.6.7 Week 36 and 52  
At Weeks 36 and 52, the following procedures will be performed: 
• Urine Tests (refer to Table 9.7.8.4.1) 
• Immunogenicity AAV5 TAb Assay 
• AAV5 TI Assay 
• hFVIII TAb 
• IFNg ELISpot  
• Complement Panel and Exploratory Cytokine Profiling 
• Serum for exploratory biomarkers 
12.6.8 Week 52  
At Week 52, the following procedures will be performed: 
• Liver ultrasound 
o Additional liver ultrasounds may be performed prior to Week 52 at the 
discretion of the Investigator 
• Haemo-QoL-A assessment 
• EQ-5D-5L 
• WPAI+CIQ:HS 
• PROBE 
12.6.9 Week 52  
At Week 52 (± 2 weeks), the following optional procedure will be performed: 
• Optional liver biopsy (refer to Section 12.9 for assessments related to liver biopsy) 
12.7 
Post-Infusion Follow-Up – Years 2-5  
During Years 2-5, at applicable sites, certain study assessments may be performed by a 
mobile nursing (MN) professional at the patient's home or another suitable location, such as 
their school or office, to improve access and convenience for patients 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 patient 

 
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and the patient gives written informed consent to participate in MN visits, the MN network 
will communicate with the patient and the patient’s site. MN visits will be allowed for the 
Q4W and Q6W visits during Years 2-5; the Q12W visits and End of Year visits during 
Years 2-5 will not be performed by an MN professional but will be done at the study site. 
Unscheduled visits may also be conducted by MN as appropriate. 
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) or Q6W 
(during Years 3-5) until vector shedding has been cleared, either by reporting to the site to 
provide samples or by providing those samples to a MN professional. Subjects who are not 
attending the Q4W/Q6W visits during Years 2-5 may receive a scheduled monthly follow-up 
telephone call from the site to ask about adverse events, concomitant medications, and 
bleeding events/FVIII replacement usage.   
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed: 
12.7.1 Year 2 (Every 4 Weeks) or Years 3-5 (Every 6 Weeks) (not required for 
treatment failure subjects)  
During Years 2 (every 4 weeks  ± 2 weeks) or 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 9.7.8.4.1) 
o LT assessment may be checked more frequently when ALT values are > 
ULN or ≥ 1.5x baseline value or based upon  discussion between the 
Medical Monitor and the Investigator.  
• FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will 
be tested as deemed necessary by the Sponsor) 
▪ If a subject tests positive in the cNBA during Years 3-5, a fresh 
sample should be collected within 4 weeks of the initial visit that 
had a positive result. 

 
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• Exploratory CK18 assessment 
• PCR of vector DNA in semen (if required) 
o Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are clear by the end of Year 1.  Subjects who have not had 
3 consecutive semen samples below the limit of detection by the end of 
Year 1 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). 
▪ 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 semen samples for 
assessment every 4 weeks (during Year 2) or 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). 
12.7.2 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 104 
• Year 3 – Week 116, Week 128, Week 140, Week 156 
• Year 4 – Week 168, Week 180, Week 192, Week 208 
• Year 5 – Week 220, Week 232, Week 244, Week 260 (final study visit) 
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: 
• Physical examination 
o Complete physical examination will be performed at the End of Year 
visits (genitourinary examination may be deferred); brief physical 
examination may be performed at other visits. 
• 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) 
• Vital Signs 

 
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• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
(at Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
• Urine Tests (refer to Table 9.7.8.2.1) (at Week 76, Week 128, Week 180, Week 232, 
and End of Year visits only) 
• Liver Tests (refer to Table 9.7.8.4.1) 
o LT assessment may be checked more frequently when ALT values are > 
ULN or ≥ 1.5x baseline value or based upon  discussion between the 
Medical Monitor and the Investigator.  
• FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will 
be tested as deemed necessary by the Sponsor) 
▪ If a subject tests positive in the cNBA during Years 3-5, a fresh 
sample should be collected within 4 weeks of the initial visit that 
had a positive result. 
• hFVIII protein assay 
• Immunogenicity AAV5 TAb Assay (at End of Year visits only) 
• AAV5 TI Assay (at End of Year 5 visit only) 
• hFVIII TAb 
• Interferon gamma (IFNg) ELISpot (at Week 76, Week 128, Week 180, Week 232, 
and End of Year visits only) 
• Plasma, PBMC, and RBC collection for exploratory biomarkers  
• Serum for exploratory biomarkers 
• Exploratory CK18 assessment 
• Liver ultrasound (at End of Year visits only) 
o Additional liver ultrasounds may be performed at interim timepoints (ie, 
between the End of Year visits) at the discretion of the investigator 
• Haemo-QoL-A assessment (at Week 76, Week 128, Week 180, Week 232, and End 
of Year visits only) 
• EQ-5D-5L (at Week 76, Week 128, Week 180, Week 232, and End of Year visits 
only) 

 
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• WPAI+CIQ:HS (at Week 76, Week 128, Week 180, Week 232, and End of Year 
visits only) 
• PROBE (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
• 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 below the limit of detection during the Post-Infusion Follow-Up 
period in Weeks 1-52.  
• Optional liver biopsy (Years 2-5) (refer to Section 12.9 for assessments related to 
liver biopsy) 
12.8 
Early Termination 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 ETV. The Early Termination Visit (ETV) will occur on the 
date the subject withdraws from the study, even if the date does not correspond to a protocol-
specific visit. At the ETV, as many of the following assessments as possible should be done: 
• Complete physical examination 
• Weight 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Vital Signs 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Tests (refer to Table 9.7.8.4.1) 
• FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will 
be tested as deemed necessary by the Sponsor) 
• hFVIII protein assay  
• PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
• Immunogenicity AAV5 TAb Assay 
• AAV5 TI Assay 

 
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• hFVIII TAb 
• IFNg ELISpot 
• Plasma, PBMC, and RBC collection for exploratory biomarkers 
• Serum for exploratory biomarkers 
• Exploratory CK18 assessment 
• Haemo-QoL-A assessment 
• EQ-5D-5L 
• WPAI+CIQ:HS 
• PROBE 
12.9 
Optional Liver Biopsy  
Details on required procedures for the optional liver biopsy are outlined in Table 9.1.5. 
Subjects may be asked to provide a liver biopsy around Week 26, Week 52, and during the 
Years 2-5 period post-BMN 270 infusion. 
Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 28 days before the procedure, as follows: 
• Liver ultrasound (subject should fast at least 8 hours prior to ultrasound) 
• Physical examination 
• Hematology, coagulation, chemistry assessments 
• Liver tests 
• FibroScan 
Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy 
assessments at least 7 days before the procedure, as follows: 
• FVIII activity level assessment (central and local) 
• Exploratory CK18 and Grp78 assessment 
• Pre-biopsy consultation (with hepatologist and/or radiologist) 
On the day of the biopsy, brief physical examination and liver and blood tests should be 
performed before the procedure (including hematology, coagulation, and chemistry). FVIII 
activity assessment should also be performed to ensure the subject has sufficient FVIII 
activity to protect against procedure-related bleeding (as discussed above). LT assessment 
and a whole blood draw for PBMC collection should be performed on the biopsy day or ± 1 
week from the biopsy day. 

 
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The optional liver biopsy should be performed in the morning if feasible, 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 Study Reference 
Manual. 
Following completion of the biopsy, the subject should remain under observation in the clinic 
for at least 4-6 hours. Overnight post-procedure observation may be done at the 
Investigator’s discretion and/or according to local guidelines. 
12.10 End of Study  
The study will end after the last subject yet to complete the Week 260 visit does so, has 
transferred to another BMN 270 study, is withdrawn from the study, or discontinues from the 
study. 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, 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.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications.  

 
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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 
analyses. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses  
No formal interim analysis is planned. Informal analyses (ie, no hypothesis testing) may be 
performed at different timepoints to assess efficacy and safety over time. The primary 
efficacy endpoint for such analyses involves hFVIII activity, as measured by chromogenic 
substrate assay, and is defined as median FVIII activity during a specific 4-week time 
interval post-BMN 270 infusion. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data  
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data. 
Missing data imputation and sensitivity analyses to assess the impact of missing data on the 
primary and secondary efficacy endpoints analyses are described in the following sections. 
Additional details regarding the handling of missing data will be provided in the SAP. 
14.2 
Primary Efficacy Endpoint  
For the primary efficacy endpoint at Week 52 (ie, the change in the hFVIII activity during 
Weeks 49-52 post-BMN 270 infusion from baseline, as measured by chromogenic substrate 
assay), a one-sample t-test will be used to test the null hypothesis that the change is 0 or less 
against the alternative hypothesis that the change is greater than 0 at the 1-sided significance 
level of 0.025 (or equivalently, at the 2-sided significance level of 0.05). Baseline value of 
1 IU/dL (eligible subjects must have residual FVIII levels ≤ 1 IU/dL as evidenced by medical 
history) will be used in the calculation of change from baseline since all the subjects will be 
on prophylactic hemophilia therapy prior to BMN 270 infusion where the FVIII activity level 
cannot be reliably measured. Descriptive summaries of the proportions of subjects whose 
hFVIII activity during Weeks 49-52 is greater than or equal to select thresholds, such as 
5, 15, 25, 30, and 40 IU/dL, and the confidence intervals of the proportions will also be 
provided.  
For a subject with a missing value of the primary endpoint, the median value in the subject’s 
last 4-week window containing a valid observation will be used. Additional analyses will be 

 
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conducted to examine the sensitivity of the results to the handling of missing data, including 
analysis using observed cases, and a mixed model for repeated measures (MMRM) approach. 
Further detail will be provided in the SAP. 
The analyses for the primary endpoint will be performed using the analysis populations as 
defined in Section 14.9. 
14.3 
Secondary Efficacy Endpoints  
The analyses of the secondary efficacy endpoints will be descriptive. Mean and associated 
95% confidence interval will be provided for the following secondary endpoints, where the 
baseline value will be derived from the data in the approximately 12-month period prior to 
BMN 270 infusion: 
• For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in 
the annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy from 
Week 5 post BMN 270 infusion to last visit by data cutoff (for Week 52 analysis); 
and separately, for subjects receiving prior emicizumab prophylaxis, change from 
baseline in the annualized utilization (mg/kg/year) of emicizumab from Week 27 post 
BMN 270 infusion to last visit by data cutoff (for Week 52 analysis)  
• For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in 
the annualized infusion rate (number/year) of exogenous FVIII replacement therapy 
from Week 5 post BMN 270 infusion to last visit by data cutoff (for Week 52 
analysis); and separately for subjects receiving prior emicizumab prophylaxis, change 
from baseline in the annualized utilization (mg/kg/year) of emicizumab from Week 
27 post BMN 270 to last visit by data cutoff (for Week 52 analysis) infusion 
• Change from baseline in the annualized number of bleeding episodes (number/year) 
requiring exogenous FVIII replacement treatment from Week 5 post-BMN 270 
infusion to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior 
FVIII prophylaxis, or from Week 27 post-BMN 270 infusion to last visit by data 
cutoff (for Week 52 analysis) for subjects receiving prior emicizumab prophylaxis 
from baseline 
Mean change from baseline and associated 95% confidence interval will be calculated for the 
total score of Haemo-QoL-A at Week 52 post-BMN 270 infusion as well. 
The missing value of the change for annualized utilization and annualized infusion rate will 
be imputed as 0. The missing value of the change for annualized number of bleeding 
episodes will be imputed using the median value of the changes of all observed cases. 
A sensitivity analysis is planned to analyze ABR using a generalized linear mixed model 
assuming negative binomial as the underlying distribution. The model will include period 
(pre- to post-BMN 270 infusion) as the only factor, repeated within subject. The actual 

 
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number of bleeding episodes will be used as the dependent variable with the time period 
adjustment (annualization) being implemented as the offset.  
To assess the impact of missing data, analyses using observed case are planned as sensitivity 
analyses for the secondary endpoints. Multiple imputation methods may also be performed. 
14.4 
Tertiary Efficacy Endpoints  
The analyses of the tertiary efficacy endpoints will be descriptive. Mean change from 
baseline and associated 95% confidence interval will be provided for EQ-5D-5L, 
WPAI+CIQ: HS and PROBE scores at Week 52 post-BMN 270 infusion. 
14.5 
Immunogenicity  
Analysis of total and neutralizing antibody response and other immunological parameters 
will be primarily descriptive and involve both inter-subject and intra-subject comparisons.  
14.6 
Pharmacodynamic Analyses  
Plasma FVIII protein concentrations and FVIII activities determined over the course of the 
study will primarily be evaluated and summarized with descriptive statistical measures 
(eg, mean, standard deviation, CV%, min, median, max).  
14.7 
Safety Analysis  
All AEs will be coded to system organ class and preferred term using the current version of 
MedDRA. The incidence of AEs will be summarized by system organ class, preferred term, 
relationship to study drug, seriousness, and severity. A by-subject listing will be provided for 
those subjects who experience an SAE, including death, EOSI, or an AE resulting in early 
withdrawal from the study.  
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. 
14.8 
Determination of Sample Size  
Approximately 20 subjects may be dosed in the study, including at least 16 subjects who are 
AAV5 antibody-negative and up to 25% of the total number of subjects with an AAV5 
antibody titer that is detectable but below the minimum required dilution (< 20) at Screening. 
For the primary endpoint, a sample size of 16 will provide 85% power to demonstrate that 

 
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the change in hFVIII activity during Weeks 49-52 from baseline is greater than 0, assuming 
an effect size of 0.8, using a one-sample t-test at the 1-sided significance level of 0.025 (or 
equivalently, at the 2-sided significance level of 0.05). The effect size of 0.8 is assumed 
conservatively based on the results from 270-201 and the interim results from 270-301. 
14.9 
Analysis Populations  
The intention-to-treat (ITT) population is defined as all subjects who received BMN 270 
infusion. The ITT population will be the primary population for safety analyses, as well as 
being used for supportive efficacy analyses. 
The modified intention-to-treat (mITT) population is the primary analysis population for 
efficacy for this study. The mITT population will include all subjects who received 
BMN 270 infusion and who were AAV5 antibody negative at Screening (ie, excludes 
subjects with an AAV5 antibody titer detectable but below the minimum required dilution). 
The AAV MRD population (ie, subjects with an AAV5 antibody titer detectable but below 
the minimum required dilution) will be used for exploratory efficacy analysis on FVIII 
activity, as measured by chromogenic substrate assay, during Weeks 49-52 post BMN 270 
infusion. 
14.10 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 must be sought, 
and the Investigator should inform BioMarin and the full IRB/IEC within 2 working days 
after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/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 IRB/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 IRB/IEC, 
and all active subjects must again provide informed consent. 

 
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15 
DATA MONITORING COMMITTEE  
An independent DMC will be convened for this study. The duties of the DMC will include: 
• Conducting an ongoing review of individual subject safety and efficacy data during 
the study. 
• Recommending whether to continue enrolling subjects based on emerging data and 
the overall risk/benefit analysis of BMN 270. 
• 
Making other recommendations on the conduct and reporting of the trial based on 
their evaluation of clinical data. 
Details on the composition of the committee, frequency of meetings, and other committee 
functions and parameters are included in the DMC Charter and in the SAP. 

 
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16 
COSTS, COMPENSATION, AND SUBJECT INJURY  
BioMarin will pay the full costs of the study-related tests, procedures, and treatments set 
forth in the protocol. In addition, after IRB/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 study drug 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 immediate 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 study drug 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 that are unrelated to this study. 

 
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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 eCRF casebook to verify its accuracy. 
eCRFs 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 eCRF 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 date and time of the correction and the identity of the operator. 
BioMarin’s policy is that study data on the eCRFs 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 direct source document verification of study data by the 
site monitor is prohibited by institutional policy or local law, then the Investigator must make 
available facilities and/or personnel to allow GCP-compliant source verification to occur. 
Examples of such methods include certified copies of records which have study data visible 
but sensitive information redacted, or other GCP-compliant means agreed between the 
Investigator and the Sponsor. 
A site monitor designated by BioMarin will compare the eCRFs 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 site monitor, 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 site monitor 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 eCRF 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 

 
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source data verified. The Investigator will then electronically sign the casebook, specifying 
that the information on the eCRFs 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. 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 ECs/IRBs. 
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, peer-reviewed 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  
Batts KP & Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg 
Pathol. 1995;19:1409-1417. 
Bedossa P, Pynard T, French METAVIR Cooperative Study Group. An algorithm for 
grading activity in chronic hepatitis C. Hepatology. 1996;24:289-293. 
Berntorp E, Dolan G, Hay C, Linari S et al. European retrospective study of real-life 
haemophilia treatment. Haemophilia. 2017;23(1):105-114. 
Berntorp E, Peake I, Budde U, Laffan M et al. von Willebrand's disease: a report from a 
meeting in the Aland islands. Haemophilia. 2012;18(Suppl.6):1-13. 
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37:53-72. 
Chai-Adisaksopha C, Skinner M, Curtis R, et al. Psychometric Properties of the Patient 
Reported Outcomes, Burdens and Experiences (PROBE) Questionnaire. Blood. 
2017;130:5645. 
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16:199-208. 
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(Suppl.4):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-
practice.html (last visited 20 January 2020). 
Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: 
a randomized dose comparison. Blood. 2012;119(6): 1335-1344. 
Haemo-QoL Study Group. Scoring Manual. Available at: http://haemoqol.de/scoring/manual 
(last accessed 17 May 2021).  
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. 

 
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Kaufman RJ, Powell JS. Molecular approaches for improved clotting factors for 
hemophilia 1. Blood. 2013;122(22):3568-3574. 
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. 2006;12(3):342-347. 
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. 2016;22(Suppl.4):151-152. 
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. 2014;371(21):1994-2004. 
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. 2011;19(5):876-885. 
National Center for Biotechnology Information (NCBI). LiverTox: Clinical and Research 
Information on Drug-Induced Liver Injury. Available at: https://livertox.nih.gov (last 
accessed 17 May 2021). 
National Hemophilia Foundation. MASAC recommendation for liver biopsies in gene 
therapy trials for hemophilia. 2019. Available at https://www.hemophilia.org/sites/ 
default/files/document/files/256.pdf (last accessed 20 August 2020). 
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. 
Reilly M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ 
WPAI_Scoring.html (last accessed 4 September 2020).  
Recht M, Neufeld EJ, Sharma VR, Solem CT et al. Impact of Acute Bleeding on Daily 
Activities of Patients with Congenital Hemophilia with Inhibitors and Their Caregivers and 
Families: Observations from the Dosing Observational Study in Hemophilia (DOSE). Value 
in Health. 2014;17:744-748. 
Rentz A, Flood E, Altisent C, Bullinger M et al. Cross-cultural development and 
psychometric evaluation of a patient-reported health-related quality of life questionnaire for 
adults with haemophilia. Haemophilia. 2008;14(5):1023-34. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: summary report—second National Institute of Allergy and 

 
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Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol. 2006;117:391-397. 
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. 2010;16(1):33-46. 
United States Department of Health and Human Services. Panel on Antiretroviral Guidelines 
for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and 
Adolescents with HIV. 2019. Available at: http://www.aidsinfo.nih.gov/ContentFiles/ 
AdultandAdolescentGL.pdf (last accessed 17 May 2021). 
 

 
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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 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 subjects. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential subjects, 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 
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 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 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 
section 4.9 are kept, and those records are available for inspection in accordance with 
21 CFR 312.68 and/or ICH E6 section 4.9.7. 
• The IRB/EC complies with the requirements of 21 CFR Part 56, ICH E6 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 subjects or others are reported to the 
IRB/EC. Additionally, he or she will not make any changes in the research without 
IRB/EC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects. 
• 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. 

 
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SIGNATURE PAGE  
Protocol Title: A Phase 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and 
Safety of BMN 270, an Adeno-Associated Virus Vector–Mediated Gene Transfer of Human 
Factor VIII, with Prophylactic Corticosteroids in Hemophilia A Patients 
Protocol Number: 270-303 Amendment 2 
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, 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, MHS, 
, Clinical Sciences 
PI
PI

 
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APPENDICES  

 
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Appendix 1:  Sampson’s Anaphylaxis Criteria  
According to the National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network (NIAID/FAAN) Second Symposium on the definition and 
management of anaphylaxis, anaphylaxis is highly likely when any one of the following 
3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, 
swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (eg, hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a. Infants and children: low systolic blood pressure (age specific) or greater than 
30% decrease is systolic BP 
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from 
that person’s baseline. 
Source: Sampson, 2006. 
 

 
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PROTOCOL AMENDMENT TEXT REVISIONS  
The following table summarizes the revisions made to the original protocol and relates the changes to the appropriate rationale (refer to 
pages 2-5). Added text is indicated by underlined font and deleted text is indicated by strikethrough font. 
Section No./Title 
Revision 
Rationale 
2/Synopsis (Study Sites) 
Approximately 1015 sites worldwide. 
12 
2/Synopsis (Study 
Rationale) 
ThreeFour-year results from 270--201 and one-year results from 270-301 have demonstrated that following gene transfer, mean and 
median FVIII activity levels above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are achievable and sustained 
following a single infusion of 6E13 vg/kg of BMN 270, with an acceptable safety profile. Preliminary results from optional liver 
biopsies (in subjects receiving lower doses of BMN 270 in 270-201) confirm dose-dependent pan-lobular and otherwise healthy liver 
transduction at 2.57-4.1 years. In addition, an interim analysis of clinical study 270-301, an ongoing phase 3 study designed to assess 
the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg, demonstrated FVIII activity levels that were also well above 15 IU/dL, 
albeit lower than what was observed for the 6E13 vg/kg cohort in 270-201.  
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects in 270-301; in 270-201, subjects 
were started onscheduled to start corticosteroids by Week 3 (either therapeuticallybefore Week 3, in response to an alanine 
aminotransferase (ALT) elevation, or prophylacticallyat Week 3 otherwise, per protocol), whereas in 270-301 subjects received 
corticosteroids only in response to an alanine aminotransferase (ALT) elevation. Possibly as a result of this difference, subjects 
receiving 6E13 vg/kg in 270-201 started corticosteroids at an earlier date in reference to the date of BMN 270 infusion, and showed 
later adventonset of first ALT elevations, and were also less likely to experience a significant decline in FVIII activity concurrently with 
an ALT elevation when compared with subjects in 270-301 (20% of subjects in 270-201 vs. 58% of subjects in 270-301). In 270-301, 
ALT elevation within the first 26 weeks was associated with decreased FVIII activity.. Recently published data from 270-201 
suggestsand recent analysis of 270-301 data suggest that corticosteroids may have assisted in rescue or protection of FVIII activity 
levels during elevations of ALT and in resolution of elevated ALT levels in some subjects. 
6, 12 
2/Synopsis (Objectives) 
The secondary efficacy objectives of the study are to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the use of exogenous FVIII replacement therapy from 
Week 5 to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior FVIII prophylaxis or on use of 
emicizumab from Week 27 to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior emicizumab 
prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the number of bleeding episodes requiring exogenous 
FVIII replacement therapy from Week 5 to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior FVIII 
prophylaxis or on use of emicizumab from Week 27 to last visit by data cutoff (for Week 52 analysis) for subjects receiving 
prior emicizumab prophylaxis 
The safety objectives of the study are to: 
11, 12 

 
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Section No./Title 
Revision 
Rationale 
• 
Evaluate the short-term safety of BMN 270 with prophylactic corticosteroids during the first 52 weeks following intravenous 
infusion of BMN 270 
2/Synopsis (Study 
Design and Plan) 
This is a Phase 3b, single arm, open-label study in hemophilia A patients with residual FVIII levels ≤ 1 IU/dL. Subjects will be enrolled 
at approximately 1015 sites worldwide. Subjects must have high-quality, well-documented historical data available concerning previous 
bleeding episodes and exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of BMN 270 as a single intravenous infusion in 
conjunction with receipt of a 19-week prophylactic corticosteroid regimen starting on the day of BMN 270 infusion (Figure 2). 
TherapeuticReactive corticosteroids, as needed for ALT elevations and/or FVIII decline, will also be availableutilized post-infusion. 
… 
In subjects who experience recurring 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 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 or Sponsor-designated Data 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. 
… 
There will be an ongoing review of individual subject safety by the Medical Monitor, and both safety and efficacy data by the DMC. 
Patients will receive prophylactic corticosteroids with tapering of the dosage based upon consideration of ALT values, FVIII activity 
levels, and if needed, consultation with the Investigator and the Medical Monitor. TherapeuticReactive oral corticosteroids may be 
initiated if a subject’s ALT values increase from baseline levels, after consultation between the Investigator and the Medical Monitor. 
6, 12 
2/Synopsis (Exclusion 
Criteria) 
Patients are excluded from the study if any of the following criteria apply: 
1. Subjects with detectable pre-existing antibodies to the AAV5 capsid. are excluded with the following exception: up to 25% of 
subjects may have detectable pre-existing AAV5 capsid antibodies, so long as the detectable with titer level is below the minimum 
required dilution (< 20).  
2. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, includingexcept for HIV infection. HIV-
positive patients who meet all other eligibility criteria may be included if they have a CD4 count > 200/mm3 and an undetectable viral 
load (unquantifiable viral load as defined as less than the limit of quantification by the testing laboratory’s assay is permitted) while 
receiving an antiretroviral therapy (ART) regimen that does not contain efavirenz or another potentially hepatotoxic ART.  
8. Liver cirrhosis or other clinically significant liver disease of any etiology as assessed by liver ultrasound/FibroScan. 
4, 12 
2/Synopsis (Criteria for 
Evaluation) 
Secondary efficacy endpoints:  
• 
Change from baseline in the annualized utilization (IU/kg/year) and infusion rate (number/year) of exogenous FVIII replacement 
therapy duringfrom Week 5 to Week 52 post-BMN 270 infusion, to last visit by data cutoff (for Week 52 analysis) for subjects 
receiving FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in the annualized utilization 
(mg/kg/year) of emicizumab duringfrom Week 27 to Week 52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 
analysis) for subjects receiving prior emicizumab prophylaxis. 
11, 12 

 
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Section No./Title 
Revision 
Rationale 
• 
Change from baseline in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment (annualized 
bleeding rate, ABR) duringfrom Week 5 to Week 52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 analysis) for 
subjects receiving prior FVIII prophylaxis, or from Week 27 to Week 52 post-BMN 270 infusion to last visit by data cutoff (for 
Week 52 analysis) for subjects receiving prior emicizumab prophylaxis 
2/Synopsis (Statistical 
Methods) 
Approximately 20 subjects may be dosed in the study, including at least 16 subjects who are AAV5 antibody-negative and up to 25% of 
the total number of subjects who havewith an AAV5 antibody titer that is detectable but below the minimum required dilution (<20) at 
Screening.   
The analyses of the secondary and tertiary efficacy endpoints will be descriptive. Mean and associated 95% confidence interval will be 
provided for the following secondary endpoints, where the baseline value will be derived from the data in the approximately 12-month 
period prior to BMN 270 infusion: 
• 
For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in the annualized utilization (IU/kg/year) of 
exogenous FVIII replacement therapy during Weeksfrom Week 5-52 post -BMN 270 infusion to last visit by data cutoff (for Week 
52 analysis); and separately, for subjects receiving FVIIIprior emicizumab prophylaxis during the 12 months prior to study entry, 
or, change from baseline in the annualized utilization (mg/kg/year) of emicizumab duringfrom Week 27 to Week 52 post -BMN 
270 infusion for subjects receiving prior emicizumab prophylaxisto last visit by data cutoff (for Week 52 analysis)  
• 
For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in the annualized infusion rate (number/year) 
of exogenous FVIII replacement therapy during Weeksfrom Week 5-52 post -BMN 270 infusion,  to last visit by data cutoff (for 
Week 52 analysis); and separately for subjects receiving FVIIIprior emicizumab prophylaxis during the 12 months prior to study 
entry, or, change from baseline in the annualized utilization (mg/kg/year) of emicizumab duringfrom Week 27 to Week 52 
post -BMN 270 to last visit by data cutoff (for Week 52 analysis) infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the annualized number of bleeding episodes (number/year) requiring exogenous FVIII replacement 
treatment during Weeksfrom Week 5-52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 analysis) for subjects 
receiving prior FVIII prophylaxis, or Weeksfrom Week 27-52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 
analysis) for subjects receiving prior emicizumab prophylaxis from baseline 
11, 12 
7.3/Study Rationale 
ThreeFour-year results from 270--201 and one-year results from 270-301 have demonstrated that following gene transfer, mean and 
median FVIII activity levels above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are achievable and sustained 
following a single infusion of 6E13 vg/kg of BMN 270, with an acceptable safety profile (Pasi, 2020).. Preliminary results from 
optional liver biopsies (in subjects receiving lower doses of BMN 270 in 270-201) confirm dose-dependent pan-lobular and otherwise 
healthy liver transduction at 2.57-4.1 years. In addition, an interim analysis of clinical study 270-301, an ongoing phase 3 study 
designed to assess the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg, demonstrated FVIII activity levels that were also well 
above 15 IU/dL, albeit lower than what was observed for the 6E13 vg/kg cohort in 270-201 (Pasi, 2020).  
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects in 270-301; in 270-201, subjects 
were started onscheduled to start corticosteroids by Week 3 (either therapeuticallybefore Week 3, in response to an alanine 
6, 12 

 
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Section No./Title 
Revision 
Rationale 
aminotransferase [(ALT]) elevation, or prophylacticallyat Week 3 otherwise, per protocol), whereas in 270-301 subjects received 
corticosteroids only in response to an ALT elevation. Possibly as a result of this difference, subjects receiving 6E13 vg/kg in 270--201 
started corticosteroids at an earlier date in reference to the date of BMN 270 infusion, and showed later adventonset of first ALT 
elevations, and were also less likely to experience a significant decline in FVIII activity concurrently with an ALT elevation when 
compared with subjects in 270-301 (20% of subjects in 270-201 vs. 58% of subjects in 270-301). In 270-301, ALT elevation within the 
first 26 weeks was associated with decreased FVIII activity.. Recently published data from 270-201 suggestsand recent analysis of 270-
301 data suggest that corticosteroids may have assisted in rescue or protection of FVIII activity levels during elevations of ALT and in 
resolution of elevated ALT levels in some subjects (Pasi , 2020). 
7.4/Summary of Risks 
and Benefits 
Transient, asymptomatic ALT elevation (grade 1 to 3 in severity) has been observed in most subjects administered BMN 270 shortly 
after dosing, with no symptoms or sequelae suggestive of clinically significant hepatocyte injury orevidence for major impacts upon 
liver dysfunctionfunction; no events meeting the Hy’s Law criteria have been identified. ALTLiver function remained stable over time. 
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 
have been reported as events of interest in 13 subjects in 270-201, 1 subject in 270-302, and 91ALT (75.7 U/L) than subjects in 270-
301. Although the majority of events have been Grade 1 or Grade 2 (112.5 U/L). The difference in severity, 11the ALT profile seen 
between the 6E13 vg/kg subjects (1 in 270-302201 and 10the subjects in 270-301) had a reported Grade 3 ALT elevation. Only one 
serious event of ALT increased has been reported 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 investigators (in addition to one event that BioMarin 
conservatively assessed as serious based on the details of the caseWeek 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, 2017 2020). 
Short-lived infusion reactions associated with one-time BMN 270 administration have included symptoms such as nausea, 
maculopapular rash, urticaria, diarrhea, watery eyes, rigors, chills, myalgia, fever, tachycardia and hypotension emerging within 24 
hours of receiving BMN 270. Most infusion-related reactions were Grade 1 or Grade 2 in severity, and all events resolved, typically 
within 48 hours following medical management. Three of theseWhile some cases required temporary interruption of the infusion, 
followed by re-initiation at a slower rate., all subjects completed their infusions. The reactions with onset during or within 
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approximately 5 hours after the end of infusion responded to treatment with systemic antihistamines and/or corticosteroids, where 
administered. Infusion-related reactions were effectively mitigated by managing infusion rate and medications.  
In this study, corticosteroids will be initiated prophylactically (ie, prior to any increase in ALT) on Day 1, prior to the BMN 270 
infusion. Close monitoring of ALT and FVIII activity is recommended to enable early and timely initiation of therapeuticreactive 
corticosteroid treatment (ie, in response to an increase in ALT). During prophylactic and therapeuticreactive corticosteroid treatment, 
emphasis will be placed on a slowtimely taper of the dose, with the aim of achieving ALT levels near the subject’s baseline to limit 
hepatocellular toxicity and possibly ameliorate reduction of transgene expression over the period when ALT elevations have been 
observedsequelae associated with prolonged corticosteroid use. 
AtSubjects given the highest6E13 vg/kg dose tested in 270--201 (6E13 vg/kg), the majority of subjectsand 270-301 have achieved mean 
FVIII activity above 5040 IU/dL at 49-52 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 will be included in the final analysis have been dosed with 6E13 vg/kg andSubjects at all dose levels 
continue to be followed.  
8/Study Objectives 
The secondary efficacy objectives of the study are to: 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the use of exogenous FVIII replacement therapy from Week 5 
to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior FVIII prophylaxis or on use of emicizumab from 
Week 27 to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior emicizumab prophylaxis 
• 
Assess the impact of BMN 270 with prophylactic corticosteroids on the number of bleeding episodes requiring exogenous FVIII 
replacement therapy from Week 5 to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior FVIII prophylaxis 
or on use of emicizumab from Week 27 to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior emicizumab 
prophylaxis 
The safety objectives of the study are to: 
• 
Evaluate the short-term safety of BMN 270 with prophylactic corticosteroids during the first 52 weeks following intravenous 
infusion  
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9.1/Overall Study 
Design and Plan 
This is a Phase 3b, single arm, open-label study in hemophilia A patients with residual FVIII levels  ≤  1 IU/dL. Subjects will be 
enrolled at approximately 1015 sites worldwide. Subjects must have high-quality, well-documented historical data available concerning 
previous bleeding episodes and exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study. 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of BMN 270 as a single intravenous infusion in 
conjunction with receipt of a 19-week prophylactic corticosteroid regimen starting on the day of the BMN 270 infusion. Post-infusion, 
subjects will be eligible to receive on-demandreactive corticosteroids, as indicated. 
… 
In subjects who experience recurring 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 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 or Sponsor-designated Data 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 are not attending the Q4W/Q6W visits during Years 2-5 may receive a 
scheduled monthly follow-up telephone call from the site to ask about adverse events, concomitant medications, and bleeding 
events/FVIII replacement usage. 
There will be an ongoing review of individual subject safety by the Medical Monitor, and both safety and efficacy data by the DMC. 
Patients will receive prophylactic corticosteroids with tapering of the dosage based upon consideration of ALT values, FVIII activity 
levels, and as indicated, consultation with the Investigator and the Medical Monitor. TherapeuticReactive oral corticosteroids may be 
initiated if a subject’s ALT values increase from baseline levels, after consultation between the Investigator and the Medical Monitor 
6, 12 
Table 9.1.1 through 
Table 9.1.4/Schedules 
of Events 
Tables 9.1.1, 9.1.2, 9.1.3, and 9.1.4 have been updated consistent with changes made in the table footnotes and elsewhere in the 
protocol. 
1, 2, 5, 7, 
8, 9, 10, 
12 
Table 9.1.1 Footnotes 
cc All patients must have a liver ultrasound performed during the Screening period to screen for significant liver disease and 
hepatocellular carcinoma. A FibroScan may also be performed at the discretion of the Investigator. 
e COVID-19f SARS-CoV-2 RT-PCR testing is required during Screening, and all subjects must have at least one negative test result 
prior to dosing. If the test is performed locally an additional 2nd test is recommended, but if performed negative results from the 2nd test 
must be received prior to dosing. A SARS-CoV-2 vaccine is recommended for subjects if indicated and if available. If a two-step 
SARS-CoV-2 vaccine is being used, sites should consider using the flexible re-screen option to allow subjects to receive both doses at 
least 14 days prior to treatment with BMN 270 (or at least 30 days prior to treatment with BMN 270 for any live-virus vaccines). It is 
1, 5, 7, 8, 
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preferable for SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. Investigators should use clinical judgment, taking into 
consideration local factors, individual risk factors, and benefit/risk related to timing of vaccine administration.  
ij Blood samples will be collected to evaluate biochemical, molecular, cellular, immunological, 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, as well as 
testing of the thrombin generation assay (TGA) sample, will be performed only as deemed necessary by the Sponsor. 
jk Complement panel should include C3, C3a, C4, Bb, and sC5b-9 (refer to Table 9.7.78.2.1) and should be collected 2 hours after 
completion of the infusion. While exploratory samples for cytokine profiling will be collected at the time points indicated above, 
testing of these samples will be performed only as deemed necessary by the Sponsor. 
lm 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. COVID-19SARS-CoV-2 RT-PCR testing is 
required during Screening, and all subjects must have at least one negative test result prior to dosing. If the test is performed locally an 
additional 2nd test is recommended, but if performed negative results from the 2nd test must be received prior to dosing. 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. 
noWith the exception of the collection of samples for polymerase chain reaction (PCR) vector DNA analysis and the collection of the 
complement panel/exploratory cytokine profiling sample, assessments on the day of infusion must be performed prior to the infusion. 
Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. 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), and 
following the infusion hourly (± 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Shedding samples for PCR of 
vector DNA analysis (blood, saliva, urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been 
completed. 
Table 9.1.2 Footnotes 
b Refer to Table 9.7.8.2.1for laboratory assessments to be included and for complement panel tests, and to Table 9.7.8.3.1 for liver tests 
(LTs). LTs LT assessment is weekly, but may be monitoredchecked more or less frequently (and in particular when ALT values are 
>  upper limit of normal (ULN) or ≥ 1.5x baseline value) or based onupon  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.. Subjects with ALT > ULN or ≥ 1.5x baseline value during the study and either an alternative etiology considered or for further 
evaluation of the lab abnormality 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 ≥ 1.5x baseline value; (2) Increases in ALT values from prior assessment are 
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accompanied by declines in FVIII activity level; or >ULN 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. In case of a safety 
concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely 
and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be 
collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. While exploratory samples for 
cytokine profiling will be collected at the time points indicated above, testing of these samples will be performed only as deemed 
necessary by the Sponsor. 
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda 
Assay for hFVIII inhibitor level, and coagulation exploratory assay, and . Chromogenic Nijmegen-Bethesda Assay for hFVIII protein 
assayinhibitor level will be tested as deemed necessary by the Sponsor. 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 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 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 TGA assay and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
Table 9.1.3 Footnotes 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included and for complement panel tests, and to Table 9.7.8.4.1 for liver tests 
(LTs). LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT values are > ULN or ≥ 1.5x 
baseline value) or based onupon  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. Subjects with > ULN or ≥ 1.5x baseline value 
during the study and either an alternative etiology considered or for further evaluation of the lab abnormality 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 ≥ 1.5x 
baseline value; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or >ULN 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 
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between the Medical Monitor and the Investigator. In case of a safety concern, additional unscheduled laboratory tests may be 
performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where 
possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same 
time as the local unscheduled sample. While exploratory samples for cytokine profiling will be collected at the time points indicated 
above, testing of these samples will be performed only as deemed necessary by the Sponsor. 
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda 
Assay for hFVIII inhibitor level, and coagulation exploratory assay, and . Chromogenic Nijmegen-Bethesda Assay for hFVIII 
proteininhibitor level will be tested as deemed necessary by the Sponsor. 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 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 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 TGA assay and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
i Additional liver ultrasounds may be performed prior to Week 52 at the discretion of the Investigator. 
Table 9.1.4 Footnotes 
b Complete physical examination should be performed at the End of Year visits; (genitourinary examination may be deferred); brief 
physical exam 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. 
c Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.4.1 for liver tests. LTsLT assessment may be 
monitoredchecked more or less frequently (and in particular when ALT values are > ULN or ≥ 1.5x baseline value) or based onupon  
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. Subjects with ALT > ULN or ≥ 1.5x baseline value during the study and 
either an alternative etiology considered or for further evaluation of the lab abnormality 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 ≥ 1.5x baseline value; 
(2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or >ULN 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 
2, 6, 7, 8, 
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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. In case of a safety concern, 
additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and 
appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected 
(using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample 
d Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), chromogenic Nijmegen-Bethesda 
Assay for hFVIII inhibitor level, coagulation exploratory assay, and hFVIII protein assay.. Chromogenic Nijmegen-Bethesda Assay 
for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. 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 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. 
f Blood samples will be collected to evaluate biochemical, molecular, cellular, immunological, 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, as well as 
testing of the TGA assay sample, will be performed only as deemed necessary by the Sponsor. 
i Additional liver ultrasounds may be performed at interim timepoints (ie, between the End of Year visits) at the discretion of the 
Investigator. 
j AAV5 TI Assay should be performed only at the end of the study (either the Year 5 End of Year Visit, or at the ETV for subjects who 
withdraw prior to the end of Year 5). 
Table 9.1.6 Footnotes 
b Following initiation or completion of corticosteroid regimen, if a recurrence of ALT values > ULN or ≥ 1.5x baseline value is 
reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical Monitor. 
Modification of the corticosteroid regimen may take into consideration timing of ALT elevation (prior to or after Week 52), as well as 
possible confounders for the ALT elevation, relationship between increases in ALT and FVIII activity, ALT levels/FVIII activity post-
corticosteroid initiation, and adverse events related to corticosteroid dosing.  Guidance for tapering oral corticosteroid dosing can be 
found in Section 9.4.8.2, although a discussion between the PI and Medical Monitor should take place prior to tapering the 
corticosteroid dose. 
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9.2/Discussion of Study 
Design 
Approximately 20 adult subjects with severe HA will receive a 6E13 vg/kg dose of BMN 270 as a single intravenous infusion in 
conjunction with receipt of a prophylactic corticosteroid regimen. Post-infusion, subjects will be eligible to receive on-demandreactive 
corticosteroids, as indicated.  
6 
9.3.2/Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
1. Subjects with detectable pre-existing antibodies to the AAV5 capsid. are excluded with the following exception: up to 25% of 
subjects may have detectable pre-existing AAV5 capsid antibodies, so long as the detectable with titer level is below the minimum 
required dilution (< 20).  
2. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, includingexcept for HIV infection. HIV-
positive patients who meet all other eligibility criteria may be included if they have a CD4 count > 200/mm3 and an undetectable viral 
load (unquantifiable viral load as defined as less than the limit of quantification by the testing laboratory’s assay is permitted) while 
receiving an antiretroviral therapy (ART) regimen that does not contain efavirenz or another potentially hepatotoxic ART.  
8. Liver cirrhosis or other clinically significant liver disease of any etiology as assessed by liver ultrasound/FibroScan. 
4, 12 
9.4.4/Directions for 
Administration 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital 
signs will be performed and additional blood samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. Additional samples will be collected at the 1 hour 
and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory cytokine bead array (CBA)profiling to 
assess inflammatory biomarkers and plasma cytokine levels. 
12 
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 eCRF. For HIV-positive patients, prior to enrollment, the Medical Monitor will review the 
patient’s ART regimen to assess that it does not contain efavirenz or another potentially hepatotoxic ART. The Investigator may 
prescribe additional medications, deemed necessary to provide adequate prophylactic or supportive care, 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 eCRF. Medications should, whenever 
possible, not be recorded in the electronic database with a frequency of as needed (PRN).  
The following medications are prohibited starting 30 days before Screening and through the end of the study, and the Sponsor must be 
notified if a subject receives any of these during the study: 
• 
Any investigational therapy other than BMN 270 
… 
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It is preferable for SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. If a two-step SARS-CoV-2 vaccine is being used, 
sites should consider using the flexible re-screen option to allow subjects to receive both doses at least 14 days prior to treatment with 
BMN 270. If a live-virus SARS-CoV-2 vaccine is being used, subjects should wait at least 30 days after vaccination to receive a BMN 
270 infusion. Investigators should use clinical judgment, taking into consideration local factors, individual risk factors, and the 
benefit/risk related to timing of vaccine administration. Administration of SARS-CoV-2 vaccine after BMN 270 infusion may occur 
after consultation between Investigator and Medical Monitor. 
9.4.8.2.1 Prophylactic 
Corticosteroids 
All subjects will be started on prophylactic corticosteroids starting on the day of infusion (Day 1). The first dose of prophylactic 
corticosteroids (40 mg of prednisone or prednisolone, or an equivalent dose of another corticosteroid) should be taken at least 3 hours 
prior to the start of the BMN 270 infusion and continued on a daily basis. Table 9.1.6 provides an example of a possiblethe 
recommended prophylactic corticosteroid course, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, 
and hepatitis B/hepatitis C reactivation. Clinical judgment, weightingweighing the potential risks and benefits of corticosteroid 
treatment, should always be exercised when considering adjustment of corticosteroid doses. Discussions between the Investigator and 
Medical Monitor are advised for any questions or concerns. 
6, 12 
9.4.8.2.2 Reactive 
Corticosteroids 
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased (eg, ≥ 1.5x baseline value 
or > ULN) and alternative etiologies have been ruled out, prompt institution of newly administered or an increased dose of therapeutic 
or on-demandreactive (ie, started in response to an ALT elevation) oral corticosteroids (prednisone or an equivalent dose of another 
corticosteroid) should be considered after consultation with the Medical Monitor (refer to Table 9.7.8.3.2). 
• 
Whenever possible, a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, prior to 
initiating reactive oral corticosteroids. 
Unless otherwise indicated, therapeuticreactive corticosteroid treatment should be initiated at a dose of 60 mg/day. If the ALT level 
immediately returns to ≤ 1.5x baseline and FVIII activity levels continue to rise and/remains stable or remain within or above the 
normal range in thedeclines after 2 weeks following corticosteroid initiation, on-demand , consider gradual taper of corticosteroids can 
be discontinued. However, if this is not the case, therapeutic corticosteroids should be tapered over a longer period of time. At 
minimum, the recommended duration of on-demand corticosteroids is 60 mg/day for 3 weeks, : 40 mg/day for 43 weeks, and 30 mg/day 
for 4 weeks, followed by a gradual taper thereafter.1 week, 20 mg/day for 1 week and 10 mg/day for 1 week. Should a scenario arise in 
which a deviationdifferences from the minimum recommended dose and/or duration of therapeuticreactive corticosteroids may be 
clinically indicated, a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose 
adjustments. TaperingManagement of corticosteroid dosagesALT elevations with reactive corticosteroids, including tapering of doses 
and managing worsening and/or recurrent ALT elevations, should be guided by the following (Table 9.74.8.2.1): 
[Table 9.4.8.2.2.1] 
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When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT workup, the following tests should be performed 
(Table 9.4.8.2.2): 
[Table 9.4.8.2.2] 
After discontinuation of on-demandreactive oral corticosteroids, labs for ALT and FVIII levels will be measured once a week for 4 
weeks to ensure stability in values. 
Following initiation or completion of therapeuticprophylactic oral corticosteroids, if increased ALT levels (eg, > ULN or ≥ 1.5x 
baseline value) are reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical 
Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation and impact 
on FVIII expression. 
Table 9.4.8.2.2.1/ 
Management of ALT 
Elevations with 
Reactive 
Corticosteroids 
Table 9.4.8.2.2.1 has been updated consistent with changes elsewhere in the protocol, and has been merged with the former Table 
9.7.8.3.1. 
6, 12 
Table 9.4.8.2.2.2/Viral 
and Autoimmune 
Hepatitis Testing 
Table 9.4.8.2.2.2 has been relocated from its previous position as Table 9.7.8.3.2. 
6, 12 
9.4.8.3/Monitoring of 
HIV-Positive Subjects  
HIV-positive subjects may be enrolled in 270-303 if the subject is well controlled on an ART regimen that does not contain efavirenz or 
another potentially hepatotoxic ART, has a CD4 count > 200/mm3, and has an undetectable viral load (unquantifiable viral load as 
defined as less than the limit of quantification by the testing laboratory’s assay is permitted). 
HIV-positive subjects were initially included in prior BMN 270 studies.  However, after an HIV-positive subject in 270-302 developed 
markedly elevated liver enzyme levels after receiving 4E13 vg/kg of BMN 270, out of an abundance of caution for the long-term liver 
health of HIV-positive patients, further enrollment of HIV-positive subjects was suspended in 270-301 (Protocol Amendment 3) and 
270-302 (Protocol Amendment 3). The subject in 270-302 referenced above was receiving efavirenz and lamivudine as part of his ART 
regimen. Following discussion with a liver advisory board and review of the accumulated 270-301 data, efavirenz and not lamivudine 
has been implicated as the most likely medication that interacted with BMN 270 and contributed to the 270-302 subject's elevated liver 
enzyme levels. Due to its hepatotoxicity, efavirenz is a prohibited medication in all BMN 270 studies. 
The two HIV-positive subjects on stable, non-efavirenz-containing ART regimens who were enrolled in and dosed in 270-301 study 
prior to Amendment 3 have been monitored closely. Following BMN 270 infusion, these subjects continued their ART as prescribed 
and followed routine monitoring of CD4 count and viral load. Results from 270-301 show similar safety results for the two HIV-
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positive subjects compared to those who are HIV-negative. The Sponsor believes that HIV infection, in and of itself, is not a 
contraindication to receive BMN 270 and has therefore removed the exclusion of HIV-positive subjects. 
Subjects should continue ART as prescribed and follow routine monitoring of CD4 count and viral load (US Dept Health Human 
Services 2019). Investigators will continue to monitor HIV-positive subjects per routine standard of care. 
9.7.2.1/FVIII Activity  
In the event of an FVIII activity level decline during the study: 
• 
If FVIII activity has declined at least 20% from the peak but less than 35% and has declined for at least 2 consecutive assessments, 
FVIII activity and LTs should be repeated every 7 days until FVIII activity is stable or increasing 
• 
If FVIII activity has declined ≥ 35% from the peak and has declined for at least 2 consecutive assessments, FVIII activity and LTs 
should be repeated every 72 hours until FVIII activity is stable or increasing 
Note that fluctuations in FVIII activity after gene therapy are common, and if no clear trend indicating a decline in more frequent 
monitoring of FVIII activity levels is observed, then this additional testing may be deferred (not needed in the absence of a concurrent 
or recent ALT elevation or upon consultation between the Investigator and the Medical Monitor) until either a more clear trend of 
decline has been demonstrated or until the FVIII activity levels stabilize or increase. 
6, 12 
9.7.3.1/FVIII 
Replacement 
Therapy/Bleeding 
Episodes 
Secondary efficacy variables include: 
• 
Change in the annualized utilization (IU/kg/year) and infusion (number/year) rates of exogenous FVIII replacement therapy 
duringfrom Week 5 to Week 52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 analysis) from the baseline 
number and utilization of exogenous FVIII replacement therapy, for subjects receiving FVIII prophylaxis during the 12 months 
prior to study entry, or change in administration of exogenous FVIII replacement therapy from Week 27 to Week 52 post-
BMN 270 infusion to last visit by data cutoff (for Week 52 analysis) for subjects receiving prior emicizumab prophylaxis.  
• 
Change in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment (annualized bleeding rate, 
ABR) duringfrom Week 5 to Week 52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 analysis) for subjects 
receiving prior FVIII prophylaxis, or from Week 27 to Week 52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 
analysis) for subjects receiving prior emicizumab prophylaxis, fromcompared to the baseline ABR during the 12 months prior to 
study entry. 
Subjects must have high quality documented historical data available concerning previous bleeding episodes and hemophilia treatment 
over the previous 12 months in order to be eligible to enroll in the study. During the study, 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. Subjects will be encouraged to discuss any bleeding episodes with the 
Investigator and attempt to objectively assess any reported bleeds through use of ultrasound or non-invasive imaging.   
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9.7.8.2/Clincal 
Laboratory Assessments 
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel (including triglycerides, total cholesterol, HDL 
cholesterol, and LDL cholesterol) and FibroTest will be assessed at the BMN 270 infusion visit. Subjects will fast for at least 8 hours 
prior to pre-infusion laboratory sampling on the day of the infusion visit. 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital 
signs will be performed and additional blood samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. Additional samples will be collected at the 1 hour 
and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory CBAcytokine profiling to assess 
inflammatory biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional blood samples can be 
collected if deemed necessary at the discretion of the Investigator and Medical Monitor. 
1, 12 
9.7.8.3/Malignancies 
A liver ultrasound (and FibroScan, at the discretion of the Investigator) will be performed at Screening to screen for hepatocellular 
carcinoma (HCC). Thereafter, liver ultrasounds will be performed annually at each End of Year visit starting at Year 1 (Week 52) 
through the end of the study to screen for HCC, or at interim timepoints 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, 2, 3 
9.7.8.4/Liver and 
Hepatitis Testing 
A liver ultrasound/FibroScan , fasting FibroTest, and liver tests (LTs) during Screening will identify anybe performed to assess for 
clinically significant hepatic dysfunction. liver disease and HCC. A FibroScan may also be performed during Screening at the discretion 
of the Investigator. Fasting FibroTest results must be available prior to BMN 270 infusion. 
Elevated ALT levels (above the upper limit of normal range) should be evaluated according to the following plan outlined in 
Table 9.4.8.2.2.1. 
1, 6 
9.7.8.5/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. Refer to Section 9.4.8.3 for guidance on monitoring of HIV-positive subjects. 
4 
9.7.8.6/Vital Signs, PEs 
and Other Safety 
Observations 
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. 
12 
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:  
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• 
Any new diagnosis of malignancy (except non-melanoma skin cancer) 
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 Investigator will determine the severity of 
each AE, SAE and EOSI using the Common Terminology Criteria for Adverse Events (NCI CTCAE) v5v4.03. Adverse events that do 
not have a corresponding CTCAE term will be assessed according to the general guidelines for grading used in the CTCAE v5asv4.03 
as stated in Table 10.3.3.2.1. 
12 
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. 
12 
12.2/Screening 
The following procedures will be performed during the Screening Period: 
• 
Full medical history, including hemophilia A history, hepatitis B, hepatitis C, and HIV. Subjects with a history of hepatitis B or, 
hepatitis C, or HIV will be asked for information about the treatments received. Any prior pharmacokinetics information obtained 
while the subject was receiving prophylactic or on-demandepisodic hemophilia therapy prior to the study should also be collected. 
• 
Liver ultrasound/ to screen for HCC and clinically significant liver disease (FibroScan can be performed additionally at the 
discretion of the Investigator) 
• 
Screen for COVID-19SARS-CoV-2 screening (local or central testing) 
o 
COVID-19SARS-CoV-2 RT-PCR testing is required during Screening, and all subjects must have at least one 
negative test result prior to dosing. If the test is performed locally an additional 2nd test is recommended, but if 
performed negative results from the 2nd test must be received prior to dosing. A SARS-CoV-2 vaccine is 
recommended for subjects if indicated and if available (refer to Section 9.4.8). 
• 
Fasting FibroTest 
o 
Subjects will fast for at least 8 hours prior to sampling on the day of the FibroTest Screening visit. Fasting 
FibroTest results must be available prior to BMN 270 infusion. 
1, 4, 5, 12 
12.2.1/Smart 
Rescreening 
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: 
• 
Screen for COVID-19SARS-CoV-2 screening (local or central testing) 
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o 
COVID-19SARS-CoV-2 RT-PCR testing is required during smart rescreening, and all subjects must have at 
least one negative test result prior to dosing. If the test is performed locally an additional 2nd test is 
recommended, but if performed negative results from the 2nd test must be received prior to dosing. A SARS-
CoV-2 vaccine is recommended for subjects if indicated and if available (refer to Section 9.4.8). 
12.3/Baseline 
The following procedures will be performed during the Baseline Period: 
• 
Complement Panel and Exploratory Cytokine Profiling 
• 
TGA Assay 
7, 12 
12.4/Day 1 
The following procedures will be performed during the BMN 270 Infusion Visit: 
• 
Brief physical examination (prior to infusion) 
• 
Assessment of adverse events and concomitant medications (prior to infusion) 
• 
Fasting FibroTest 
• 
Immunogenicity AAV5 TAb Assay (sample collected pre-infusion) 
• 
AAV5 TI Assay (sample collected pre-infusion) 
• 
Serum for exploratory biomarkers (sample collected pre-infusion) 
• 
Complement Panel and Exploratory Cytokine Profiling (should be collected 2 hours after completion of the infusion) 
In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital 
signs will be performed and additional blood samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity 
reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. Additional samples will be collected at the 1 hour 
and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory CBAcytokine profiling to assess 
inflammatory biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional blood samples can be 
collected if deemed necessary at the discretion of the Investigator and Medical Monitor. 
1, 12 
12.5.1/Once per Week 
Weeks 1-26 
• 
Liver Tests (refer to Table 9.7.8.3.1) 
o 
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT values are > 
ULN or ≥ 1.5x baseline value) or based onupon  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..  
• 
Samples for FVIII Assays 
6, 8, 10, 
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o 
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will be tested as deemed necessary by the 
Sponsor) 
• 
FVIII protein assay 
• 
Exploratory CK18 and Grp78 assessment 
12.5.2/Day 8 
On Day 8, the following procedures will be performed, in addition to the weekly assessments required in Section 12.5.1: 
• 
Complement Panel and Exploratory Cytokine Profiling 
12 
12.5.4/Weeks 2, 4, 8, 
12, 16, 20, 24, 26 
At Weeks 2, 4, 8, 12, 16, 20, 24, and 26, the following procedure will be performed: 
• 
Complement Panel and Exploratory Cytokine Profiling 
12 
12.5.6/Weeks 4, 8, 12, 
16, 20, 24, 26 
At Weeks 4, 8, 12, 16, 20, 24, and 26, the following procedures will be performed: 
• 
hFVIII protein assay 
8 
12.5.13/Weeks 16, 20, 
26 
At Weeks 16, 20, and 26, the following procedure will be performed: 
• 
TGA Assay 
7 
12.6.1/Each Visit 
Weeks 27-52 
• 
Liver Tests (refer to Table 9.7.8.3.1) 
o 
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT values are > 
ULN or ≥ 1.5x baseline value) or based onupon  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..  
• 
Samples for FVIII Assays 
o 
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will be tested as deemed necessary by the 
Sponsor) 
• 
FVIII protein assay 
• 
Exploratory CK18 and Grp78 assessment 
6, 8, 10, 
12 
12.6.5/Weeks 32, 36, 
40, 44, 48, 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedure will be performed: 
• 
hFVIII protein assay 
8 
12.6.6/Weeks 32, 36, 
44, 52 
At Weeks 32, 36, 44, and 52, the following procedures will be performed: 
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TGA Assay 
12.6.7/Week 36 and 52 
At Weeks 36 and 52, the following procedures will be performed: 
• 
Complement Panel and Exploratory Cytokine Profiling 
12 
12.6.8/Week 52 
At Week 52, the following procedure will be performed: 
• 
Liver ultrasound 
o 
Additional liver ultrasounds may be performed prior to Week 52 at the discretion of the Investigator 
2 
12.7.1/Every 4-6 Weeks 
Years 2-5 
During Years 2 (every 4 weeks  ± 2 weeks) or Years 3-5 (every 6 weeks  ± 2 weeks), the following procedures will be performed: 
• 
Liver Tests (refer to Table 9.7.8.3.1) 
o 
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT values are > 
ULN or ≥ 1.5x baseline value) or based onupon  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..  
• 
FVIII Assays 
o 
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will be tested as deemed necessary 
by the Sponsor) 
• 
FVIII protein assay 
• 
Exploratory CK18 and Grp78 assessment 
6, 8, 10, 
12 
12.7.2/Years 2-5 Every 
12 Weeks or End of 
Year Visits 
At the every 12 week and End of Year visits, the following procedures will be performed: 
• 
Physical examination 
o 
Complete physical examination will be performed at the End of Year visits; (genitourinary examination may be 
deferred); brief physical examination may be performed at other visits. 
• 
Liver Tests (refer to Table 9.7.8.3.1) 
o 
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT values are > 
ULN or ≥ 1.5x baseline value) or based onupon  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..  
2, 6, 8, 10. 
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• 
FVIII Assays 
o 
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will be tested as deemed necessary 
by the Sponsor) 
• 
FVIIIhFVIII protein assay 
• 
AAV5 TI Assay (at End of Year visits5 visit only) 
• 
Exploratory CK18 and Grp78 assessment 
• 
TGA AssayLiver ultrasound (at End of Year visits only) 
o 
Additional liver ultrasounds may be performed at interim timepoints (ie, between the End of Year visits) at the 
discretion of the investigator 
12.8/Early Termination 
Visit 
At the ETV, as many of the following assessments as possible should be done: 
• 
FVIII Assays 
o 
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level (assay will be tested as deemed necessary by the 
Sponsor) 
• 
FVIIIhFVIII protein assay  
• 
Exploratory CK18 and Grp78 assessment 
• 
TGA Assay 
7, 8, 10, 
12 
14.3/Secondary Efficay 
Endpoints 
The analyses of the secondary efficacy endpoints will be descriptive. Mean and associated 95% confidence interval will be provided for 
the following secondary endpoints, where the baseline value will be derived from the data in the approximately 12-month period prior to 
BMN 270 infusion: 
• 
For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in the annualized utilization (IU/kg/year) of 
exogenous FVIII replacement therapy during Weeksfrom Week 5-52 post -BMN 270 infusion to last visit by data cutoff (for Week 
52 analysis); and separately, for subjects receiving FVIIIprior emicizumab prophylaxis during the 12 months prior to study entry, 
or, change from baseline in the annualized utilization (mg/kg/year) of emicizumab duringfrom Week 27 to Week 52 post -BMN 
270 infusion for subjects receiving prior emicizumab prophylaxisto last visit by data cutoff (for Week 52 analysis)  
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• 
For subjects receiving FVIII prophylaxis prior to study entry, change from baseline in the annualized infusion rate (number/year) 
of exogenous FVIII replacement therapy during Weeksfrom Week 5-52 post -BMN 270 infusion, to last visit by data cutoff (for 
Week 52 analysis); and separately for subjects receiving FVIIIprior emicizumab prophylaxis during the 12 months prior to study 
entry, or, change from baseline in the annualized utilization (mg/kg/year) of emicizumab duringfrom Week 27 to Week 52 post -
BMN 270 to last visit by data cutoff (for Week 52 analysis) infusion for subjects receiving prior emicizumab prophylaxis 
• 
Change from baseline in the annualized number of bleeding episodes (number/year) requiring exogenous FVIII replacement 
treatment during Weeksfrom Week 5-52 post-BMN 270 infusion to last visit by data cutoff (for Week 52 analysis) for subjects 
receiving prior FVIII prophylaxis, or Weeks from Week 27-52 post--BMN 270 infusion to last visit by data cutoff (for Week 52 
analysis) for subjects receiving prior emicizumab prophylaxis from baseline 
14.8/Determination of 
Sample Size 
Approximately 20 subjects may be dosed in the study, including at least 16 subjects who are AAV5 antibody-negative and up to 25% of 
the total number of subjects who havewith an AAV5 antibody titer that is detectable but below the minimum required dilution (< 20) at 
Screening. 
12 
14.9/Analysis 
Populations 
The AAV MRD population (ie, subjects with an AAV5 antibody titer detectable but below the minimum required dilution) will be used 
for exploratory efficacy analysis on FVIII activity, as measured by chromogenic substrate assay, during Weeks 49-52 post BMN 270 
infusion. 
12 
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. 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 ECs/IRBs. 
12 
21/References 
Pasi KJ, Rangarajan S, Kim B et al. Achievement of Normal Circulating Factor VIII Activity Following BMN 270 AAV5-FVIII Gene 
Transfer: Interim, Long-Term Efficacy and Safety Results from a Phase 1/2 Study in Patients with Severe Hemophilia A. Blood 
130[Suppl. 1], 603. 2017. 
United States Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for 
the Use of Antiretroviral Agents in Adults and Adolescents with HIV. 2019. Available at: http://www.aidsinfo.nih.gov/ContentFiles/ 
AdultandAdolescentGL.pdf (last accessed 17 May 2021). 
4, 12