A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII at a Dose of 4E13vg/kg in Hemophilia A Patients With Residual FVIII Levels ≤1IU/dL Receiving Prophylactic FVIII Infusions
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: BioMarin Pharmaceutical



 
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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment 4 
Date: 9 November 2018 
 
RATIONALE AND SUMMARY OF CHANGES 
A summary of major changes covered by Amendment 4 to the 270-302 protocol is 
provided below: 
1. Some visits during Year 1 of the study have been designated as optional mobile nursing 
or lab draw-only visits. 
Rationale: The number of full study visits at the site through Week 52 creates high subject 
and site staff burden, in terms of frequent travel to and lengthy time spent at the site by 
subjects and assessments deemed to no longer be mandatory performed by investigators.  
This amendment will reduce the number of site visits for subjects who have the option to 
conduct visits via a mobile nursing professional (similar to the option already available 
starting in Year 2 of the study).  For subjects who must still go to the site for all 
assessments, this amendment will decrease the time they will spend on-site. 
As part of this change, several minor adjustments have been made to the Schedule of 
Events: 
• The PBMC assessment at Week 34 has been eliminated. 
• The VWF-Ag assessment at Week 38 has been moved to Week 36. 
• The exploratory biomarker assessment at Week 13 has been moved to Week 12. 
• The urinalysis assessment at Week 38 has been moved to Week 36. 
• At visits where the mobile nursing or lab draw-only option is used, physical 
examination and vital signs assessments will not be performed. 
• At mobile nursing visits, the service will collect information regarding adverse 
events, changes to concomitant medications, bleeding episodes, and FVII use.  For 
lab draw-only visits, this information will be collected by site staff, by calling or 
emailing the subjects. 

 
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2. Development of anti-FVIII inhibitory antibodies (inhibitors) has been added as an 
Event of Special Interest for safety reporting purposes. 
Rationale: While development of FVIII neutralizing antibodies has not yet been observed 
in BMN 270 clinical studies, this change is being made to ensure timely reporting to health 
authorities. 
3. Assessment of the Direct Thrombin Activity test has been removed. 
Rationale: Based on the lack of correlation observed between FVIII activity levels and 
Direct Thrombin Activity test results in Study 270-201, it has been determined that samples 
for this exploratory test will no longer be collected in Study 270-302. 
4. Changes have been made to correct minor errors and for purposes of clarity and 
consistency.  
Refer to Section 25 for a summary of revisions to Amendment 3 (dated 28 August 2018). 

 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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TITLE OF STUDY:  
A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of  BMN 270, 
an Adeno-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII at a dose of 
4E13 vg/kg in Hemophilia A Patients with Residual FVIII Levels ≤ 1 IU/dL Receiving 
Prophylactic FVIII Infusions 
PROTOCOL NUMBER: 
270-302 
STUDY SITES: 
Approximately 40 sites worldwide. 
PHASE OF DEVELOPMENT: 
Phase 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 wild-type (< 1 IU/dL), 
moderate disease comprises 1-5% of wild-type activity and the mild form is 5-40% activity. The 
clinical manifestations of severe HA 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 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 

 
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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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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 
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 3.2 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 (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 1). 

 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
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• 
Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous 
FVIII replacement therapy from Week 5 to Week 52 
The tertiary efficacy objective of the study is to: 
• 
Assess the impact of BMN 270 on patient-reported outcomes (PROs) at Week 52 of the 
study compared to baseline 
The safety objectives of the study are to: 
• 
Evaluate the safety of BMN 270 during the first 52 weeks following intravenous 
infusion  
• 
Assess the long-term safety of BMN 270 
STUDY DESIGN AND PLAN:  
This is a Phase 3, single-arm, open-label study in hemophilia A patients with residual FVIII 
levels ≤ 1 IU/dL treated continuously with prophylactic exogenous FVIII for a minimum of one 
year prior to enrollment. Subjects will be enrolled at approximately 40 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 40 adult subjects with severe HA will receive a 4E13 vg/kg dose of BMN 270 as 
a single intravenous infusion. Approximately 5 subjects will enroll in the study with at least 
12 months of well-documented high-quality historical data concerning previous bleeding 
episodes and exogenous FVIII usage, while approximately 35 subjects will enroll in the study 
after having completed approximately 6 months’ participation in the BioMarin-sponsored 
non-interventional study 270-902, in which bleeding and FVIII use data prior to gene therapy 
will be prospectively collected. 
 

 
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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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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, has been convened. The DMC will have sole 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 at 
4E13 vg/kg should be discontinued in favor of a different dose of BMN 270, not to exceed 
6E13 vg/kg.  If the DMC recommends a dosing modification, then additional subjects may be 
enrolled, up to a total of approximately 40 subjects, at the new BMN 270 dose level (regardless 
of the number of subjects previously enrolled at 4E13 vg/kg). 
An interim analysis is planned after approximately 20 treated HIV-negative subjects have 
completed the Week 26 visit. Data will be reviewed by the DMC, based on the statistical 
analysis plan, and a formal recommendation will be made whether to continue the study as 
designed. 
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion.  After the final analysis, safety and efficacy will then continue 
to be assessed long-term in all subjects for a total of approximately 5 years. 
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic FVIII 
replacement therapy after 4 weeks following infusion of BMN 270. Four weeks represents the 
time by which endogenous production of FVIII following gene transfer is expected to be 
efficacious, based on earlier results. 
In subjects who experience recurring bleeding episodes, the Investigator and Medical Monitor 
will discuss whether to resume prior FVIII prophylaxis. 

 
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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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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. Therapeutic oral corticosteroids may be initiated when a 
subject’s ALT values are elevated, and subsequent dosage adjustments made, after consultation 
between the Investigator and the Medical Monitor. 
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). 
NUMBER OF SUBJECTS PLANNED:  
Approximately 40 subjects may enroll into the study. 
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 FVIII replacement therapy for at least 12 months prior 
to study entry.  High-quality, well-documented historical data concerning bleeding 
episodes and FVIII 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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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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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 no detectable viral vector 
DNA. 
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. 
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. 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. 

 
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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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8. Liver cirrhosis of any etiology as assessed by 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. 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. 
14. 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. 
15. Prior treatment with any vector or gene transfer agent. 
16. Major surgery planned in the 52-week period following the infusion with BMN 270. 
17. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines 
within 30 days before the BMN 270 infusion. 
18. 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. 
19. Known allergy or hypersensitivity to BMN 270 investigational product formulation. 
20. Unwilling to receive blood or blood products for treatment of an adverse event and/or a 
bleeding episode. 

 
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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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INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single intravenous infusion of BMN 270 at 4E13 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 in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy 
during Week 5 to Week 52 post-BMN 270 infusion from the baseline utilization 
of exogenous FVIII replacement therapy.  
• 
Change in the annualized number of bleeding episodes requiring exogenous FVIII 
replacement treatment (annualized bleeding rate, ABR) during Week 5 to Week 52 of 
the study post-BMN 270 infusion from the baseline ABR.  
Tertiary efficacy endpoints:   
 
• 
Change from baseline in the total score of HAEMO-QoL-A at Week 52 of the study 
post-BMN 270 infusion. 
• 
Change from baseline in the EQ-5D-5L score at Week 52 of the study post-BMN 270 
infusion. 
• 
Change from baseline in the Haemophilia Activities List (HAL) score at Week 52 of the 
study 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 of the 
study 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 
SUMMARY TABLE 
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• 
Change from baseline in Patient Reported Outcomes, Burdens, and Experiences 
(PROBE) score at Week 52 of the study 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, feces, saliva) 
• 
Liver tests (LTs, including ALT, AST, GGT, total bilirubin, and alkaline phosphatase) 
• 
Immune response to FVIII transgene product and AAV5 capsid proteins 
Each subject will have comprehensive surveillance monitoring of LTs (once per week for 
Weeks 1-36, and then once every 2 weeks from Weeks 37-52) during Year 1. LTs will be 
monitored every four weeks during Year 2 and then every 6 weeks during Years 3-5 post-dose in 
the safety extension; the frequency and duration of LT testing may be changed based on 
discussion between the Medical Monitor and the Investigator, review of subject data, and/or by 
independent DMC feedback.  
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 40 subjects may be dosed in the study. The sample size for this study is based on 
clinical and statistical considerations in order to provide sufficient data to assess both safety and 
efficacy of BMN 270.  
For the primary endpoint, a sample size of 40 will provide at least 90% power to demonstrate 
that the change in hFVIII activity during Weeks 49-52 from baseline is greater than 0, assuming 
an effect size of 0.6, using a one-sample t-test with a 2-sided significance level of 0.05.  

 
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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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For the secondary endpoints, the analyses will be performed utilizing exogenous FVIII use and 
bleeding episode data from the 35 subjects whose baseline data will be prospectively collected 
for approximately 6 months in the non-interventional study 270-902, prior to their enrollment in 
270-302. An analytic sample size of 35 will provide at least 90% power to demonstrate that the 
change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy during 
Week 5 to Week 52 post-BMN 270 infusion from baseline is less than 0, assuming an effect size 
of 0.6, using a one-sample t-test with a 2-sided significance level of 0.05. 
An analytic sample size of 35 will also have at least 95% power to demonstrate that the change 
in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment 
(ABR) during Week 5 to Week 52 of the study post-BMN 270 infusion from the baseline ABR is 
less than 3.5 (non-inferiority margin), assuming the pre- and post-BMN 270 infusion population 
mean ABRs are 3.5 and 1 respectively, using a one-sample t-test with a 2-sided significance 
level of 0.05. 
Overall, a sample size of 40 will have greater than 80% power for testing the primary and 
secondary efficacy endpoints hierarchically at the final analysis with a 2-sided significance level 
of 0.025. 
Analysis Population 
The intention-to-treat (ITT) population is defined as all subjects who receive BMN 270 infusion, 
and the modified intention-to-treat (mITT) population is defined as subjects who receive 
BMN 270 infusion and are HIV-negative.  The mITT population will be used for the primary 
efficacy analysis, and the ITT population will be used for the supportive efficacy analysis. The 
ITT population will also be used for the safety analysis. 
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. Descriptive summaries of the 
proportions of subjects whose FVIII activity during Weeks 49-52 is greater than or equal to 
select thresholds, such as 15, 25 and 30 IU/dL, and the confidence intervals of the proportions 
will also be provided.  
For the secondary endpoints, the analyses will be performed on subjects in the mITT population 
whose baseline data will be prospectively collected for approximately 6 months in the 
non-interventional study 270-902 prior to their enrollment in 270-302. 

 
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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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For the first secondary efficacy endpoint at Week 52 (ie, the change in the annualized utilization 
(IU/kg) of exogenous FVIII replacement therapy during Weeks 5-52 post-BMN 270 infusion 
from baseline), a one-sample t-test will be performed to test the null hypothesis that the change is 
0 or greater against the alternative hypothesis that the change is less than 0.  
For the second secondary efficacy endpoint at Week 52 (ie, the change in the annualized number 
of bleeding episodes requiring exogenous FVIII replacement treatment during Weeks 5-52 
post-BMN 270 infusion from baseline), a one-sample t-test will be performed to test for 
non-inferiority of BMN 270 against FVIII prophylaxis (ie, the baseline ABR calculated using 
subjects’ data collected in 270-902) using a margin of 3.5, ie, to test the null hypothesis that the 
change is 3.5 or greater against the alternative hypothesis that the change is less than 3.5. If 
non-inferiority is demonstrated, the test for superiority of BMN 270 against FVIII prophylaxis 
will be performed. 
The primary efficacy endpoint and secondary efficacy endpoints will be tested hierarchically at 
the final analysis at Week 52 according to the order described above. 
An interim analysis is planned after approximately 20 treated HIV-negative subjects have 
completed the Week 26 visit (or have discontinued participation prior to Week 26). The primary 
efficacy endpoint for the interim analysis involves hFVIII activity, as measured by chromogenic 
substrate assay, achieved post-BMN 270 infusion, as detailed in the Statistical Analysis Plan 
(SAP).  
Adjustment for multiplicity of the interim analysis at Week 26 and the final analysis at Week 52 
will be described in the SAP (regardless of the interim analysis results, the study is planned to 
continue upon the DMC’s recommendation, and the final analysis will be performed at 
Week 52). At the final analysis at Week 52, the secondary efficacy endpoints will be tested 
hierarchically.  
The secondary efficacy endpoints at the interim analysis (Week 26) will be summarized 
descriptively.   
The tertiary endpoints will be analyzed at the interim (Week 26) and final (Week 52) analyses, 
irrespective of the aforementioned hierarchical testing. 
Details of the interim analysis, including the control of Type I error rate, will be specified in the 
SAP. 
Analysis of safety endpoints will be primarily descriptive. 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. 

 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY .............................2 
2 SYNOPSIS ............................................................................................................4 
3 TABLE OF CONTENTS ....................................................................................16 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .....................22 
5 ETHICS...............................................................................................................25 
5.1 Institutional Review Board or Independent Ethics Committee .................25 
5.2 Ethical Conduct of Study ...........................................................................26 
5.3 Subject Information and Informed Consent ...............................................26 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .........27 
7 INTRODUCTION ..............................................................................................28 
7.1 Nonclinical Studies ....................................................................................28 
7.2 Previous Clinical Studies ...........................................................................29 
7.3 Study Rationale ..........................................................................................29 
7.4 Summary of Overall Risks and Benefits ....................................................32 
8 STUDY OBJECTIVES .......................................................................................34 
9 INVESTIGATIONAL PLAN .............................................................................35 
9.1 Overall Study Design and Plan ..................................................................35 
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 ....................57 
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 ...............................................58 
9.4.3 
Storage ..........................................................................................58 
9.4.4 
Directions for Administration ......................................................58 

 
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9.4.5 
Method of Assigning Subjects to Treatment Groups ...................60 
9.4.6 
Selection of Dose Used in the Study ............................................60 
9.4.7 
Blinding ........................................................................................61 
9.4.8 
Prior and Concomitant Medications .............................................61 
9.4.9 
Treatment Compliance .................................................................64 
9.5 Investigational Product Accountability ......................................................64 
9.5.1 
Return and Disposition of Clinical Supplies ................................64 
9.6 Dietary or Other Protocol Restrictions.......................................................65 
9.7 Safety and Efficacy Variables ....................................................................65 
9.7.1 
Safety and Efficacy Measurements Assessed ..............................65 
9.7.2 
Primary Efficacy Variables ..........................................................65 
9.7.3 
Secondary Efficacy Variables ......................................................66 
9.7.4 
Tertiary Efficacy Variables ..........................................................67 
9.7.5 
Immunogenicity ............................................................................68 
9.7.6 
Pharmacodynamics .......................................................................68 
9.7.7 
Exploratory Assessments .............................................................68 
9.7.8 
Safety Variables ...........................................................................69 
10 REPORTING ADVERSE EVENTS ..................................................................77 
10.1 Safety Parameters and Definitions .............................................................77 
10.1.1 Adverse Events .............................................................................77 
10.2 Serious Adverse Events .............................................................................78 
10.2.1 Events of Special Interest (EOSI) ................................................79 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters ......79 
10.3.1 Adverse Event Reporting Period ..................................................79 
10.3.2 Eliciting Adverse Events ..............................................................79 
10.3.3 Assessment of Seriousness, Severity, and Causality ....................79 
10.4 Procedures for Recording Adverse Events ................................................82 
10.4.1 Recording Adverse Events on a eCRF .........................................82 
10.5 Reporting Requirements ............................................................................85 
10.5.1 Expedited Reporting Requirements ..............................................85 

 
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10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements...............................................................86 
10.6 Follow-up of Subjects after Adverse Events ..............................................86 
10.7 Post-Study Adverse Events ........................................................................86 
10.8 Urgent Safety Measures .............................................................................87 
10.9 BioMarin Pharmacovigilance Contact Information ...................................88 
11 APPROPRIATENESS OF MEASUREMENTS ................................................89 
12 STUDY PROCEDURES ....................................................................................90 
12.1 Prestudy ......................................................................................................90 
12.2 Screening Visit ...........................................................................................90 
12.2.1 “Smart Rescreening” Visit ...........................................................91 
12.3 Baseline Visit .............................................................................................92 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) .....................................93 
12.5 BMN 270 Infusion Follow-Up Visits – Weeks 1-26 .................................94 
12.5.1 Once per week (Weeks 1 through 26) ..........................................94 
12.5.2 Week 1 – Day 4 ............................................................................95 
12.5.3 Week 1 – Day 8 ............................................................................95 
12.5.4 Every 2 Weeks (Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 
and 26) ..........................................................................................95 
12.5.5 Weeks 2, 4, 10, 16, 22, and 26 .....................................................95 
12.5.6 Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26 ...................................95 
12.5.7 Weeks 4, 12, and 26 .....................................................................95 
12.5.8 Every 4 Weeks (Weeks 4, 8, 12, 16, 20, and 24) Plus Week 26 ..96 
12.5.9 Every 8 Weeks (Weeks 8, 16, and 24) .........................................96 
12.5.10 Weeks 6, 12, 16, 20, 24, and 26 ...................................................96 
12.5.11 Weeks 12 and 26 ..........................................................................96 
12.5.12 Week 16 ........................................................................................96 
12.5.13 Week 20, 24, and 26 .....................................................................96 
12.6 Post-Infusion Follow-Up – Weeks 27-52 ..................................................97 
12.6.1 Every Visit ....................................................................................97 
12.6.2 Weeks 28, 30, 32, 36, 44, and 52 .................................................98 

 
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12.6.3 Every 4 Weeks (Weeks 28, 32, 36, 40, 44, 48, 52) ......................98 
12.6.4 Weeks 32, 36, 44, and 52 .............................................................98 
12.6.5 Weeks 32, 36, 40, 44, 48, and 52 .................................................98 
12.6.6 Week 32, 36, and 52 .....................................................................98 
12.6.7 Week 36 and 52 ............................................................................98 
12.6.8 Week 52 ........................................................................................99 
12.7 Post-Infusion Follow-Up – Years 2-5 ........................................................99 
12.7.1 Year 2 – Every 4 Weeks (not required for treatment failure) ....100 
12.7.2 Years 3-5 – Every 6 Weeks (not required for treatment failure) 101 
12.7.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects).................................................................................102 
12.8 Early Termination Visit ...........................................................................103 
12.9 End of Study.............................................................................................105 
13 DATA QUALITY ASSURANCE ....................................................................106 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .107 
14.1 Statistical and Analytical Plans ................................................................107 
14.1.1 Interim Analyses .........................................................................107 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious 
Data ............................................................................................107 
14.2 Primary Efficacy Endpoint.......................................................................107 
14.3 Secondary Efficacy Endpoints .................................................................108 
14.4 Immunogenicity .......................................................................................109 
14.5 Pharmacodynamic Analyses ....................................................................109 
14.6 Safety Analysis ........................................................................................109 
14.7 Determination of Sample Size .................................................................110 
14.8 Analysis Populations ................................................................................110 
14.9 Changes in the Conduct of the Study or Planned Analyses .....................111 
15 DATA MONITORING COMMITTEE ............................................................112 
16 COSTS, COMPENSATION, AND SUBJECT INJURY .................................113 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS .............................114 
18 STUDY MONITORING AND AUDITING ....................................................116 

 
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19 RETENTION OF RECORDS ..........................................................................117 
20 USE OF INFORMATION AND PUBLICATION ..........................................118 
21 REFERENCES .................................................................................................119 
22 INVESTIGATOR RESPONSIBILITIES .........................................................122 
22.1 Conduct of Study and Protection of Human Patients ..............................122 
23 SIGNATURE PAGE ........................................................................................123 
24 APPENDICES ..................................................................................................124 
25 PROTOCOL AMENDMENT TEXT REVISIONS .........................................125 
 
LIST OF TABLES 
Table 9.1.1:  Schedule of Events – Screening and Infusion .....................................38 
Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) .............41 
Table 9.1.3:  Schedule of Events – Post-Infusion Follow-Up (Week 17-32) ...........44 
Table 9.1.4:  Schedule of Events – Post-Infusion Follow-Up (Week 33 – Week 
52) ...................................................................................................47 
Table 9.1.5:  Schedule of Events – Post-Infusion Follow-Up (Year 2 – Year 5) .....49 
Table 9.1.6:  Schedule of Events – Therapeutic Corticosteroids for ALT 
Elevations .......................................................................................52 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen ........................................63 
Table 9.7.8.2.1:  Clinical Laboratory Tests ..............................................................70 
Table 9.7.8.3.1:  Liver Tests .....................................................................................72 
Table 9.7.8.3.2:  Evaluation of ALT Elevations .......................................................73 
Table 9.7.8.3.3:  Viral and Autoimmune Hepatitis Testing ......................................74 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale .....................................80 
Table 10.3.3.3.1:  Causality Attribution Guidance ...................................................81 
 

 
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LIST OF FIGURES 
Figure 1:  hFVIII-SQ Vector Genome Schematic ......................................................6 
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic ..............................................31 
 
LIST OF APPENDICES 
Appendix 1:  Sampson’s Anaphylaxis Criteria .......................................................124 
 

 
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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 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
APTT 
activated partial thromboplastin time 
ART 
anti-retroviral therapy 
AST 
aspartate aminotransferase 
BPV 
BioMarin Pharmacovigilance 
BU 
Bethesda Unit 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
eCRF 
electronic case report form 
ED 
exposure days 
EOSI 
events of special interest 
ETV 
early termination visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FVIII 
coagulation factor VIII 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HA 
Hemophilia A 
HAL 
Haemophilia Activities List 
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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HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice 
E6 
IEC 
independent ethics committee 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intention-to-treat 
IV 
intravenous 
LT 
liver test 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention-to-treat 
MN 
mobile nursing 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
TGA 
thrombin generation assay 
ULN 
upper limit of normal 
vg 
vector genomes 
VWF:Ag 
von Willebrand factor antigen 
WPAI+CIQ:HS 
Work Productivity and Activity Impairment plus Classroom Impairment 
Questions: Hemophilia Specific 

 
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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) [for Canadian 
protocols, Research Ethics Board (REB)] is properly constituted and compliant with 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) requirements, 
applicable laws and local regulations. A copy of the confirmation from the IRB/IEC/REB 
will be provided to BioMarin or its designee. The Investigator will provide the 
IRB/IEC/REB with all appropriate material, including the protocol, Investigator’s Brochure 
(IB), the Informed Consent Form (ICF) including compensation procedures, and any other 
written information provided to the subjects, including all ICFs translated 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/REB confirming unconditional approval of the protocol, the 
ICF and all subject recruitment materials are obtained in writing by the Investigator and 
copies are received at BioMarin or its designee. The approval document should refer to the 
study by protocol title and BioMarin protocol number (if possible), identify the documents 
reviewed, and include the date of the review and approval. BioMarin will ensure that the 
appropriate reports on the progress of the study are made to the IRB/IEC/REB and 
BioMarin by the Investigator in accordance with applicable guidance documents and 
governmental regulations. 

 
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5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, 
but is not limited to: establishing and meeting enrollment commitments, including 
providing eligible subjects for study enrollment; adhering to 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/REB 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 informed consent form (ICF), in compliance with ICH E6 
(Section 4.8), United States Code of Federal Regulations (CFR) 21 CFR §50, European 
Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC, and 
other applicable local regulations, will be obtained for each subject prior to entering the 
subject into the study. The Investigator will prepare the ICF and provide the documents to 
BioMarin for approval prior to submission to the IRB/IEC/REB. BioMarin and the 
IRB/IEC/REB must approve the documents before they are implemented. A copy of the 
approved ICF, and if applicable, a copy of the approved subject information sheet and all 
ICFs translated to a language other than the native language of the clinical site must also be 
received by BioMarin or designee prior to any study-specific procedures being performed. 
The Investigator will provide copies of the signed ICF to each subject and will maintain the 
original in the record file of the subject. 

 
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6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
During administration of informed consent, expectations regarding participation in the 
study should be made clear to subjects. Patients who are not willing and/or are not able to 
comply with all aspects of the study should not be encouraged to participate. 
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee a fully executed and signed 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 (Nathwani, 1992). 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 liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs, and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is 
contained in the IB supplied by BioMarin. Investigators are to review this document prior 
to initiating this study. 
7.1 
Nonclinical Studies 
The nonclinical program supports a single IV 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 therapy medicinal 

 
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products under 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 
Study BMN 270-201 is an ongoing Phase 1/2, dose-escalation study to assess the safety, 
tolerability, and efficacy of BMN 270 in patients with severe hemophilia A (FVIII 
<1 IU/dL).  Subjects received a single BMN 270 infusion and are to be followed for safety 
and efficacy for up to 5 years.  A total of 15 subjects have been enrolled at one of 4 dose 
levels (6E12, 2E13, 4E13, and 6E13 vg/kg). 
A comprehensive review of safety, efficacy, and immunogenicity results from 270-201 as 
of the latest data cut is contained in the IB supplied by BioMarin. Investigators are to 
review this document prior to initiating this study. 
7.3 
Study Rationale 
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 wild type (< 1 IU/dL), moderate disease comprises 1-5% of wild-type activity 
and the mild form is 5-40% activity. The clinical manifestations of severe HA 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 presently consists of intravenous injection of plasma derived or 
recombinant human FVIII protein (rhFVIII) concentrates both as prophylaxis 2-3 times per 

 
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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 1% 
trough for a greater proportion of the dosing interval. However, these extended half-life 
FVIII variants remain dependent on multiple infusions to maintain critical levels of FVIII 
activity in severe HA patients. There is therefore a strong unmet need for a fully preventive 
treatment of HA to give patients a FVIII level compatible with a normal and 
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 the disease.  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 on-going gene therapy clinical trial for a related disorder, 

 
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The current study is a Phase 3, single-arm, open-label study designed to assess whether, in 
an expanded sample, BMN 270 at a dose of 4E13 vg/kg can safely alter the clinical 
phenotype of hemophilia A patients with residual FVIII activity ≤ 1 IU/dL. 
7.4 
Summary of Overall Risks and Benefits 
The majority of subjects in the ongoing 270-201 clinical study who have received 4E13 or 
6E13 vg/kg doses of BMN 270 have had Grade 1 asymptomatic elevations in ALT. For 
most subjects, the elevations have reached only slightly above the ULN.  Based on the 
effectiveness of transient oral corticosteroid used to suppress a presumed cytotoxic T-cell 
response in prior studies with hepatic transduction with AAV vectors (Mingozzi, 2013), 
subjects were treated with 7-32 weeks of oral corticosteroids preventatively or in response 
to the elevations in ALT to ensure preservation of the transduced hepatocytes. Using this 
approach, no sustained loss of FVIII activity has been observed in subjects with ALT 
elevations, consistent with maintaining a high level of hepatocyte function. Moreover, the 
rise in ALT levels were not accompanied by significant or lasting aberrations in other liver 
tests such as AST, bilirubin or albumin, indicating that extent of toxicity is limited. There 
has been one HIV-positive subject in the ongoing 270-302 clinical study who experienced 
Grade 3 asymptomatic elevations in ALT and AST, which has been attributed to an 
interaction between one or more of his antiretroviral therapy medications and/or 
unsuspected underlying hepatic disease with BMN 270. In addition, there has been one 
subject with Gilbert’s syndrome in the ongoing 270-301 clinical study who has experienced 
Grade 3 asymptomatic elevations in ALT and AST. These cases have led to the exclusion 
of subsequent HIV-positive subjects and requirement of liver tests at Screening that are 
<1.25 times the upper limit of the normal range in the ongoing 270-301 and 270-302 
clinical studies. Of note, two HIV-positive subjects in 270-301 and one presumed Gilbert’s 
syndrome subject in 270-201 have received BMN 270 without experiencing any elevations 
in ALT to date. Overall, the literature and clinical experiences with BMN 270 thus far 
suggest that transient elevations in liver enzymes are expected following AAV-based gene 
therapy for the treatment for hemophilia B without any long-term concerns of hepatic 
injury (Manno, 2006); (Nathwani 2011); (George, 2016); (Miesbach, 2016), (Pasi, 2017).  
At the highest dose tested in 270-201 (6E13 vg/kg), the majority of subjects achieved FVIII 
levels above 50 IU/dL at 52 weeks post-infusion. Similarly, subjects who received 
4E13 vg/kg have achieved FVIII levels within or approaching the normal range. Subjects in 
both cohorts 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. 

 
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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. No hypersensitivity 
reactions were observed during dosing of BMN 270 in the 270-201 clinical study, although 
one SAE of pyrexia was reported approximately 16 hours after the infusion in a subject in 
the 4E13 vg/kg cohort. The subject was treated with acetaminophen, and the fever resolved 
within 48 hours (see Investigator’s Brochure for full details). Infusion-related reactions, 
including allergic reaction, maculopapular rash, and presyncope, have been reported from 
ongoing, actively dosing clinical studies of BMN 270. All of the infusion-related reactions 
were effectively managed clinically and resolved without any clinical sequelae. Refer to the 
Investigator’s Brochure for additional details. 
The current data available for BMN 270 does not yet permit adequate assessment of the 
benefit:risk profile of this investigational drug. Given the monitoring measures in place in 
the clinical protocol(s) to minimize the risk to subjects participating in the existing studies, 
the identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-302 will have a comprehensive surveillance plan that monitors LTs 
during the study, and elevations in LT will be addressed according to the guidelines set 
forth in the protocol. Safety will be assessed by adverse event reporting and clinical 
laboratory assessments. 
For additional information on findings in 270-201, refer to the current version of the 
Investigator’s Brochure. 

 
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8 
STUDY OBJECTIVES 
The primary efficacy objective of the study is to: 
• Assess the efficacy of BMN 270 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 on usage of exogenous FVIII replacement therapy 
from Week 5 to Week 52 
• Assess the impact of BMN 270 on the number of bleeding episodes requiring 
exogenous FVIII replacement therapy from Week 5 to Week 52 
The tertiary efficacy objective of the study is to: 
• Assess the impact of BMN 270 on patient-reported outcomes (PROs) at Week 52 of 
the study compared to baseline 
The safety objectives of the study are to: 
• Evaluate the safety of BMN 270 during the first 52 weeks following intravenous 
infusion  
• Assess the long-term safety of BMN 270 

 
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 3, single-arm, open-label study in hemophilia A patients with residual FVIII 
levels ≤ 1 IU/dL treated continuously with prophylactic exogenous FVIII for a minimum of 
one year prior to enrollment. Subjects will be enrolled at approximately 40 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 40 adult subjects with severe HA will receive a 4E13 vg/kg dose of 
BMN 270 as a single intravenous infusion. Approximately 5 subjects will enroll in the 
study with at least 12 months of well-documented high-quality historical data concerning 
previous bleeding episodes and exogenous FVIII usage, while approximately 35 subjects 
will enroll in the study after having completed approximately 6 months’ participation in the 
BioMarin-sponsored non-interventional study 270-902, in which bleeding and FVIII use 
prior to gene therapy will be prospectively collected. 
 
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, has been convened.  The DMC will have sole 
access during the trial to amalgamated FVIII activity levels, FVIII usage, and bleeding data 
and will 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 at 4E13 vg/kg should be discontinued in favor of a different dose of 
BMN 270, not to exceed 6E13 vg/kg.  If the DMC recommends a dosing modification, then 

 
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additional subjects may be enrolled, up to a total of approximately 40 subjects, at the new 
BMN 270 dose level (regardless of the number of subjects previously enrolled at 
4E13 vg/kg). 
An interim analysis is planned after approximately 20 treated HIV-negative subjects have 
completed the Week 26 visit.  
The final analysis for the study will be performed after all subjects have been followed for 
52 weeks post-BMN 270 infusion.  After the final analysis, safety and efficacy will then 
continue to be assessed long-term in all subjects for a total of approximately 5 years. 
To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic 
FVIII replacement therapy after 4 weeks following infusion of BMN 270. Four weeks 
represents the time by which endogenous production of FVIII following gene transfer is 
expected to be efficacious, based on earlier results. 
As the relationship between activity assay results of the BMN 270 gene product and 
bleeding remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. 
Subjects who do not respond to BMN 270 treatment 
 
 
ay, 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. Therapeutic oral corticosteroids may be initiated 
when a subject’s ALT values are elevated, and subsequent dosage adjustments made, after 
consultation between the Investigator and the Medical Monitor.  Management of ALT 
elevations is discussed in more detail in Section 9.7.8.3. 
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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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 Table 9.1.5), 
and during the use of oral corticosteroids (Table 9.1.6) 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)k 
Screening* 
(Day -28 to Day -1) 
Smart Rescreeningi  
(Day -28 to Day -1) 
Baseline (Day -7 
to Day -1)h 
Informed consent 
X 
 
 
 
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 FVIII usage for previous 12 months 
(by either subject or clinical information) 
X 
X 
X 
 
Distribution of subject diaries and training in their usel 
X 
 
 
 
Electrocardiogram 
X 
 
 
 
Liver Ultrasound 
X 
 
 
 
hFVIII Assaysb 
X 
Xj 
X 
 
AAV5 TAb Assaysc 
X 
X 
X 
X 
AAV5 TI Assay 
 
 
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 
Urine Testse 
X 
X 
X 
 
Liver Testse  
X 
X 
X 
 
PBMC collection (for baseline determination of AAV5 and FVIII specific 
cellular immunity) 
 
 
X 
 

 
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Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion Visit 
(Day 1)k 
Screening* 
(Day -28 to Day -1) 
Smart Rescreeningi  
(Day -28 to Day -1) 
Baseline (Day -7 
to Day -1)h 
Von Willebrand Factor Antigen (VWF:Ag) 
 
 
X  
 
TGA Assayg 
 
 
X 
 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
 
 
X 
X 
Biomarker testingf 
X 
 
 
 
Exploratory biomarker assessmentsg 
 
 
X 
X 
Haemo-QOL-A assessment 
 
 
X 
 
EQ-5D-5L  
 
 
X 
 
HAL 
 
 
X 
 
WPAI+CIQ:HS 
 
 
X 
 
PROBE 
 
 
X 
 
BMN 270 Infusion 
 
 
 
X 
Hypersensitivity blood assessmentsm 
 
 
 
Xm 
* 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 Includes baseline FVIII activity (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), coagulation exploratory assay, hFVIII inhibitor level (Bethesda assay with 
Nijmegen modification), hFVIII total antibody titer, 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). 
c Sample collection on the day of the infusion visit must be performed before the BMN 270 infusion is given. Screening, Smart Re-screening, and Infusion Day samples will be tested in an 
AAV5 TAb pre-screening assay specifically developed for enrollment purposes. Baseline and all post-dose samples will be tested in a different AAV5 TAb post-dose immunogenicity 
monitoring assay 
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 as part of the hematology 
assessment (at Baseline, or at another regularly scheduled visit prior to the end of the subject’s participation in the study). 
f Includes HLA genotyping and FVIII genotyping. 

 
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g Blood samples will be collected from subjects 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. 
h Should the screening visit occur within 30 days of the drug infusion, physical examination, blood chemistry, LTs, hematology, urine tests, and coagulation tests do not need to be repeated 
at Baseline. 
i Smart rescreening should only be performed if a patient has been determined to be eligible for the study and is unable to complete the Baseline assessments and Infusion prior to the closing 
of the original Screening window.  Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion within 90 days of signing the original 
consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures.  Subjects may not undergo smart rescreening more than 
once. 
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening. 
k With the exception of the collection of samples for 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 (blood, saliva, urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been completed.  
l 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. 
m In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination and vital signs, will be done and additional blood samples will be collected 
 
 
 In-patient observation can be extended and additional blood samples can be collected if deemed necessary at the 
discretion of the Investigator and Medical Monitor. 

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Table 9.1.2:  Schedule of Events – Post-Infusion Follow-Up (Week 1-16) 
Assessment 
Follow-Up After BMN 270 Infusion – Weeks* 
Week 1 
2 
3 
4 
5g 
6 
7g 
8 
9g
10 
11g 
12 
13g 
14 
15g 
16 
D4 
D8 
Study Day* 
4 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
Physical examinationa 
X 
X 
X 
X 
Xg
X 
Xg
X 
Xg 
X 
Xg
X 
Xg 
X 
Xg
X 
Weighta 
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 
Xg
X 
Xg
X 
Xg 
X 
Xg
X 
Xg 
X 
Xg
X 
Blood chemistry, 
hematology, and 
coagulation testsb    
X 
X 
X 
X 
Urine Testsb
X 
Liver Testsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer 
X 
X 
X 
X 
PCR of vector DNA in 
blood, saliva, urine, semen, 
and stoolsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker 
assessmentse 
X 
X 
X 
Haemo-QOL-A assessment 
X 
X 
EQ-5D-5L 
X 
X 
HAL 
X 
X 

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Assessment 
Follow-Up After BMN 270 Infusion – Weeks* 
Week 1 
2 
3 
4 
5g 
6 
7g 
8 
9g
10 
11g 
12 
13g 
14 
15g 
16 
D4 
D8 
Study Day* 
4 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
WPAI+CIQ:HS 
X 
X 
PROBE 
X 
X 
AAV5 TAb Assay 
X 
X 
AAV5 TI Assay 
X 
X 
Testing for reactivation of 
hepatitis B and hepatitis C 
Xf 
PBMC collection (for 
determination of AAV5 and 
FVIII specific immunity) 
X 
X 
X 
X 
X 
X 
X 
X 
VWF:Ag 
X 
* Visit windows are ± 48 hours (and include the Day 4 visit).
a Brief physical examination should be done at all weekly 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  ≥ 1.5x ULN or > ULN and > 2x 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 ≥ 1.5x ULN or > ULN and > 2x 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 above ULN; (2) Increases in 
ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the Investigator based on a review of subject 
data.  If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical 
Monitor and the Investigator.

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Table 9.1.3:  Schedule of Events – Post-Infusion Follow-Up (Week 17-32) 
Assessment 
Follow-Up After BMN 270 Infusion – Weeks* 
17f 
18 
19f 
20 
21f 
22 
23f 
24 
25f 
26 
27f 
28 
29f 
30f 
31f 
32 
Study Day* 
120 
127 
134 
141 
148 
155 
162 
169 
176 
183 
190 
197 
204 
211 
218 
225 
Physical examinationa 
Xf
X 
Xf
X 
Xf
X 
Xf
X 
Xf
X 
Xf
X 
Xf
Xf
Xf
X 
Weighta 
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 
Xf
X 
Xf
X 
Xf
X 
Xf
X 
Xf
X 
Xf
X 
Xf
Xf
Xf
X 
Blood chemistry, 
hematology, and 
coagulation testsb    
X 
X 
X 
Urine Testsb
X 
Liver Testsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII antibody titer 
X 
X 
X 
X 
PCR of vector DNA in 
blood, saliva, urine, 
semen, and stoolsd 
X 
X 
X 
X 
Exploratory biomarker 
assessmentse 
X 
X 
X 
X 
Haemo-QOL-A 
assessment
X 
EQ-5D-5L 
X 

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Assessment 
Follow-Up After BMN 270 Infusion – Weeks* 
17f 
18 
19f 
20 
21f 
22 
23f 
24 
25f 
26 
27f 
28 
29f 
30f 
31f 
32 
Study Day* 
120 
127 
134 
141 
148 
155 
162 
169 
176 
183 
190 
197 
204 
211 
218 
225 
HAL 
X 
WPAI+CIQ:HS 
X 
PROBE 
X 
AAV5 TAb Assay 
X 
X 
AAV5 TI Assay 
X 
X 
PBMC collection  (for 
determination of AAV5 
and FVIII specific 
cellular immunity) 
X 
X 
X 
X 
X 
X 
X 
X 
VWF:Ag 
X 
TGA Assaye 
X 
X 
X 
X 
* Visit windows are ± 48 hours.
a Brief physical examination should be done at all weekly visits except Week 26, where a complete physical examination should be performed.  Weight should be recorded at Week 20 and 
every 4 weeks.
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular when ALT values 
are ≥ 1.5x ULN or > ULN and > 2x 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 ≥ 1.5x ULN or > ULN and > 2x 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 above ULN; (2) Increases in 
ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the Investigator based on a review of subject 
data.  If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical 
Monitor and the Investigator.
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with Nijmegen modification) 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 

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Table 9.1.4:  Schedule of Events – Post-Infusion Follow-Up (Week 33 – Week 52) 
Assessment 
Year 1 – Weeks* 
33e 
34e 
35e 
36 
38e 
40 
42e 
44 
46e 
48 
50e 
52 
Study Day* 
232 
239 
246 
253 
267 
281 
295 
309 
323 
337 
351 
365 
Physical examinationa 
Xe 
Xe 
Xe 
X 
Xe
X 
Xe 
X 
Xe 
X 
Xe
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 
Vital Signs 
Xe
Xe
Xe
X 
Xe
X 
Xe
X 
Xe
X 
Xe
X 
Blood chemistry, hematology, and coagulation testsb 
X 
X 
X 
Urine Testsb
X 
X 
Liver Testsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII assaysc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AAV5 TAb Assay 
X 
X 
AAV5 TI Assay 
X 
X 
FVIII antibody titer 
X 
X 
X 
Exploratory biomarker assessmentsd 
X 
X 
X 
X 
X 
PBMC Collection (for determination of FVIII and Capsid specific 
cellular immunity) 
X 
X 
X 
VWF:Ag 
X 
X 
TGA Assayd 
X 
X 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
X 
X 
X 
X 
X 
Haemo-QOL-A assessment 
X 
EQ-5D-5L 
X 
HAL 
X 
WPAI+CIQ:HS 
X 

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Table 9.1.5:  Schedule of Events – Post-Infusion Follow-Up (Year 2 – Year 5) 
Assessment 
Years 2-5* 
Year 2* 
Years 3-5* 
End of Year Visit 
ETV 
Q12W 
Q4Wg
Q6Wg
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
W104 
W156 
W208 
W260 
Physical examinationa 
Xa 
Xa 
X 
Weighta 
Xa 
Xa 
X 
Assessment of Adverse Events and Concomitant Medications 
(including review of subject diary for bleeding and FVIII use) 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
Blood chemistry, hematology, and coagulation testsb 
Xb 
Xb 
X 
Urine Testsb
Xb 
Xb 
X 
Liver Testsb 
X 
X 
X 
X 
X 
FVIII assaysc 
X 
X 
X 
X 
X 
AAV5 TAb Assay 
X 
X 
X 
AAV5 TI Assay 
X 
X 
X 
FVIII antibody titer 
X 
X 
X 
Exploratory biomarker assessmentse 
X 
X 
X 
PBMC Collection (for determination of FVIII and Capsid specific 
cellular immunity) 
X 
X 
X 
VWF:Ag 
X 
X 
X 
TGA Assaye 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and stoolsd 
(X)d 
(X)d 
(X)d 
(X)d 
(X)d 
Haemo-QOL-A assessment 
Xf
Xf 
X 
EQ-5D-5L 
Xf 
Xf 
X 
HAL 
Xf 
Xf 
X 
WPAI+CIQ:HS 
Xf 
Xf 
X 

 
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Assessment 
Years 2-5* 
Year 2* 
Years 3-5* 
End of Year Visit 
ETV 
Q12W 
Q4Wg 
Q6Wg 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
W104 
W156 
W208 
W260 
PROBE 
Xf 
 
 
Xf 
X 
* Visit windows are ± 2 weeks for visits in Years 2-5. At applicable sites, the Q4W (during Year 2) and Q6W (during Years 3-5) assessments may be conducted by a trained mobile nursing 
(MN) professional at the subject’s home or another suitable location, if the subject has given written informed consent to participate in mobile nursing visits. Q12W and End of Year visits 
during Years 2-5 cannot be done by a MN professional and must be done at the study site. 
a 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. 
b Refer to Table 9.7.8.2.1 for laboratory assessments to be included, and to Table 9.7.8.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular when ALT values 
are ≥ 1.5x ULN or > ULN and > 2x 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 ≥ 1.5x ULN or > ULN and > 2x 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 above ULN or increased by 
> 10 U/L from prior assessment; (2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor 
and the Investigator based on a review of subject data.  If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be 
adjusted based on discussion between the Medical Monitor and the Investigator.  During Years 2-5 of the Post-Infusion Follow-Up period, urine tests and blood, chemistry, and coagulation 
tests should be performed at the second Q12W visit each year and at every End of Year visit. 
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with Nijmegen modification) 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. 
d Sample testing during Long-Term Follow-Up is not required if at least 3 consecutive samples were negative during the Post-Infusion Follow-Up period.  Subjects who have not had 
3 consecutive negative semen samples by Week 52 should continue to have PCR testing of semen every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 3 consecutive 
negative samples are documented (or upon consultation between the Investigator and Medical Monitor). 
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A disease, coagulation, and/or AAV gene transfer, and to 
develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known 
to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for TGA assay and any other 
exploratory assessments) will be performed only as deemed necessary by the Sponsor. 

 
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f  PRO assessments during Years 2-5 of Long-Term Follow-up should be performed at the second Q12W visit each year and at every End of Year visit. 
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 all fluids 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. 

 
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Table 9.1.6:  Schedule of Events – Therapeutic Corticosteroids for ALT Elevations  
 
Steroid Treatment Periodb 
Post-Steroid Periodc 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 
8b 
Week 1 
Week 2 
Week 3 
Week 4 
Week 
13 
Therapeutic 
corticosteroids 
(dose in mg/day) a  
60 mg 
60 mg 
40 mg 
40 mg 
40 mg 
30 mg 
20 mg 
10 mg 
 
 
 
 
 
FVIII activity 
testing  
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Liver tests 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Hepatitis B 
testingd 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
HCV Viral Loadd 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
a Therapeutic oral corticosteroids may be initiated according to the parameters set out in Section 9.4.8.2. 
b Following initiation or completion of steroid regimen, if a recurrence of ALT values ≥ 1.5x ULN or > ULN and > 2x baseline value is reported, steroid management decisions will based on 
discussions between the Investigator and Medical Monitor.  Modification of the steroid regimen may take into consideration possible confounders for the ALT elevation, relationship 
between increases in ALT and FVIII activity, ALT/FVIII levels post steroid initiation, and adverse events related to steroid dosing.  Guidance for tapering oral corticosteroid dosing can be 
found in Section 9.4.8.2. 
c After discontinuation of oral corticosteroids, weekly labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values.  If these assessments are already 
being done as part of normal study follow-up, they do not need to be duplicated. 
d Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry. 
 

 
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9.2 
Discussion of Study Design, Including Choice of Control Group 
Study 270-302 is designed to be a Phase 3, single-arm, open-label study in hemophilia A 
patients with residual FVIII levels ≤ 1 IU/dL previously treated with prophylactic exogenous 
FVIII. Hemophilia A patients who provide written informed consent, meet the entry criteria 
definition of residual FVIII activity, have well-documented historical data for the previous 
12 months concerning exogenous FVIII usage and bleeding episodes, and do not have 
antibodies to AAV5 will be eligible to enroll in the study. 
Approximately 40 subjects will be enrolled at the 4E13 vg/kg BMN 270 dose.  Subjects will 
be followed for 52 weeks post-BMN 270 infusion during which safety and efficacy 
assessments will be taken. After the final analysis at 52 weeks post-infusion, safety and 
efficacy will then continue to be assessed long-term for approximately a total of 5 years.  
During enrollment, the DMC will review available safety and efficacy data on an ongoing 
basis and may decide to recommend dosing subjects at a different dose level (not to exceed 
6E13 vg/kg) based on emerging data from 270-302 and their overall benefit:risk assessment. 
Study 270-302 is a self-controlled study. Parameters for each subject will be compared to a 
pre-treatment assessment of safety (liver function) and efficacy (number of bleeds, use of 
FVIII replacement therapy).  
9.3 
Selection of Study Population 
Approximately 40 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 FVIII replacement therapy for at least 12 months 
prior to study entry.  High-quality, well-documented historical data concerning 
bleeding episodes and FVIII 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 no 
detectable viral vector DNA. 
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. 
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.   

 
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4. 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 liver ultrasound.  
9. Chronic or active hepatitis B as evidenced by positive serology testing (HBsAg, 
HBsAb, and 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. 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. 
14. 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. 
15. Prior treatment with any vector or gene transfer agent. 
16. Major surgery planned in the 52-week period following the infusion with BMN 270. 
17. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion. 
18. 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. 
19. Known allergy or hypersensitivity to BMN 270 investigational product formulation. 
20. Unwilling to receive blood or blood products for treatment of an adverse event and/or 
a bleeding episode. 

 
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9.3.3 Removal of Subjects from Treatment or Assessment 
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn. 
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.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 

 
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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. 
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 
eCRF pages. In legal jurisdictions where use of initials is not permitted, a substitute identifier 
will be used. 

 
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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, 52 weeks of Post-Infusion Follow-Up, 
and 208 weeks of Long-Term 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 
 
 
 
 
 
The study drug 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 or butterfly needle will be inserted into a suitable 
peripheral vein (eg, the median cubital vein) and flushed with saline. FVIII replacement 

 
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therapy will not be given since venipuncture is a minimally invasive procedure in these 
individuals under ordinary conditions. 
 
 
 
 
 
 
 
 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 by an infusion-related reaction. At the 
restart, the infusion rate may be adjusted 
 
 
with careful monitoring of the subject. 
In case of hypersensitivity or adverse drug reaction, safety assessment, including physical 
examination and vital signs, will be done and additional blood samples will be collected 
 
 
 
 

 
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 In-
patient 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; in-patient observation can be extended 
beyond 8 hours if needed per Investigator discretion, 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 40 subjects will be enrolled at 4E13 vg/kg. 
9.4.6 Selection of Dose Used in the Study 
Data from an ongoing first in human study (Clinical Study 270-201) indicates that following 
single escalated doses of BMN 270 (6E12, 2E13, 4E13, 6E13 vg/kg), dose-related increases 
in FVIII activity were observed, with concurrent improvements in bleeding episodes and 
exogenous FVIII utilization, particularly at the 4E13 and 6E13 vg/kg dose levels. At all dose 
levels, BMN 270 is considered to be well-tolerated with mild increases in ALT as the most 
common adverse event. Please refer to the IB for detailed efficacy and safety data.  
In order to further evaluate the dose-response relationship of BMN 270, subjects will be 
enrolled at a dose of 4E13 vg/kg. This dose is expected to be safe and effective based on 
clinical experience to date in 270-201.  The DMC will review emerging safety and efficacy 
data and may recommend that a different dose (not to exceed 6E13 vg/kg) be administered.  
In such a case, up to 40 additional subjects may be enrolled at the new dose. 

 
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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 
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 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 
• Systemic immunosuppressive agents, except for corticosteroids 
• Emicizumab 
• Fitusiran 
• Concizumab 
• Efavirenz 
• Lamivudine 
The following medications 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 
Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated. 

 
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The following medications should be avoided during oral corticosteroid therapy: 
• Vaccines 
• NSAIDs 
9.4.8.1 
Concomitant Hemophilia Treatments 
Subjects on prophylactic FVIII therapy will discontinue their regular treatment regimen 
starting 4 weeks after the day of infusion and switch to an “on-demand” schedule. 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 On 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 Glucocorticoid Treatment of Elevated Hepatic Transaminases 
Therapeutic oral corticosteroids (prednisone or converted equivalent) should be initiated 
when either of the following occurs post-BMN 270 infusion in any subject and after 
consultation with the Medical Monitor: 
• ALT ≥ 1.5x ULN or ALT > ULN & > 2x baseline value in 2 consecutive assessments 
within 72 hours and alternative etiologies have been ruled out, or ALT ≥ 3x ULN in 
2 consecutive assessments within 48 hours (refer to Table 9.7.8.3.2) 
o Whenever possible, a confirmatory lab draw for ALT should be 
performed, along with FVIII activity, prior to initiating oral 
corticosteroids. 

 
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o Corticosteroids may be delayed if elevations in ALT are clearly not related 
to BMN 270 (eg, elevated in ALT with concurrent increase in CPK due to 
intensive exercise)  
The prescribed regimen for therapeutic oral corticosteroids is detailed in Table 9.1.6.  
Changes to the corticosteroid regimen should be made as follows: 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen 
Tapering 
Corticosteroid 
Dose 
Subject has been 
receiving oral 
corticosteroids 
<3 weeks 
Corticosteroids may be discontinued if: 
• 
ALT < 1.5x ULN or ALT  ≤  ULN &  ≤  2x baseline value; 
and 
• 
FVIII levels > 20 IU/dL and within 10% of the pre-decline 
FVIII levels; and 
• 
There is no concern for adrenal insufficiency post-withdrawal 
Subject has been 
receiving oral 
corticosteroids 
≥3 weeks 
Corticosteroids may be tapered by 10 mg weekly if: 
• 
ALT < 1.5x ULN or ALT  ≤  ULN &  ≤  2x baseline value; 
and 
• 
FVIII levels > 20 IU/dL and within 10% of the pre-decline 
FVIII levels; and 
• 
There is no concern for adrenal insufficiency post-withdrawal 
Increasing 
Corticosteroid 
Dose 
If ALT level is increasing or FVIII 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 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 ALT elevation 
≥1.5x ULN or ALT  ≥  ULN &  ≥  2x 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 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 schedule of events. The use of COX-2 inhibitors, 
while not contraindicated during corticosteroid treatment, should be limited, if possible.  
Practical management to prevent complications related to oral corticosteroid therapy may be 
undertaken at the discretion of the Investigator (eg, evaluation of glucose intolerance, 

 
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hyperlipidemia etc.). Hepatitis B status and HCV viral load will be rechecked 6 weeks after 
the start of oral corticosteroid treatment and then 1 week and 13 weeks after the completion 
of oral corticosteroid 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 use) should be reported as outlined in Section 10 of the protocol. 
9.4.8.3 
Monitoring of HIV-Positive Subjects 
HIV-positive subjects who have previously enrolled in 270-302 should continue anti-
retroviral therapy (ART) as prescribed and follow routine monitoring of CD4 count and viral 
load (US Dept Health Human Services, 2014).  No alterations in the monitoring are indicated 
for enrolled immunocompetent HIV-positive subjects who receive corticosteroids as part of 
their enrollment in 270-302. 
9.4.9 Treatment Compliance 
Study drug 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 
study drug containers. 
9.5 
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data, if allowed by local SOPs. 
9.5.1 Return and Disposition of Clinical Supplies 
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials (or must be referenced in their institution 
SOPs). 
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after BioMarin has granted approval for drug destruction. The monitor must account for 
all study drug in a formal reconciliation process prior to study drug destruction. All study 
drug destroyed on site must be documented. Documentation must be provided to BioMarin or 
designee and retained in the Investigator study files. If a site is unable to destroy study drug 
appropriately, the site can return unused study drug to BioMarin upon request. The return of 

 
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study drug or study drug materials must be accounted for on a Study Drug Return Form 
provided by BioMarin. 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures.  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 
for the first 52 weeks of the study, and particularly within 48 hours prior to lab work. 
Subjects should be advised to abstain from any blood or sperm donation after BMN 270 
infusion, until there is no further evidence of vector shedding from PCR analysis of samples. 
9.7 
Safety and Efficacy Variables 
9.7.1 Safety and Efficacy Measurements Assessed 
The Schedule of Events (Table 9.1.1 through Table 9.1.5) describes the timing of required 
evaluations. 
9.7.2 Primary Efficacy Variables 
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. 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 FVIII activity will be excluded if obtained within 72 hours 
since the last infusion of exogenous FVIII protein concentrates. 
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. 
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 

 
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• 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 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. 
Subjects who do not respond to BMN 270 treatment
 
 
 
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.  
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 are: 
• Change of the annualized utilization (IU/kg) of exogenous FVIII replacement therapy 
during Week 5 to Week 52 post BMN 270 infusion from the baseline utilization of 
exogenous FVIII replacement therapy.  
• Change in the annualized number of bleeding episodes requiring exogenous FVIII 
replacement treatment during Week 5 to Week 52 of the study post BMN 270 
infusion from the baseline ABR.   
Subjects must have high quality 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. 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. 

 
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In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. 
9.7.4 Tertiary Efficacy Variables 
9.7.4.1 
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 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).  
Details regarding the Haemo-QoL-A assessment will be included in the On Site File Binder. 
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.  A sample copy of the 
EQ-5D-5L and additional information are provided in the On Site File Binder. 
The Haemophilia Activities List (HAL) measures the impact of hemophilia on self-perceived 
functional abilities in adults (Van Genderen, 2006).  The instrument consists of multiple 
domains including lying/sitting/kneeling/standing, leg and arm function, use of 
transportation, self-care, household tasks, and leisure activities where subjects are asked to 
rate their level of difficulty with activities of daily living on a 6-point Likert-type scale from 
1 (Impossible) to 6 (Never). For some items, subjects are given the choice to answer ‘Not 
applicable’.  A sample copy of the HAL and additional information are provided in the On 
Site File Binder. 
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).  A 
sample copy of the WPAI+CIQ:HS and additional information are provided in the On Site 
File Binder. 

 
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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).  A sample 
copy of the PROBE questionnaire and additional information are provided in the On Site File 
Binder. 
9.7.5 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 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. 
9.7.6 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. 
9.7.7 Exploratory Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1, 
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5 to evaluate biochemical, molecular, 
cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV 
gene transfer, and to develop assays used for these evaluations.  Subjects may choose to opt 
out of the exploratory genetic/genomic research being done to study or try to discover genes 
that are not yet known to be associated with hemophilia A. 
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.   

 
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9.7.8 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity. 
9.7.8.1 
Adverse Events 
The 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. 

 
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Exploratory biomarker 
plasma samples collected at Baseline and at post-infusion study visits may also be used to 
assess the magnitude of biomarker changes. 
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 (during Year 2) and Q6W (during Years 3-5) visits; 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. 
MN visits may also be available during Year 1 at Weeks 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 
25, 27, 29, 30, 31, 33, 35, 38, 42, 46, and 50 (as indicated in the Schedule of Events). 
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 positive surface antigen for hepatitis B or positive RNA testing for 
hepatitis C) 30 days prior to providing signed informed consent do not need to 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 Week 16. Subjects with a history of hepatitis B or hepatitis C 
will be asked for information about the treatments received as part of their medical history 
assessment at Screening.  
Subjects with a previous history of hepatitis B or hepatitis C who receive therapeutic oral 
corticosteroids prior to Week 16 do not need to complete the Week 16 reactivation 
assessment; instead, they will be tested for hepatitis B and hepatitis C reactivation at the time 
points listed in Table 9.1.6. 

 
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A liver ultrasound and liver tests (LTs) during Screening will identify any significant hepatic 
dysfunction. 
Liver tests 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 
 
Elevated ALT levels (above the upper limit of normal range) should be evaluated according 
to the following plan: 

 
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Table 9.7.8.3.2:  Evaluation of ALT Elevations 
ALT Level 
Work-Up 
Above 
ULN and 
<1.5x ULN 
• 
Continue to monitor LTs and FVIII per protocol (repeat within 7 days if next 
protocol scheduled visit is >7 days 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 & > 2x baseline 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). 
1.5 - <3x 
ULN 
• 
Repeat LTs and FVIII within 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 ≥ 1.5x ULN in 2 consecutive assessments within 72 hours and 
alternative etiologies have been ruled out, start oral corticosteroids (refer to 
Section 9.4.8.2) 
≥3x ULN 
• 
Consult with Medical Monitor 
• 
Evaluate and rule out alternative etiologies (as above) 
• 
Repeat LTs and FVIII within 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 
 
When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT 
workup, the following tests should be performed: 

 
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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 Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and Long-Term Follow-Up periods.  On the day of the BMN 270 
Infusion, vital signs will be monitored prior to infusion, during the infusion every 15 minutes 
(± 5 minutes), following the infusion hourly (± 5 minutes) for 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 is necessary during Screening/Baseline, at Week 26 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.  During Year 1, at visits where the MN services are used or shortened lab 
draw-only visits are conducted at the sites, the physical examination and vital signs 
assessments indicated in the Schedule of Events will not be performed. 

 
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A complete physical examination will include general appearance (head, eyes, ears, nose, and 
throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems. 
A brief physical examination will include general appearance, cardiovascular, dermatologic, 
respiratory, gastrointestinal, musculoskeletal, and neurologic assessments. 
Height will be recorded at Screening only.  Weight will be recorded at Screening and then 
every 4 weeks thereafter through Week 52, and at the second Q12W visit each year and at 
every End of Year visit during Years 2-5. 
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, at the time points 
indicated in Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5. Testing will continue until 
at least 3 consecutive negative results are obtained.  Testing of semen will continue at least 
through Week 12, even if 3 consecutive negative results have been recorded in that 
compartment prior to that time point.  Subjects who have not had 3 consecutive negative 
semen samples by Week 52 should continue to have PCR testing in semen every 4 weeks 
(during Year 2) and every 6 weeks (during Years 3-5) until 3 consecutive negative samples 
are documented (or upon consultation between the Investigator and Medical Monitor). 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule (refer to Section 12.7) but who have not cleared vector shedding from all fluids 
must still provide samples for assessment every 4 weeks (during Year 2) or every 6 weeks 
(during Years 3-5) until vector shedding has cleared. Such subjects may provide samples on 
the designated study visit dates either at the sites or through use of a MN professional. 
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 

 
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analysis (saliva, blood, semen, urine, feces).  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 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 negative for vector DNA on at least three consecutive visits. 
Contraception use may need to be extended beyond 26 weeks in individual subjects based on 
observed vector shedding in semen.  After 26 weeks, subjects may stop contraception use 
only if they have had 3 consecutive negative semen samples (upon consultation between the 
Investigator and Medical Monitor). 
Details for sample collection and storage are provided in the Laboratory Manual. 

 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified 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 (refer to 
Section 10.4.1.7). 
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 

 
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• 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)  
10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
• Elevation of ALT  ≥ 1.5x ULN or ALT > ULN & >2x baseline value, regardless of 
whether that elevation triggers an initiation or modification of oral corticosteroid 
treatment 
• Thromboembolic event 
• Systemic hypersensitivity, anaphylactic, or anaphylactoid reactions (refer to 
Appendix 1) 
• 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 

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

 
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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 
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. 

 
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A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
For 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.  
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 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 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/REB is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• 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:  
+1 (415) 506-6179 
Fax: 
 
+1 (415) 532-3144 
E-mail: 
drugsafety@bmrn.com 
The Investigator is encouraged to discuss with the Medical Monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the Medical Monitor is 
as follows: 
Name:  
  
Address: 
 
 
 
 
Phone:  
 
E-mail: 
 

 
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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic 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.  
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 FVIII 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 
• 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 On Site File Binder. 
• Distribution of subject diaries and training in diary completion 
• Electrocardiogram 
• Liver Ultrasound 
• 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 (collected but not tested 
prior to enrollment) 
o hFVIII inhibitors (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay (collected but not tested prior to enrollment) 
o hFVIII protein assay (collected but not tested prior to enrollment) 
• Blood sample for AAV5 total antibody (TAb) assay 
• Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested) 
o Hepatitis B screening should include HBsAg, HBsAb, and HBcAb. 
• 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) 
• Blood samples for Biomarker testing (including HLA genotyping and FVIII 
genotyping status) 
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)) 
• AAV5 Total Antibody assay 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 

 
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• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Tests (refer to Table 9.7.8.3.1) 
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following 
procedures will be performed during the Baseline Period: 
• 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) 
• Blood sample for AAV5 TI assay 
• Blood sample for AAV5 TAb assay 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
o ABO blood typing assessment should be performed as part of the 
hematology assessment (at Baseline, or at another regularly scheduled 
visit prior to the end of the subject’s participation in the study). 
• Urine Tests (refer to Table 9.7.8.2.1) 
• Liver Tests (refer to Table 9.7.8.3.1) 
• 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 hFVIII inhibitors (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay 
o hFVIII protein assay 
• PBMC collection for CTL baseline 
• Von Willebrand Factor Antigen (VWF:Ag) 
• TGA Assay 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
• Exploratory biomarker assessments 

 
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• Haemo-QoL-A assessment 
• EQ-5D-5L 
• Hemophilia Activities List (HAL) 
• Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire 
• Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire 
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: 
• Brief physical examination 
• Assessment of Adverse Events and Concomitant Medications 
• AAV5 TAb Assay (sample collected pre-infusion for analysis) 
• 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. 
• Exploratory biomarker assessments 
• BMN 270 Infusion 
• Vital Signs 
o Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for at least 
8 hours during the subject’s stay in the clinic. 
• 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 hypersensitivity or adverse drug reaction, safety assessment, including physical 
examination and vital signs, will be done and additional blood samples will be collected 
 
 
 
 

 
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In-patient 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 return to the study site every week 
(± 48 hours) during Weeks 1-26. Optional MN services or shortened lab draw-only visits 
may be conducted for the visits at Week 5, Week 7, Week 9, Week 11, Week 13, Week 15, 
Week 17, Week 19, Week 21, Week 23, and Week 25. 
At the Weeks 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: 
• Brief physical examination (complete physical examination at Week 26) 
o For visits where a MN service is being used or a lab draw-only site visit is 
conducted, physical examination will not be performed.  
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
o For visits where a MN service is being used, the service will contact the 
subject via e-mail or phone call to collect information regarding adverse 
events, changes to concomitant medications, bleeding episodes, and FVIII 
use. 
• Vital Signs 
o For visits where a MN service is being used or a lab draw-only site visit is 
conducted, vital signs will not be performed. 
• 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  ≥ 1.5x ULN or > ULN & > 2x 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 

 
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o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o FVIII protein assay 
12.5.2 Week 1 – Day 4 
On Day 4 of Week 1, the following procedures will be performed: 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
• Liver Tests (refer to Table 9.7.8.3.1) 
12.5.3 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 
12.5.4 Every 2 Weeks (Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26) 
At Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 the following procedure will be 
performed: 
• PBMC collection 
12.5.5 Weeks 2, 4, 10, 16, 22, and 26 
At Weeks 2, 4, 10, 16, 22, and 26 the following procedure will be performed: 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)  
12.5.6 Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26 
At Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26, the following procedure will be performed: 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Collection to occur until at least 3 consecutive negative results are 
obtained.  Semen samples should continue to be collected and tested 
through Week 12, even if 3 consecutive negative results in that 
compartment have been recorded prior to that time point. 
12.5.7 Weeks 4, 12, and 26 
At Weeks 4, 12, and 26, the following procedure will be performed: 
• Haemo-QoL-A assessment  
• EQ-5D-5L 
• HAL 

 
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• WPAI+CIQ:HS 
• PROBE 
12.5.8 Every 4 Weeks (Weeks 4, 8, 12, 16, 20, and 24) Plus Week 26 
At Weeks 4, 8, 12, 16, 20, 24, and 26, the following procedures will be performed: 
• Weight (not performed at Week 26) 
• FVIII antibody titer 
12.5.9 Every 8 Weeks (Weeks 8, 16, and 24) 
At Weeks 8, 16, and 24, the following procedures will be performed: 
• AAV5 TAb assay 
• AAV5 TI assay 
12.5.10  Weeks 6, 12, 16, 20, 24, and 26 
At Weeks 6, 12, 16, 20, 24, and 26, the following procedures will be performed: 
• Exploratory biomarker assessments 
12.5.11  Weeks 12 and 26 
At Weeks 12 and 26, the following procedures will be performed: 
• Urine Tests (refer to Table 9.7.8.2.1)  
• VWF:Ag 
12.5.12  Week 16 
At Week 16, the following procedure will be performed: 
• Test for Hepatitis B and Hepatitis C reactivation (only in subjects with evidence of 
prior exposure to hepatitis B and/or hepatitis C) 
o Subjects who receive therapeutic oral corticosteroids prior to Week 16 do 
not need to complete the Week 16 reactivation assessment; instead, they 
will be tested for hepatitis B and hepatitis C reactivation at the time points 
listed in Table 9.1.6. 
12.5.13  Week 20, 24, and 26 
At Week 20, 24, and 26, the following procedure will be performed: 
• TGA Assay 

 
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12.6 
Post-Infusion Follow-Up – Weeks 27-52 
During Weeks 27-36, subjects will return to the study site weekly (± 48 hours).  During 
Weeks 37-52, subjects will return to the study site every 2 weeks (Week 38, 40, 42, 44, 46, 
48, 50, and 52) (± 1 week). Optional MN services or shortened lab draw-only site visits may 
be conducted for the visits at Week 27, Week 29, Week 30, Week 31, Week 33, Week 34, 
Week 35, Week 38, Week 42, Week 46, and Week 50. 
At these visits, the following procedures will be completed: 
12.6.1 Every Visit 
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures 
will be performed: 
• Physical examination 
o Brief physical examination should be performed at all weeks except 
Week 26, when a complete physical examination should be performed 
o For visits where a MN service is being used or a lab draw-only site visit is 
conducted, physical examination will not be performed. 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
o For visits where a MN service is being used, the service will contact the 
subject via e-mail or phone call to collect information regarding adverse 
events, changes to concomitant medications, bleeding episodes, and FVIII 
use. 
• Vital Signs 
o For visits where a MN service is being used or a lab draw-only site visit is 
conducted, vital signs will not be performed. 
• 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  ≥ 1.5x ULN or > ULN & > 2x 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 

 
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o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII protein assay  
12.6.2 Weeks 28, 30, 32, 36, 44, and 52 
At Weeks 28, 30, 32, 36, 44, and 52, the following procedure will be performed: 
• PBMC collection 
12.6.3 Every 4 Weeks (Weeks 28, 32, 36, 40, 44, 48, 52) 
At Weeks 28, 32, 36, 40, 44, 48, and 52, the following procedure will be performed: 
• Weight 
12.6.4 Weeks 32, 36, 44, and 52 
At Weeks 32, 36, 44, and 52, the following procedures will be performed: 
• Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1) 
• FVIII antibody titer 
12.6.5 Weeks 32, 36, 40, 44, 48, and 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed: 
• Exploratory biomarker assessments 
• TGA Assay 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing to occur until at least 3 consecutive negative sample results 
have been obtained.  Subjects who have not had 3 consecutive negative 
semen samples by Week 52 should continue to have PCR testing of semen 
every 4 weeks until 3 consecutive negative samples are documented (or 
upon consultation between the Investigator and Medical Monitor). 
12.6.6 Week 32, 36, and 52 
At Week 32, 36, and 52, the following procedure will be performed: 
• AAV5 TAb Assay 
• AAV5 TI 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)  

 
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• VWF:Ag 
12.6.8 Week 52 
At Week 52, the following procedures will be performed: 
• Haemo-QoL-A assessment 
• EQ-5D-5L 
• HAL 
• WPAI+CIQ:HS 
• PROBE 
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 (during Year 2) and Q6W (during Years 3-5) visits; the Q12W visits and End of Year 
during Years 2-5 will not be performed by an MN professional but will be done at the study 
site. 
Subjects who do not respond to BMN 270 treatment 
 
 
 
 
 
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 meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 

 
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vector shedding has cleared. Such subjects may provide samples on the designated study visit 
dates either at the sites or through use of a MN professional. 
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed: 
12.7.1 Year 2 – Every 4 Weeks (not required for treatment failure) 
During Year 2, every 4 weeks ( ± 2 weeks), the following procedures will be performed: 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Liver Tests (refer to Table 9.7.8.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are  ≥ 1.5x ULN or > ULN & > 2x 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 Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII protein assay  
• PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Year 2 is not required if at least 3 consecutive samples 
are negative during the Post-Infusion Follow-Up period in Weeks 1-52.  
Subjects who have not had 3 consecutive negative semen samples by Week 52 
should continue to have PCR testing of semen every 4 weeks during Years 2 
until 3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor). 
o Subjects who meet the definition of treatment failure and wish to follow 
an abbreviated schedule but who have not cleared vector shedding from all 
fluids must still provide samples for assessment every 4 weeks during 
Year 2 until vector shedding has cleared. Such subjects may provide 
samples on the designated study visit dates either at the sites or through 
use of a MN professional. 

 
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12.7.2 Years 3-5 – Every 6 Weeks (not required for treatment failure) 
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
• Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
• Liver Tests (refer to Table 9.7.8.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are  ≥ 1.5x ULN or > ULN & > 2x 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 Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o 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. 
o FVIII protein assay  
• PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Years 3-5 is not required if at least 3 consecutive 
samples are clear by the end of Year 2.  Subjects who have not had 
3 consecutive negative semen samples by the end of Year 2 should continue to 
have PCR testing of semen every 6 weeks during Years 3-5 until 
3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor). 
o Subjects who meet the definition of treatment failure and wish to follow 
an abbreviated schedule but who have not cleared vector shedding from all 
fluids must still provide samples for assessment every 6 weeks during 
Years 3-5 until vector shedding has cleared. Such subjects may provide 
samples on the designated study visit dates either at the sites or through 
use of a MN professional. 

 
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12.7.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects) 
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks ( ± 2 weeks): 
• Year 2 – Week 64, Week 76, Week 88, Week 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 
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. The every 12 week and End of Year visits may 
not be performed remotely by MN services. 
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; 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) 
• 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  ≥ 1.5x ULN or > ULN & > 2x 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 Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII protein assay  
• 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) 

 
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• 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) 
• Vital Signs 
• AAV5 TAb Assay 
• AAV5 TI Assay 
• FVIII antibody titer 
• 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) 
• HAL (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) 
• Exploratory biomarker assessments 
• PBMC collection 
• VWF:Ag 
• TGA Assay 
• PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are negative during the Post-Infusion Follow-Up period in 
Weeks 1-52.  Subjects who have not had 3 consecutive negative semen 
samples by Week 52 should continue to have PCR testing of semen every 
4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor). 
12.8 
Early Termination Visit 
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
• Physical examination 

 
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• 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) 
• 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 Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o 
FVIII protein assay  
• AAV5 TAb Assay 
• AAV5 TI Assay 
• FVIII antibody titer 
• Exploratory biomarker assessments 
• PBMC collection 
• VWF:Ag 
• TGA Assay 
• PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing at the ETV is not required if at least 3 consecutive samples 
were clear during the Post-Infusion Follow-Up period. 
• Haemo-QoL-A assessment 
• EQ-5D-5L 
• HAL 
• WPAI+CIQ:HS 
• PROBE 

 
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12.9 
End of Study 
The study will end after the last subject yet to complete the last Long-Term Follow-Up visit 
(Week 260) 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.  
Data quality control and analysis will be performed by BioMarin or a designee, based on a 
predefined analysis plan. 

 
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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. Descriptive summaries of 
the proportions of subjects whose FVIII activity during Weeks 49-52 is greater than or equal 
to select thresholds, such as 15, 25 and 30 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 
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 14.8. 
14.3 
Secondary Efficacy Endpoints 
The primary analyses for the secondary endpoints will be performed on the 35 subjects in the 
mITT population who will be followed up for approximately 6 months in the 
non-interventional study 270-902 prior to their enrollment in 270-302. The baseline values 
will be derived from the prospectively collected data in 270-902. 
For the first secondary efficacy endpoint at Week 52 (ie, the change in the annualized 
utilization (IU/kg) of exogenous FVIII replacement therapy during Weeks 5-52 
post-BMN 270 infusion from baseline), a one-sample t-test will be performed to test the null 
hypothesis that the change is 0 or greater against the alternative hypothesis that the change is 
less than 0.   
For the second secondary efficacy endpoint at Week 52 (ie, the change in ABR, annualized 
bleeding rate, during Weeks 5-52 post-BMN 270 infusion from baseline), a one-sample t-test 
will be performed to test for non-inferiority of BMN 270 against FVIII prophylaxis (ie, the 
baseline ABR calculated using subjects’ data collected as part of 270-902) using a 
non-inferiority margin of 3.5, ie, to test the null hypothesis that the change is 3.5 or greater 
against the alternative hypothesis that the change is less than 3.5. If non-inferiority is 
demonstrated, the test for superiority of BMN 270 against FVIII prophylaxis will be 
performed. 
 
 
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. The actual number of bleeding episodes 

 
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will be used as the independent variable with the time period adjustment (animalization) 
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. 
The primary and secondary efficacy hypotheses will be tested hierarchically according to the 
order described above. Multiple comparison procedures are described in greater detail in the 
SAP. 
14.4 
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.  
14.5 
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).   
14.6 
Safety Analysis 
The Medical Dictionary for Regulatory Activities terminology (MedDRA) will be used by 
the Sponsor to assign system organ class and preferred term classification to events and 
diseases, based on the original terms entered on the eCRF. 
All AEs will be coded using the current version of MedDRA. The incidence of AEs will be 
summarized by system organ class, preferred term, relationship to study drug, and severity. A 
by-subject listing will be provided for those subjects who experience a serious AE (SAE), 
including death, or experience an AE associated with early withdrawal from the study or 
study drug.  
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. 

 
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14.7 
Determination of Sample Size 
Approximately 40 subjects may be dosed in the study. The sample size for this study is based 
on clinical and statistical considerations in order to provide sufficient data to assess both 
safety and efficacy of BMN 270.  
For the primary endpoint, a sample size of 40 will provide at least 90% power to demonstrate 
that the change in  hFVIII activity at Weeks 49-52 from baseline is greater than 0, assuming 
an effect size of 0.6, using a one-sample t-test with a 2-sided significance level of 0.05.  
For the secondary endpoints, the analysis will be performed utilizing exogenous FVIII use 
and bleeding episode data from the 35 subjects whose baseline data will be prospectively 
collected for approximately 6 months in the non-interventional study 270-902, prior to their 
enrollment in 270-302. An analytic sample size of 35 will provide at least 90% power to 
demonstrate that the change in the annualized utilization (IU/kg) of exogenous FVIII 
replacement therapy during Week 5 to Week 52 post-BMN 270 infusion from the baseline is 
less than 0, assuming an effect size of 0.6, using  one-sample t-test with a 2-sided 
significance level of 0.025. 
For the analytic sample size calculation of the second secondary endpoint, ABR, it is 
assumed that the pre- and post-BMN 270 infusion population mean ABRs are 3.5 and 
1 respectively, and the distribution of ABRs is negative binomial distribution with a 
dispersion parameter of 2.2. 
 
 
 
 
Under this assumption, an analytic sample size of 35 will also have at 
least 95% power to demonstrate that the change in the annualized number of bleeding 
episodes requiring exogenous FVIII replacement treatment (ABR) during Week 5 to 
Week 52 of the study post-BMN 270 infusion from the baseline ABR is less than 3.5 
(non-inferiority margin), using a one-sample t-test with a 2-sided significance level of 0.05. 
Overall, a sample size of 40 will have greater than 80% power for testing the primary and 
secondary efficacy endpoints hierarchically at the final analysis with a 2-sided significance 
level of 0.05. 
14.8 
Analysis Populations 
The intention-to-treat (ITT) population is defined as all subjects who receive BMN 270 
infusion, and the modified intention-to-treat (mITT) population is defined as subjects who 
receive BMN 270 infusion and are HIV-negative. The mITT population will be used for the 

 
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primary efficacy analysis and ITT will be used for the supportive efficacy analysis. The ITT 
population will also be used for the safety analysis. 
14.9 
Changes in the Conduct of the Study or Planned Analyses 
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the Investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
Investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the Investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active subjects must again provide informed consent. 

 
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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 enroll subjects at a different dose level (not to exceed 
6E13 vg/kg) based on emerging data from 270-302 and the overall risk/benefit 
analysis of BMN 270. 
• Reviewing ongoing safety and efficacy data for comparability of drug manufacturing 
lots within 270-302 and between 270-201 and 270-302. 
• 
Making other recommendations on the conduct and reporting of the trial based on 
their evaluation of clinical data, including data from 270-301. 
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 Statistical Analysis 
Plan (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/REB 
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 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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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 19:1409-1417.  1995. 
Bedossa P, Pynard T, French METAVIR Cooperative Study Group.  An algorithm for 
grading activity in chronic hepatitis C.  Hepatology 24;289-293.  1996. 
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 18 Suppl 6, 1-13. 2012. 
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 22[Suppl. 4], 151-152.  
2016. 
Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: 
a randomized dose comparison. Blood 119[6], 1335-1344. 2012. 
Haemo-QoL Study Group.  Scoring Manual.  Available at: http://haemoqol.de/scoring/ 
manual. Last accessed 28 July 2017.  
Kaufman RJ, Powell JS. Molecular approaches for improved clotting factors for hemophilia. 
Blood 122[22], 3568-3574. 2013. 
Manno CS, Pierce GF, Arruda VR, Glader B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006. 
Miesbach W, Tangelder M, Klamroth R, Schutgens R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016. 

 
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Mingozzi F and High KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013. 
Nathwani AC, Reiss UM, Tuddenham EG, Rosales C et. al. Long-term safety and efficacy of 
factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014. 
Nathwani AC, Rosales, C, McIntosh J, Rastegarlari G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011. 
Nathwani AC, Tuddenham EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992. 
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. 
Rangarajan S, Kim B, Lester W et al. Achievement of normal factor VIII activity following 
gene transfer with valoctocogene roxaparvovec (BMN 270): Long- term efficacy and safety 
results in patients with severe hemophilia A. Haemophilia 24[Suppl. 5], 65. 2018 
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 19[1], e1-47. 2013. 

 
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Stonebraker JS, Brooker M, Amand RE, Farrugia A et. al. A study of reported factor VIII use 
around the world. Haemophilia 16[1], 33-46. 2010. 
United States Department of Health and Human Services.  Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.  2014.  Available at 
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/ 
458/plasma-hiv-1-rna--viral-load--and-cd4-count-monitoring. Last accessed 28 July 2017.   
Van Genderen FR, Westers P, Heijnen L, De Kleijn P et al.  Measuring patients’ perceptions 
on their functional abilities: validation of the Haemophilia Activities List.  Haemophilia.  
2006;12:36-46. 
Wiens BL, Dmitrienko A. The fallback procedure for evaluating a single family of 
hypotheses. J Biopharm Stat. 2005; 15:929–942. 

 
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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/REB 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/REB. Additionally, he or she will not make any changes in 
the research without IRB/EC/REB 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 3 Open-Label, Single Arm Study To Evaluate The Efficacy and 
Safety of BMN 270, an Adenovirus-Associated Virus Vector–Mediated Gene Transfer of 
Human Factor VIII at a dose of 4E13 vg/kg in Hemophilia A Patients with Residual FVIII 
Levels ≤ 1 IU/dL Receiving Prophylactic FVIII Infusions 
Protocol Number: 270-302 Amendment 4 
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
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:   
 
  

 
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APPENDICES 
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): 
e. Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease is systolic BP 
f. 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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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, Direct Thrombin Activity test, and any 
other exploratory assessments) will be performed only as deemed necessary by the Sponsor.   
g The scheduled visits at Week 5, Week 7, Week 9, Week 11, Week 13, and Week 15 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 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.  The physical examination and vital signs assessments listed in the Schedule of Events will not 
be performed at these MN or lab draw-only visits. 
Table 9.1.3 notes 
e Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects 
relevant to hemophilia A disease, coagulation, and/or AAV gene transfer, and to develop assays used for these 
evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the 
time points indicated above, testing of these samples (including those for TGA assay, Direct Thrombin Activity test, and any 
other exploratory assessments) will be performed only as deemed necessary by the Sponsor.  
f The scheduled visits at Week 17, Week 19, Week 21, Week 23, Week 25, Week 27, Week 29, Week 30, and Week 31 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 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.  The physical examination and vital signs assessments listed in 
the Schedule of Events will not be performed at these MN or lab draw-only visits. 
1, 3 
Table 9.1.4 notes 
d Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A disease, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations.  Subjects 
may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not 
yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated 
1, 3 

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above, testing of these samples (including those for TGA assay, Direct Thrombin Activity test, and any other exploratory 
assessments) will be performed only as deemed necessary by the Sponsor. 
e The scheduled visits at Week 33, Week 34, Week 35, Week 38, Week 42, Week 46, and Week 50 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 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.  The physical examination and vital signs assessments listed in the 
Schedule of Events will not be performed at these MN or lab draw-only visits. 
Table 9.1.5 notes 
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A disease, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations.  Subjects 
may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not 
yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated 
above, testing of these samples (including those for TGA assay, Direct Thrombin Activity test, and any other exploratory 
assessments) will be performed only as deemed necessary by the Sponsor. 
3 
9.7.2.1/FVIII Activity 
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.  
4 
9.7.7/Exploratory 
Assessments 
Blood samples will be collected from subjects at the time points indicated in Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, 
and Table 9.1.5 to evaluate biochemical, molecular, cellular, ABO blood typing, 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. 
4 
9.7.8.2/Clinical 
Laboratory Assessments 
MN visits may also be available during Year 1 at Weeks 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 30, 31, 33, 35, 38, 42, 
46, and 50 (as indicated in the Schedule of Events). 
1 

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Table 9.7.8.2.1 
ABO blood typing has been added to this table, with the note: 
*ABO blood typing assessment should be performed as part of the hematology assessment (at Baseline, or at another
regularly scheduled visit prior to the end of the subject’s participation in the study).
4 
9.7.8.3/Vital Signs, 
Physical Examinations, 
and Other Safety 
Observations 
A complete physical examination is necessary during Screening/Baseline, at Week 26 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.  
During Year 1, at visits where the MN services are used or shortened lab draw-only visits are conducted at the sites, the 
physical examination and vital signs assessments indicated in the Schedule of Events will not be performed. 
1 
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:  
•
Development of anti-FVIII inhibitory antibodies (inhibitors)
2 
12.3/Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the treatment visit.  The following procedures will be performed 
during the Baseline Period: 
•
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.8.2.1)
o
ABO blood typing assessment should be performed as part of the hematology assessment (at Baseline,
or at another regularly scheduled visit prior to the end of the subject’s participation in the study).
•
Direct Thrombin test
3, 4 
12.4/Day 1 Visit 
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: 
•
Exploratory biomarker assessments
4 
12.5/Weeks 1-26 
After BMN 270 has been infused, subjects will return to the study site every week (± 48 hours) during Weeks 1-26. Optional 
MN services or shortened lab draw-only site visits may be conducted for the visits at Week 5, Week 7, Week 9, Week 11, 
Week 13, Week 15, Week 17, Week 19, Week 21, Week 23, and Week 25. 
At the Weeks 1-26 visits, , when the following procedures will be completed: 
1 

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12.5.1/Once per Week 
(Weeks 1-26) 
The following procedures will be performed at one visit per week from Weeks 1 through 26: 
•
Brief physical examination (complete physical examination at Week 26)
o
For visits where a MN service is being used or a lab draw-only site visit is conducted, physical
examination will not be performed.
•
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and
FVIII use)
o
For visits where a MN service is being used, the service will contact the subject via e-mail or phone call
to collect information regarding adverse events, changes to concomitant medications, bleeding
episodes, and FVIII use.
•
Vital Signs
o
For visits where a MN service is being used or a lab draw-only site visit is conducted, vital signs will
not be performed.
1 
12.5.10/Weeks 6, 13 12, 
16, 20, 24, and 26 
At Weeks 6, 1312, 16, 20, 24, and 26, the following procedures will be performed: 
•
Exploratory biomarker assessments
1 
12.5.11/Weeks 12 and 
26 
At Weeks 12 and 26, the following procedures will be performed: 
•
Urine Tests (refer to Table 9.7.8.2.1)
•
VWF:Ag
1 
12.5.12/Week 13 and 26 
At Weeks 13 and 26, the following procedures will be performed: 
•
Direct Thrombin test
•
VWF:Ag
1, 3 
12.6/Weeks 27-52 
During Weeks 27-36, subjects will return to the study site weekly (± 48 hours). During Weeks 37-52, subjects will return to 
the study site every 2 weeks (Week 38, 40, 42, 44, 46, 48, 50, and 52) (± 1 week). Optional MN services or shortened lab 
draw-only site visits may be conducted at Week 27, Week 29, Week 30, Week 31, Week 33, Week 34, Week 35, Week 38, 
Week 42, Week 46, and Week 50. 
1 

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12.6.1/Every Visit 
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures will be performed: 
•
Physical examination
o
Brief physical examination should be performed at all weeks except Week 26, when a complete
physical examination should be performed
o
For visits where a MN service is being used or a lab draw-only site visit is conducted, physical
examination will not be performed.
•
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding and
FVIII use)
o
For visits where a MN service is being used, the service will contact the subject via e-mail or phone call
to collect information regarding adverse events, changes to concomitant medications, bleeding
episodes, and FVIII use.
•
Vital Signs
o
For visits where a MN service is being used or a lab draw-only site visit is conducted, vital signs will
not be performed.
1 
12.6.2/Weeks 28, 30, 
32, 34, 36, 44, and 52 
At Weeks 28, 30, 32, 34, 36, 44, and 52, the following procedure will be performed: 
•
PBMC collection
1 
12.6.7/Week 38 36 and 
52 
At Weeks 38 36 and 52, the following procedures will be performed: 
•
Urine Tests (refer to Table 9.7.8.2.1)
•
Direct Thrombin test
•
VWF:Ag
1, 3 
12.7/Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
activity ≥ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due to joint 
bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor 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. 
4 

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12.7.3/Years 2-5 Every 
12 Weeks and End of 
Year Visits 
At the every 12 week and End of Year visits, the following procedures will be performed: 
•
Direct Thrombin test
3 
12.8/ETV 
At the Early Termination visit, as many of the following assessments as possible should be done: 
•
Direct Thrombin test
3