A Phase 1/2 Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL and Pre-existing Antibodies Against AAV5
Phase: PHASE1
Conditions: Hemophilia A, Gene Therapy, Clotting Disorders, Blood Disorder
Sponsor: BioMarin Pharmaceutical

 
 
 
 
    
 
 
 
 
 
 
Official Title:  A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated 
Virus Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients 
with Residual FVIII levels ≤1 IU/dL and Pre-existing Antibodies Against AAV5 
 
NCT Number: NCT03520712 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 07 July 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 

Proprietary and Confidential
16
APPENDICES
16.1
Study Information
16.1.1 Protocol and Protocol Amendments
This appendix includes the original 270-203 study protocol and protocol amendments 1-4,
France-specific protocol amendments 2-3, and Tawain-specific protocol amendment 4 (no 
participants were enrolled in France or Taiwan):
Original Protocol (dated 29 September 2017)
Protocol Amendment 1 (dated 5 October 2018)
Protocol Amendment 2 (dated 4 October 2019)
Protocol Amendment 2 France-Specific (dated 01 November 2019)
Protocol Amendment 3 France-Specific (dated 21 August 2020)
Protocol Amendment 3 (dated 24 August 2020)
Protocol Amendment 4 (dated 04 August 2021)
Protocol Amendment 4 Taiwan-Specific (dated 07 July 2022)
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protocol.pdf Page 1
270-203 End of Study CSR
Page 1

C LI NI C A L S T U D Y P R O T O C O L
St u d y Title:
A P hase 1/ 2 Safet y, T olera bilit y, a n d Efficac y St u d y of 
B M N 2 7 0, a n A de n o- Ass ociate d Vir us Vect or – Me diate d 
Ge ne Tra nsfer of H u ma n Fact or VIII i n He m o p h ilia A 
Pre-e xisti n g A nti b o dies A gai nst A A V 5
P r ot oc ol N u m ber:
2 7 0- 2 0 3
Acti ve I n vesti g ati o n al P r o d uct:
A A V 5- h F VIII- S Q
E ur o pe a n U ni o n Dr u g 
Re g ul ati n g A ut h orities Cli nic al 
Tri als ( E u dr a C T) N u m ber:
2 0 1 7- 0 0 0 6 6 2- 2 9
I n dic ati o n:
He m o p hilia A
S p o ns or:
Bi o Mari n P har mace utical I nc.
1 0 5 Di gital Dri ve
N o vat o, C A 9 4 9 4 9 
De vel o p me nt P h ase:
P hase 1/ 2
S p o ns or's Res p o nsi ble Me dic al 
M o nit or: 
 M D
1 0 5 Di gital Dri ve
N o vat o, C A 9 4 9 4 9 
U. S. A.
St u d y Desi g n:
Si n gle-ar m, o pe n-la bel
D ur ati o n of S u bject 
P artici p ati o n:
U p t o 2 6 4 wee ks  
D ose:
6 E 1 3 v g/ k g as si n gle i nf usi o n
St u d y P o p ul ati o n:
detecta ble pre-e xisti n g a nti b o dies a gai nst A A V 5 vect or 
ca psi d
D ate of Ori gi n al P r ot oc ol:
2 9 Se pte m ber 2 0 1 7 
P r o pert y of Bi o M ari n 
C O N FI D E N TI A L
M a y n ot be di v ul ge d, p u blis he d, or ot her wise disc l ose d t o ot hers wit h o ut pri or w ritte n a p pr o v al 
fr o m Bi o M ari n.
T his st u d y will be c o n d ucte d acc or di n g t o t he pri n ci ples of G o o d Cli nic al P r actice as descri be d 
i n t he U. S. C o de of F e der al Re g ul ati o ns a n d t he I nter n ati o n al C o nfere nce o n H ar m o nis ati o n 
G ui deli nes, i ncl u di n g t he arc hi vi n g of esse nti al d oc u me nts.
PI

270-203 
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29 September 2017 
2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
TITLE OF STUDY: 
A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus 
Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual 
)9,,, /HYHOV   ,8G/ DQG 3UH-existing Antibodies Against AAV5
PROTOCOL NUMBER: 
270-203 
STUDY SITES:
Approximately 2-3 sites in the United Kingdom 
PHASE OF DEVELOPMENT:
Phase 1/2
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.   
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 
or 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. While infusion 
of FVIII is a major advance in the treatment of HA, severe HA patients continue to have bleeding 
events on prophylactic therapy; median ABRs were 1-4 with prophylactic treatment in a recently 
published retrospective observational study (Berntorp, 2017) and between 1-2 in 6 prospective 
FVIII interventional studies.  Median ABRs were 4.5-18 and between 20-60 with on-demand-only 
therapy in the same studies, respectively. Continued repeated bleeding events compound 
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29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
debilitating multiple-joint arthropathies as well as the risk of catastrophic events such as 
intracranial hemorrhage and death. 
Chemical modification (eg, direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can only extend half-life to maximum of 
18 hours, leaving critical periods when FVIII activity levels are below the therapeutic range and 
leaving patients vulnerable to bleeding and concomitant sequelae. As such, despite currently 
available FVIII replacement therapies, a high unmet need remains for maintenance of a sustained, 
consistent 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. 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. Moreover, the circulating FVIII response to gene transduction 
can be assessed using validated quantitative endpoints that are easily assayed using established 
laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 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 (eg serotypes 2, 5, and 8).
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
over 7 years of stable human factor IX (hFIX) expression at levels sufficient for conversion of their 
bleeding phenotype from severe to moderate or mild, following a single peripheral vein infusion of 
AAV8-hFIX vector (Nathwani, 2014). Several participants in this trial have been able to 
discontinue factor prophylaxis without suffering spontaneous hemorrhages, even when they 
undertook activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted 
in a substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a hybrid human liver-specific promoter (Figure 1).
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29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Figure 1. hFVIII-SQ Vector Genome Schematic
Legend –Note that schematic is not to scale; nt = nucleotides
BMN 270 is delivered by a single IV dose and is designed to achieve stable, potentially life-long 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
BMN 270 is currently being evaluated in clinical study 270-201, an ongoing first-in-human, phase 
1/2 dose escalation study in subjects with severe HA designed to assess the safety and efficacy of 
BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 
270-201 explores the relationship of vector dose to the augmentation of residual FVIII activity and 
whether these levels are sufficient to alter the clinical phenotype. Preliminary results from 270-201 
have demonstrated that following gene transfer, sustained FVIII activity above 5% (5 IU/dL) up to 
a year’s observation is achievable at doses of 4-6E13 vg/kg with an acceptable safety profile 
(Pasi, 2016). The majority of subjects achieved FVIII levels within the normal range for FVIII, 
with few to no bleeding episodes and discontinuation of FVIII prophylaxis. 
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, as the 
prevailing expectation has been that vector-specific antibodies could interfere with receptor 
binding and effectively neutralize efficient transduction of the target cell population. As this was 
the first FVIII gene therapy with AAV5 in humans, this criterion was adopted out of an abundance 
of caution. These pre-existing vector-specific antibodies are thought to arise from previous 
exposure to AAV, with seroprevalence varying across human populations and across studies. 
AAV5 has consistently been shown to have the lowest seroprevalence among the common AAV 
serotypes. 
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29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Current data describing the extent of neutralization or inhibited transduction has been inconsistent 
across studies, each employing one of several varying methodologies to evaluate both vector-
specific antibodies and transduction inhibition (TI). Early studies using AAV2 for the treatment of 
hemophilia B described inhibited transduction in patients with neutralizing antibody titers of 2 or 3 
(Manno, 2006), but more recent studies have described successful transduction in patients who, in 
retrospect, were determined to have pre-existing antibody to the vector capsid (Majowicz, 2017).  
Importantly, no drug-related adverse events were described in these patients.  As the sensitivity of 
assays used to detect pre-existing antibody has increased greatly in recent years, the biological 
relevance of any given titer determination, and comparisons across studies using assays with 
differing titer sensitivities, requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing anti-
AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of available 
data shows the effect of pre-existing immunogenicity to AVV delivery vectors is not completely 
understood, and indicates that some patients may benefit from AAV5 gene therapy who are 
currently excluded.  
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be enrolled to 
evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate the safety, 
tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing antibodies 
against AAV5 vector capsid at various levels of AAV5 antibody titers.
OBJECTIVES: 
The primary objective of the study is to:
x
Assess the safety of a single intravenous administration of BMN 270 in severe HA subjects 
with pre-existing antibody to AAV5 vector capsid, including development of FVIII 
neutralizing antibody 
Secondary objectives of the study are to: 
x
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26 
x
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy 
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29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
x
Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous 
FVIII therapy
x
Evaluate the pharmacodynamics of FVIII expression following IV infusion of BMN 270 
x
Assess the impact of BMN 270 on patient-reported outcomes (PROs) 
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Proprietary and Confidential 
29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
STUDY DESIGN AND PLAN: 
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), with a
history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with pre-existing 
antibodies to the AAV5 vector capsid as measured by total antibody [TAb] assay. Approximately 
10 subjects will be enrolled at 2-3 sites in 2 cohorts (5 subjects in each cohort) and will receive a 
single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a Screening 
$$9 7$E WLWHU   ZKLOH VXEMHFWV LQ &RKRUW  ZLOO KDYH D 6FUHHQLQJ $$9 7$E titer > 500.  
Choosing a titer cutoff of 500 reflects the observed distribution of existing titer data with the 
BioMarin titer assay seen to date.
The Data Review Board (DRB) will consist of the 2 Principal Investigators and Sponsor’s Medical 
Monitor, as well as hemophilia expert advisors experienced in the conduct and evaluation of safety 
and efficacy parameters from 270-201.  The DRB will review available safety and efficacy data 
throughout the study and provide recommendations based on their review (Figure 2 represents one 
dosing schedule scenario):
Figure 2:  270-203 Dosing Schedule (One Possible Scenario) 
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Proprietary and Confidential 
29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening 
AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a maximum of 
5 subjects have been dosed in Cohort 1 and had their safety and efficacy data (from a minimum of 
6 weeks post-LQIXVLRQ UHYLHZHG )9,,, DFWLYLW\   DIWHU VL[ ZHHNV SRVW-infusion is expected to 
be the earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who 
later achieved normal FVIII activity levels, compared with the one subject who had a slightly
lower response, based on data from 270-201. Up to 6 weeks post-infusion will provide an 
appropriate timeframe to evaluate the development of any potential delayed hypersensitivity 
reaction (eg, serum sickness).  
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on 
DRB evaluation of safety and efficacy in treated subjects, with the following triggers that may 
potentially pause further enrollment:  
x
any related SAE; 
x
any related AE with a severity > CTCAE Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks post-BMN 270 
infusion.
Following a temporary halt of enrolment, the DRB may approve resumption of enrolment in either 
cohort at a later date at its discretion based on further analysis of accumulating data. 
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 
24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In case of 
suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to physical 
examination and vital signs, will be performed and additional blood samples will be collected 
(tryptase, C3, C3a, C4, C5, and C5a within 1 hour of hypersensitivity reaction, and IgE between 
8-24 hours after the reaction). Any safety signal may trigger a review of the data and possible 
additional immunogenicity studies or other diagnostics deemed necessary to assess cellular 
immune responses using collected peripheral blood mononuclear cells (PBMCs).  The duration of 
observation may be extended and additional blood samples collected at the discretion of the 
Investigator and Medical Monitor. 
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Proprietary and Confidential 
29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Data from 270-201 suggest that achievement of therapeutic FVIII OHYHOV  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII protection 
while subjects are projected to reach clinically UHOHYDQW )9,,, OHYHOV   ,8G/ SULRU )9,,,
prophylaxis for each subject will be continued at the discretion of the DRB based on individual 
subject status and data review or when FVIII activity has reached at least 5 IU/dL. Throughout the 
study, subjects with FVIII activity below 5 IU/dL may be monitored more frequently at the 
discretion of the Investigator and the Medical Monitor. In subjects who show an initial response to 
BMN 270 but who later have FVIII activity decline to < 5 IU/dL, the investigator and medical 
monitor will review the subject’s FVIII activity levels and discuss whether to resume prior FVIII 
prophylaxis. In addition, the investigator will notify the subject of his FVIII activity levels and will 
discuss with the subject the risk of bleeding and when (and if) prior FVIII prophylaxis will be 
resumed.
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. After the 
safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, long-term safety and 
efficacy will be assessed in all subjects for up to a total of 5 years post-infusion. During the trial, 
additional subjects may be recruited into each cohort at any time, if deemed necessary by the DRB.  
NUMBER OF SUBJECTS PLANNED:
Approximately 10 subjects  
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following criteria:
1.
0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as evidenced 
by medical history, at the time of signing the informed consent.  
2.
Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total 
antibody ELISA
3.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days 
(EDs)
4.
Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior 
to study entry.   
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29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
5.
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.
6.
No history of FVIII inhibitor, and results from a Bethesda assay with Nijmegen modification 
of less than 0.6 Bethesda Units (BU) on 2 consecutive occasions (the most recent one of which 
should be tested at the central laboratory) at least one week apart within the past 12 months 
7.
HIV positive patients may be enrolled, only if the patient has a CD4 count > 200/mm3 and an 
undetectable viral load. 
8.
Sexually active participants must agree to use an acceptable method of double barrier 
contraception for at least 6 months post-infusion, which may include hormonal contraception 
for a female partner.  After 6 months, subjects may stop contraception use only if they have 
had 3 consecutive semen samples with no detectable viral vector DNA.
9.
Willing to abstain from consumption of alcohol for at least the first 26 weeks following 
BMN 270 infusion. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1.
Any evidence of active infection or any immunosuppressive disorder, except for HIV infection 
as described in the inclusion criterion above.  
2.
Significant liver dysfunction with any of the following abnormal laboratory results:
o
ALT (alanine transaminase) or AST >2X ULN
o
Total bilirubin >2X ULN
o
Alkaline phosphatase >2X ULN or
o
,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR  
Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat 
testing and, if eligibility criteria are met on retest, may be enrolled after confirmation by the 
Medical Monitor.  In addition, subjects with abnormal laboratory results related to confirmed 
benign liver conditions (eg, Gilbert’s syndrome) are considered eligible for the study 
notwithstanding their abnormal laboratory results and may be enrolled after discussion with the 
Medical Monitor.
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29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
3.
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
4.
Evidence of any bleeding disorder not related to hemophilia A 
5.
Platelet count of < 100 x 109/L
6.
Creatinine   PJG/
7.
Liver cirrhosis of any etiology as assessed by liver ultrasound 
8.
Chronic or active hepatitis B as evidenced by positive serology testing 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.
9.
Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy
10. Active malignancy, except non-melanoma skin cancer
11. History of hepatic malignancy
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, non-
hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with the 
exception of catheter-associated thrombosis for which anti-thrombotic treatment is not 
currently ongoing.  
13. Known inherited or acquired thrombophilia, including conditions associated with increased 
thromboembolic risk, such as atrial fibrillation.
14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, vasculitis). 
15. Treatment with any Investigational Product within 30 days prior to the screening period. For 
subjects who have received a prior investigational product, all ongoing adverse events (AEs) 
experienced while receiving that investigational product must have resolved prior to screening 
for this study
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including possible corticosteroid 
treatment outlined in the protocol) and/or would impact or interfere with evaluation and 
interpretation of subject safety or efficacy result.
17. Prior treatment with any vector or gene transfer agent
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29 September 2017 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
18. Major surgery planned in the 26-week period following the infusion with BMN 270
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines 
within 30 days before the BMN 270 infusion 
20. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of safety and efficacy of BMN 270 and 
with prior consultation with the Medical Monitor
21. Known allergy or hypersensitivity to investigational product formulation
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single IV infusion of BMN 270 at 6E13 vg/kg. The volume of infusion 
will depend on the subject’s weight.
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
No reference therapy will be evaluated in this study. 
DURATION OF TREATMENT:
BMN 270 is given as a single dose by IV infusion.
CRITERIA FOR EVALUATION:
Safety:
The following safety outcome measurements will be assessed:
x
Incidence of adverse events (AEs), including serious AEs (SAEs) 
x
Change in clinical laboratory tests (serum chemistry and hematology)
x
Change in vital signs
x
Change in physical examination  
x
Vector shedding (blood, urine, semen, feces, saliva) 
x
Liver function tests (LFTs, including ALT, AST, GGT, LDH, bilirubin, alkaline 
phosphatase) 
x
Immune response to FVIII transgene product and AAV5 vector capsid
No major toxicity is expected based on 270-201 data and non-clinical studies. Each subject will 
have comprehensive surveillance monitoring of LFTs (once per week for Weeks 1-26). During the 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
long-term safety evaluation, LFTs will be monitored every three months for up to 5 years post-
infusion; the frequency and duration of LFT testing may be changed based on discussion between 
the Medical Monitor and the Investigator and review of subject data. 
There will be a detailed assessment of cellular and humoral responses to AAV5 vector capsid and 
FVIII.  
Efficacy: 
The efficacy measure will be to assess plasma FVIII activity. The efficacy goal is to achieve FVIII 
DFWLYLW\   ,8G/ DW  ZHHNV SRVW-BMN 270 administration. Other efficacy measures include 
assessing the impact of BMN 270 on the use of FVIII replacement therapy and on the number of 
bleeding episodes during the study. Subjects will be asked to keep a subject diary, provided by the 
sponsor, to record the relevant details.  
Other efficacy endpoints:  
x
Change from baseline in the total score of HAEMO-QoL-A at Week 26 of the study post-
BMN 270 infusion
x
Change from baseline in the EQ-5D-5L score at Week 26 of the study post-BMN 270 
infusion.
x
Change from baseline in the Haemophilia Activities List (HAL) score at Week 26 of the 
study post-BMN 270 infusion. 
x
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 26 of the 
study post-BMN 270 infusion. 
Pharmacodynamics: 
The FVIII antigen and activity level, as measured by a validated immunoassay and a validated 
FVIII activity assay, respectively, will be used for plasma profiles; FVIII antigen and activity will 
be used to determine PD parameters.
STATISTICAL METHODS: 
Approximately 10 subjects may be dosed in the study. The subjects will be followed in a 
longitudinal manner, and all the relevant information will be collected. The analysis of the data 
will be descriptive in nature, but data collected in a longitudinal manner may be analyzed using 
longitudinal methods, such as a mixed effect model, which take into account the correlation among 
the observations taken at various time points within a subject. Efficacy is a secondary endpoint, 
GHILQHG DV ELRORJLFDOO\ DFWLYH )9,,, DW  5 IU/dL at 26 weeks following study treatment. FVIII 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
activity will be assessed weekly during the study period. Assessment of the true steady state of 
FVIII will require that FVIII activity is measured after a minimum of 72 hours (or 5x the known 
half-life of the FVIII replacement therapy administered) has elapsed since the last infusion of FVIII
concentrates. 
Analysis of neutralizing antibody response, other immunological parameters, and vector shedding 
will be primarily descriptive and involve both inter-subject and intra-subject comparisons across 
cohorts.
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TABLE OF CONTENTS
1
TITLE PAGE ....................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................2 
3 TABLE OF CONTENTS ...................................................................................................15 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................19 
5 ETHICS..............................................................................................................................22 
5.1 Institutional Review Board or Independent Ethics Committee ................................22 
5.2 Ethical Conduct of Study ..........................................................................................23 
5.3 Subject Information and Informed Consent ..............................................................23 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................24 
7 INTRODUCTION .............................................................................................................25 
7.1 Nonclinical Studies ...................................................................................................26 
7.2 Previous Clinical Studies ..........................................................................................26 
7.3 Study Rationale .........................................................................................................27 
7.4 Summary of Overall Risks and Benefits ...................................................................30 
8 STUDY OBJECTIVES ......................................................................................................32 
9 INVESTIGATIONAL PLAN ............................................................................................33 
9.1 Overall Study Design and Plan .................................................................................33 
9.2 Discussion of Study Design, Including Choice of Control Group ............................46 
9.3 Selection of Study Population ...................................................................................46 
9.3.1 
Inclusion Criteria .........................................................................................46 
9.3.2 
Exclusion Criteria ........................................................................................47 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................48 
9.3.4 
Subject Identification and Replacement of Subjects ...................................51 
9.3.5 
Duration of Subject Participation ................................................................51 
9.4 Treatments .................................................................................................................51 
9.4.1 
Treatments Administered ............................................................................51 
9.4.2 
Identity of Investigational Product ..............................................................51 
9.4.3 
Storage .........................................................................................................52 
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9.4.4 
Directions for Administration .....................................................................52 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................53 
9.4.6 
Selection of Dose Used in the Study ...........................................................53 
9.4.7 
Blinding .......................................................................................................53 
9.4.8 
Prior and Concomitant Medications ............................................................53 
9.4.9 
Treatment Compliance ................................................................................56 
9.5 Investigational Product Accountability .....................................................................56 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................57 
9.6 Dietary or Other Protocol Restrictions......................................................................57 
9.7 Efficacy and Safety Variables ...................................................................................57 
9.7.1 
Efficacy and Safety Measurements Assessed .............................................57 
9.7.2 
Efficacy Variables .......................................................................................57 
9.7.3 
Immunogenicity ...........................................................................................60 
9.7.4 
Pharmacodynamics ......................................................................................60 
9.7.5 
Exploratory Assessments ............................................................................60 
9.7.6 
Safety Variables ..........................................................................................60 
10 REPORTING ADVERSE EVENTS .................................................................................67 
10.1 Safety Parameters and Definitions ............................................................................67 
10.1.1 Adverse Events ............................................................................................67 
10.2 Serious Adverse Events ............................................................................................68 
10.2.1 Events of Special Interest (EOSI) ...............................................................69 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................69 
10.3.1 Adverse Event Reporting Period .................................................................69 
10.3.2 Eliciting Adverse Events .............................................................................69 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................69 
10.4 Procedures for Recording Adverse Events ...............................................................72 
10.4.1 Recording Adverse Events on a eCRF ........................................................72 
10.5 Reporting Requirements ...........................................................................................75 
10.5.1 Expedited Reporting Requirements .............................................................75 
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10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements..............................................................................76 
10.6 Follow-up of Subjects after Adverse Events .............................................................76 
10.7 Post-Study Adverse Events .......................................................................................76 
10.8 Urgent Safety Measures ............................................................................................77 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................78 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................79 
12 STUDY PROCEDURES ...................................................................................................80 
12.1 Prestudy .....................................................................................................................80 
12.2 Screening Visit(s) ......................................................................................................80 
12.2.1 “Smart Rescreening” Visit ..........................................................................81 
12.3 Baseline Visit ............................................................................................................82 
12.4 Infusion Visit/BMN 270 Infusion Visit (Day 1) .......................................................83 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................83 
12.5.1 Week 1 .........................................................................................................83 
12.5.2 Weeks 2-26 ..................................................................................................85 
12.5.3 Post-Infusion Follow-Up – Weeks 27-260 ..................................................87 
12.6 Early Termination Visit ............................................................................................89 
12.7 End of Study..............................................................................................................91 
13 DATA QUALITY ASSURANCE .....................................................................................92 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................93 
14.1 Statistical and Analytical Plans .................................................................................93 
14.1.1 Interim Analyses ..........................................................................................93 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ..........93 
14.2 Efficacy Analysis ......................................................................................................93 
14.3 Safety Analysis .........................................................................................................93 
14.4 Determination of Sample Size ..................................................................................94 
14.5 Analysis Populations .................................................................................................94 
14.6 Changes in the Conduct of the Study or Planned Analyses ......................................94 
15 DATA REVIEW BOARD .................................................................................................96 
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16 COSTS, COMPENSATION, AND SUBJECT INJURY ..................................................97 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................98 
18 STUDY MONITORING AND AUDITING ...................................................................100 
19 RETENTION OF RECORDS .........................................................................................101 
20 USE OF INFORMATION AND PUBLICATION .........................................................102 
21 REFERENCES ................................................................................................................103 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................106 
22.1 Conduct of Study and Protection of Human Subjects.............................................106 
23 SIGNATURE PAGE .......................................................................................................107 
LIST OF TABLES
Table 9.1.1: Schedule of Activities ..........................................................................................36 
Table 9.1.2:  Schedule of Activities – Post-Infusion Follow-Up (Week 1-16) .......................39 
Table 9.1.3:  Schedule of Activities – Post-Infusion Follow-Up (Week 17-260) ...................42 
Table 9.1.4:  Therapeutic Corticosteroids for LFT Elevations or Decreased FVIII 
Activity ..........................................................................................................45 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen .......................................................55 
Table 9.7.6.2.1:  Clinical Laboratory Tests .............................................................................61 
Table 9.7.6.3.1:  Liver Function Tests .....................................................................................62 
Table 9.7.6.3.2:  Evaluation of ALT Elevations ......................................................................63 
Table 9.7.6.3.3:  Viral and Autoimmune Hepatitis Testing .....................................................64 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................70 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................71 
LIST OF FIGURES
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic .............................................................29 
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario) ........................................................33 
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations 
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
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
DRB
Data Review Board
EC
ethics 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
FAS
Full Analysis Set
FDA
Food and Drug Administration 
FIH
first-in-human
FVIII
coagulation factor VIII
GCP
Good Clinical Practice
HA
Hemophilia A
HAL
Haemophilia Activities List
hFIX
human coagulation factor IX 
hFVIII
human coagulation factor VIII
HIPAA
Health Insurance Portability and Accountability Act
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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
IND
Investigational New Drug (application)
INR
international normalized ratio 
IP
investigational product
IRB
institutional review board
IV
intravenous 
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
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
SAE
serious adverse event
SAP
statistical analysis plan
SDV
source data verification
SoA
schedule(s) of activities
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 (EC) 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/EC will be provided to BioMarin Pharmaceutical Inc. (BioMarin) 
or its designee. The Investigator will provide the IRB/EC 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/EC 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/EC 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: 
x
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
x
US Code of Federal Regulations (CFR) Sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
x
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R2) 
(ICH E6R2) 
x
The ethical principles established by the Declaration of Helsinki
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/EC and will be conducted by scientifically and medically qualified persons. The benefits 
of the study are in proportion to the risks. The rights and welfare of the subjects will be 
respected and the investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each subject will provide written, informed consent before any
study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed informed consent form (ICF), in compliance with ICH E6R2 
(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/EC approval. BioMarin and the 
IRB/EC 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.
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INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Subjects 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 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.  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 (12-18 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 validated quantitative endpoints that can be easily assayed in most clinical 
laboratories.
BMN 270 contains the cDNA for the B-domain-deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs, and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study.
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7.1
Nonclinical Studies
The nonclinical program supports a single IV 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 
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. 
The comparative pharmacodynamics of BMN 270 in cynomolgus monkeys with varying 
pre-existing AAV5 transduction inhibition (TI) titer and AAV5 TAb status was evaluated in 
study BMN270-16-021. BMN 270 was administered to 4 groups of monkeys, a control group 
(Group 1, n=3) that tested negative for both TI and AAV5 TAb, Group 2 (n=4) that was 
AAV5 TAb negative, and low TI titer (2-5) positive. Group 3 (n=4) was also AAV5 TAb 
negative, but had higher TI titers (5-10). Group 4 (n=5) tested positive for both AAV5 TAb 
and TI (TI titers were >5). Administration of BMN 270 by a single intravenous bolus 
injection was well-tolerated in cynomolgus monkeys regardless of baseline TI titer or TAb 
status. After dosing, all monkeys showed FVIII-SQ levels above the LLOQ, with the 
exception of two monkeys in the group that presented with both positive TI and TAb titers at 
baseline. Though these TAb+ monkeys, regardless of TI titers, showed a significant mean 
reduction in FVIII expression (68% less) compared to TAb negative monkeys, three of five 
monkeys showed detectable levels of FVIII-SQ, with one having levels similar to that 
observed in the TI and TAb negative control group. Monkeys that were TI+ but TAb-at 
baseline had FVIII expression levels that were similar to those of the TI and TAb negative 
control group.  
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 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 and dosed 
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with a single IV infusion of BMN 270 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.   
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 or 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. While infusion of FVIII is a major advance in the treatment of HA, severe HA 
patients continue to have bleeding events on prophylactic therapy; median ABRs were 1-4 
with prophylactic treatment in a recently published retrospective observational study 
(Berntorp, 2016) and between 1-2 in 6 prospective FVIII interventional studies.  Median 
ABRs were 4.5-18 and between 20-60 with on-demand-only therapy in the same studies, 
respectively. Continued repeated bleeding events compound debilitating multiple-joint 
arthropathies as well as the risk of catastrophic events such as intracranial hemorrhage and 
death.
Chemical modification (eg, direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can only extend half-life to maximum 
of 18 hours, leaving critical periods when FVIII activity levels are below the therapeutic 
range and leaving patients vulnerable to bleeding and concomitant sequelae. As such, despite 
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currently available FVIII replacement therapies, a high unmet need remains for maintenance 
of a sustained, consistent 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. 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. Moreover, the 
circulating FVIII response to gene transduction can be assessed using validated quantitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 
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 (eg 
serotypes 2, 5, and 8).  Indeed, an ongoing gene therapy clinical trial for a related disorder, 
hemophilia B, has established over 7 years of stable human factor IX (hFIX) expression at 
levels sufficient for conversion of their bleeding phenotype from severe to moderate or mild, 
following a single peripheral vein infusion of AAV8-hFIX vector (Nathwani, 2014). 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.  
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BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a hybrid human liver-specific promoter (Figure 7.3.1).
Figure 7.3.1: hFVIII-SQ Vector Genome Schematic
Legend –Note that schematic is not to scale; nt = nucleotides
BMN 270 is delivered by a single IV dose and is designed to achieve stable, potentially life-
long expression of active hFVIII in the plasma, synthesized from vector-transduced liver 
tissue.  
BMN 270 is currently being evaluated in clinical study 270-201, an ongoing first-in-human, 
phase 1/2 dose escalation study in subjects with severe HA designed to assess the safety and 
efficacy of BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 
6E13 vg/kg). Specifically, 270-201 explores the relationship of vector dose to the 
augmentation of residual FVIII activity and whether these levels are sufficient to alter the 
clinical phenotype. Preliminary results from 270-201 have demonstrated that following gene 
transfer, sustained FVIII activity above 5% (5 IU/dL) up to a year’s observation is achievable 
at doses of 4-6E13 vg/kg with an acceptable safety profile (Pasi, 2016). The majority of 
subjects achieved FVIII levels within the normal range for FVIII, with few to no bleeding 
episodes and discontinuation of FVIII prophylaxis. 
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, 
as the prevailing expectation has been that vector-specific antibodies could interfere with 
receptor binding and effectively neutralize efficient transduction of the target cell population. 
As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted 
out of an abundance of caution. These pre-existing vector-specific antibodies are thought to 
arise from previous exposure to AAV, with seroprevalence varying across human 
populations and across studies. AAV5 has consistently been shown to have the lowest 
seroprevalence among the common AAV serotypes. 
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Current data describing the extent of neutralization or inhibited transduction has been 
inconsistent across studies, each employing one of several varying methodologies to evaluate 
both vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 
for the treatment of hemophilia B described inhibited transduction in patients with 
neutralizing antibody titers of 2 or 3 (Manno, 2006), but more recent studies have described 
successful transduction in patients who, in retrospect, were determined to have pre-existing 
antibody to the vector capsid (Majowicz, 2017).  Importantly, no drug-related adverse events 
were described in these patients.  As the sensitivity of assays used to detect pre-existing 
antibody has increased greatly in recent years, the biological relevance of any given titer 
determination, and comparisons across studies using assays with differing titer sensitivities, 
requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of 
available data shows the effect of pre-existing immunogenicity to AVV delivery vectors is 
not completely understood, and indicates that some patients may benefit from AAV5 gene 
therapy who are currently excluded. 
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be 
enrolled to evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate 
the safety, tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing 
antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers. 
7.4
Summary of Overall Risks and Benefits 
The majority of subjects in the ongoing 270-201 clinical study who have received 4E13 or 
6E13 vg/kg doses of BMN 270 have had Grade 1 asymptomatic elevations in ALT. For most 
subjects, the elevations have reached only slightly above the upper limit of normal (ULN).  
Based on the effectiveness of transient oral corticosteroid use to suppress a presumed Class 1 
(cytotoxic T-cell) response to hepatocytes transduced in prior studies with hepatic 
transduction with AAV vectors (Mingozzi, 2013), subjects were treated with 7-32 weeks of 
oral corticosteroids prophylactically or in response to the elevations in ALT to ensure 
preservation of the transduced hepatocytes. Using this approach, no sustained loss of FVIII 
activity has been observed in subjects with ALT elevations, consistent with maintaining a 
high level of hepatocyte function. Moreover, the rise in ALT levels were not accompanied by 
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significant or lasting aberrations in other liver function tests such as AST, bilirubin or 
albumin, indicating that extent of toxicity is limited. Overall, the literature suggests 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). 
At the highest dose evaluated in 270-201 (6E13 vg/kg), the majority of subjects achieved 
FVIII levels above 50 IU/dL at 52 weeks post-infusion.  Subjects in that cohort also reported 
markedly decreased bleeding episodes compared with pre-study rates and the ability to 
discontinue prophylactic FVIII infusions. Subjects at all dose levels continue to be followed. 
Subjects in 270-203, who have pre-existing immunity to the AAV5 vector capsid, may get no 
benefit from the study (in terms of increased FVIII activity) while possibly creating 
cross-reactive antibodies that may potentially preclude dosing with other serotypes. 
The current data available for BMN 270 does not yet permit comprehensive assessment of 
the benefit:risk profile of this investigational drug. Given the monitoring measures in place in 
the clinical protocol(s) to minimize the risk to subjects participating in the existing studies, 
the identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-203 will have a comprehensive surveillance plan that monitors LFTs 
during the study, and elevations in LFT 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 IB. 
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8
STUDY OBJECTIVES
The primary objective of the study is to:
x
Assess the safety of a single intravenous administration of BMN 270 in severe HA 
subjects with pre-existing antibody to AAV5 vector capsid, including development of 
FVIII neutralizing antibody 
The secondary objectives of the study are to: 
x
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at 
Week 26
x
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy 
x
Assess the impact of BMN 270 on the number of bleeding episodes requiring 
exogenous FVIII therapy
x
Evaluate the pharmacodynamics of FVIII expression following IV infusion of 
BMN 270 
x
Assess the impact of BMN 270 on patient-reported outcomes (PROs) 
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), 
with a history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with pre-
existing antibodies to AAV5 vector capsid as measured by total antibody [TAb] assay. 
Approximately 10 subjects will be enrolled at 2-3 sites in 2 cohorts (5 subjects in each 
cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in 
Cohort 1 will have a SFUHHQLQJ $$9 7$E   ZKLOH VXEMHFWV LQ &RKRUW 2 will have a 
Screening AAV5 TAb > 500. Choosing a titer cutoff of 500 reflects the observed distribution 
of existing titer data with the BioMarin titer assay seen to date.
The Data Review Board (DRB) will consist of the 2 Principal Investigators and Sponsor’s 
Medical Monitor, as well as hemophilia expert advisors experienced in the conduct and 
evaluation of safety and efficacy parameters from 270-201.  The DRB will review available 
safety and efficacy data throughout the study and provide recommendations based on their 
review (Figure 9.1.1 represents one dosing schedule scenario):
Figure 9.1.1: 270-203 Dosing Schedule (One Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their 
Screening AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a 
maximum of 5 subjects have been dosed in Cohort 1 and had their safety and efficacy data 
(from a minimum of 6 weeks post-infusion) reviewed.  Based on data from 270-201, FVIII 
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DFWLYLW\   DIWHU VL[ ZHHNV SRVW-infusion is expected to be the earliest differentiating time 
point for the majority of subjects dosed with 6E13 vg/kg who later achieved normal FVIII 
activity levels, compared with the one subject who had a slightly lower response. Up to 
6 weeks post-infusion will provide an appropriate timeframe to evaluate the development of 
any potential delayed hypersensitivity reaction (eg, serum sickness).   
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DRB evaluation of safety and efficacy in treated subjects with the following 
triggers that may potentially pause further enrollment:  
x
any related SAE;
x
any related AE with a severity > CTCAE Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects at 6 weeks post-BMN 270 infusion.
Following a temporary halt of enrolment, the DRB may approve resumption of enrolment in 
either cohort at a later date at its discretion based on further analysis of accumulating data. 
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at 
least 24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In 
case of suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to 
physical examination and vital signs, will be performed and additional blood samples will be 
collected (tryptase, C3, C3a, C4, C5, and C5a within 1 hour of hypersensitivity reaction, and 
IgE between 8-24 hours after the reaction). Any safety signal may trigger a review of the data 
and possible additional immunogenicity studies or other diagnostics deemed necessary to 
assess cellular immune responses using collected peripheral blood mononuclear cells 
(PBMCs).  The duration of observation may be extended and additional blood samples 
collected at the discretion of the Investigator and Medical Monitor. 
Data from 270-201 suggest that achievement of therapeutic FVIII levels  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII 
protection while subjects are projected to reach clinically relevaQW )9,,, OHYHOV  5 IU/dL, 
prior FVIII prophylaxis for each subject will be continued at the discretion of the DRB based 
on individual subject status and data review or when FVIII activity has reached at least 
5 IU/dL. Throughout the study, subjects with FVIII activity below 5 IU/dL may be monitored 
more frequently at the discretion of the Investigator and the Medical Monitor. In subjects 
who show an initial response to BMN 270 but who later have FVIII activity decline to 
< 5 IU/dL, the investigator and medical monitor will review the subject’s FVIII activity 
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levels and discuss whether to resume prior FVIII prophylaxis. In addition, the investigator 
will notify the subject of his FVIII activity levels and will discuss with the subject the risk of 
bleeding and when (and if) prior FVIII prophylaxis will be resumed. 
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. 
After the safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, 
long-term safety and efficacy will be assessed in all subjects for up to a total of 5 years 
post-infusion. During the trial, additional subjects may be recruited into each cohort at any 
time, if deemed necessary by the DRB.  
A summary of all assessments is provided in the Schedule of Activities (SoA) in Table 9.1.1,
Table 9.1.2, and Table 9.1.3.
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d Subjects with documented negative results within the last 30 days do not need to be retested.
e Detailed in the Section of laboratory assessments and liver function tests.  Urine tests will be performed locally; all other laboratory assessments will be performed at the 
central laboratory.   
f Includes HLA genotyping and FVIII genotyping; may include TNFD and IL10a single nucleotide polymorphisms.
g Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A disease. The exploratory 
genetic/genomic testing on these samples is optional.
h Should the screening visit occur within 30 days of the drug infusion, physical examination, blood chemistry, LFTs, hematology, urine tests, and coagulation tests do not need 
to be repeated at Baseline.
i Smart rescreening should only be performed if a subject 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 (28 + 14 days). 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. Any screening assessment has not been done at the Screening, it must be done during Smart 
Rescreening. 
j Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening.
k Assessments on the day of infusion must be performed prior to the infusion.  On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, during 
the infusion every 15 minutes (± 5 minutes), and following the infusion hourly (± 5 minutes) for a total time of 24 hours during the subject’s stay in the clinic.
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.
mIn case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will be done and additional blood samples will be 
collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, and C5a) and one sample for IgE between 8-24 hours after the reaction, if possible. 
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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e Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A disease. The exploratory 
genetic/genomic testing on these samples is optional.
f Testing for reactivation of hepatitis B and hepatitis C at Week 16 should be performed only in subjects with evidence of prior exposure and who have not received 
therapeutic oral corticosteroids prior to Week 16; subjects who have received therapeutic oral corticosteroids will have hepatitis B and hepatitis C testing at the time points 
indicated in Table 9.1.4. 
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e Blood samples will be collected from subjects to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A disease. The exploratory 
genetic/genomic testing on these samples is optional.
f Patient-reported outcome (PRO) assessments will be done once each year after Week 26.
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9.2
Discussion of Study Design, Including Choice of Control Group
Study 270-203 is designed to be a Phase 1/2, single-arm, open-label study in hemophilia A 
SDWLHQWV ZLWK UHVLGXDO )9,,, OHYHOV   ,8G/ DQG SUH-existing antibodies to the AAV5 vector 
capsid. Hemophilia A patients who provide written informed consent and meet the entry 
criteria will be eligible to enroll in the study.
Approximately 10 subjects will be enrolled at the 6E13 vg/kg BMN 270 dose.  Subjects will 
be followed for 26 weeks post-BMN 270 infusion during which safety and efficacy 
assessments will be taken. After the final analysis at 26 weeks post-infusion, safety and 
efficacy will then continue to be assessed long-term for approximately a total of 5 years.  
9.3
Selection of Study Population 
Approximately 10 hemophilia A patients with residual FVIII levels < 1 IU/dL and 
pre-existing antibodies to the AAV5 vector capsid 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 criteria:
1. 0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as 
evidenced by medical history, at the time of signing the informed consent.  
2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by 
AAV5 total antibody ELISA 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs) 
4. Subject must have been on prophylactic FVIII replacement therapy for at least 
12 months prior to study entry.   
5. 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.
6. No history of FVIII inhibitor, and results from a Bethesda assay with Nijmegen 
modification of less than 0.6 Bethesda Units (BU) on 2 consecutive occasions (the 
most recent one of which should be tested at the central laboratory) at least one week 
apart within the past 12 months 
7. HIV positive patients may be enrolled, only if the patient has a CD4 count > 200/mm3
and an undetectable viral load. 
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8. Sexually active participants must agree to use an acceptable method of double barrier 
contraception for at least 6 months post-infusion, which may include hormonal 
contraception for a female partner.  After 6 months, subjects may stop contraception 
use only if they have had 3 consecutive semen samples with no detectable viral vector 
DNA.
9. Willing to abstain from consumption of alcohol for at least the first 26 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. Any evidence of active infection or any immunosuppressive disorder, except for HIV 
infection as described in the inclusion criterion above. 
2. Significant liver dysfunction with any of the following abnormal laboratory results: 
o
ALT (alanine transaminase) or AST >2X ULN
o
Total bilirubin >2X ULN 
o
Alkaline phosphatase >2X ULN or 
o
,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR  
Subjects whose laboratory assessments fall outside of these ranges may undergo 
repeat testing and, if eligibility criteria are met on retest, may be enrolled after 
confirmation by the Medical Monitor.  In addition, subjects with abnormal laboratory 
results related to confirmed benign conditions (eg, Gilbert’s syndrome) are 
considered eligible for the study notwithstanding their abnormal laboratory results 
and may be enrolled after discussion with the Medical Monitor. 
3. 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
4. Evidence of any bleeding disorder not related to hemophilia A 
5. Platelet count of < 100 x 109/L
6. Creatinine   PJG/
7. Liver cirrhosis of any etiology as assessed by liver ultrasound  
8. Chronic or active hepatitis B as evidenced by positive serology testing 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.
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9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral 
therapy
10. Active malignancy, except non-melanoma skin cancer
11. History of hepatic malignancy 
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial 
embolus), with the exception of catheter-associated thrombosis for which anti-
thrombotic treatment is not currently ongoing.  
13. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, 
vasculitis).
15. Treatment with any Investigational Product within 30 days prior to the screening 
period. For subjects who have received a prior investigational product, all ongoing 
adverse events (AEs) experienced while receiving that investigational product must 
have resolved prior to screening for this study 
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the 
patient from fully complying with the requirements of the study (including possible 
corticosteroid treatment outlined in the protocol) and/or would impact or interfere 
with evaluation and interpretation of subject safety or efficacy result. 
17. Prior treatment with any vector or gene transfer agent
18. Major surgery planned in the 26-week period following the infusion with BMN 270 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion 
20. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study that does not interfere with the requirements of the 
current protocol or have the potential to impact the evaluation of safety and efficacy 
of BMN 270 and with prior consultation with the Medical Monitor 
21. Known allergy or hypersensitivity to investigational product formulation 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or 
a bleed
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 
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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: 
x
Subject requires medication or medical procedure prohibited by the protocol 
x
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 
x
Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/EC It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study. 
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9.3.3.1
Study Safety Evaluation Criteria
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DRB evaluation of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment: 
x
any related SAE;
x
an related AE with a severity > Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.
Additionally, the DRB should consider whether to restrict dosing to subjects with anti-AAV5 
titers below levels that appear to be causing clinically significant inhibition of transduction.
Following a temporary halt of enrolment, the DRB may approve resumption of enrolment in 
either cohort at a later date at its discretion based on further analysis of accumulating data. 
If a Grade 4 or Grade 5 adverse event assessed as related to study drug occurs in a study 
subject, further enrollment into the trial will be halted until a full safety review of the data by 
the DRB has taken place. Relevant reporting and discussion with the Sponsor and the DRB 
will take place before resumption of dosing. 
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, further enrollment into the trial will be temporarily put on hold pending prompt 
evaluation by the DRB.   
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 an AE of hepatic failure.
3. The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in two subjects. 
4. The occurrence of any cancer (except non-melanoma skin cancer) at any point after 
BMN 270 infusion. 
5. The occurrence of a thromboembolic event with FVIII activity > 150 IU/dL in one 
subject.
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If any of the following events occurs in a subject in the study who has received BMN 270 
infusion, a prompt evaluation by the DRB will be required.  Further enrollment into the trial 
will continue while DRB evaluation is ongoing, unless deemed otherwise by the DRB. 
1. Acute hypersensitivity assessed as related to BMN 270
2. The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in one subject 
3. Occurrence of a thromboembolic event 
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. 
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, 26 weeks of Post-Infusion Follow-Up, 
and 234 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
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 
The study drug label includes the following information: lot number, required storage 
conditions, a precautionary statement, expiry date, study number, and BioMarin name and 
address.  Labelling will be done according to country specific requirements. 
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9.4.3
Storage 
At the study site, all IP must be stored under the conditions specified in the 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
After a physical examination performed by the Investigator or designee, subjects will be 
admitted on the day of BMN 270 infusion. If the subject is found to have an active acute 
illness at the time of planned infusion, then the infusion should be deferred until the illness 
has resolved; screening procedures may require repetition if outside the specified window.  
An IV catheter will be inserted into a suitable peripheral vein (eg, the median cubital vein) 
and flushed with saline. FVIII replacement therapy will not be given since venipuncture is a 
minimally invasive procedure in these individuals under ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at a 
constant rate of 4 mL/min while monitoring the vital signs (pulse, blood pressure, respiration 
rate and temperature) at 15 minute (±5 minutes) intervals. The anticipated maximum interval 
from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, although the 
IP has been shown to be stable at room temperature for 6 hours. 
Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes).  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 24 hours to 
observe for any immediate toxicity of the procedure; in-patient observation can be extended 
beyond 24 hours if needed per Investigator discretion. After 24 hours, subjects will be 
discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
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9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the 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 by the Sponsor. 
9.4.6
Selection of Dose Used in the Study
Data from an ongoing first in human 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. The 
6E13 vg/kg dose has been selected for this study to maximize the likelihood of transduction 
in the face of pre-existing AAV5 antibodies.
9.4.6.1
Selection of Timing of Dose for Each Subject
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.   
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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: 
x
Any investigational therapy
x
Systemic immunosuppressive agents, except for corticosteroids 
The following medications should be avoided, starting 30 days prior to and for at least 
26 weeks after BMN 270 infusion and minimized throughout the remaining duration of the 
study.
x
Alcohol  
x
Herbal and natural remedies and dietary supplements
x
Medications which may be hepatotoxic 
Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated.
The following medications should be avoided during oral corticosteroid therapy:
x
Vaccines
x
NSAIDs
9.4.8.1
Concomitant Hemophilia Treatments 
Subjects on prophylactic FVIII therapy will discontinue their regular treatment regimen 
starting 4 weeks following the day of infusion or after FVIII activity has reached at least 
5 IU/dL (whichever is earlier) 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 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 will be 
collected from subjects for the 12-month period immediately preceding study enrollment.   
9.4.8.2
Therapeutic Glucocorticoid Treatment for 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 
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between the Investigator and Medical Monitor. Modification of the corticosteroid regimen 
may take into consideration possible confounders for the ALT elevation and impact on FVIII 
expression.   
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This 
includes the contraindicated use of NSAIDs during corticosteroid treatment and specific 
monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not 
contraindicated during corticosteroid treatment, should be limited, if possible.  Practical 
management to prevent complications related to oral corticosteroid therapy may be 
undertaken at the discretion of the Investigator (eg, evaluation of glucose intolerance, 
hyperlipidemia etc.). 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. 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 may be enrolled in 270-203 if the subject has a CD4 count > 200/mm3 
and an undetectable viral load. 
Subjects should continue anti-retroviral therapy (ART) as prescribed and follow routine 
monitoring of CD4 count and viral load (Angus, 2016).  No alterations in the monitoring are 
indicated for enrolled immunocompetent HIV-positive subjects who receive corticosteroids 
as part of their enrollment in 270-203. 
9.4.9
Treatment Compliance
Study drug will be administered to subjects at the dosing facility by a qualified health care 
professional.  The quantity dispensed, returned, used, lost, etc. must be recorded on the 
dispensing log provided for the study.  Sites will be instructed to return or destroy all used 
and unused study drug containers. 
9.5
Investigational Product Accountability 
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received and IP lost or accidentally or deliberately destroyed. The 
Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data.
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9.5.1
Return and Disposition of Clinical Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the study monitor. The Investigator or designee must provide an explanation for any 
destroyed or missing study drug or study materials.
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 
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 Study 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 26 weeks of the study, and particularly within 48 hours prior to lab work. 
9.7
Efficacy and Safety Variables 
9.7.1
Efficacy and Safety Measurements Assessed
The SoA (Table 9.1.1, Table 9.1.2, Table 9.1.3) describe the timing of required evaluations.
9.7.2
Efficacy Variables
9.7.2.1
FVIII Activity
(IILFDF\ UHVSRQVH WR WUHDWPHQW ZLOO EH GHILQHG DV )9,,, DFWLYLW\  5 IU/dL at Week 26 
following BMN 270 infusion. 
Values for FVIII activity will be excluded from analysis if obtained within 72 hours since the 
last infusion of exogenous FVIII protein concentrates (or within 5x the known half-life of the 
FVIII concentrates administered).
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In the event of an FVIII activity level decline during the study: 
x
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 LFTs should be 
repeated every 7 days until FVIII activity is stable or increasing 
x
If FVIII activity has declined >35% from the peak and has declined for at least 
2 consecutive assessments, FVIII activity and LFTs should be repeated every 72 
hours until FVIII activity is stable or increasing. 
In subjects who show an initial response to BMN 270 but who later have FVIII activity 
decline to < 5 IU/dL, the investigator and medical monitor will review the subject’s FVIII 
activity levels and discuss whether to resume prior FVIII prophylaxis. In addition, the 
investigator will notify the subject of his FVIII activity levels and will discuss with the 
subject the risk of bleeding and when (and if) prior FVIII prophylaxis will be resumed.
Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline 
in FVIII activity is observed, then this additional testing may be deferred (upon consultation 
between the Investigator and the Medical Monitor) until either a more clear trend of decline 
has been demonstrated or until the FVIII activity levels stabilize or increase.
Details on collecting FVIII activity samples are included in the Laboratory Manual.
9.7.2.2
Factor VIII Replacement Therapy/Bleeding Episodes
Additional efficacy variables are:
x
Change of annualized utilization (IU/kg) of exogenous FVIII replacement therapy 
during Week 5 to Week 26 post BMN 270 infusion from the baseline utilization of 
exogenous FVIII replacement therapy calculated using subjects’ historical medical 
records during the year prior to the enrollment.  
x
Change of ABRs requiring exogenous FVIII replacement treatment during Week 5 to 
Week 26 of the study post BMN 270 infusion from the baseline ABR calculated using 
subjects’ historical medical records during the year prior to the enrollment.  
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 
6 weeks post BMN 270 infusion. 
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9.7.2.3
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 Study Reference 
Manual.
The EQ-5D-5L instrument is a self-reported questionnaire designed to measure general 
health status (The EuroQol Group, 1990, Health Policy) (Brooks, 1996, Health Policy). 
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 Study Reference Manual.
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 Study 
Reference Manual.
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 Study 
Reference Manual.
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9.7.3
Immunogenicity
Immunogenicity assays will be performed on plasma and PBMCs. The assays will include 
detection of anti-AAV5 vector capsid and anti-FVIII total antibodies, as well as 
determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the 
AAV5 vector 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 vector capsid-
specific cellular immunogenicity. FVIII- and vector capsid-specific cellular immunity will be 
assessed by stimulated cytokine secretion using an ELISpot assay performed on collected 
PBMCs.
9.7.4
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.
9.7.5
Exploratory Assessments 
A cytokine bead array assay assessment will be performed at Baseline and then weekly 
through Week 26. 
In addition, blood samples will be collected from subjects at the time points indicated in 
Table 9.1.1, Table 9.1.2, and Table 9.1.3 to evaluate biochemical, molecular, cellular, and 
genetic/genomic aspects relevant to hemophilia A, and to develop assays used for these 
evaluations.  The exploratory genetic/genomic research to study or try to discover genes that 
are not yet known to be associated with hemophilia A is optional. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research, including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes in this study may be used for exploratory 
research once testing for the primary purpose has been completed.   
9.7.6
Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity.
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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 20, at Week 26, and then every 3 months thereafter 
until the end of the study. 
9.7.6.6
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 PCR.  Fluids tested will include:
x
Blood 
x
Saliva
x
Semen
x
Urine
x
Stool 
Vector shedding will also be extensively studied in the present clinical trial, at the time points 
indicated in Table 9.1.1, Table 9.1.2, and Table 9.1.3. Testing will continue until at least 3 
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 26 should 
continue to have PCR testing in semen every 4 weeks until 3 consecutive negative samples 
are documented (or upon consultation between the Investigator and Medical Monitor). 
Samples may be fractionated prior to shedding analysis in order to better characterize the 
presence, structure, and location of vector DNA and/or vector capsid within each matrix.  If 
needed, the fractionation will be performed with samples collected specifically for shedding 
analysis (saliva, blood, semen, urine, stool).  Alternatively, the vector DNA characterization 
during shedding analysis may utilize already fractionated exploratory samples obtained from 
the above biofluids, such as exploratory plasma samples, exploratory PBMC samples, and 
red blood cells recovered during PBMC/plasma isolations.   
Fractionation of semen to collect purified sperm separately from non-sperm cells may be 
performed 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 
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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.
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:
x
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
x
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
x
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Events not meeting the AE definition include:
x
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. 
x
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. 
x
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
x
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x
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: 
x
All bleeding events and suspected bleeding events which meet one or more of the 
criteria for being serious (refer to Section 10.1) 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:
x
Results in death
x
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.
x
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. 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.  
x
Results in persistent or significant disability or incapacity
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x
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
x
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require 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: 
x
Elevation of ALT > 1.5x ULN, regardless of whether that elevation triggers an 
initiation or modification of oral corticosteroid treatment
x
Thromboembolic event
x
Drug-related anaphylactoid or hypersensitivity reactions
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.  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 10.1.
10.3.2 Eliciting Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences.  The Investigator will record all relevant AE/SAE/EOSI information in the 
subject’s medical record and AE Case Report Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.2 for 
SAE definitions).  These assessments must be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS).
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The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators and applicable regulatory authorities. 
10.4
Procedures for Recording Adverse Events
10.4.1 Recording Adverse Events on a eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology.
10.4.1.1
Diagnosis versus Signs and Symptoms 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. Using accepted medical terminology, 
enter the diagnosis (if known).  If not known, enter sign(s) and/or symptom(s).  If a diagnosis 
subsequently becomes available, then this diagnosis should be entered on the AE (or SAE, as 
appropriate) eCRF, replacing the original entries where appropriate.
10.4.1.2
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 
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necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
For example, if a subject has an adverse event of ALT increased that subsequently resolves, 
but 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 (including any local FVIII activity or liver function 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:
x
Accompanied by clinical symptoms
x
Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).
x
The abnormality suggests a disease and/or organ toxicity 
x
The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
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explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of 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:
x
Perform a protocol-mandated efficacy measurement
x
Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not worsened 
x
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 
x
Receive scheduled therapy (study drug or otherwise) for the study indication 
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10.4.1.8
Deaths
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in 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 
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soon as it becomes available. IND safety reports will be submitted within 7 calendar days for 
unexpected fatal or life-threatening unexpected suspected adverse reactions (SUSARs) and 
within 15 calendar days for other non-life-threatening SUSARs.
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 (EC) or Institutional Review Board 
(IRB) will be done in compliance with the standard operating procedures and policies of the 
IRB/EC and with applicable regulatory requirements. Adequate documentation must be 
obtained by BioMarin showing that the IRB/EC 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.
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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 
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/EC is notified at the same time.” 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
x
Lack of study scientific value, or detrimental study conduct or management 
x
Discovery that the quality or safety of the IP does not meet established safety 
requirements
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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 FVIII assay and the one-stage clot 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 subject, the Investigator or designee and witness (if 
required) before any study-related procedures are performed.
12.2
Screening Visit(s)
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, 
LFTs, hematology, urine tests, and coagulation tests do not need to be repeated at Baseline.  
The following procedures will be performed during the Screening Period:
x
Demographics (age, sex, race, ethnicity)
x
Full medical history, including hemophilia A history, Hepatitis B, Hepatitis C, and 
HIV
x
Complete Physical Examination 
x
Height and weight 
x
Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature) 
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) for the previous 12 months 
x
Distribution of subject diaries and training in diary completion
x
Electrocardiogram
x
Liver Ultrasound 
x
Samples for hFVIII Assays
o
Baseline FVIII activity – chromogenic FVIII assay
o
Baseline FVIII activity level – one-stage clot FVIII assay
o
hFVIII coagulation activity exploratory assay (collected but not tested 
prior to enrollment) 
o
hFVIII inhibitors (Bethesda assay with Nijmegen modification)
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o
hFVIII total antibody assay (collected but not tested prior to enrollment) 
o
hFVIII antigen assay (collected but not tested prior to enrollment) 
x
Blood sample for AAV5 total antibody (TAb) assay 
o
Screening sample will be tested in an AAV5 Tab pre-screening assay 
specifically developed for enrolment purposes. 
x
Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested)
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
x
Von Willebrand Factor Antigen (VWF:Ag) 
x
Blood samples for Biomarker testing (may include HLA genotyping, FVIII 
genotyping status, TNFD and IL10a single nucleotide polymorphisms) 
12.2.1 “Smart Rescreening” Visit
Subjects who undergo smart rescreening must complete the rescreening assessments and 
receive the infusion within 90 days of signing the original consent.  Subjects who do not 
complete dosing within 90 days will be required to re-consent and undergo all screening 
procedures.  Subjects may not undergo smart rescreening more than once. 
If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study:
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification))
x
Blood sample for AAV5 Total Antibody assay 
o
Smart Re-screening sample will be tested in an AAV5 Tab pre-screening 
assay specifically developed for enrolment purposes. 
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x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the infusion visit.  The following 
procedures will be performed during the Baseline Period: 
x
Brief physical examination
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
Samples for hFVIII Assays
o
Baseline FVIII activity – chromogenic FVIII assay
o
Baseline FVIII activity level – one-stage clot FVIII assay
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 antigen assay (collected but not tested prior to enrollment) 
x
Blood sample for AAV5 Total Antibody assay 
o
Baseline sample will be tested with a AAV5 TAb post-dose 
immunogenicity monitoring assay
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
x
PBMC collection for CTL baseline 
x
Direct Thrombin test
x
Blood sample for AAV5 TI assay
x
Thrombin Generation Assay
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
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x
Exploratory biomarker assessments
x
Cytokine bead array assay
x
Hypersensitivity blood assessments 
x
Haemo-QoL-A QoL assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire 
12.4
Infusion Visit/BMN 270 Infusion Visit (Day 1) 
There will be one infusion visit for each subject.  Subjects will remain in the clinic for at 
least 24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Blood sample for AAV5 TAb Assay (sample collected pre-infusion for analysis) 
o
Infusion Day sample will be tested in an AAV5 Tab pre-screening assay
specifically developed for enrolment purposes. 
x
Blood sample for AAV5 TI assay (sample collected pre-infusion for analysis) 
x
Fasting lipid panel (blood triglycerides, total cholesterol, HDL cholesterol, and LDL 
cholesterol)
x
BMN 270 Infusion
x
Vital Signs
o
Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for at least 
8 hours during the subject’s stay in the clinic.
12.5
BMN 270 Infusion Follow-Up Visits
12.5.1 Week 1
During Week 1, the subject will be assessed on Study Day 2, Study Day 4, and Study Day 8. 
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12.5.1.1
Week 1, Study Day 2 
On Study Day 2, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
x
Blood sample for AAV5 TAb Assay (sample collected pre-infusion for analysis) 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
PBMC collection
x
Cytokine bead array assay
12.5.1.2
Week 1, Study Day 4 
On Study Day 4, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
12.5.1.3
Week 1, Study Day 8 
On Study Day 8, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
x
Samples for FVIII Assays
o
FVIII activity level (chromogenic FVIII assay)
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o
FVIII activity level (one-stage clot FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
hFVIII antigen assay
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
x
Cytokine bead array assay
12.5.2 Weeks 2-26 
After Week 1 (Day 8), subjects will return to the study site once a week (± 48 hours) during 
Weeks 2-26. 
12.5.2.1
Once per week (Weeks 2 through 26)  
The following procedures will be performed once per week from Weeks 1 through 26: 
x
Brief physical examination (complete physical examination at Week 26) 
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
x
Vital Signs
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
o
LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical
Monitor and the Investigator and review of subject data, but LFTs will be 
monitored at least twice weekly during periods when a subject’s ALT is 
 3x ULN.. 
x
Samples for FVIII Assays
o
FVIII activity level (chromogenic FVIII assay)
o
FVIII activity level (one-stage clot FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
hFVIII antigen assay
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12.5.2.2
Every Other Week (Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26) 
The following procedures will be performed every other week (at Weeks 2, 4, 6, 8, 10, 12, 
14, 16, 18, 20, 22, 24, and 26): 
x
Blood sample for AAV5 TAb Assay 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
PBMC collection
12.5.2.3
Weeks 2, 3, 4, 6, 8, 12, 16, 20, and 26 
The following procedures will be performed at Weeks 2, 3, 4, 6, 8, 12, 16, 20, and 26: 
x
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 timepoint.
12.5.2.4
Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 16 
The following procedures will be performed at Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 26: 
x
hFVIII total antibody assay
12.5.2.5
Weeks 2, 4, 6, 8, 14, 20, and 16 
The following procedures will be performed at Weeks 2, 4, 6, 8, 14, 20, and 26: 
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
12.5.2.6
Weeks 2, 6, 10, 14, 18, 22, and 26 
The following procedures will be performed at Weeks 2, 6, 10, 14, 18, 22, and 26: 
x
Exploratory biomarker assessments 
x
Cytokine bead array assay
12.5.2.7
Weeks 4, 8, 12, 16, 20, and 26 
The following procedures will be performed at Weeks 4, 8, 12, 16, 20, and 26: 
x
Weight
x
VWF:Ag 
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12.5.2.8
Weeks 12 and 26 
The following procedures will be performed at Weeks 12 and 26: 
x
Urine tests (to be performed locally) 
x
Haemo-QoL-A QoL assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
12.5.2.9
Weeks 13 and 26 
The following procedure will be performed at Weeks 13 and 26: 
x
Direct thrombin activity test
12.5.2.10 Week 16
The following procedure will be performed at Week 16: 
x
Testing for reactivation of hepatitis B and hepatitis C
o
Subjects with evidence of prior exposure will be tested for hepatitis B and 
hepatitis C reactivation at Week 16.  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 9.1.4. 
12.5.2.11 Weeks 20, 24, and 26 
The following procedure will be performed at Weeks 20, 24, and 26: 
x
Thrombin Generation Assay 
12.5.3 Post-Infusion Follow-Up – Weeks 27-260 
Subjects will continue with assessments at Weeks 39, 52, 65, 78, 91, 104, 117, 130, 143, 156, 
169, 182, 195, 208, 221, 234, 247, and 260.  Visit windows during this period are ± 2 weeks. 
12.5.3.1
Every 3 months (Weeks 39, 52, 65, 78, 91, 104, 117, 130, 143, 156, 169, 182, 
195, 208, 221, 234, 247, and 260) 
The following procedures will be performed every 3 months (Weeks 39, 52, 65, 78, 91, 104, 
117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247, and 260) (± 2 weeks): 
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x
Brief physical examination (complete physical examination should be done at 
Week 52, 104, 156, 208, and 260) 
x
Weight
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
Vital signs
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
o
LFTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data, but LFTs will be 
PRQLWRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV 
3x ULN..
x
Samples for hFVIII Assays
o
Baseline FVIII activity – chromogenic FVIII assay
o
Baseline FVIII activity level – one-stage clot FVIII assay
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 antigen assay (collected but not tested prior to enrollment) 
x
hFVIII total antibody assay
x
Exploratory biomarker assessments 
x
Blood sample for AAV5 Total Antibody assay 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
PBMC collection for CTL baseline 
x
VWF:Ag 
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x
Direct Thrombin test
x
Thrombin Generation Assay 
12.5.3.2
Every 12 months (Weeks 52, 104, 156, 208, and 260) 
The following procedures will be performed every 12 months (Weeks 52, 104, 156, 208, and 
260) (± 2 weeks): 
x
Haemo-QoL-A QoL assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
12.5.3.3
Every 4 Weeks (As Needed)
The following assessment should be performed every 4 weeks during Years 2-5, as needed:
x
PCR of vector DNA in blood, saliva, urine, semen, and stool 
Sample testing during Weeks 27-260 is not required if at least 3 consecutive samples are 
clear during the Post-Infusion Follow-Up period in Weeks 1-26.  Subjects who have not had 
3 consecutive negative semen samples by Week 26 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
Early Termination Visit
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit.
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
x
Complete physical examination
x
Weight
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
Vital signs
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x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Function Tests (refer to Table 9.7.6.3.1) 
x
Samples for hFVIII Assays
o
Baseline FVIII activity – chromogenic FVIII assay
o
Baseline FVIII activity level – one-stage clot FVIII assay
o
hFVIII coagulation activity exploratory assay 
o
hFVIII inhibitors (Bethesda assay with Nijmegen modification)
o
hFVIII antigen assay 
x
hFVIII total antibody assay
x
Exploratory biomarker assessments 
x
Blood sample for AAV5 Total Antibody assay 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
PBMC collection for CTL baseline 
x
VWF:Ag 
x
Direct Thrombin test
x
Thrombin Generation Assay 
x
Haemo-QoL-A QoL assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
x
PCR of vector DNA in blood, saliva, urine, semen, and stool 
o
Sample testing at the Early Termination Visit is not required if at least 
3 consecutive samples are clear during the period of the subject’s participation 
in the study. 
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12.7
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, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications. 
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS.
14.1.1 Interim Analyses
No interim analysis is planned. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data. 
Sensitivity analyses will be conducted to assess the impact of missing data on the primary 
efficacy endpoint analysis. Additional details regarding the handling of missing data will be 
provided in the SAP.
14.2
Efficacy Analysis 
The subjects will be followed in a longitudinal manner, and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature, but data collected in a 
longitudinal manner may be analyzed using longitudinal methods, such as mixed effect 
model, which take into account the correlation among the observations taken at various time 
points within a subject. Efficacy is a secondary endpoint, defined as biologically active FVIII 
DW   ,8G/ DW  ZHHNV IROORZLQJ VWXG\ WUHDWPHQW )9,,, DFWLYLW\ ZLOO EH DVVHVVHG ZHHNO\
during the study period. We can only assess the true steady state of FVIII produced from 
BMN 270 after a minimum of 72 hours (or 5x the known half-life of the FVIII replacement 
therapy administered) has elapsed since the last infusion of FVIII concentrates. 
14.3
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), 
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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.  
Analysis of neutralizing antibody response and other immunological parameters as well as 
vector shedding will be primarily descriptive and involve both inter-subject and intra-subject 
comparisons across doses.  
Detailed statistical methods will be provided in the SAP.
14.4
Determination of Sample Size
The sample size is based upon clinical considerations and is sufficient to detect a strong 
clinical efficacy signal. Approximately 10 subjects may be dosed in the study. 
14.5
Analysis Populations 
The efficacy analysis set will be comprised of all subjects who have received the BMN 270 
infusion. 
The safety population will consist of all subjects who receive BMN 270 infusion during the 
study.
14.6
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/EC must be sought, and 
the Investigator should inform BioMarin and the full IRB/EC within 2 working days after the 
emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/EC 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/EC prior to their implementation.
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When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the IRB/EC, and 
all active subjects must again provide informed consent. 
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15
DATA REVIEW BOARD
The Data Review Board (DRB) will consist of the 2 Principal Investigators and Sponsor’s 
Medical Monitor, as well as hemophilia expert advisors experienced in the conduct and 
evaluation of safety and efficacy parameters from 270-201.  The DRB will review available 
safety and efficacy data during the study on an ongoing basis to determine, based on 
emerging data and the benefit/risk profile, whether further enrollment should continue. The 
DRB will meet weekly until all subjects have completed Week 26, and then monthly 
thereafter.
Duties of the DRB include: 
x
Conducting an ongoing review of individual subject safety and efficacy data during 
the study; 
x
Recommending whether to proceed with enrollment of subjects at a different gating 
schedules based on emerging data from 270-203 and the overall risk/benefit analysis 
of BMN 270; 
x
If applicable, considering whether to restrict dosing to subjects with anti-AAV5 titers 
below levels that appear to be causing clinically significant inhibition of transduction. 
x
Making other recommendations on the conduct and reporting of the trial based on 
their evaluation of clinical data including institution of any pause or stopping stages. 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DRB determination of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment:  
x
any related SAE;
x
any related AE with a severity > Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.
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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/EC 
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.  
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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 
source data verified.  The Investigator will then electronically sign the casebook, specifying 
that the information on the eCRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 
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STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
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
Angus B, Brook G, Awosusi F, Barker G et al. British HIV Association guidelines for the 
routine investigation and monitoring of adult HIV-1-positive individuals. 2016. Available at 
http://www.bhiva.org/documents/Guidelines/Monitoring/2016-BHIVA-Monitoring-
Guidelines.pdf. Last accessed 12 September 2017. 
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, et. al. European retrospective study of real-life haemophilia 
treatment. Haemophilia. 2017 Jan;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. 
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. 
Majowicz A, Lampen M, Petry H, Meyer C et al. Pre-existing Anti-AAV5 Neutralizing 
Antibodies Measured Using a Highly Sensitive Assay in Sera of Hemophilia B Patients in a 
Phase I/II Clinical Trial of AMT-060 Do Not Predict Efficacy of AAV5-mediated 
Liver-directed Gene Transfer. Res Pract Thromb Haemostasis. 2017;1(Suppl. 1):766. 
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Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006. 
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016. 
Mingozzi, F and High, KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013. 
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, J, Wong, W, Rangarajan, S, Wilde, J et al.  Interim results of an open-label, phase 1/2 
study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A.  Haemophilia 
22[Suppl. 4], 151-152.  2016. 
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. 
Reilly, M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ 
WPAI_Scoring.html. Last accessed 28 July 2017.   
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. 
Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS et. al. Guidelines for the 
management of hemophilia 128. Haemophilia 19[1], e1-47. 2013. 
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010.
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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. 
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22
INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Subjects 
In accordance with FDA Form 1572 and/or principles of ICH E6[R2] GCP, the Investigator 
will ensure that:
x
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects.
x
He or she will personally conduct or supervise the study. 
x
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 
Sections 2.9 and 4.8 are met.  As well, he or she will ensure that IRB/EC review and 
approval in 21 CFR Part 56 and/or ICH E6[R2] Section 2.6 are met.  
x
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6[R2] Section 4.11. 
x
He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
x
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments
x
Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6[R2] 
Section 4.9 are kept, and those records are available for inspection in accordance with 
21 CFR 312.68 and/or ICH E6[R2] Section 4.9.7. 
x
The IRB/EC complies with the requirements of 21 CFR Part 56, ICH E6[R2] Section
3.0, and other applicable regulations, and conducts initial and ongoing reviews and 
approvals of the study. He or she will also ensure that any change in research activity 
and all problems involving risks to human subjects or others are reported to the 
IRB/EC. Additionally, he or she will not make any changes in the research without 
IRB/EC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects. 
x
He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6[R2]. 
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C LI NI C A L S T U D Y P R O T O C O L
St u d y Title:
A P hase 1/ 2 Safet y, T olera bilit y, a n d Efficac y St u d y of B M N 2 7 0, 
a n A de n o- Ass ociate d Vir us V ect or – Me diate d Ge ne Tra nsfer of 
H u ma n Fact or VIII i n He m o p hilia A P atie nts wit h Resi d ual F VIII 
-e xisti n g A nti b o dies A gai nst A A V 5
Pr ot oc ol N u m ber:
2 7 0- 2 0 3
Acti ve I n vesti g ati o n al Pr o d uct:
A A V 5- h F VIII- S Q
E ur o pe a n U ni o n Dr u g Re g ul ati n g 
A ut h orities Cli nic al Tri als 
( E u dr a C T) N u m ber:
2 0 1 7- 0 0 0 6 6 2- 2 9
I n dic ati o n:
He m o p hilia A
S p o ns or:
Bi o Mari n P har mace utical I nc.
1 0 5 Di gital Dri ve
N o vat o, C A 9 4 9 4 9
De vel o p me nt P h ase:
P hase 1/ 2
S p o ns or's Res p o nsi ble M e dic al 
M o nit or:
 M A M B B C hir M Sc
Bi o Mari n ( U K) Lt d.
1 0 Bl o o ms b ur y Wa y
L o n d o n, W C 1 A 2 S L
St u d y Desi g n:
Si n gle-ar m, o pe n-la bel
D ur ati o n of S u bject 
P artici p ati o n:
U p t o 2 6 4 wee ks 
D ose:
6 E 1 3 v g/ k g as si n gle i nf usi o n
St u d y P o p ul ati o n:
1 8 years of a ge wit h s e vere he m o p hilia A a n d detecta ble 
pre-e xisti n g a nti b o dies a gai nst A A V 5 vect or ca psi d
D ate of Ori gi n al Pr ot oc ol:
2 9 Se pte m ber 2 0 1 7
D ate of A me n d me nt 1:
5 Oct o ber 2 0 1 8
Pr o pert y of Bi o Mari n 
C O N FI D E N TI A L
Ma y n ot be di v ul ge d, p u blis he d, or ot her wise discl ose d t o ot hers wit h o ut pri or writte n a p pr o val fr o m 
Bi o Mari n. 
T his st u d y will be c o n d ucte d acc or di n g t o t he pri nci ples of G o o d Cli nical Practice as descri be d i n t he 
U. S. C o de of Fe deral Re g ulati o ns a n d t he I nter nati o nal C o nfere nce o n Har m o nisati o n G ui deli nes, 
i ncl u di n g t he arc hi vi n g of esse ntial d oc u me nts. 
D o c u Si g n E n v el o p e I D: E E 6 D 8 5 3 8- E C C A- 4 0 3 1- 9 2 4 4- D 2 0 E 3 4 2 8 8 1 4 0
PI

 
270-203 Amendment 1 
 
 
 
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5 October 2018 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY
Amendment 1
Date: 5 October 2018 
RATIONALE AND SUMMARY OF CHANGES
A summary of major changes covered by Amendment 1 to the 270-203 protocol is provided 
below: 
1. Language concerning the occurrence and management of infusion-related reactions 
has been added.
Rationale: Three subjects experienced medically important infusion-related reactions (all 
grade 2) associated with valoctocogene roxaparvovec administration that were reported as 
serious adverse events due to prolonged observation in the hospital. Two subjects were 
enrolled in Study 270-301 (Phase 3 open-label single-arm study in subjects with severe 
hemophilia A receiving the 6E13 vg/kg dose of BMN 270), and one subject was enrolled in 
270-203. All of these infusion-related reactions were effectively managed clinically and 
resolved without any clinical sequelae.
The initial infusion rate will be changed from 4 mL/min to 1 mL/min and should be increased 
every 30 minutes by 1 mL/min to a maximum of 4 mL/min, provided that the subject is 
asymptomatic and tolerates the infusion. Adjustment/interruption of the infusion rate and/or 
duration may be required in the event of an adverse reaction occurring during the infusion. If 
necessary, anti-histamine, anti-pyretic, and/or corticosteroid administration is permitted prior 
to restarting an infusion interrupted by an infusion-related reaction.
To better elucidate the mechanisms of infusion-related hypersensitivity reactions, exploratory 
biomarker plasma samples collected at Baseline and at post-infusion study visits may also be 
used to assess the magnitude of biomarker changes. Samples will be used to assess acute 
phase response reactants, complement activation, inflammatory biomarkers, and IgE.  
2. HIV-positive patients are now excluded from the study. 
Rationale: An HIV-positive subject in Study 270-302 developed markedly elevated 
transaminase levels after receiving 4E13 vg/kg of BMN 270. The subject was receiving 
HAART treatment for his HIV infection, and it is hypothesized that the combination of 
BMN 270, one or more of his HAART medications, and/or unsuspected underlying hepatic 
disease may have contributed to the subject’s elevated transaminase levels. Out of an 
abundance of caution for the long-term liver health of HIV-positive patients who are 
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receiving HAART and may be interested in receiving gene therapy, further enrollment of 
HIV-positive subjects will be suspended in 270-203. 
3. Efavirenz, lamivudine, and experimental hemophilia treatments (emicizumab, 
fitusiran, and concizumab) have been added to the list of prohibited concomitant 
medications.
Rationale: The subject in 270-302 referenced above was receiving efavirenz and lamivudine 
as part of his HAART regimen, and these are considered the most potentially likely 
medications to have contributed to his elevated transaminase levels. Experimental 
hemophilia treatments are prohibited during the study as they could affect the assessment of 
FVIII levels in 270-203 subjects. 
4. The exclusion criterion concerning liver test levels at Screening have been changed to 
require all assessed liver tests (ie, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, and total 
bilirubin) to be no higher than the 1.25 times the upper limit of normal for eligibility 
purposes. 
Rationale: A subject with Gilbert’s syndrome in Study 270-301 developed elevated 
transaminase levels after receiving 6E13 vg/kg of BMN 270. Although other subjects with 
Gilbert’s syndrome or HIV infection have been safely treated in small numbers in BMN 270 
clinical trials to-date, the purpose of this amendment is to focus development excluding 
groups of patients hypothesized to have potential risk factors for interactions with BMN 270. 
Restricting the range of acceptable baseline liver test levels will help ensure that entering 
subjects have the best chance to tolerate BMN 270 without experiencing potential 
hepatocellular injury subsequently. 
5. The visit schedule after Week 26 has been expanded. 
Rationale: The original protocol required subjects to return once every 3 months between 
Week 26 and Year 5. The expanded schedule is in line with the visit schedules used in other 
BMN 270 treatment studies (270-301, 270-302) and will allow for more granular assessment 
of BMN 270 efficacy and monitoring of subject safety. 
6. An abbreviated visit schedule has been made available after Week 26 or after 
Week 52 for subjects who are considered to have not responded to BMN 270 therapy. 
Rationale: Treatment failure—manifesting as either failure to achieve FVIII 
activity 5 IU/dL by Week 26/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 
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Monitor, enable subjects to follow an abbreviated visit schedule after Week 26 or Week 52 of 
the study, as applicable and at the discretion of the Investigator. 
Subjects who meet the “treatment failure” definition and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment according to the Schedules of Assessments until vector shedding has cleared. 
7. An additional fasting serum sample will be drawn on Day 1, in case it is needed for 
future exploratory assessments.
Rationale: The additional sample will enable the conduct of exploratory assessments prior to 
BMN 270 infusion. 
8. Additional details have been included concerning information to be collected as part 
of the medical history assessment at Screening.
Rationale: In subjects with a history of hepatitis B or hepatitis C infection, information on 
the specific treatments received for that infection should be collected. In addition, any 
previous pharmacokinetic data collected at the time the subject was receiving on-demand or 
prophylactic FVIII treatment should be collected. This additional history data could help 
explain a subject’s FVIII response (or lack of FVIII response) to BMN 270. 
9. Language in the inclusion criterion related to a subject’s history of FVIII inhibitors 
has been clarified.
Rationale: The original language caused some issues of misinterpretation of Sponsor intent. 
The revised language removes the ambiguity.
10. Language concerning when to consider restarting FVIII prophylaxis following 
BMN 270 infusion has been modified. 
Rationale: The decision for reinstitution of FVIII prophylaxis should be based on clinical 
grounds (eg, the advent of bleeding episodes), in consultation with the Medical Monitor. The 
need to reinstitute FVIII prophylaxis if the FVIII activity is below a certain level 
post-BMN 270 has not yet been clinically established but will be informed by results from 
this study.
11. An additional criterion to initiate therapeutic oral corticosteroids for elevated alanine 
aminotransferase (ALT) levels, following consultation with the Medical Monitor, of 
ALT > ULN and > 2x baseline value has been added.
Rationale: The addition will provide flexibility to initiate therapeutic oral corticosteroids, 
following consultation with the Medical Monitor, in a timely manner with respect to 
elevations in ALT levels.
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12. Language has been added to include ABO testing at Baseline.
Rationale: ABO blood group results will be collected at Baseline to potentially correlate 
with FVIII activity level results in an exploratory manner. For subjects already enrolled in 
the study, ABO blood group results should be collected at the next regularly scheduled visit 
(or at least prior to the end of the study). 
13. Clarified that the requirement for contraception use can end as early as Week 12, in 
the case that a subject has had 3 consecutive negative semen vector shedding 
assessments prior to that time point.
Rationale: Language in the protocol that stated that all subjects must continue with 
contraception for at least 26 weeks after infusion was inconsistent with the statement that 
semen sampling could be stopped as early as Week 12 if a subject had had 3 consecutive 
negative assessments. Revised language makes it clear that all subjects must remain on 
contraception and provide semen samples for assessment through Week 12, but after that 
timepoint, both contraception and semen sample assessment can be discontinued once 
3 consecutive negative results have been obtained. 
14. Added language to clarify that local laboratory testing is permitted at the 
Investigator’s discretion when required to make clinical management decisions. 
Where possible, a matched sample for testing at the central laboratory should be taken 
at the same time.
Rationale: Local laboratory test results may be available more quickly compared with the 
central laboratory therefore to avoid potential delays in clinical management decisions, a 
local test may be performed at the Investigator’s discretion. To provide a complete dataset of 
central laboratory results for reporting purposes, where possible, a matched sample for the 
central laboratory should also be taken from the subject at the same time as the local sample.
15. Added language that subjects will fast for at least 8 hours prior to collection of pre-
infusion laboratory samples on the day of infusion. 
Rationale: A fasting lipid panel is part of the infusion day laboratory assessment; as such, 
subjects need to fast for an adequate amount of time prior to the assessment to allow for 
accurate results.
16. Assessment of dermatologic and musculoskeletal systems has been added to the brief 
physical examination.
Rationale: Both organ systems are routinely assessed as part of comprehensive hemophilia 
care visits.
17. Testing of the exploratory samples for the Direct Thrombin Activity Test and TGA 
Assay has been clarified as optional.
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Rationale:  While exploratory samples for Direct Thrombin Activity Test and TGA Assay 
will be collected at the time points indicated in the protocol, analysis of these samples will be 
optional. 
18. Specific testing of TNF-Į DQG ,/D VLQJOH QXFOHRWLGH SRO\PRUSKLVPV KDV EHHQ
removed from biomarker testing. 
Rationale: These biomarkers are designed to inform the risk of FVIII inhibitor development. 
There have not been any cases of FVIII inhibitor development observed in Study 270-201, so 
analyses of TNF-Į DQG ,/D VLQJOH QXFOHRWLGH SRO\PRUSKLVPV KDYH QRW EHHQ LQGLFDWHG
FVIII inhibitors are not expected to develop in this study; however, in the event that 
inhibitors are observed, sufficient exploratory samples will have been collected to perform 
these tests.
19. The initial von Willebrand Factor antigen (VWF:Ag) assessment has been moved 
from the Screening visit to the Baseline visit.
Rationale: This was moved to only evaluate this laboratory test in individuals who have been 
deemed eligible to receive BMN 270.
20. It has been clarified that post-steroid testing for hepatitis B/C reactivation should be 
performed only in subjects who have a previous history of positive hepatitis B/C tests.
Rationale: The previous language in the protocol was unclear and may have led some 
investigators to think all subjects (including those with no prior evidence of viral hepatitis 
exposure) should be retested. 
21. Subjects will be advised to abstain from blood or sperm donation after BMN 270 
infusion until there is no further evidence of vector shedding. 
Rationale: Vector shedding in the blood and semen following BMN 270 infusion has been 
observed, which could serve for vector transmission if subjects were to donate blood or 
semen following the BMN 270 infusion.  
22. In the event of a positive Bethesda assay result during Years 3-5, an additional 
sample has been added to be collected within 4 weeks of the visit where the positive 
result was obtained. 
Rationale: During Years 3-5, samples are being regularly collected every 6 weeks. However, 
to align with EMA guidance (which suggests that a confirmatory test on a second sample 
should be done within a month after a positive Bethesda assay result), language has been 
added to require the site to conduct an unscheduled visit within 4 weeks after the date when 
the positive Bethesda result was obtained. 
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23. Visit windows (±24 hours) have been added to the Week 1 visits (Day 2, Day 4, and 
Day 8).
Rationale: Visit windows will ease site and subject burden. 
24. Testing of AAV5 antibody titers has been added to the Day 8 visit. 
25. Clarified that hepatitis B testing at Screening should include hepatitis B surface 
antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core 
antibody (HBcAb) testing.
26. The vector genome schematic figure has been updated.
27. The identity of the Medical Monitor has been updated. 
28. 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 the original protocol (dated 
29 September 2017). 
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2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
TITLE OF STUDY: 
A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus 
Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual 
)9,,, /HYHOV   ,8G/ DQG 3UH-existing Antibodies Against AAV5
PROTOCOL NUMBER:
270-203 
STUDY SITES:
Approximately 2-3 sites in the United Kingdom 
PHASE OF DEVELOPMENT:
Phase 1/2
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.   
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 
or 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. While infusion 
of FVIII is a major advance in the treatment of HA, severe HA patients continue to have bleeding 
events on prophylactic therapy; median ABRs were 1-4 with prophylactic treatment in a recently 
published retrospective observational study (Berntorp, 2017) and between 1-2 in 6 prospective 
FVIII interventional studies.  Median ABRs were 4.5-18 and between 20-60 with on-demand-only 
therapy in the same studies, respectively. Continued repeated bleeding events compound 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
debilitating multiple-joint arthropathies as well as the risk of catastrophic events such as 
intracranial hemorrhage and death. 
Chemical modification (eg, direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can only extend half-life to maximum of 
18 hours, leaving critical periods when FVIII activity levels are below the therapeutic range and 
leaving patients vulnerable to bleeding and concomitant sequelae. As such, despite currently 
available FVIII replacement therapies, a high unmet need remains for maintenance of a sustained, 
consistent 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. 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. Moreover, the circulating FVIII response to gene transduction 
can be assessed using validated quantitative endpoints that are easily assayed using established 
laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 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 (eg serotypes 2, 5, and 8).
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
over 7 years of stable human factor IX (hFIX) expression at levels sufficient for conversion of their 
bleeding phenotype from severe to moderate or mild, following a single peripheral vein infusion of 
AAV8-hFIX vector (Nathwani, 2014). Several participants in this trial have been able to
discontinue factor prophylaxis without suffering spontaneous hemorrhages, even when they 
undertook activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted 
in a substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a hybrid human liver-specific promoter (Figure 1).
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Figure 1. hFVIII-SQ Vector Genome Schematic
Legend –Note that schematic is not to scale; nt = nucleotides
BMN 270 is delivered by a single IV dose and is designed to achieve stable, potentially life-long 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose 
escalation study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 
at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201 
explores the relationship of vector dose to the augmentation of residual FVIII activity and whether 
these levels are sufficient to alter the clinical phenotype. Preliminary results from 270-201 have 
demonstrated that following gene transfer, sustained FVIII activity above 15% (15 IU/dL) up to a 
year’s observation is achievable with a dose of 4-6E13 vg/kg with an acceptable safety profile 
(Pasi, 2017).  
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, as the 
prevailing expectation has been that vector-specific antibodies could interfere with receptor 
binding and effectively neutralize efficient transduction of the target cell population. As this was 
the first FVIII gene therapy with AAV5 in humans, this criterion was adopted out of an abundance 
of caution. These pre-existing vector-specific antibodies are thought to arise from previous 
exposure to AAV, with seroprevalence varying across human populations and across studies. 
AAV5 has consistently been shown to have the lowest seroprevalence among the common AAV 
serotypes. 
Current data describing the extent of neutralization or inhibited transduction has been inconsistent 
across studies, each employing one of several varying methodologies to evaluate both vector-
specific antibodies and transduction inhibition (TI). Early studies using AAV2 for the treatment of 
hemophilia B described inhibited transduction in patients with neutralizing antibody titers of 2 or 
3 (Manno, 2006), but more recent studies have described successful transduction in patients who, 
in retrospect, were determined to have pre-existing antibody to the vector capsid (Majowicz, 2017).  
Importantly, no drug-related adverse events were described in these patients.  As the sensitivity of 
assays used to detect pre-existing antibody has increased greatly in recent years, the biological 
relevance of any given titer determination, and comparisons across studies using assays with 
differing titer sensitivities, requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of available 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
data shows the effect of pre-existing immunogenicity to AVV delivery vectors is not completely 
understood, and indicates that some patients may benefit from AAV5 gene therapy who are 
currently excluded.  
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be enrolled to 
evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate the safety, 
tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing antibodies 
against AAV5 vector capsid at various levels of AAV5 antibody titers.
OBJECTIVES: 
The primary objective of the study is to:
x
Assess the safety of a single intravenous administration of BMN 270 in severe HA subjects 
with pre-existing antibody to AAV5 vector capsid, including development of FVIII 
neutralizing antibody 
Secondary objectives of the study are to: 
x
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26 
x
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy 
x
Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous 
FVIII therapy 
x
Evaluate the pharmacodynamics of FVIII expression following IV infusion of BMN 270 
x
Assess the impact of BMN 270 on patient-reported outcomes (PROs) 
STUDY DESIGN AND PLAN: 
This is a Phase 1/2, single-arm, open-label study in severe HA patients (FV,,,  1 IU/dL), with a 
history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with pre-existing 
antibodies to the AAV5 vector capsid as measured by total antibody [TAb] assay. Approximately 
10 subjects may be enrolled at 2-3 sites in 2 cohorts (5 subjects in each cohort) and will receive a 
single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a Screening 
$$9 7$E WLWHU   ZKLOH VXEMHFWV LQ &RKRUW  ZLOO KDYH D 6FUHHQLQJ $$9 7$E titer > 500.  
Choosing a titer cutoff of 500 reflects the observed distribution of existing titer data with the 
BioMarin titer assay seen to date.
The Data Review Board (DRB) will consist of the Principal Investigators and Sponsor’s Medical 
Monitor, as well as hemophilia expert advisors experienced in the conduct and evaluation of safety 
and efficacy parameters from 270-201.  The DRB will review available safety and efficacy data 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
throughout the study and provide recommendations based on their review (Figure 2 represents one 
dosing schedule scenario):
Figure 2:  270-203 Dosing Schedule (One Possible Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening 
AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a maximum of 
5 subjects have been dosed in Cohort 1 and had their safety and efficacy data (from a minimum of 
6 weeks post-LQIXVLRQ UHYLHZHG )9,,, DFWLYLW\   DIWHU VL[ ZHHNV SRVW-infusion is expected to 
be the earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who 
later achieved normal FVIII activity levels, compared with the one subject who had a slightly 
lower response, based on data from 270-201. Up to 6 weeks post-infusion will provide an 
appropriate timeframe to evaluate the development of any potential delayed hypersensitivity 
reaction (eg, serum sickness).  
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on 
DRB evaluation of safety and efficacy in treated subjects, with the following triggers that may 
potentially pause further enrollment:  
x
any related SAE; 
x
any related AE with a severity > CTCAE Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks post-BMN 270 
infusion.
Following a temporary halt of enrolment, the DRB may approve resumption of enrolment in either 
cohort at a later date at its discretion based on further analysis of accumulating data. 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 
24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In case of 
suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to physical 
examination and vital signs, will be performed. Additional blood samples will be collected 
(tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory 
testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) will be collected between 8-24 hours after the 
reaction. In addition, a blood sample should be taken 1 week after the hypersensitivity reaction for 
assessment of the cytokine bead array. Exploratory biomarker samples at baseline and at post-
infusion study visits may also be used to assess changes in these biomarkers to better elucidate the 
mechanisms of infusion-related hypersensitivity reactions. Any safety signal may trigger a review 
of the data and possible additional immunogenicity studies or other diagnostics deemed necessary 
to assess cellular immune responses using collected peripheral blood mononuclear cells (PBMCs).  
The duration of observation may be extended and additional blood samples collected at the 
discretion of the Investigator and Medical Monitor.
Data from 270-201 suggest that achievement of therapeutic FVII, OHYHOV  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII protection 
while subjects are projected to reach clinicall\ UHOHYDQW )9,,, OHYHOV   ,8G/ SULRU )9,,,
prophylaxis for each subject will be continued at the discretion of the DRB based on individual 
subject status and data review or when FVIII activity has reached at least 5 IU/dL. In subjects who 
experience recurring bleeding episodes, the Investigator and Medical Monitor will discuss whether 
to resume prior FVIII prophylaxis.  
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either 
failure to achieve FVIII activity   ,8/dL by either Week 26 or Week 52 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in the 
judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor, follow an abbreviated visit schedule after either Week 26 or Week 52, as 
applicable and at the discretion of the Investigator. 
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. After the 
safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, long-term safety and 
efficacy will be assessed in all subjects for up to a total of 5 years post-infusion. During the trial, 
additional subjects may be recruited into each cohort at any time, if deemed necessary by the DRB.  
NUMBER OF SUBJECTS PLANNED:
Approximately 10 subjects  
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following criteria:
1.
0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as evidenced 
by medical history, at the time of signing the informed consent.  
2.
Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total 
antibody ELISA 
3.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days 
(EDs)
4.
Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior 
to study entry.   
5.
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.
6.
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)  
7.
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.
8.
Willing to abstain from consumption of alcohol for at least the first 26 weeks following 
BMN 270 infusion. 
Individuals who meet any of the following exclusion criteria will not be eligible to 
participate in the study:
1.
Any evidence of active infection or any immunosuppressive disorder, including HIV infection.  
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
2.
Significant liver dysfunction with any of the following abnormal laboratory results:
o
ALT (alanine aminotransferase) > 1.25x ULN; 
o
AST (aspartate aminotransferase) > 1.25x ULN; 
o
GGT (gamma-glutamyltransferase) > 1.25x ULN; 
o
Total bilirubin > 1.25x ULN; 
o
Alkaline phosphatase > 1.25x ULN; or 
o
,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR  
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. 
3.
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
4.
Evidence of any bleeding disorder not related to hemophilia A 
5.
Platelet count of < 100 x 109/L
6.
Creatinine   PJG/
7.
Liver cirrhosis of any etiology as assessed by liver ultrasound 
8.
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 .
9.
Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy
10. Active malignancy, except non-melanoma skin cancer
11. History of hepatic malignancy
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with 
the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not 
currently ongoing.  
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
13. Known inherited or acquired thrombophilia, including conditions associated with increased 
thromboembolic risk, such as atrial fibrillation.
14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, vasculitis). 
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational 
product (whichever is longer) prior to the screening period. For subjects who have received a 
prior investigational product, all ongoing adverse events (AEs) experienced while receiving 
that investigational product must have resolved prior to screening for this study 
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including possible corticosteroid 
treatment outlined in the protocol) and/or would impact or interfere with evaluation and 
interpretation of subject safety or efficacy result.
17. Prior treatment with any vector or gene transfer agent
18. Major surgery planned in the 26-week period following the infusion with BMN 270
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines 
within 30 days before the BMN 270 infusion 
20. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of safety and efficacy of BMN 270 and 
with prior consultation with the Medical Monitor
21. Known allergy or hypersensitivity to investigational product formulation
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single IV infusion of BMN 270 at 6E13 vg/kg. The volume of infusion 
will depend on the subject’s weight.
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
No reference therapy will be evaluated in this study. 
DURATION OF TREATMENT:
BMN 270 is given as a single dose by IV infusion.
CRITERIA FOR EVALUATION:
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Safety:
The following safety outcome measurements will be assessed:
x
Incidence of adverse events (AEs), including serious AEs (SAEs) 
x
Change in clinical laboratory tests (serum chemistry and hematology)
x
Change in vital signs
x
Change in physical examination  
x
Vector shedding (blood, urine, semen, feces, saliva)
x
Liver tests (LTs, including ALT, AST, GGT, total bilirubin, and alkaline phosphatase) 
x
Immune response to FVIII transgene product and AAV5 vector capsid
No major toxicity is expected based on 270-201 data and non-clinical studies. Each subject will 
have comprehensive surveillance monitoring of LTs (once per week for Weeks 1-26). During the 
long-term safety evaluation, LTs will be monitored every three months for up to 5 years 
post-infusion; the frequency and duration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator and review of subject data. 
There will be a detailed assessment of cellular and humoral responses to AAV5 vector capsid and 
FVIII.  
Efficacy: 
The efficacy measure will be to assess plasma FVIII activity. The efficacy goal is to achieve FVIII 
DFWLYLW\   ,8G/ DW  ZHHNV SRVW-BMN 270 administration. Other efficacy measures include 
assessing the impact of BMN 270 on the use of FVIII replacement therapy and on the number of 
bleeding episodes during the study. Subjects will be asked to keep a subject diary, provided by the 
sponsor, to record the relevant details.  
Other efficacy endpoints:  
x
Change from baseline in the total score of HAEMO-QoL-A at Week 26 of the study post-
BMN 270 infusion
x
Change from baseline in the EQ-5D-5L score at Week 26 of the study post-BMN 270 
infusion.
x
Change from baseline in the Haemophilia Activities List (HAL) score at Week 26 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
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
x
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 26 of the 
study post-BMN 270 infusion. 
Pharmacodynamics: 
The FVIII antigen and activity level, as measured by a validated immunoassay and a validated 
FVIII activity assay, respectively, will be used for plasma profiles; FVIII antigen and activity will 
be used to determine PD parameters.
STATISTICAL METHODS: 
Approximately 10 subjects may be dosed in the study. The subjects will be followed in a 
longitudinal manner, and all the relevant information will be collected. The analysis of the data 
will be descriptive in nature, but data collected in a longitudinal manner may be analyzed using 
longitudinal methods, such as a mixed effect model, which take into account the correlation among 
the observations taken at various time points within a subject. Efficacy is a secondary endpoint, 
GHILQHG DV ELRORJLFDOO\ DFWLYH )9,,, DW  5 IU/dL at 26 weeks following study treatment. FVIII 
activity will be assessed weekly during the study period. Assessment of the true steady state of 
FVIII will require that FVIII activity is measured after a minimum of 72 hours (or 5x the known 
half-life of the FVIII replacement therapy administered) has elapsed since the last infusion of FVIII 
concentrates. 
Analysis of neutralizing antibody response, other immunological parameters, and vector shedding 
will be primarily descriptive and involve both inter-subject and intra-subject comparisons across 
cohorts.
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
7,7/( 3$*(
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2 
2 SYNOPSIS ...........................................................................................................................8 
3 TABLE OF CONTENTS ...................................................................................................19 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................24 
5 ETHICS..............................................................................................................................27 
5.1 Institutional Review Board or Independent Ethics Committee ................................27 
5.2 Ethical Conduct of Study ..........................................................................................28 
5.3 Subject Information and Informed Consent ..............................................................28 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................29 
7 INTRODUCTION .............................................................................................................30 
7.1 Nonclinical Studies ...................................................................................................31 
7.2 Previous Clinical Studies ..........................................................................................31 
7.3 Study Rationale .........................................................................................................32 
7.4 Summary of Overall Risks and Benefits ...................................................................35 
8 STUDY OBJECTIVES ......................................................................................................38 
9 INVESTIGATIONAL PLAN ............................................................................................39 
9.1 Overall Study Design and Plan .................................................................................39 
9.2 Discussion of Study Design, Including Choice of Control Group ............................57 
9.3 Selection of Study Population ...................................................................................57 
9.3.1 
Inclusion Criteria .........................................................................................57 
9.3.2 
Exclusion Criteria ........................................................................................58 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................60 
9.3.4 
Subject Identification and Replacement of Subjects ...................................62 
9.3.5 
Duration of Subject Participation ................................................................62 
9.4 Treatments .................................................................................................................62 
9.4.1 
Treatments Administered ............................................................................62 
9.4.2 
Identity of Investigational Product ..............................................................62 
9.4.3 
Storage .........................................................................................................63 
3
TABLE OF CONTENTS
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9.4.4 
Directions for Administration .....................................................................63 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................65 
9.4.6 
Selection of Dose Used in the Study ...........................................................65 
9.4.7 
Blinding .......................................................................................................65 
9.4.8 
Prior and Concomitant Medications ............................................................65 
9.4.9 
Treatment Compliance ................................................................................68 
9.5 Investigational Product Accountability .....................................................................68 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................68 
9.6 Dietary or Other Protocol Restrictions......................................................................69 
9.7 Efficacy and Safety Variables ...................................................................................69 
9.7.1 
Efficacy and Safety Measurements Assessed .............................................69 
9.7.2 
Efficacy Variables .......................................................................................69 
9.7.3 
Immunogenicity ...........................................................................................71 
9.7.4 
Pharmacodynamics ......................................................................................72 
9.7.5 
Exploratory Assessments ............................................................................72 
9.7.6 
Safety Variables ..........................................................................................72 
10 REPORTING ADVERSE EVENTS .................................................................................80 
10.1 Safety Parameters and Definitions ............................................................................80 
10.1.1 Adverse Events ............................................................................................80 
10.2 Serious Adverse Events ............................................................................................81 
10.2.1 Events of Special Interest (EOSI) ...............................................................81 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................82 
10.3.1 Adverse Event Reporting Period .................................................................82 
10.3.2 Eliciting Adverse Events .............................................................................82 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................82 
10.4 Procedures for Recording Adverse Events ...............................................................85 
10.4.1 Recording Adverse Events on a eCRF ........................................................85 
10.5 Reporting Requirements ...........................................................................................88 
10.5.1 Expedited Reporting Requirements .............................................................88 
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10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements..............................................................................89 
10.6 Follow-up of Subjects after Adverse Events .............................................................89 
10.7 Post-Study Adverse Events .......................................................................................89 
10.8 Urgent Safety Measures ............................................................................................90 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................91 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................92 
12 STUDY PROCEDURES ...................................................................................................93 
12.1 Prestudy .....................................................................................................................93 
12.2 Screening Visit(s) ......................................................................................................93 
12.2.1 “Smart Rescreening” Visit ..........................................................................94 
12.3 Baseline Visit ............................................................................................................95 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................96 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................97 
12.5.1 Week 1 .........................................................................................................97 
12.5.2 Weeks 2-26 ..................................................................................................99 
12.5.3 Post-Infusion Follow-Up – Weeks 27-52 ..................................................101 
12.6 Post-Infusion Follow-Up – Years 2-5 .....................................................................103 
12.6.1 Year 2 – Every 4 Weeks (not required for treatment failure) ...................104 
12.6.2 Years 3-5 – Every 6 Weeks (not required for treatment failure) ...............105 
12.6.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)................................................................................................106 
12.7 Early Termination Visit ..........................................................................................107 
12.8 End of Study............................................................................................................109 
13 DATA QUALITY ASSURANCE ...................................................................................110 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................111 
14.1 Statistical and Analytical Plans ...............................................................................111 
14.1.1 Interim Analyses ........................................................................................111 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........111 
14.2 Efficacy Analysis ....................................................................................................111 
14.3 Safety Analysis .......................................................................................................111 
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14.4 Determination of Sample Size ................................................................................112 
14.5 Analysis Populations ...............................................................................................112 
14.6 Changes in the Conduct of the Study or Planned Analyses ....................................112 
15 DATA REVIEW BOARD ...............................................................................................114 
16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................115 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................116 
18 STUDY MONITORING AND AUDITING ...................................................................118 
19 RETENTION OF RECORDS .........................................................................................119 
20 USE OF INFORMATION AND PUBLICATION .........................................................120 
21 REFERENCES ................................................................................................................121 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................124 
22.1 Conduct of Study and Protection of Human Subjects.............................................124 
23 SIGNATURE PAGE .......................................................................................................125 
 $33(1',;  6$03621¶6 $1$3+</$;,6 &5,7(5,$................................126 
25 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................127 
LIST OF TABLES
Table 9.1.1: Schedule of Activities ..........................................................................................42 
Table 9.1.2:  Schedule of Activities – Post-Infusion Follow-Up (Week 1-16) .......................45 
Table 9.1.3:  Schedule of Activities – Post-Infusion Follow-Up (Week 17-32) .....................48 
Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52) .....................51 
Table 9.1.5:  Schedule of Events – Long-Term Follow-Up (Year 2 – Year 5) .......................53 
Table 9.1.6:  Therapeutic Corticosteroids for LT Elevations ..................................................56 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen .......................................................67 
Table 9.7.6.2.1:  Clinical Laboratory Tests .............................................................................74 
Table 9.7.6.3.1:  Liver Tests ....................................................................................................75 
Table 9.7.6.3.2:  Evaluation of ALT Elevations ......................................................................76 
Table 9.7.6.3.3:  Viral and Autoimmune Hepatitis Testing .....................................................77 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................83 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................83 
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LIST OF FIGURES
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic .............................................................34 
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario) ........................................................39 
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations 
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
DRB
Data Review Board
EC
ethics 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
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hFIX
human coagulation factor IX
hFVIII
human coagulation factor VIII
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICH E6 [R2]
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6
IND
Investigational New Drug (application)
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IV
intravenous
LT
liver test
MedDRA
Medical Dictionary for Regulatory Activities
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
SAE
serious adverse event
SAP
statistical analysis plan
SDV
source data verification
SoA
schedule(s) of activities
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 (EC) 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/EC will be provided to BioMarin Pharmaceutical Inc. (BioMarin) 
or its designee. The Investigator will provide the IRB/EC 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/EC 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/EC 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: 
x
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
x
US Code of Federal Regulations (CFR) Sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
x
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R2) 
(ICH E6R2) 
x
The ethical principles established by the Declaration of Helsinki
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/EC and will be conducted by scientifically and medically qualified persons. The benefits 
of the study are in proportion to the risks. The rights and welfare of the subjects will be 
respected and the investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed informed consent form (ICF), in compliance with ICH E6R2 
(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/EC approval. BioMarin and the 
IRB/EC 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.
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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. Subjects 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 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.  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 (12-18 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 validated quantitative endpoints that can be easily assayed in most clinical 
laboratories.
BMN 270 contains the cDNA for the B-domain-deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs, and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study.
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7.1
Nonclinical Studies
The nonclinical program supports a single IV 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 
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. 
The comparative pharmacodynamics of BMN 270 in cynomolgus monkeys with varying 
pre-existing AAV5 transduction inhibition (TI) titer and AAV5 TAb status was evaluated in 
study BMN270-16-021. BMN 270 was administered to 4 groups of monkeys, a control group 
(Group 1, n=3) that tested negative for both TI and AAV5 TAb, Group 2 (n=4) that was 
AAV5 TAb negative, and low TI titer (2-5) positive. Group 3 (n=4) was also AAV5 TAb 
negative, but had higher TI titers (5-10). Group 4 (n=5) tested positive for both AAV5 TAb 
and TI (TI titers were >5). Administration of BMN 270 by a single intravenous bolus 
injection was well-tolerated in cynomolgus monkeys regardless of baseline TI titer or TAb 
status. After dosing, all monkeys showed FVIII-SQ levels above the LLOQ, with the 
exception of two monkeys in the group that presented with both positive TI and TAb titers at 
baseline. Though these TAb+ monkeys, regardless of TI titers, showed a significant mean 
reduction in FVIII expression (68% less) compared to TAb negative monkeys, three of five 
monkeys showed detectable levels of FVIII-SQ, with one having levels similar to that 
observed in the TI and TAb negative control group. Monkeys that were TI+ but TAb-at 
baseline had FVIII expression levels that were similar to those of the TI and TAb negative 
control group.  
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 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 and dosed 
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with a single IV infusion of BMN 270 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.   
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 or 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. While infusion of FVIII is a major advance in the treatment of HA, severe HA
patients continue to have bleeding events on prophylactic therapy; median ABRs were 1-4 
with prophylactic treatment in a recently published retrospective observational study
(Berntorp, 201) and between 1-2 in 6 prospective FVIII interventional studies.  Median 
ABRs were 4.5-18 and between 20-60 with on-demand-only therapy in the same studies, 
respectively. Continued repeated bleeding events compound debilitating multiple-joint 
arthropathies as well as the risk of catastrophic events such as intracranial hemorrhage and
death.
Chemical modification (eg, direct conjugation of polyethylene glycol (PEG) polymers) and 
bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can only extend half-life to maximum 
of 18 hours, leaving critical periods when FVIII activity levels are below the therapeutic 
range and leaving patients vulnerable to bleeding and concomitant sequelae. As such, despite 
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currently available FVIII replacement therapies, a high unmet need remains for maintenance 
of a sustained, consistent 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. 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. Moreover, the 
circulating FVIII response to gene transduction can be assessed using validated quantitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 
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 (eg 
serotypes 2, 5, and 8). Indeed, an ongoing gene therapy clinical trial for a related disorder, 
hemophilia B, has established over 7 years of stable human factor IX (hFIX) expression at 
levels sufficient for conversion of their bleeding phenotype from severe to moderate or mild, 
following a single peripheral vein infusion of AAV8-hFIX vector (Nathwani, 2014). 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.  
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BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a hybrid human liver-specific promoter (Figure 7.3.1).
Figure 7.3.1:  hFVIII-SQ Vector Genome Schematic
Legend –Note that schematic is not to scale; nt = nucleotides
BMN 270 is delivered by a single IV dose and is designed to achieve stable, potentially life-
long expression of active hFVIII in the plasma, synthesized from vector-transduced liver 
tissue.  
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 
dose escalation study in subjects with severe HA designed to assess the safety and efficacy of 
BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. 
Preliminary results from 270-201 have demonstrated that following gene transfer, sustained 
FVIII activity above 15% (15 IU/dL) up to a year’s observation is achievable with a dose of 
4-6E13 vg/kg with an acceptable safety profile (Pasi, 2017). For additional information on 
preliminary data in 270-201, refer to the current version of the Investigator’s Brochure. 
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, 
as the prevailing expectation has been that vector-specific antibodies could interfere with 
receptor binding and effectively neutralize efficient transduction of the target cell population. 
As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted 
out of an abundance of caution. These pre-existing vector-specific antibodies are thought to 
arise from previous exposure to AAV, with seroprevalence varying across human 
populations and across studies. AAV5 has consistently been shown to have the lowest 
seroprevalence among the common AAV serotypes. 
Current data describing the extent of neutralization or inhibited transduction has been 
inconsistent across studies, each employing one of several varying methodologies to evaluate 
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both vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 
for the treatment of hemophilia B described inhibited transduction in patients with 
neutralizing antibody titers of 2 or 3 (Manno, 2006), but more recent studies have described 
successful transduction in patients who, in retrospect, were determined to have pre-existing 
antibody to the vector capsid (Majowicz, 2017).  Importantly, no drug-related adverse events 
were described in these patients.  As the sensitivity of assays used to detect pre-existing 
antibody has increased greatly in recent years, the biological relevance of any given titer 
determination, and comparisons across studies using assays with differing titer sensitivities, 
requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of 
available data shows the effect of pre-existing immunogenicity to AVV delivery vectors is 
not completely understood, and indicates that some patients may benefit from AAV5 gene 
therapy who are currently excluded.  
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be 
enrolled to evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate 
the safety, tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing 
antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers. 
7.4
Summary of Overall Risks and Benefits 
The majority of subjects in the ongoing 270-201 clinical study who have received 4E13 or 
6E13 vg/kg doses of BMN 270 have had Grade 1 asymptomatic elevations in ALT. For most 
subjects, the elevations have reached only slightly above the upper limit of normal (ULN).  
Based on the effectiveness of transient oral corticosteroid used to suppress a presumed 
Class 1 (cytotoxic T-cell) response in prior studies with hepatic transduction with AAV 
vectors (Mingozzi, 2013), subjects were treated with 7-32 weeks of oral corticosteroids 
prophylactically or in response to the elevations in ALT to ensure preservation of the 
transduced hepatocytes. Using this approach, no sustained loss of FVIII activity has been 
observed in subjects with ALT elevations, consistent with maintaining a high level of 
hepatocyte function. Moreover, the rise in ALT levels were not accompanied by significant 
or lasting aberrations in other liver tests such as AST, bilirubin or albumin, indicating that 
extent of toxicity is limited. There has been one HIV-positive subject in the ongoing 270-302 
clinical study who experienced Grade 3 asymptomatic elevations in ALT and AST, which 
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has been attributed to an interaction between one or more of his antiretroviral therapy 
medications and/or unsuspected underlying hepatic disease with BMN 270. In addition, there 
has been one subject with Gilbert’s syndrome in the ongoing 270-301 clinical study who has 
experienced Grade 3 asymptomatic elevations in ALT and AST. These cases have led to the 
exclusion of subsequent HIV-positive subjects and requirement of liver tests at Screening 
that are <1.25 times the upper limit of the normal range in the ongoing 270-301 and 270-302 
clinical studies. Of note, two HIV-positive subjects in 270-301 and one presumed Gilbert’s 
syndrome subject in 270-201 have received BMN 270 without experiencing any elevations in 
ALT to date. Overall, the literature and clinical experience with BMN 270 suggests that 
transient elevations in liver enzymes are expected following AAV-based gene therapy for the 
treatment for hemophilia A or B without any long-term concerns of hepatic injury (Manno, 
2006; Nathwani, 2011; George, 2016; Miesbach, 2016; Pasi, 2017). 
At the highest dose evaluated in 270-201 (6E13 vg/kg), the majority of subjects achieved 
FVIII levels above 50 IU/dL at 52 weeks post-infusion.  Subjects in that cohort also reported 
markedly decreased bleeding episodes compared with pre-study rates and the ability to 
discontinue prophylactic FVIII infusions. Subjects at all dose levels continue to be followed. 
Subjects in 270-203, who have pre-existing immunity to the AAV5 vector capsid, may get no 
benefit from the study (in terms of increased FVIII activity) while possibly creating 
cross-reactive antibodies that may potentially preclude dosing with other serotypes. 
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, including this study. 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 comprehensive assessment of 
the benefit:risk profile of this investigational drug. Given the monitoring measures in place in 
the clinical protocol(s) to minimize the risk to subjects participating in the existing studies, 
the identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-203 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 
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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 IB. 
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8
STUDY OBJECTIVES
The primary objective of the study is to:
x
Assess the safety of a single intravenous administration of BMN 270 in severe HA 
subjects with pre-existing antibody to AAV5 vector capsid, including development of 
FVIII neutralizing antibody 
The secondary objectives of the study are to:
x
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at 
Week 26
x
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy
x
Assess the impact of BMN 270 on the number of bleeding episodes requiring 
exogenous FVIII therapy
x
Evaluate the pharmacodynamics of FVIII expression following IV infusion of 
BMN 270 
x
Assess the impact of BMN 270 on patient-reported outcomes (PROs)
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), 
with a history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with 
pre-existing antibodies to AAV5 vector capsid as measured by total antibody [TAb] assay. 
Approximately 10 subjects may be enrolled at 2-3 sites in 2 cohorts (5 subjects in each 
cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in 
CohoUW  ZLOO KDYH D 6FUHHQLQJ $$9 7$E   ZKLOH VXEMHFWV LQ &RKRUW 2 will have a 
Screening AAV5 TAb > 500. Choosing a titer cutoff of 500 reflects the observed distribution 
of existing titer data with the BioMarin titer assay seen to date.
The Data Review Board (DRB) will consist of the Principal Investigators and Sponsor’s 
Medical Monitor, as well as hemophilia expert advisors experienced in the conduct and 
evaluation of safety and efficacy parameters from 270-201.  The DRB will review available 
safety and efficacy data throughout the study and provide recommendations based on their 
review (Figure 9.1.1 represents one dosing schedule scenario):
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their 
Screening AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a 
maximum of 5 subjects have been dosed in Cohort 1 and had their safety and efficacy data 
(from a minimum of 6 weeks post-infusion) reviewed.  Based on data from 270-201, FVIII 
DFWLYLW\   DIWHU VL[ ZHHNV SRVW-infusion is expected to be the earliest differentiating time 
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point for the majority of subjects dosed with 6E13 vg/kg who later achieved normal FVIII 
activity levels, compared with the one subject who had a slightly lower response. Up to 
6 weeks post-infusion will provide an appropriate timeframe to evaluate the development of 
any potential delayed hypersensitivity reaction (eg, serum sickness).   
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DRB evaluation of safety and efficacy in treated subjects with the following 
triggers that may potentially pause further enrollment: 
x
any related SAE;
x
any related AE with a severity > CTCAE Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects at 6 weeks post-BMN 270 infusion.
Following a temporary halt of enrolment, the DRB may approve resumption of enrolment in 
either cohort at a later date at its discretion based on further analysis of accumulating data.
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at 
least 24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In 
case of suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to 
physical examination and vital signs, will be performed. Additional blood samples will be 
collected (tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible 
additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) will be collected 
between 8-24 hours after the reaction. In addition, a blood sample should be taken 1 week 
after the hypersensitivity reaction for assessment of the cytokine bead array. Exploratory 
biomarker samples at baseline and at post-infusion study visits may also be used to assess 
changes in these biomarkers to better elucidate the mechanisms of infusion-related 
hypersensitivity reactions. Any safety signal may trigger a review of the data and possible 
additional immunogenicity studies or other diagnostics deemed necessary to assess cellular 
immune responses using collected peripheral blood mononuclear cells (PBMCs).  The 
duration of observation may be extended and additional blood samples collected at the 
discretion of the Investigator and Medical Monitor. 
Data from 270- VXJJHVW WKDW DFKLHYHPHQW RI WKHUDSHXWLF )9,,, OHYHOV  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII 
SURWHFWLRQ ZKLOH VXEMHFWV DUH SURMHFWHG WR UHDFK FOLQLFDOO\ UHOHYDQW )9,,, OHYHOV  5 IU/dL, 
prior FVIII prophylaxis for each subject will be continued at the discretion of the DRB based 
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on individual subject status and data review or when FVIII activity has reached at least 
5 IU/dL. 
As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not 
respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve 
FVIII activity   ,8G/ by either Week 26 or Week 52 or inability to maintain independence 
from prophylactic FVIII replacement therapy due to joint bleeding episodes, in the judgment 
of the Investigator) may, at the Investigator’s discretion and after discussion with the Medical 
Monitor, follow an abbreviated visit schedule after either Week 26 or Week 52, as applicable 
and at the discretion of the Investigator.  
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. 
After the safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, 
long-term safety and efficacy will be assessed in all subjects for up to a total of 5 years 
post-infusion. During the trial, additional subjects may be recruited into each cohort at any 
time, if deemed necessary by the DRB.  
A summary of all assessments is provided in the Schedule of Activities (SoA) in Table 9.1.1,
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5.
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Table 9.1.1: Schedule of Activities
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 (including hemophilia A history, Hepatitis B, Hepatitis 
C, and HIV)
X 
Physical Examinationa 
X 
X 
X 
Height and Weighta
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 Assayc
X
X
Screen for Hepatitis B, Hepatitis C, HIVd
X
Blood chemistry, hematology, and coagulation testse
X
X
X
Blood fasting lipid panel
X
Urine Testse
X
X
X
Liver Testse 
X
X
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
PBMC collection (for baseline determination of AAV5 and FVIII 
specific cellular immunity)
X 
Von Willebrand Factor Antigen (VWF:Ag) 
X
Direct Thrombin Activity Test
X
Thrombin Generation Assay
X
PCR of vector DNA in blood, saliva, urine, semen, and stools
X
Xk
Biomarker testingf
X
Exploratory biomarker assessmentsg
X
X
Cytokine bead array assay
X 
Hypersensitivity blood assessmentsm
X
(X)
Haemo-QOL-A assessment
X
EQ-5D-5L assessment
X
HAL assessment
X
WPAI+CIQ:HS assessment
X
BMN 270 Infusion
X
a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.
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 antigen 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 Subjects 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).
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e Detailed in the Section of laboratory assessments and liver tests.  Urine tests will be performed locally and centrally; all other laboratory assessments will be performed at 
the central laboratory. 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.
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 those 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.
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 subject 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 (28 + 14 days).  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 a total time of 24 hours during the subject’s stay in the 
clinic. Shedding samples for PCR of vector DNA analysis (blood, saliva, urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been 
completed.
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.
mIn case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will be done and additional blood samples will be
collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory testing) and 
samples for IgE and cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. In addition, a blood sample should 
be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead array. Exploratory biomarker samples at baseline and at post-infusion study visits 
may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 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 Activities – Post-Infusion Follow-Up (Week 1-16) 
Assessment
Follow-Up After BMN 270 Infusion – Weeks*
Week 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
D2
D4
D8
Study Day* 
2 
4 
8 
15
22
29
36
43
50
57
64
71
78
85
92
99
106
113
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight
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 
X 
X 
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, hematology, and 
coagulation testsb
X 
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 
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 
X 
X 
X 
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolsd
Xd
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker assessmentse
X
X
X
X
Haemo-QOL-A assessment
X
EQ-5D-5L assessment
X
HAL assessment
X
WPAI+CIQ:HS assessment
X
AAV5 TAb Assay
X
X
X
X
X
X
X
X
X
X
AAV5 TI Assay
X
X
X
X
X
X
X
X
X
X
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Assessment
Follow-Up After BMN 270 Infusion – Weeks*
Week 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
D2
D4
D8
Study Day*
2
4
8
15
22
29
36
43
50
57
64
71
78
85
92
99
106
113
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 
X 
VWF:Ag 
X
X
X
X
Direct Thrombin Activity test
X
Cytokine bead array assay
X
X
X
X
X
X
* Visit windows are ± 24 hours during Week 1 and ± 48 hours starting with the Week 2 visit.  
a Brief physical examination should be done at all weekly visits.
b Detailed in the Section of laboratory assessments and liver tests. Urine tests will be performed locally and centrally; all other laboratory assessments will be performed at the 
central laboratory. 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 monitRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [
ULN.  Subjects with ALT 1.5x ULN or > ULN & > 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 antigen 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 pHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,   IU/dL 
at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in 
which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. 
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d Collection for each matrix to occur until at least 3 consecutive negative results are obtained.  Collection and testing of semen samples must continue through Week 12, even 
if 3 consecutive negative results in that compartment have already been recorded. Separate collection on Day 2 is not required if vector shedding samples were collected on 
Day 1 post-BMN 270 infusion; if collection on Day 2 is needed, it must occur within 24 hours of the time of the BMN 270 infusion.
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes 
that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples 
(including those for TGA assay, Direct Thrombin Activity test, and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
f Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry, should be 
performed only in subjects who have not received therapeutic oral corticosteroids prior to Week 16; subjects who have received therapeutic oral corticosteroids will have 
hepatitis B and hepatitis C testing at the time points indicated in Table 9.1.6. 
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Table 9.1.3:  Schedule of Activities – Post-Infusion Follow-Up (Week 17-32) 
Assessment
Follow-Up After BMN 270 Infusion – Weeks*
17
18
19
20
21
22
23
24
25
26
27f 
28f
29f
30f 
31f 
32f 
Study Day*
120
127
134
141
148
155
162
169
176
183
190
197
204
211
218
225
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta
X 
X 
X 
Assessment of Adverse Events and 
Concomitant Medications  (including 
review of subject diary for bleeding 
and FVIII use)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, 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
HAL
X
WPAI+CIQ:HS
X
AAV5 TAb Assay
X
X
X
X
X
X
X
X
AAV5 TI Assay
X
X
X
X
X
X
X
X
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Assessment
Follow-Up After BMN 270 Infusion – Weeks*
17
18
19
20
21
22
23
24
25
26
27f 
28f
29f
30f 
31f 
32f 
Study Day*
120
127
134
141
148
155
162
169
176
183
190
197
204
211
218
225
PBMC collection (for determination of 
AAV5 and FVIII specific cellular 
immunity)
X
X
X
X
X
X
X
X
VWF:Ag
X
X
Direct Thrombin Activity Teste
X
Thrombin Generation Assaye
X
X
X
X
Cytokine bead array assay
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 Week 26.
b Detailed in the Section of laboratory assessments and liver tests. Urine tests will be performed locally and centrally; all other laboratory assessments will be performed at the 
central laboratory. /7V PD\ EH PRQLWRUHG PRUH RU OHVV IUHTXHQWO\ DQG LQ SDUWLFXODU ZKHQ $/7 YDOXHV DUH 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 GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  3x 
8/1 6XEMHFWV ZLWK $/7 1.5x ULN or > ULN & > 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 antigen. 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 intendHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  5 IU/dL 
at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in 
which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. 
d Collection for each matrix to occur until at least 3 consecutive negative results are obtained.
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e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes 
that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples 
(including those for TGA assay, Direct Thrombin Activity test, and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
f Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 26 (refer to Section 12.5.3) may omit Week 27-32 visits. Such subjects following the 
abbreviated schedule who have not yet cleared vector shedding in all fluids must still provide samples at Week 32 (but do not need to do other scheduled assessments on that 
date).
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Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52) 
Assessment
Year 1 – Weeks*
33e 
34e 
35e 
36
38e 
40e 
42e 
44
46e 
48e 
50e 
52
Study Day*
232
239
246
253
267
281
295
309
323
337
351
365
Physical examinationa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta
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
X
X
X
X
X
X
X
X
X
X
X
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
X
X
X
X
AAV5 TI Assay
X
X
X
X
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 
X 
VWF:Ag
X 
X 
Direct Thrombin Activity Testd
X 
X 
Thrombin Generation Assayd
X 
X 
X 
X 
X 
Cytokine bead array assay
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 
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Assessment
Year 1 – Weeks*
33e 
34e 
35e 
36
38e 
40e 
42e 
44
46e 
48e 
50e 
52
HAL
X
WPAI+CIQ:HS
X
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52.
a Complete physical examination should be performed at Week 52; brief physical exam may be performed at other study visits. Weight should be recorded at Week 36 and 
every 4 weeks through Week 52.
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular 
when ALT values are 1.5x ULN or > ULN & > 2x baseline value) based on discussion between the Medical Monitor and the Investigator and review of subject data, but 
/7V ZLOO EH PRQLWRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7  1.5x ULN or > ULN & > 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. 
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 inteQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  5 IU/dL 
at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in 
which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.
d Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes 
that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples 
(including those for TGA assay, Direct Thrombin Activity test, and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor.
e Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 26 (refer to Section 12.5.3) must attend the Week 36, Week 44, and Week 52 visits but 
may omit the visits at Weeks 33, 34, 35, 38, 40, 42, 46, 48, and 50. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in all fluids 
must still provide samples at Week 40 and Week 48, if necessary (but do not need to do other scheduled assessments on that date).
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Table 9.1.5:  Schedule of Events – Long-Term 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 
Direct Thrombin Activity Teste
X 
X 
X 
Thrombin Generation Assaye
X 
X 
X 
Cytokine bead array assay
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
X 
EQ-5D-5L
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
HAL
Xf
X
WPAI+CIQ:HS
Xf
X 
* Visit windows are ± 2 weeks for visits in Years 2-5. The Q6W visits during Years 3-5 should restart after each End of Year visit (eg, the first Q6W visit during Year 3 
should be ~6 weeks after the End of Year 2 visit).
a Brief physical examination should be performed at all visits during Years 2-5. 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 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular 
when ALT values are 1.5x ULN or > ULN & > 2x baseline value) based on discussion between the Medical Monitor and the Investigator and review of subject data, but 
LTs will be monitored at leDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7  1.5x ULN or > ULN & > 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-RXW SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,   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, 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 
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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 PRO assessments during Years 2-5 of Long-Term Follow-up should be performed at every End of Year visit. 
g Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 (refer to Section 12.6) may omit the Q4W and Q6W visits during Years 2-5, and 
must attend only the Q12W and End of Year visits. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in all fluids must still 
provide samples Q4W (during Year 2) or Q6W (during Years 3-5) until vector shedding has been cleared (but do not need to do other scheduled assessments at those visit 
dates). 
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9.2
Discussion of Study Design, Including Choice of Control Group
Study 270-203 is designed to be a Phase 1/2, single-arm, open-label study in hemophilia A 
patients with residual )9,,, OHYHOV   ,8G/ DQG SUH-existing antibodies to the AAV5 vector 
capsid. Hemophilia A patients who provide written informed consent and meet the entry 
criteria will be eligible to enroll in the study.
Approximately 10 subjects may be enrolled at the 6E13 vg/kg BMN 270 dose.  Subjects will 
be followed for 26 weeks post-BMN 270 infusion during which safety and efficacy 
assessments will be taken. After the final analysis at 26 weeks post-infusion, safety and 
efficacy will then continue to be assessed long-term for approximately a total of 5 years.  
9.3
Selection of Study Population 
Approximately 10 hemophilia A patients with residual FVIII levels < 1 IU/dL and 
pre-existing antibodies to the AAV5 vector capsid 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 criteria:
1. 0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as 
evidenced by medical history, at the time of signing the informed consent
2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by 
AAV5 total antibody ELISA 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs) 
4. Subject must have been on prophylactic FVIII replacement therapy for at least 
12 months prior to study entry.   
5. 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.
6. 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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7. 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.
8. Willing to abstain from consumption of alcohol for at least the first 26 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. Any evidence of active infection or any immunosuppressive disorder, including HIV 
infection. 
2. Significant liver dysfunction with any of the following abnormal laboratory results:
o
ALT (alanine aminotransferase) > 1.25x ULN; 
o
AST (aspartate aminotransferase) > 1.25x ULN;
o
GGT (gamma-glutamyltransferase) > 1.25x ULN;
o
Total bilirubin > 1.25x ULN; 
o
Alkaline phosphatase > 1.25x ULN; or 
o
,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR  
Subjects whose 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.
1. 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
2. Evidence of any bleeding disorder not related to hemophilia A 
3. Platelet count of < 100 x 109/L
4. Creatinine   PJG/
5. Liver cirrhosis of any etiology as assessed by liver ultrasound  
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6. 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.
7. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral 
therapy
8. Active malignancy, except non-melanoma skin cancer
9. History of hepatic malignancy
10. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial 
embolus), with the exception of catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing. 
11. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
12. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, 
vasculitis).
13. Treatment with any Investigational Product within 30 days or 5 half-lives of the 
investigational product (whichever is longer) 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 26-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 safety and efficacy 
of BMN 270 and with prior consultation with the Medical Monitor 
19. Known allergy or hypersensitivity to investigational product formulation 
20. Unwilling to receive blood or blood products for treatment of an adverse event and/or 
a bleed
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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: 
x
Subject requires medication or medical procedure prohibited by the protocol 
x
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 
x
Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/EC It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
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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
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DRB evaluation of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment:  
x
any related SAE;
x
an related AE with a severity > Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.
Additionally, the DRB should consider whether to restrict dosing to subjects with anti-AAV5 
titers below levels that appear to be causing clinically significant inhibition of transduction.  
Following a temporary halt of enrolment, the DRB may approve resumption of enrolment in 
either cohort at a later date at its discretion based on further analysis of accumulating data.
If a Grade 4 or Grade 5 adverse event assessed as related to study drug occurs in a study 
subject, further enrollment into the trial will be halted until a full safety review of the data by 
the DRB has taken place. Relevant reporting and discussion with the Sponsor and the DRB 
will take place before resumption of dosing. 
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, further enrollment into the trial will be temporarily put on hold pending prompt 
evaluation by the DRB.   
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 an AE of hepatic failure.
3. The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in two subjects. 
4. The occurrence of any cancer (except non-melanoma skin cancer) at any point after
BMN 270 infusion. 
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5. 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, a prompt evaluation by the DRB will be required.  Further enrollment into the trial 
will continue while DRB evaluation is ongoing, unless deemed otherwise by the DRB. 
1. Acute hypersensitivity assessed as related to BMN 270
3. The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in one subject 
4. Occurrence of a thromboembolic event 
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. 
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, 26 weeks of Post-Infusion Follow-Up, 
and 234 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
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 2 mL polypropylene cryovial. Each vial contains 1.1 mL of AAV5-hFVIII-SQ at a 
concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 
The study drug is labelled according to the particulars approved by the relevant regulatory 
agencies.
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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 
therapy will not be given since venipuncture is a minimally invasive procedure in these 
individuals under ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at an 
initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min 
up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an 
increase. Of note, the IP has been shown to be stable at room temperature for 7.5 hours 
following completion of product thaw. Vital signs (pulse, blood pressure, respiration rate and 
temperature) should be monitored at 15 minute (±5 minutes) intervals throughout the 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).   
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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 (ie, to a slower rate [minimum of 1 mL/min], with 
the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the 
subject’s clinical condition permits such an increase) with careful monitoring of the subject. 
In 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 
within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and 
cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours 
after the reaction, if possible. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead array. Exploratory biomarker 
samples at baseline and at post-infusion study visits may also be used to assess changes in 
these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity 
reactions. 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 24 hours to 
observe for any immediate toxicity of the procedure; in-patient observation can be extended 
beyond 24 hours if needed per Investigator discretion. After 24 hours, subjects will be 
discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
Prior to discharging subjects from the clinic, the Investigator or designee should instruct 
subjects how to recognize signs and symptoms of potential (delayed) hypersensitivity 
reactions and anaphylaxis, and to contact a medical practitioner or seek emergency care in 
case of such an event.
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9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the 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. 
9.4.6
Selection of Dose Used in the Study
Data from an ongoing first in human 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. The 
6E13 vg/kg dose has been selected for this study to maximize the likelihood of transduction 
in the face of pre-existing AAV5 antibodies.
9.4.6.1
Selection of Timing of Dose for Each Subject
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: 
x
Any investigational therapy
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x
Systemic immunosuppressive agents, except for corticosteroids 
x
Emicizumab
x
Fitusiran
x
Concizumab 
x
Efavirenz
x
Lamivudine 
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their 
participation in 270-203 must have their antiretroviral medication regimen approved by the 
Investigator and Medical Monitor prior to starting antiretroviral treatment.
The following medications should be avoided, starting 30 days prior to and for at least 
26 weeks after BMN 270 infusion and minimized throughout the remaining duration of the 
study.
x
Alcohol  
x
Herbal and natural remedies and dietary supplements
x
Medications which may be hepatotoxic 
Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated.
The following medications should be avoided during oral corticosteroid therapy:
x
Vaccines
x
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 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 will be 
collected from subjects for the 12-month period immediately preceding study enrollment.   
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Modification of the corticosteroid regimen may take into consideration possible confounders 
for the ALT elevation and impact on FVIII expression.   
Management and monitoring of reactions to corticosteroids should be determined by the 
Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This 
includes the contraindicated use of NSAIDs during corticosteroid treatment and specific 
monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not 
contraindicated during corticosteroid treatment, should be limited, if possible.  Practical 
management to prevent complications related to oral corticosteroid therapy may be 
undertaken at the discretion of the Investigator (eg, evaluation of glucose intolerance, 
hyperlipidemia etc.). 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. 
9.4.9
Treatment Compliance
Study drug will be administered to subjects at 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 
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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 
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 Study 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 26 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
Efficacy and Safety Variables 
9.7.1
Efficacy and Safety Measurements Assessed
The SoA (Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5) describe the 
timing of required evaluations.
9.7.2
Efficacy Variables
9.7.2.1
FVIII Activity
(IILFDF\ UHVSRQVH WR WUHDWPHQW ZLOO EH GHILQHG DV )9,,, DFWLYLW\  5 IU/dL at Week 26 
following BMN 270 infusion. 
Values for FVIII activity will be excluded from analysis 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 
SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  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: 
x
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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x
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 (ie, treatment failure, manifesting as 
HLWKHU IDLOXUH WR DFKLHYH )9,,, DFWLYLW\   ,8G/ E\ either Week 26 or Week 52 or inability 
to maintain independence from prophylactic FVIII replacement therapy due to joint bleeding 
episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after 
discussion with the Medical Monitor, follow an abbreviated visit schedule after either 
Week 26 or Week 52, as applicable and at the discretion of the Investigator.  
Details on collecting FVIII activity samples are included in the Laboratory Manual. 
9.7.2.2
Factor VIII Replacement Therapy/Bleeding Episodes
Additional efficacy variables are:
x
Change of annualized utilization (IU/kg) of exogenous FVIII replacement therapy 
during Week 5 to Week 26 post BMN 270 infusion from the baseline utilization of 
exogenous FVIII replacement therapy.  
x
Change of ABRs requiring exogenous FVIII replacement treatment during Week 5 to 
Week 26 of the study post BMN 270 infusion from the baseline ABR.   
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 
6 weeks post BMN 270 infusion. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. 
9.7.2.3
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 
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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 Study Reference 
Manual.
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 Study Reference Manual. 
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 Study 
Reference Manual.
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 Study 
Reference Manual.
9.7.3
Immunogenicity
Immunogenicity assays will be performed on plasma and PBMCs. The assays will include 
detection of anti-AAV5 vector capsid and anti-FVIII total antibodies, as well as 
determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the 
AAV5 vector capsid (Transduction Inhibitors, TI). FVIII Inhibitors will be assessed using the 
Bethesda assay with Nijmegen modification. Any abnormality of the liver parameters will 
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lead to a retrospective immunogenicity assessment to evaluate FVIII-and vector 
capsid-specific cellular immunogenicity. FVIII- and vector capsid-specific cellular immunity 
will be assessed by stimulated cytokine secretion using an ELISpot assay performed on 
collected PBMCs.
9.7.4
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.
9.7.5
Exploratory Assessments 
A cytokine bead array assay assessment will be performed at Baseline and then weekly 
through Week 26. 
In addition, 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 AAV5 gene transfer, and to develop assays used for these evaluations. Subject may 
choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research, including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes in this study may be used for exploratory 
research once testing for the primary purpose has been completed.   
9.7.6
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.
9.7.6.1
Adverse Events
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10.
9.7.6.2
Clinical Laboratory Assessments 
The scheduled clinical laboratory tests are listed in Table 9.7.6.2.1. Refer to the Study 
Reference Manual for instructions on obtaining and shipping samples.  Urine tests will be 
performed locally and centrally; all other laboratory assessments will be performed at the 
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central laboratory. In case of a safety concern, additional unscheduled laboratory tests may 
be performed locally (at the Investigator’s discretion) in order to facilitate timely and 
appropriate clinical management decisions; where possible, a matched sample for testing at 
the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same 
time as the local unscheduled sample.
Any 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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Height will be recorded at Screening only.  Weight will be recorded at Screening and then 
every 4 weeks thereafter through Week 20, at Week 26, every 4 weeks through Week 52, and 
then at the second Q12W visit each year and at every End of Years visit during Years 2-5. 
9.7.6.6
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:
x
Blood 
x
Saliva
x
Semen
x
Urine
x
Stool 
Vector shedding will also be extensively studied in the present clinical trial, 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. Testing will 
continue until at least 3 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 26 should continue to have PCR testing in semen every 4 weeks 
until 3 consecutive negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor). Subjects who meet the definition of treatment failure and 
wish to follow an abbreviated schedule (refer to Section 12.5.3) but who have not cleared 
vector shedding from all fluids must still provide samples for assessment until vector 
shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 (during Year 1), every 4 weeks 
(during Year 2), or every 6 weeks (during Years 3-5).
Samples may be fractionated prior to shedding analysis in order to better characterize the 
presence, structure, and location of vector DNA and/or vector capsid within each matrix.  If 
needed, the fractionation may be performed with samples collected specifically for shedding 
analysis (saliva, blood, semen, urine, 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 
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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:
x
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
x
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
x
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Events not meeting the AE definition include: 
x
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. 
x
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. 
x
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
x
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x
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: 
x
All bleeding events and suspected bleeding events which meet one or more of the
criteria for being serious (refer to Section 10.1) 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:
x
Results in death
x
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.
x
Requires inpatient hospitalization or prolongation of existing hospitalizationNote: 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. 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.
x
Results in persistent or significant disability or incapacity
x
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP
prior to conception or during pregnancy
x
Is an important medical event or reaction – that, based on medical judgment, may
jeopardize the subject or require 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: 
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x
(OHYDWLRQ RI $/7 1.5x ULN or ALT > ULN & >2x baseline value, regardless of
whether that elevation triggers an initiation or modification of oral corticosteroid
treatment
x
Thromboembolic event
x
Systemic hypersensitivity, anaphylactic, or anaphylactoid reactions (refer to
Appendix 1)
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.  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 10.1.
10.3.2 Eliciting Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences.  The Investigator will record all relevant AE/SAE/EOSI information in the 
subject’s medical record and AE Case Report Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.2 for 
SAE definitions).  These assessments must be made by a study clinician with the training and 
authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or 
DDS).
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. 
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10.4
Procedures for Recording Adverse Events
10.4.1 Recording Adverse Events on a eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology.
10.4.1.1
Diagnosis versus Signs and Symptoms 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. Using accepted medical terminology, 
enter the diagnosis (if known).  If not known, enter sign(s) and/or symptom(s).  If a diagnosis 
subsequently becomes available, then this diagnosis should be entered on the AE (or SAE, as 
appropriate) eCRF, replacing the original entries where appropriate. 
10.4.1.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the AE eCRF.  
However, medically important events that may be linked and/or separated in time should be 
recorded as independent events on the AE eCRF.  For example, if severe hemorrhage leads to 
renal failure, both events should be recorded separately on the AE eCRF. 
10.4.1.3
Persistent or Recurrent Adverse Events
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
For example, if a subject has an adverse event of ALT increased that subsequently resolves, 
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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 (including any local FVIII activity or liver test results) will be 
recorded on the laboratory results pages of the eCRF, or appear on electronically produced 
laboratory reports submitted directly from the central laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF. 
Any laboratory result abnormality of CTCAE Grade 4 or 5 should be recorded as an SAE in 
the AE eCRF.
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met: 
x
Accompanied by clinical symptoms
x
Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).
x
The abnormality suggests a disease and/or organ toxicity
x
The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of 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).
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10.4.1.5
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF.
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches).
10.4.1.6
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and 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:
x
Perform a protocol-mandated efficacy measurement
x
Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not worsened 
x
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 
x
Receive scheduled therapy (study drug or otherwise) for the study indication
10.4.1.8
Deaths
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
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is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.9
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to BPV within 
24 hours of the site becoming aware of the event. The Investigator must make every effort to 
follow the subject’s partner (with that partner’s consent) through resolution of the pregnancy 
(delivery or termination) and to report the resolution on the Pregnancy Follow-up 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 
unexpected fatal or life-threatening unexpected suspected adverse reactions (SUSARs) and 
within 15 calendar days for other non-life-threatening SUSARs.
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.
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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 (EC) or Institutional Review Board 
(IRB) will be done in compliance with the standard operating procedures and policies of the 
IRB/EC and with applicable regulatory requirements. Adequate documentation must be 
obtained by BioMarin showing that the IRB/EC 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 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study.  
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10.8
Urgent Safety Measures
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
patients, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/EC is notified at the same time.” 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
x
Lack of study scientific value, or detrimental study conduct or management 
x
Discovery that the quality or safety of the IP does not meet established safety 
requirements
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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 subject, the Investigator or designee and witness (if 
required) before any study-related procedures are performed.
12.2
Screening Visit(s)
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: 
x
Demographics (age, sex, race, ethnicity)
x
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.  
x
Complete Physical Examination 
x
Height and weight 
x
Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature) 
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) for the previous 12 months 
x
Distribution of subject diaries and training in diary completion
x
Electrocardiogram
x
Liver Ultrasound 
x
Samples for hFVIII Assays
o
Baseline FVIII activity – chromogenic substrate FVIII assay 
o
Baseline FVIII activity level – one-stage clotting FVIII assay
o
hFVIII coagulation activity exploratory assay (collected but not tested 
prior to enrollment) 
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o
hFVIII inhibitors (Bethesda assay with Nijmegen modification)
o
hFVIII total antibody assay (collected but not tested prior to enrollment) 
o
hFVIII antigen assay (collected but not tested prior to enrollment) 
x
Blood sample for AAV5 total antibody (TAb) assay 
o
Screening sample will be tested in an AAV5 Tab pre-screening assay 
specifically developed for enrolment purposes. 
x
Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested)
o
Hepatitis B screening should include HBsAg, HBsAb, and HBcAb 
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Tests (refer to Table 9.7.6.3.1) 
x
Blood samples for Biomarker testing (may include 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:
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification))
x
AAV5 Total Antibody assay 
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Smart Re-screening sample will be tested in an AAV5 Tab pre-screening 
assay specifically developed for enrolment purposes. 
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Tests (refer to Table 9.7.6.3.1) 
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the infusion visit.  The following 
procedures will be performed during the Baseline Period: 
x
Brief physical examination
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
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 antigen assay
x
Von Willebrand Factor Antigen (VWF:Ag)  
x
Blood sample for AAV5 Total Antibody assay 
o
Baseline sample will be tested with a AAV5 TAb post-dose 
immunogenicity monitoring assay
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
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). 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Tests (refer to Table 9.7.6.3.1) 
x
PBMC collection for CTL baseline 
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x
Direct Thrombin test
x
Blood sample for AAV5 TI assay
x
Thrombin Generation Assay 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
x
Exploratory biomarker assessments 
x
Cytokine bead array assay
x
Hypersensitivity blood assessments 
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
12.4
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one infusion visit for each subject.  Subjects will remain in the clinic for at 
least 24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Blood sample for AAV5 TAb Assay (sample collected pre-infusion for analysis) 
o
Infusion Day sample will be tested in an AAV5 Tab pre-screening assay 
specifically developed for enrolment purposes. 
x
Blood sample for AAV5 TI assay (sample collected pre-infusion for analysis) 
x
Fasting blood sample for future exploratory analysis (sample collected pre-infusion) 
x
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. 
x
BMN 270 Infusion
x
Vital Signs
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o
Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for at least 
8 hours during the subject’s stay in the clinic. 
x
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 
within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and 
cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours 
after the reaction, if possible. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead array. 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. Exploratory biomarker samples at 
baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" 
as described in the rationale of changes. 
12.5
BMN 270 Infusion Follow-Up Visits
12.5.1 Week 1
During Week 1, the subject will be assessed on Study Day 2, Study Day 4, and Study Day 8. 
12.5.1.1
Week 1, Study Day 2 
On Study Day 2, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.3.1) 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
o
Separate collection on Day 2 is not required if vector shedding samples 
were collected on Day 1 post-BMN 270 infusion; if collection on Day 2 is 
needed, it must occur within 24 hours of the time of the BMN 270 
infusion. 
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x
Blood sample for AAV5 TAb Assay (sample collected pre-infusion for analysis) 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
PBMC collection
x
Cytokine bead array assay
12.5.1.2
Week 1, Study Day 4 
On Study Day 4, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.3.1) 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
12.5.1.3
Week 1, Study Day 8 
On Study Day 8, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications 
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.3.1) 
x
Blood sample for AAV5 TAb Assay 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
Samples for FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
hFVIII antigen assay
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x
PCR of vector DNA in blood, saliva, urine, semen, and stools 
x
Cytokine bead array assay
12.5.2 Weeks 2-26 
After Week 1 (Day 8), subjects will return to the study site once a week (± 48 hours) during 
Weeks 2-26. 
12.5.2.1
Once per week (Weeks 2 through 26) 
The following procedures will be performed once per week from Weeks 1 through 26: 
x
Brief physical examination (complete physical examination at Week 26) 
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.3.1) 
o
LTs may be monitored more or less frequently (and in particular when 
ALT values are >1.5x ULN) based on discussion between the Medical 
Monitor and the Investigator and review of subject data, but LTs will be 
monitored at least twice weekly during periods when a subject’s ALT is 
 3x ULN..
x
Samples for FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
hFVIII antigen assay
12.5.2.2
Every Other Week (Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26) 
The following procedures will be performed every other week (at Weeks 2, 4, 6, 8, 10, 12, 
14, 16, 18, 20, 22, 24, and 26): 
x
Blood sample for AAV5 TAb Assay 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
PBMC collection
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12.5.2.3
Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26 
The following procedures will be performed at Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26: 
x
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.
12.5.2.4
Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 26 
The following procedures will be performed at Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 26: 
x
hFVIII total antibody assay
12.5.2.5
Weeks 2, 4, 6, 8, 14, 20, and 26 
The following procedures will be performed at Weeks 2, 4, 6, 8, 14, 20, and 26: 
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
12.5.2.6
Weeks 2, 6, 10, 14, 18, 22, and 26 
The following procedures will be performed at Weeks 2, 6, 10, 14, 18, 22, and 26: 
x
Exploratory biomarker assessments 
12.5.2.7
Weeks 2, 6, 10, 14, 20, 24, and 26 
The following procedures will be performed at Weeks 2, 6, 10, 14, 20, 22, and 26: 
x
Cytokine bead array assay
12.5.2.8
Weeks 4, 8, 12, 16, 20, and 26 
The following procedures will be performed at Weeks 4, 8, 12, 16, 20, and 26: 
x
Weight
x
VWF:Ag 
12.5.2.9
Weeks 12 and 26 
The following procedures will be performed at Weeks 12 and 26: 
x
Urine tests (to be performed locally) 
x
Haemo-QoL-A QoL assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
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x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
12.5.2.10 Weeks 13 and 26 
The following procedure will be performed at Weeks 13 and 26: 
x
Direct thrombin activity test
12.5.2.11 Week 16
The following procedure will be performed at Week 16: 
x
Testing for reactivation of hepatitis B and hepatitis C (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.
12.5.2.12 Weeks 20, 24, and 26 
The following procedure will be performed at Weeks 20, 24, and 26: 
x
Thrombin Generation Assay 
12.5.3 Post-Infusion Follow-Up – Weeks 27-52 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
either failure to achieve FVIII activity   ,8G/ by Week 26 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 26 of the study by 
attending only the Week 36, 44, and 52 visits during the remainder of Year 1.  Such subjects 
following the abbreviated schedule who have not yet cleared vector shedding in all fluids 
must still provide samples at Week 32, Week 40, and Week 48, if necessary (but do not need 
to do other scheduled assessments on that date). 
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).  At these visits, the following procedures will be completed:  
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12.5.3.1
Every Visit
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures 
will be performed: 
x
Physical examination
o
Brief physical examination should be performed at all weeks except 
Week 52, when a complete physical examination should be performed 
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.3.1) 
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 
VXEMHFW¶V $/7 LV  [ 8/1
x
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 
12.5.3.2
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: 
x
PBMC collection
12.5.3.3
Weeks 32, 36, 44, and 52 
At Weeks 32, 36, 44, and 52, the following procedures will be performed: 
x
Weight
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.4.8.2.1) 
x
FVIII antibody titer
x
AAV5 TAb Assay
x
AAV5 TI Assay
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x
Cytokine bead array assay
12.5.3.4
Weeks 32, 36, 40, 44, 48, and 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed: 
x
Exploratory biomarker assessments 
x
TGA Assay
x
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). 
o
Subjects considered to be treatment failures must continue to provide samples 
for PCR assessment at these timepoints until vector shedding has cleared (in 
such a case, these subjects do not need to perform other assessments except 
for PCR sample delivery scheduled at these timepoints) 
12.5.3.5
Week 36 and 52 
At Weeks 36 and 52, the following procedures will be performed: 
x
Urine Tests (refer to Table 9.7.6.2.1)
x
Direct Thrombin test
x
VWF:Ag
12.5.3.6
Week 52
At Week 52, the following procedures will be performed: 
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
HAL
x
WPAI+CIQ:HS
12.6
Post-Infusion Follow-Up – Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
HLWKHU IDLOXUH WR DFKLHYH )9,,, DFWLYLW\  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 
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with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by 
attending only the Q12W and End of Year visits during Years 2-5. 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
vector shedding has cleared (but do not have to perform other scheduled assessments at those 
study visits).
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed:
12.6.1 Year 2 – Every 4 Weeks (not required for treatment failure)
During Year 2, every 4 weeks (±2 weeks), the following procedures will be performed: 
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
x
Liver Tests (refer to Table 9.7.6.3.1) 
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 
VXEMHFW¶V $/7 LV  [ 8/1
x
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 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o
Sample testing during Year 2 is not required if at least 3 consecutive samples 
are negative during the Post-Infusion Follow-Up period in Weeks 1-52.  
Subjects who have not had 3 consecutive negative semen samples by Week 52 
should continue to have PCR testing of semen every 4 weeks during Years 2 
until 3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor). 
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o
Subjects who meet the definition of treatment failure and wish to follow 
an abbreviated schedule but who have not cleared vector shedding from all 
fluids must still provide samples for assessment every 4 weeks during 
Year 2 until vector shedding has cleared (in such a case, these subjects do 
not need to perform other assessments except for PCR sample delivery 
scheduled at these timepoints). 
12.6.2 Years 3-5 – Every 6 Weeks (not required for treatment failure)
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
x
Liver Tests (refer to Table 9.7.6.3.1) 
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 
VXEMHFW¶V $/7 LV  [ 8/1
x
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 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o
Sample testing during Years 3-5 is not required if at least 3 consecutive 
samples are 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). 
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o
Subjects who meet the definition of treatment failure and wish to follow 
an abbreviated schedule but who have not cleared vector shedding from all 
fluids must still provide samples for assessment every 6 weeks during 
Years 3-5 until vector shedding has cleared (in such a case, these subjects 
do not need to perform other assessments except for PCR sample delivery 
scheduled at these timepoints). 
12.6.3 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects)
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks (±2 weeks):
x
Year 2 – Week 64, Week 76, Week 88, Week 104 
x
Year 3 – Week 116, Week 128, Week 140, Week 156 
x
Year 4 – Week 168, Week 180, Week 192, Week 208 
x
Year 5 – Week 220, Week 232, Week 244, Week 260 
For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and 
Week 260) will serve as an End of Year visit. 
At the every 12 week and End of Year visits, the following procedures will be performed: 
x
Brief physical examination (at every 12 week visits) or complete physical 
examination (at End of Year visits)
x
Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
x
Liver Tests (refer to Table 9.7.6.3.1) 
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 
VXEMHFW¶V $/7 LV  [ 8/1
x
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
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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 
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) (at 
Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
x
Urine Tests (refer to Table 9.7.6.2.1 ) (at Week 76, Week 128, Week 180, Week 232, 
and End of Year visits only) 
x
Vital Signs
x
AAV5 TAb Assay
x
AAV5 TI Assay
x
FVIII antibody titer
x
Haemo-QoL-A assessment (at End of Year visits only) 
x
EQ-5D-5L (at End of Year visits only) 
x
HAL (at End of Year visits only) 
x
WPAI+CIQ:HS (at End of Year visits only) 
x
Exploratory biomarker assessments 
x
PBMC collection
x
VWF:Ag
x
Direct Thrombin test 
x
TGA Assay
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are negative during the Post-Infusion Follow-Up period in 
Weeks 1-52.  Subjects who have not had 3 consecutive negative semen 
samples by Week 52 should continue to have PCR testing of semen every 
4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 
3 consecutive negative samples are documented (or upon consultation 
between the Investigator and Medical Monitor). 
12.7
Early Termination Visit
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit.
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If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
x
Complete physical examination
x
Weight
x
Assessment of Adverse Events and Concomitant Medications 
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x
Vital signs
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x
Urine Tests (refer to Table 9.7.6.2.1) 
x
Liver Tests (refer to Table 9.7.6.3.1) 
x
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 antigen assay 
x
hFVIII total antibody assay
x
Exploratory biomarker assessments 
x
Blood sample for AAV5 Total Antibody assay 
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x
Blood sample for AAV5 TI assay
x
PBMC collection for CTL baseline 
x
VWF:Ag 
x
Direct Thrombin test
x
Thrombin Generation Assay 
x
Haemo-QoL-A QoL assessment
x
EQ-5D-5L
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x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
x
PCR of vector DNA in blood, saliva, urine, semen, and stool 
o
Sample testing at the Early Termination Visit is not required if at least 
3 consecutive samples are clear during the period of the subject’s participation 
in the study. 
12.8
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, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications. 
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS.
14.1.1 Interim Analyses
No interim analysis is planned. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data. 
Sensitivity analyses will be conducted to assess the impact of missing data on the primary 
efficacy endpoint analysis. Additional details regarding the handling of missing data will be 
provided in the SAP.
14.2
Efficacy Analysis 
The subjects will be followed in a longitudinal manner, and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature, but data collected in a 
longitudinal manner may be analyzed using longitudinal methods, such as mixed effect 
model, which take into account the correlation among the observations taken at various time 
points within a subject. Efficacy is a secondary endpoint, defined as biologically active FVIII 
DW   ,8G/ DW  ZHHNV IROORZLQJ VWXG\ WUHDWPHQW )9,,, DFWLYLW\ ZLOO EH DVVHVVHG ZHHNly 
during the study period. We can only assess the true steady state of FVIII produced from 
BMN 270 after a minimum of 72 hours (or 5x the known half-life of the FVIII replacement 
therapy administered) has elapsed since the last infusion of FVIII concentrates. 
14.3
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), 
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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.  
Analysis of neutralizing antibody response and other immunological parameters as well as 
vector shedding will be primarily descriptive and involve both inter-subject and intra-subject 
comparisons across doses.  
Detailed statistical methods will be provided in the SAP.
14.4
Determination of Sample Size
The sample size is based upon clinical considerations and is sufficient to detect a strong 
clinical efficacy signal. Approximately 10 subjects may be dosed in the study. 
14.5
Analysis Populations 
The efficacy analysis set will be comprised of all subjects who have received the BMN 270 
infusion. 
The safety population will consist of all subjects who receive BMN 270 infusion during the 
study.
14.6
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/EC must be sought, and 
the Investigator should inform BioMarin and the full IRB/EC within 2 working days after the 
emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/EC 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/EC prior to their implementation.
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When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the IRB/EC, and 
all active subjects must again provide informed consent. 
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15
DATA REVIEW BOARD
The Data Review Board (DRB) will consist of the Principal Investigators and Sponsor’s 
Medical Monitor, as well as hemophilia expert advisors experienced in the conduct and 
evaluation of safety and efficacy parameters from 270-201.  The DRB will review available 
safety and efficacy data during the study on an ongoing basis to determine, based on 
emerging data and the benefit/risk profile, whether further enrollment should continue. The 
DRB will meet weekly until all subjects have completed Week 26, and then monthly 
thereafter.
Duties of the DRB include:
x
Conducting an ongoing review of individual subject safety and efficacy data during 
the study; 
x
Recommending whether to proceed with enrollment of subjects at a different gating 
schedules based on emerging data from 270-203 and the overall risk/benefit analysis 
of BMN 270; 
x
If applicable, considering whether to restrict dosing to subjects with anti-AAV5 titers 
below levels that appear to be causing clinically significant inhibition of transduction. 
x
Making other recommendations on the conduct and reporting of the trial based on 
their evaluation of clinical data including institution of any pause or stopping stages. 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DRB determination of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment:  
x
any related SAE;
x
any related AE with a severity > Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.
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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/EC 
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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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.  
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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 
source data verified.  The Investigator will then electronically sign the casebook, specifying
that the information on the eCRFs is accurate and complete. The Data Manager, or designee, 
will then set the status of the forms, visits, and the entire casebook to Locked. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 
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STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
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
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routine investigation and monitoring of adult HIV-1-positive individuals. 2016. Available at 
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Batts KP & Ludwig J.  Chronic hepatitis: an update on terminology and reporting.  Am J 
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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, et. al. European retrospective study of real-life haemophilia 
treatment. Haemophilia. 2017 Jan;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. 
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of 
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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 
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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. 
Majowicz A, Lampen M, Petry H, Meyer C et al. Pre-existing Anti-AAV5 Neutralizing 
Antibodies Measured Using a Highly Sensitive Assay in Sera of Hemophilia B Patients in a 
Phase I/II Clinical Trial of AMT-060 Do Not Predict Efficacy of AAV5-mediated 
Liver-directed Gene Transfer. Res Pract Thromb Haemostasis. 2017;1(Suppl. 1):766. 
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Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006. 
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016. 
Mingozzi, F and High, KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013. 
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. 
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. 
Reilly, M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ 
WPAI_Scoring.html. Last accessed 28 July 2017.   
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. 
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Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS et. al. Guidelines for the 
management of hemophilia 128. Haemophilia 19[1], e1-47. 2013. 
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010.
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. 
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INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Subjects 
In accordance with FDA Form 1572 and/or principles of ICH E6 GCP, the Investigator will 
ensure that:
x
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects.
x
He or she will personally conduct or supervise the study. 
x
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/EC review and 
approval in 21 CFR Part 56 and/or ICH E6 Section 2.6 are met.  
x
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 Section 4.11. 
x
He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug.
x
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments
x
Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 
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. 
x
The IRB/EC complies with the requirements of 21 CFR Part 56, ICH E6 Section 3.0, 
and other applicable regulations, and conducts initial and ongoing reviews and 
approvals of the study. He or she will also ensure that any change in research activity 
and all problems involving risks to human subjects or others are reported to the 
IRB/EC. Additionally, he or she will not make any changes in the research without 
IRB/EC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects. 
x
He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6.
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APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA
According to the National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network (NIAID/FAAN) Second Symposium on the definition and 
management of anaphylaxis, anaphylaxis is highly likely when any one of the following 3 
criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) 
2. 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) 
3. 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)
4. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a.
Infants and children: low systolic blood pressure (age specific) or greater than 
30% decrease is systolic BP
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline.
Source: Sampson, 2006.
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PROTOCOL AMENDMENT TEXT REVISIONS
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale (see pages 2-7). 
Added text is indicated by underlined font and deleted text is indicated by strikethrough font. 
Section No./Title
Revision
Rationale
2/Synopsis (Study 
Rationale)
The vector genome schematic figure has been updated.
BMN 270 is currently being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose escalation 
study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 at various dose levels (6E12 
vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201 explores the relationship of vector dose to the 
augmentation of residual FVIII activity and whether these levels are sufficient to alter the clinical phenotype. 
Preliminary results from 270-201 have demonstrated that following gene transfer, sustained FVIII activity above 5% 
(515% (15 IU/dL) up to a year’s observation is achievable at doseswith a dose of 4-6E13 vg/kg with an acceptable 
safety profile (Pasi, 2016). The majority of subjects achieved FVIII levels within the normal range for FVIII, with few 
to no bleeding episodes and discontinuation of FVIII prophylaxis.2017). 
26, 28
2/Synopsis (Study 
Design and Plan)
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), with a history of at least 150 
exposure days to FVIII concentrates/cryoprecipitates, with pre-existing antibodies to the AAV5 vector capsid as 
measured by total antibody [TAb] assay. Approximately 10 subjects willmay be enrolled at 2-3 sites in 2 cohorts (5 
subjects in each cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 
ZLOO KDYH D 6FUHHQLQJ $$9 7$E WLWHU   Zhile subjects in Cohort 2 will have a Screening AAV5 TAb titer > 500.  
Choosing a titer cutoff of 500 reflects the observed distribution of existing titer data with the BioMarin titer assay seen 
to date.
The Data Review Board (DRB) will consist of the 2 Principal Investigators and Sponsor’s Medical Monitor, as well as 
hemophilia expert advisors experienced in the conduct and evaluation of safety and efficacy parameters from 270-201.  
The DRB will review available safety and efficacy data throughout the study and provide recommendations based on 
their review (Figure 2 represents one dosing schedule scenario):
...
1, 5, 6, 10, 
28
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Section No./Title
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Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 24 hours post-
infusion for any immediate hypersensitivity or adverse drug reaction. In case of suspected hypersensitivity or adverse 
drug reaction, safety assessments, in addition to physical examination and vital signs, will be performed and. Additional 
blood samples will be collected (tryptase, C3, C3a, C4, C5, and C5aC5a, and cytokine bead array, as well as possible 
additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) will be collected between 8-24 hours after the reaction).. In addition, a 
blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead array. 
Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. Any safety signal may 
trigger a review of the data and possible additional immunogenicity studies or other diagnostics deemed necessary to 
assess cellular immune responses using collected peripheral blood mononuclear cells (PBMCs).  The duration of 
observation may be extended and additional blood samples collected at the discretion of the Investigator and Medical 
Monitor.
Data from 270- VXJJHVW WKDW DFKLHYHPHQW RI WKHUDSHXWLF )9,,, OHYHOV  5 IU/dL occurs approximately 4 weeks after 
BMN 270 infusion, although the FVIIII PD in AAV+ subjects is unknown and requires close monitoring. As such, in 
order to provide adequate FVIII protecWLRQ ZKLOH VXEMHFWV DUH SURMHFWHG WR UHDFK FOLQLFDOO\ UHOHYDQW )9,,, OHYHOV  
IU/dL, prior FVIII prophylaxis for each subject will be continued at the discretion of the DRB based on individual 
subject status and data review or when FVIII activity has reached at least 5 IU/dL. Throughout the study, subjects with 
FVIII activity below 5 IU/dL may be monitored more frequently at the discretion of the Investigator and the Medical 
Monitor. In subjects who show an initial response to BMN 270 but who later have FVIII activity decline to < 5 
IU/dLexperience recurring bleeding episodes, the Investigator and Medical Monitor will review the subject’s FVIII 
activity levels and discuss whether to resume prior FVIII prophylaxis. In addition, the investigator will notify the 
subject of his FVIII activity levels and will discuss with the subject the risk of bleeding and when (and if) prior FVIII 
prophylaxis will be resumed.
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
DFWLYLW\   ,8G/ E\ HLWKHU :HHN  RU :HHN  RU LQDELOLW\ WR PDLQWDLQ LQGHSHQGHQFH IURP SURSK\ODFWLF )9,,,
replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s 
discretion and after discussion with the Medical Monitor, follow an abbreviated visit schedule after either Week 26 or 
Week 52, as applicable and at the discretion of the Investigator. 
2/Synopsis (Inclusion 
and Exclusion 
Criteria)
Individuals eligible to participate in this study must meet all of the following criteria:
6.  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 
2, 4, 9, 13, 
25, 28
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most recentpast 12 months (at least one of which should be tested at the central laboratory) at least one week apart 
within the past 12 months
7.  HIV positive patients may be enrolled, only if the patient has a CD4 count > 200/mm3 and an undetectable viral 
load.
8.  Sexually active participants must agree to use an acceptable method of effective contraception, either double-barrier 
contraception for at least 6 months(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, which may include hormonal contraception for a female partner.  
After 6 months; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples 
with no detectable viral vector DNA.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
1. Any evidence of active infection or any immunosuppressive disorder, except forincluding HIV infection as described 
in the inclusion criterion above.
2. Significant liver dysfunction with any of the following abnormal laboratory results:
o
ALT (alanine transaminase) or AST >2Xaminotransferase) > 1.25x ULN; 
o
AST (aspartate aminotransferase) > 1.25x ULN;
o
GGT (gamma-glutamyltransferase) > 1.25x ULN;
o
Total bilirubin >2X 1.25x ULN; 
o
Alkaline phosphatase >2X 1.25x ULN; or
o
,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR  
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. In addition, subjects with abnormal laboratory results related to confirmed 
benign liver conditions (eg, Gilbert’s syndrome) are considered eligible for the study notwithstanding their 
abnormal laboratory results and may be enrolled after discussion with the Medical Monitor.
8.  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.  
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Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results in the Laboratory 
Manual. 
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational product (whichever 
is longer) 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.
7.3/Study Rationale
The vector genome schematic figure has been updated.
BMN 270 is currently being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose escalation 
study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 at various dose levels (6E12 
vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201 explores the relationship of vector dose to the 
augmentation of residual FVIII activity and whether these levels are sufficient to alter the clinical phenotype. 
Preliminary results from 270-201 have demonstrated that following gene transfer, sustained FVIII activity above 5% 
(515% (15 IU/dL) up to a year’s observation is achievable at doseswith a dose of 4-6E13 vg/kg with an acceptable 
safety profile (Pasi, 2016). The majority2017). For additional information on preliminary data in 270-201, refer to the 
current version of subjects achieved FVIII levels within the normal range for FVIII, with few to no bleeding episodes 
and discontinuation of FVIII prophylaxisthe Investigator’s Brochure. 
26, 28
7.4/Summary of 
Overall Risks and 
Benefits
The majority of subjects in the ongoing 270-201 clinical study who have received 4E13 or 6E13 vg/kg doses of BMN 
270 have had Grade 1 asymptomatic elevations in ALT. For most subjects, the elevations have reached only slightly 
above the upper limit of normal (ULN).  Based on the effectiveness of transient oral corticosteroid useused to suppress a 
presumed Class 1 (cytotoxic T-cell) response to hepatocytes transduced in prior studies with hepatic transduction with 
AAV vectors (Mingozzi, 2013), subjects were treated with 7-32 weeks of oral corticosteroids prophylactically or in 
response to the elevations in ALT to ensure preservation of the transduced hepatocytes. Using this approach, no 
sustained loss of FVIII activity has been observed in subjects with ALT elevations, consistent with maintaining a high 
level of hepatocyte function. Moreover, the rise in ALT levels were not accompanied by significant or lasting 
aberrations in other liver function tests such as AST, bilirubin or albumin, indicating that extent of toxicity is limited. 
Overall, the literaturetests 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 
1, 4, 28
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and/or unsuspected underlying hepatic disease with BMN 270. In addition, there has been one subject with Gilbert’s 
syndrome in the ongoing 270-301 clinical study who has experienced Grade 3 asymptomatic elevations in ALT and 
AST. These cases have led to the exclusion of subsequent HIV-positive subjects and requirement of liver tests at 
Screening that are <1.25 times the upper limit of the normal range in the ongoing 270-301 and 270-302 clinical studies. 
Of note, two HIV-positive subjects in 270-301 and one presumed Gilbert’s syndrome subject in 270-201 have received 
BMN 270 without experiencing any elevations in ALT to date. Overall, the literature and clinical experience with BMN 
270 suggests that transient elevations in liver enzymes are expected following AAV-based gene therapy for the
treatment for hemophilia A or B without any long-term concerns of hepatic injury (Manno, 2006; Nathwani, 2011; 
George, 2016; Miesbach, 2016; Pasi, 2017). 
...
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, including this study. 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.
9.1/Overall Study 
Design and Plan
This is a Phase 1/2, single-arm, open-labeO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), with a history of at least 150 
exposure days to FVIII concentrates/cryoprecipitates, with pre-existing antibodies to AAV5 vector capsid as measured 
by total antibody [TAb] assay. Approximately 10 subjects willmay be enrolled at 2-3 sites in 2 cohorts (5 subjects in 
each cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a 
6FUHHQLQJ $$9 7$E   ZKLOH VXEMHFWV LQ &RKRUW 2 will have a Screening AAV5 TAb > 500. Choosing a titer 
cutoff of 500 reflects the observed distribution of existing titer data with the BioMarin titer assay seen to date.
The Data Review Board (DRB) will consist of the 2 Principal Investigators and Sponsor’s Medical Monitor, as well as 
hemophilia expert advisors experienced in the conduct and evaluation of safety and efficacy parameters from 270-201.  
The DRB will review available safety and efficacy data throughout the study and provide recommendations based on 
their review (Figure 9.1.1 represents one dosing schedule scenario):
1, 5, 6, 10, 
28
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...
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 24 hours post-
infusion for any immediate hypersensitivity or adverse drug reaction. In case of suspected hypersensitivity or adverse 
drug reaction, safety assessments, in addition to physical examination and vital signs, will be performed and. Additional 
blood samples will be collected (tryptase, C3, C3a, C4, C5, and C5aC5a, and cytokine bead array, as well as possible 
additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) will be collected between 8 -24 hours after the reaction).. In addition, a 
blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead array. 
Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. Any safety signal may 
trigger a review of the data and possible additional immunogenicity studies or other diagnostics deemed necessary to 
assess cellular immune responses using collected peripheral blood mononuclear cells (PBMCs).  The duration of 
observation may be extended and additional blood samples collected at the discretion of the Investigator and Medical 
Monitor.
Data from 270-201 suggest that achievement of WKHUDSHXWLF )9,,, OHYHOV  5 IU/dL occurs approximately 4 weeks after 
BMN 270 infusion, although the FVIIII PD in AAV+ subjects is unknown and requires close monitoring. As such, in 
order to provide adequate FVIII protection while subjects are projected to reach clinically relevant FVIII levels 
 5 IU/dL, prior FVIII prophylaxis for each subject will be continued at the discretion of the DRB based on individual 
subject status and data review or when FVIII activity has reached at least 5 IU/dL. Throughout the study, subjects with 
FVIII activity below 5 IU/dL may be monitored more frequently at the discretion of the Investigator and the Medical 
Monitor. In subjects who show an initial response to BMN 270 but who later have FVIII activity decline to < 5 IU/dL, 
the investigator and medical monitor will review the subject’s FVIII activity levels and discuss whether to resume prior 
FVIII prophylaxis. In addition, the investigator will notify the subject of his FVIII activity levels and will discuss with 
the subject the risk of bleeding and when (and if) prior FVIII prophylaxis will be resumed.
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.
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 2 7 0- 2 0 3
 
A me n d me nt
 
1
  
 
 
 
 
 Pa ge
 
1 3 3
Pr o prietar y a n d C o nfi de ntial 
5 Oct o ber 2 0 1 8 
Secti o n N o./ Title  
Re visi o n
R ati o n ale
I n s u bj ects w h o e x perie nce rec urre nt blee di n g e pis o des, t he I n vesti gat or a n d Me dical M o nit or will disc uss w het her t o 
res u me pri or F VIII pr o p h yla xis. S u bj ects w h o d o n ot res p o n d t o B M N 2 7 0 treat me nt (ie, tr eat me nt fail ure, ma nifesti n g 
i n de pe n de nce fr o m pr o p h ylactic F VIII re place me nt t hera p y d ue t o j oi nt blee di n g e pis o des, i n t he j u d g me nt of t he 
I n vesti gat or) ma y, at t he I n vesti gat or’s discreti o n a n d after disc ussi o n wit h t he Me dical M o nit or, f oll o w a n a b bre viate d 
visit sc he d ule after eit her W ee k 2 6 or W ee k 5 2, as a p plica ble a n d at t he discreti o n of t he I n vesti gat or. 
T a ble 9. 1. 1- 9. 1. 5 
( Sc he d ules of 
Acti vities)
T a bles 9. 1. 1, 9. 1. 2, a n d 9. 1. 3 h ave bee n u p d ate d ( a n d t heir f o ot n otes u p d ate d) c o nsiste nt wit h t he c h a n ges else w here i n 
t he pr ot oc ol. T a bles 9. 1. 4 a n d 9. 1. 5 ( a n d t heir f o ot n otes) h ave bee n a d de d as p art of t his a me n d me nt.
1, 5, 6, 7, 
8, 1 1, 1 2, 
1 3, 1 5, 1 7, 
1 8, 1 9, 2 0, 
2 2, 2 3, 2 4, 
2 5, 2 8
T a ble 9. 1. 1 
( F o ot n otes)
b I ncl u des baseli ne F VIII acti vit y (c hr o m o ge nic s u bstrate F VIII assa y a n d o ne-sta g e cl otcl otti n g F VIII assa y), 
c oa g ulati o n e x pl orat or y assa y, h F VIII i n hi bit or le vel ( B et hes da assa y wit h Nij me ge n m o dificati o n), h F VIII t otal 
a nti b o d y titer, a n d h F VIII a nti ge n assa y. B aseli ne acti vit y s h o ul d be assesse d at tr o u g h (at l east > 7 2 h o urs after last 
d ose of re place me nt F VIII t hera p y, or 5 x t he k n o w n half-life of t he F VIII re place me nt t her a p yc o nce ntrates
a d mi nistere d).
d S u bj ects wit h d oc u me nte d ne gati ve res ults wit hi n t he last 3 0 da ys d o n ot nee d t o be reteste d.  He patitis B scree ni n g 
s h o ul d i ncl u de he patitis B s urface a nti ge n ( H Bs A g), he patitis B s urface a nti b o d y ( H Bs A b), a n d he patitis B c ore 
a nti b o d y ( H Bc A b).
e Detaile d i n t he Secti o n of la b orat or y assess me nts a n d li ver f u ncti o n tests.  Uri ne tests will be perf or me d l ocall y a n d 
ce ntrall y; all ot her la b orat or y assess me nts will be perf or me d at t he ce ntral la b orat or y. A B O bl o o d t y pi n g assess me nt 
s h o ul d be perf or me d as part of t he he mat ol o g y assess me nt (at Baseli ne, or at a n ot her re g ularl y sc he d ule d visit pri or t o 
t he e n d of t he s u bj ect’s partici pati o n i n t he st u d y).   
f I ncl u des H L A ge n ot y pi n g a n d F VIII ge n ot y pi n g; ma y i ncl u d e T N F
. 
g Bl o o d sa m ples will be c ollecte d fr o m s u bj ects t o e val uate bi oc he mical, m olec ular, cell ular, a n d ge netic/ ge n o mic 
as pects rele va nt t o he m o p hilia A disease. T he e x pl orat or y ge netic/ ge n o mic testi n g o n t hes e sa m ples is o pti o nal,
c oa g ulati o n, a n d/ or A A V ge ne tra nsfer, a n d t o de vel o p assa ys use d f or t h ose e val uati o ns. S u bj ects ma y c h o ose t o o pt 
o ut of t he e x pl orat or y ge netic/ ge n o mic researc h bei n g d o ne t o st u d y or tr y t o disc o ver ge nes t hat are n ot yet k n o w n t o 
be ass ociate d wit h he m o p hilia A. W hile e x pl orat or y sa m ples will be c ollecte d at t he ti me p oi nts i n dicate d a b o ve, 
1, 1 2, 1 4, 
1 5, 1 7, 2 5, 
2 8
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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. 
i Smart rescreening should only be performed if a subject 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 (28 + 14 
days).  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. Any 
screening assessment has not been done at the Screening, it must be done during 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 a total time of 
24 hours during the subject’s stay in the clinic. Shedding samples for PCR of vector DNA analysis (blood, saliva, 
urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been completed.
mIn case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will 
be done and additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, 
C3a, C4, C5, and C5a) and one sample for IgE between 8 24 hours after the reaction, if possible.C5a, and cytokine 
bead array, as well as possible additional exploratory testing) and samples for IgE and cytokine bead array (and 
possible additional exploratory testing) between 8-24 hours after the reaction, if possible. In addition, a blood sample 
should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead array. Exploratory 
biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these biomarkers 
to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 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.
Table 9.1.2 
(Footnotes)
* Visit windows are ± 24 hours during Week 1 and ± 48 hours starting with the Week 2 visit.  
b Detailed in the Section of laboratory assessments and liver function tests. Urine tests will be performed locally and 
centrally; all other laboratory assessments will be performed at the central laboratory. LFTsLTs 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 LFTsLTs will be 
11, 17, 20, 
23, 28
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PRQLWRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7 >  1.5x ULN
or > ULN & > 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 
LFTsLTs 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 liver enzymesALT 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 clotclotting FVIII assay), Bethesda 
assay (with Nijmegen modification) for hFVIII inhibitor level, coagulation exploratory assay, and hFVIII antigen 
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 
LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,   ,8G/ DW  weeks after BMN 270 infusion and who have not 
resumed FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. 
A D-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological 
range and/or if there is a concern for a venous thromboembolism. 
d Collection for each matrix to occur until at least 3 consecutive negative results are obtained.  Collection and testing of 
semen samples must continue through Week 12, even if 3 consecutive negative results in that compartment have 
already been recorded. Separate collection on Day 2 is not required if vector shedding samples were collected on Day 
1 post-BMN 270 infusion; if collection on Day 2 is needed, it must occur within 24 hours of the time of the BMN 270
infusion.
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 on these samples is optionalof 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. 
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f Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of hepatitis 
B or hepatitis C prior to study entry, should be performed only in subjects with evidence of prior exposure and who 
have not received therapeutic oral corticosteroids prior to Week 16; subjects who have received therapeutic oral 
corticosteroids will have hepatitis B and hepatitis C testing at the time points indicated in Table 9.1.6.
Table 9.1.3 
(Footnotes)
* Visit windows are ± 48 hours through Week 26, and then ± 2 weeks through the end of Year 5. 
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 every 4 weeks and Week 26.  After Week 26, 
complete physical examination should be done at Week 52 and then yearly, brief physical examination at other 
visitsWeek 20 and Week 26.
b Detailed in the Section of laboratory assessments and liver function tests. Urine tests will be performed locally and 
centrally; all other laboratory assessments will be performed at the central laboratory. LFTsLTs 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 LFTsLTs will be 
PRQLWRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7 > 1.5x ULN
or > ULN & > 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 
LFTsLTs 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 liver enzymesALT 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 clotclotting FVIII assay), Bethesda 
assay (with Nijmegen modification) for hFVIII inhibitor level, coagulation exploratory assay, and hFVIII antigen. 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 
VXEMHFWV ZKR KDYH DFKLHYHG )9,,,   ,8G/ DW  ZHHNV DIWHU %01  LQIXVLRQ DQG ZKR KDYH QRW UHVXPHG )9,,,
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 
5, 6, 11, 
28
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considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there 
is a concern for a venous thromboembolism. 
d Collection for each matrix to occur until at least 3 consecutive negative results are obtained.
f Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 26 (refer to Section 12.5.3) may 
omit Week 27-32 visits. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in 
all fluids must still provide samples at Week 32 (but do not need to do other scheduled assessments on that date).
Table 9.1.6 
(Footnotes)
d Should only be performed in subjects with a history of hepatitis B or hepatitis C prior to study entry. 
20
9.2/Discussion of 
Study Design
Approximately 10 subjects will may be enrolled at the 6E13 vg/kg BMN 270 dose.  Subjects will be followed for 
26 weeks post-BMN 270 infusion during which safety and efficacy assessments will be taken. After the final analysis at 
26 weeks post-infusion, safety and efficacy will then continue to be assessed long-term for approximately a total of 
5 years.
28
9.3.1/Inclusion 
Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
6.  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 
most recentpast 12 months (at least one of which should be tested at the central laboratory) at least one week apart 
within the past 12 months
7.  HIV positive patients may be enrolled, only if the patient has a CD4 count > 200/mm3 and an undetectable viral 
load.
8.  Sexually active participants must agree to use an acceptable method of effective contraception, either double-barrier 
contraception for at least 6 months(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, which may include hormonal contraception for a female partner.  
After 6 months; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples 
with no detectable viral vector DNA.
2, 9, 13, 
28
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9.3.2/Exclusion 
Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
1. Any evidence of active infection or any immunosuppressive disorder, except forincluding HIV infection as described 
in the inclusion criterion above.
2. Significant liver dysfunction with any of the following abnormal laboratory results:
o
ALT (alanine transaminase) or AST >2Xaminotransferase) > 1.25x ULN; 
o
AST (aspartate aminotransferase) > 1.25x ULN;
o
GGT (gamma-glutamyltransferase) > 1.25x ULN;
o
Total bilirubin >2X 1.25x ULN; 
o
Alkaline phosphatase >2X 1.25x ULN; or
o
,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR  
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. In addition, subjects with abnormal laboratory results related to confirmed 
benign liver conditions (eg, Gilbert’s syndrome) are considered eligible for the study notwithstanding their 
abnormal laboratory results and may be enrolled after discussion with the Medical Monitor.
8.  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. 
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational product (whichever 
is longer) 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.
2, 4, 25, 
28
9.4.2.1/Product 
Characteristics and 
Labeling
The study drug label includes the following information: lot number, required storage conditions, a precautionary 
statement, expiry date, study number, and BioMarin name and address.  Labelling will be done according to country 
specific requirements.
28
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The study drug is labelled according to the particulars approved by the relevant regulatory agencies.
9.4.4/Directions for 
Administration
AfterOn the day of infusion, the subject will come to the infusion site, where a physical examination will be performed 
by the Investigator or designee, subjects will be admitted on the day of BMN 270 infusion. 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 therapy will not be given since venipuncture is a minimally invasive procedure in these individuals under 
ordinary conditions.
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. Prepared drug will be kept at 
room temperature prior to administration. An electric syringe pump will be used to infuse through an in-line, low 
protein binding 0.22 micron filter. BMN 270 will be infused through the catheter using an appropriate infusion pump at 
a constantan initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min up to a 
maximum of 4 mL/min while monitoring the, provided that the subject’s clinical condition permits such an increase. Of 
note, the IP has been shown to be stable at room temperature for 7.5 hours following completion of product thaw. Vital 
signs (pulse, blood pressure, respiration rate and temperature) should be monitored at 15 minute (±5 minutes) intervals.
The anticipated maximum interval from initiation of thawing of BMN 270 to completion of the infusion is 4 hours, 
although the IP has been shown to be stable at room temperature for 6 hours. throughout the 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 (ie, to a slower rate [minimum of 1 mL/min], with the rate increased every 30 minutes by 
1, 28
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1 mL/min up to a maximum rate of 4 mL/min, if the subject’s clinical condition permits such an increase) with careful 
monitoring of the subject.
In 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 within 1 hour of the hypersensitivity reaction (eg, tryptase, 
C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. 
In addition, a blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine 
bead array. Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess 
changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 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.
...
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 by the Sponsor. 
28
9.4.8/Prior and 
Concomitant 
Medications
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:
x
Any investigational therapy
x
Systemic immunosuppressive agents, except for corticosteroids
x
Emicizumab
x
Fitusiran
x
Concizumab
x
Efavirenz
2, 3, 28
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x
Lamivudine
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their participation in 270-203 must 
have their antiretroviral medication regimen approved by the Investigator and Medical Monitor prior to starting 
antiretroviral treatment.
9.4.8.1/Concomitant 
Hemophilia 
Treatments
Subjects on prophylactic FVIII therapy will discontinue their regular treatment regimen starting 4 weeks followingafter
the day of infusion or after FVIII activity has reached at least 5 IU/dL (whichever is earlier) and switch to an “on-
demand” schedule.
10
9.4.8.2/Therapeutic 
Glucocorticoid 
Treatment for 
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 (or their designee if 
consultation is required outside of the Medical Monitor's waking hours):: 
x
$/7  [ 8/1 or ALT > ULN & > 2x baseline value in 2 consecutive assessments within 72 hours and 
DOWHUQDWLYH HWLRORJLHV KDYH EHHQ UXOHG RXW RU $/7  [ 8/1 LQ  FRQVHFXWLYH DVVHVVPHQWV ZLWhin 48 hours 
(refer to Table 9.7.6.3.2)
In addition, if FVIII activity drops > 50% at any time post-BMN 270 infusion, a course of therapeutic oral 
corticosteroids should be considered upon consultation between the Investigator and the Medical Monitor.
...
)ROORZLQJ LQLWLDWLRQ RU FRPSOHWLRQ RI WKHUDSHXWLF RUDO FRUWLFRVWHURLGV LI $/7 HOHYDWLRQ [ 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 SoA. The use of COX-2 inhibitors, while 
not contraindicated during corticosteroid treatment, should be limited, if possible.  Practical management to prevent 
complications related to oral corticosteroid therapy may be undertaken at the discretion of the Investigator (eg, 
evaluation of glucose intolerance, hyperlipidemia etc.). 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 
10, 11, 20, 
28
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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.
Table 9.4.8.2.1/ 
Adjustments to 
Corticosteroid 
Regimen
Table 9.4.8.2.1 has been updated to reflect changes in the text of this section.
11, 28
Section 9.4.9/ 
Monitoring of HIV
Positive Subjects
HIV positive subjects may be enrolled in 270 203 if the subject has a CD4 count > 200/mm3 and an undetectable viral 
load.
Subjects should continue anti retroviral therapy (ART) as prescribed and follow routine monitoring of CD4 count and 
viral load (Angus, 2016).  No alterations in the monitoring are indicated for enrolled immunocompetent HIV positive 
subjects who receive corticosteroids as part of their enrollment in 270-203.
2 
9.4.10/Treatment 
Compliance
Study drug will be administered to subjects at the dosing facility by a qualified health care professional.  The quantity 
dispensed, returned, used, lost, etc. must be recorded on thea dispensing log provided for the study.  Sites will be 
instructed to return or destroy all used and unused study drug containers.
28
9.5/IP Accountability
The Investigator or designee is responsible for maintaining accurate records (including dates and quantities) of IP(s) 
received and IP lost or accidentally or deliberately destroyed. The Investigator or designee must retain all unused or 
expired study supplies until the study monitor (on-site CRA) has confirmed the accountability data, if allowed by local 
SOPs. 
28
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). 
28
9.6/Dietary or Other 
Restrictions
Subjects should be advised to abstain from any blood or sperm donation after BMN 270 infusion, until there is no 
further evidence of vector shedding from PCR analysis of samples.
21
9.7.2.1/FVIII Activity
Values for FVIII activity will be excluded from analysis if obtained within 72 hours since the last infusion of exogenous 
FVIII protein concentrates (or within 5x the known half life of the FVIII concentrates administered).. If a subject has 
used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements 
6, 10, 28
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when a 72-hour interval without FVIII use is achieved; The 72-hour wash-out period is only intended for subjects who 
KDYH DFKLHYHG )9,,,   ,8G/ DW  ZHHNV DIWHU %01  LQIXVLRQ DQG ZKR KDYH QRW UHVXPHG )9,,, UHSODFHPHQW
therapy.
In subjects who show an initial response to BMN 270 but who later have FVIII activity decline to < 5 IU/dL, the 
investigator and medical monitor will review the subject’s FVIII activity levels and discuss whether to resume prior 
FVIII prophylaxis. In addition, the investigator will notify the subject of his FVIII activity levels and will discuss with 
the subject the risk of bleeding and when (and if) prior FVIII prophylaxis will be resumed.
...
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
aFWLYLW\   ,8G/ E\ HLWKHU :HHN  RU :HHN  RU LQDELOLW\ WR PDLQWDLQ LQGHSHQGHQFH IURP SURSK\ODFWLF )9,,,
replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s 
discretion and after discussion with the Medical Monitor, follow an abbreviated visit schedule after either Week 26 or 
Week 52, as applicable and at the discretion of the Investigator. 
9.7.2.2/FVIII 
Replacement 
Therapy/Bleeding 
Episodes
Additional efficacy variables are:
x
Change of annualized utilization (IU/kg) of exogenous FVIII replacement therapy during Week 5 to Week 26 
post BMN 270 infusion from the baseline utilization of exogenous FVIII replacement therapy calculated using 
subjects’ historical medical records during the year prior to the enrollment..  
x
Change of ABRs requiring exogenous FVIII replacement treatment during Week 5 to Week 26 of the study 
post BMN 270 infusion from the baseline ABR calculated using subjects’ historical medical records during the 
year prior to the enrollment..
...
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to 
resume prior FVIII prophylaxis.
10, 28
9.7.5/Exploratory 
Assessments
In addition, 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 AAV5 gene transfer, and to develop assays used for these 
28
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evaluations. Subject 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 is optional. 
9.7.6.2/Clinical 
Laboratory 
Assessments
The scheduled clinical laboratory tests are listed in Table 9.7.6.2.1. Refer to the Study Reference Manual for 
instructions on obtaining and shipping samples.  Urine tests will be performed locally and centrally; all other laboratory 
assessments will be performed at the central laboratory. In case of a safety concern, additional unscheduled laboratory 
tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical 
management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using 
the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. 
...
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel (including triglycerides, total 
cholesterol, HDL cholesterol, and LDL cholesterol) will be assessed at the BMN 270 infusion visit. Subjects will fast 
for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit.
In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination and vital signs, 
will be done and additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, 
C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction. In addition,
a blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead array. 
Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" as described in the 
rationale of changes.
1, 14, 15, 
28
Table 9.7.6.2.1/ 
Clinical Lab Tests
Table 9.7.6.2.1 has been updated to reflect changes in the text of the protocol amendment.
12
9.7.6.3/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.  
20, 25, 28
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Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects who have cleared a Hepatitis B 
infection or are seronegative do not need to receive the Subjects with history of hepatitis B vaccination.  Subjects with 
evidence of or hepatitis C infection prior exposureto 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 9.1.46. 
Section 9.7.6.3 
(Tables)
Table 9.7.6.3.1 (Liver Tests), Table 9.7.6.3.2 (Evaluation of ALT Elevations), and Table 9.7.6.3.3 (Viral and 
Autoimmune Hepatitis Workup Testing) have been updated to reflect changes made as part of this amendment.
4, 28
Section 9.7.6.5/Vital 
Signs, Physical 
Exams and Other 
Safety Observations
A complete physical examination should be performed at Screening, Week 26, Week 52, and then yearly until the end 
of the study.  At other visits, brief physical examinations may be performed at the discretion of the Investigator based 
on the subject’s clinical condition. Particular attention should be given to signs of bleeding, as well as assessing possible 
hemarthroses. at the End of Year visits. A complete physical examination will include general appearance (head, eyes, 
ears, nose, and throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, 
musculoskeletal, and neurologic systems. 
At other visits, brief physical examinations may be performed at the discretion of the Investigator based on the subject’s 
clinical condition. A brief physical examination will include general appearance, cardiovascular, dermatologic, 
respiratory, gastrointestinal, musculoskeletal, and neurologic assessments. Particular attention should be given to signs 
of bleeding, as well as assessing possible hemarthroses.
Height will be recorded at Screening only.  Weight will be recorded at Screening and then every 4 weeks thereafter 
through Week 20, at Week 26, every 4 weeks through Week 52, and then every 3 months thereafter untilat the second 
Q12W visit each year and at every End of the studyYears visit during Years 2-5. 
5, 16, 28
9.7.6.6/Vector 
Shedding
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule (refer to Section 
12.5.3) but who have not cleared vector shedding from all fluids must still provide samples for assessment until vector 
shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 (during Year 1), every 4 weeks (during Year 2), or every 
6 weeks (during Years 3-5).
6, 13, 28
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 2 7 0- 2 0 3
 
A me n d me nt
 
1
  
 
 
 
 
 Pa ge
 
1 4 7
Pr o prietar y a n d C o nfi de ntial 
5 Oct o ber 2 0 1 8 
Secti o n N o./ Title  
Re visi o n
R ati o n ale
 ( m o bile)
E- mail: 
1 2. 2/ Scree ni n g
T he f oll o wi n g pr oce d ures will be perf or me d d uri n g t he Scree ni n g Peri o d:
F ull me dical hist or y, i ncl u di n g he m o p hilia A hist or y, He patitis B, He patitis C, a n d HI V. S u bj ects wit h a 
hist or y of he patitis B or he patitis C will be as ke d f or i nf or mati o n a b o ut t he treat me nts recei ve d. A n y pri or 
p har mac o ki netics i nf or mati o n o btai ne d w hile t he s u bj ect was recei vi n g pr o p h ylactic or o n- de ma n d F VIII 
t hera p y pri or t o t he st u d y s ho ul d als o be c ollecte d.  
Scree n f or He patitis B, He patitis C, a n d HI V if re q uire d (s u bj ects wit h d oc u me nte d ne gati ve res ults 3 0 da ys 
pri or t o i nf or me d c o nse nt bei n g o btai ne d d o n ot nee d t o be reteste d)
o
He patitis B scree ni n g s h o ul d i ncl u de H Bs A g, H Bs A b, a n d H B c A b
V o n Wille bra n d Fact or A nti ge n ( V W F: A g)
Bl o o d sa m ples f or Bi o mar ker testi n g ( ma y i ncl u de H L A ge n ot y pi n g, a n d F VIII ge n ot y pi n g stat us
I L 1 0a si n gle n ucle oti de p ol y m or p his ms) 
8, 1 8, 1 9, 
2 5
1 2. 3/ B aseli ne
T he f oll o wi n g pr oce d ures will be perf or me d d uri n g t he Baseli ne Peri o d:
Sa m ples f or h F VIII Assa ys
o
Baseli ne F VIII acti vit y – c hr o m o ge nic s u bstrate F VIII assa y
o
Baseli ne F VIII acti vit y le vel – o ne-sta ge cl otcl otti n g F VIII assa y
o
h F VIII c oa g ulati o n acti vit y e x pl orat or y assa y (c ollecte d b ut n ot teste d pri or t o e nr oll me nt)
o
h F VIII i n hi bit ors ( B et hes da assa y wit h Nij me ge n m o dificati o n)
o
h F VIII t otal a nti b o d y assa y (c ollecte d b ut n ot teste d pri or t o e nr oll me nt)
o
h F VIII a nti ge n assa y (c ollecte d b ut n ot teste d pri or t o e nr oll me nt)
V o n Wille bra n d Fact or A nti ge n ( V W F: A g) 
Bl o o d c he mistr y, he mat ol o g y, a n d c oa g ul ati o n tests (refer t o T a ble 9. 7. 6. 2. 1) 
1 2, 1 9, 2 8
D o c u Si g n E n v el o p e I D: E E 6 D 8 5 3 8- E C C A- 4 0 3 1- 9 2 4 4- D 2 0 E 3 4 2 8 8 1 4 0
PI
PI

 
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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).
12.4/Treatment Visit/ 
Day 1
The following procedures will be performed during the BMN 270 Infusion Visit:
x
Fasting blood sample for future exploratory analysis (sample collected pre-infusion)
x
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.
x
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 within 1 hour of the hypersensitivity reaction (eg, tryptase, 
C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. 
In addition, a blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine 
bead array. 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. Exploratory biomarker samples at baseline and at post-infusion 
study visits may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-
related hypersensitivity reactions" as described in the rationale of changes. 
1, 7, 15, 
28
12.5.1.1/Day 2
On Study Day 2, the following assessments will be performed:
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Separate collection on Day 2 is not required if vector shedding samples were collected on Day 1 
post-BMN 270 infusion; if collection on Day 2 is needed, it must occur within 24 hours of the 
time of the BMN 270 infusion.
28
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12.5.1.3/Day 8
On Study Day 8, the following assessments will be performed:
x
Blood sample for AAV5 TAb Assay
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity monitoring assay
x
Blood sample for AAV5 TI assay
24
12.5.2.3/Weeks 2, 3, 
4, 6, 8, 12, 16, 20, 24, 
and 26
The following procedures will be performed at Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26:
x
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.
28
12.5.2.7/Weeks 2, 6, 
10, 14, 20, 24, and 26
The following procedures will be performed at Weeks 2, 6, 10, 14, 20, 22, and 26:
x
Cytokine bead array assay
1
12.5.2.11/Week 16
The following procedure will be performed at Week 16:
x
Testing for reactivation of hepatitis B and hepatitis C (only in subjects with evidence of prior exposure will be 
tested forto hepatitis B and/or hepatitis C reactivation at Week 16.  
20
12.5.3/Weeks 27-260
52
Every 3 months (Weeks 39, 52, 65, 78, 91, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247, and 260)
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
DFWLYLW\   ,8G/ E\ :HHN  RU LQDELOLW\ WR PDLQWDLQ LQGHSHQGHQFH IURP SURSK\ODFWLF )9,,, UHSODFHPHQW WKHUDS\ GXH
to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 26 of the study by attending only the Week 
36, 44, and 52 visits during the remainder of Year 1. Such subjects following the abbreviated schedule who have not 
yet cleared vector shedding in all fluids must still provide samples at Week 32, Week 40, and Week 48, if necessary 
(but do not need to do other scheduled assessments on that date).
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).  At these visits, the 
following procedures will be completed: 
5, 6
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12.5.3.1/Every Visit
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures will be performed every 3 
months (Weeks 39, 52, 65, 78, 91, 104, 117, 130, 143, 156, 169, 182, 195, 208, 221, 234, 247, and 260) (± 2 weeks):: 
x
Physical examination
o
Brief physical examination (should be performed at all weeks except Week 52, when a complete 
physical examination should be done at Week 52, 104, 156, 208, and 260)performed
x
Weight
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding 
and FVIII use)
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical information)
x
Vital Signs
x
Blood chemistry, hematology, and coagulation tests (refer to )
x
Urine Tests (refer to )
x
Liver Function Tests (refer to Table 9.8.8.3.1) 
o
LFTsLTs 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 LFTsLTs will be monitored at least twice weekly during 
SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1... 
x
Samples for hFVIII FVIII Assays
o
Baseline FVIII activity  chromogenic FVIII assay
o
Baseline FVIII activity level  (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotclotting FVIII assay) 
o
hFVIIIFVIII coagulation activity exploratory assay (collected but not tested prior to enrollment)
o
hFVIII inhibitors (Bethesda assay (with Nijmegen modification) for FVIII inhibitor level
o
hFVIII total antibody assay (collected but not tested prior to enrollment)
o
hFVIII antigen assay (collected but not tested prior to enrollment)
5, 11, 28
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o
hFVIII total antibody assay
o
Exploratory biomarker assessments
o
Blood sample for AAV5 Total Antibody assay
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity monitoring assay
o
Blood sample for AAV5 TI assay
o
PBMC collection for CTL baseline
o
VWF:Ag 
o
Direct Thrombin test
o
Thrombin Generation Assay
o
Every 12 months (FVIII protein assay 
12.5.3.2/Weeks 52, 
104, 156, 20828, 30, 
32, 34, 36, 44, and 
260)52
The following procedures will be performed every 12 months (At Weeks 52, 104, 156, 20828, 30, 32, 34, 36, 44, and 
260) (± 2 weeks):
Haemo-QoL-A QoL assessment
EQ 5D 5L
Hemophilia Activities List (HAL)
Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific 
(WPAI+CIQ:HS) questionnaire
5, 28
12.5.3.3/Weeks 32, 
36, 44, and 52
At Weeks 32, 36, 44, and 52, the following procedures will be performed:
x
Weight
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.8.8.2.1) 
x
FVIII antibody titer
x
AAV5 TAb Assay
x
AAV5 TI Assay
5 
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x
Cytokine bead array assay
12.5.3.4/Weeks 32, 
36, 40, 44, 48, and 52
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed:
x
Exploratory biomarker assessments
x
TGA Assay
x
PCR of vector DNA in blood, saliva, urine, semen, and stoolstools
o
Sample testing during Weeks 27-260 is not required ifto occur until at least 3 consecutive samples are 
clear during the Post Infusion Follow Up period in Weeks 1 26negative sample results have been 
obtained.  Subjects who have not had 3 consecutive negative semen samples by Week 2652 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).
o
Subjects considered to be treatment failures must continue to provide samples for PCR assessment at 
these timepoints until vector shedding has cleared (in such a case, these subjects do not need to 
perform other assessments except for PCR sample delivery scheduled at these timepoints)
5, 6, 17, 
28
12.5.3.5/Week 36 and 
52
At Weeks 36 and 52, the following procedures will be performed:
x
Urine Tests (refer to Table 9.8.8.2.1)
x
Direct Thrombin test
x
VWF:Ag
5, 17
12.5.3.6/Week 52
At Week 52, the following procedures will be performed:
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
HAL
x
WPAI+CIQ:HS
5 
12.6/Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII 
DFWLYLW\   ,8G/ E\ :HHN  RU LQDELOLW\ WR PDLQWDLQ LQGHSHQGHQFH IURP SURSK\ODFWLF )9,,, UHSODFHPHQW WKHUDS\ GXH
to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
5, 6
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with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W 
and End of Year visits during Years 2-5.
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule but who have not 
cleared vector shedding from all fluids must still provide samples for assessment every 4 weeks (during Year 2) or 
every 6 weeks (during Years 3-5) until vector shedding has cleared (but do not have to perform other scheduled 
assessments at those study visits).
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed:
12.6.1/Year 2 – Every 
4 Weeks
During Year 2, every 4 weeks ( ± 2 weeks), the following procedures will be performed:
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding 
and FVIII use)
x
Liver Tests (refer to Table 9.8.8.3.1) 
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 
SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1
x
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 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Year 2 is not required if at least 3 consecutive samples are negative during the 
Post-Infusion Follow-Up period in Weeks 1-52.  Subjects who have not had 3 consecutive negative 
semen samples by Week 52 should continue to have PCR testing of semen every 4 weeks during 
Years 2 until 3 consecutive negative samples are documented (or upon consultation between the 
Investigator and Medical Monitor).
5
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o
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule 
but who have not cleared vector shedding from all fluids must still provide samples for 
assessment every 4 weeks during Year 2 until vector shedding has cleared (in such a case, these 
subjects do not need to perform other assessments except for PCR sample delivery scheduled at 
these timepoints).
12.6.2/Years 3-5 –
Every 6 Weeks
During Years 3-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding 
and FVIII use)
x
Liver Tests (refer to Table 9.8.8.3.1) 
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 subjecW¶V $/7 LV  [ 8/1
x
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 
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Years 3-5 is not required if at least 3 consecutive samples are 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).
5
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o
Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule 
but who have not cleared vector shedding from all fluids must still provide samples for 
assessment every 6 weeks during Years 3-5 until vector shedding has cleared (in such a case, 
these subjects do not need to perform other assessments except for PCR sample delivery 
scheduled at these timepoints).
12.6.3/Years 2-5 –
Every 12 Weeks and 
End of Year Visits
During Years 2-5, subjects will be asked to return to the study site for visits at the following study weeks ( ± 2 weeks):
x
Year 2 – Week 64, Week 76, Week 88, Week 104
x
Year 3 – Week 116, Week 128, Week 140, Week 156
x
Year 4 – Week 168, Week 180, Week 192, Week 208
x
Year 5 – Week 220, Week 232, Week 244, Week 260
For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and Week 260) will serve as an End 
of Year visit.
At the every 12 week and End of Year visits, the following procedures will be performed:
x
Brief physical examination (at every 12 week visits) or complete physical examination (at End of Year visits)
x
Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
x
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for bleeding 
and FVIII use)
x
Liver Tests (refer to Table 9.8.8.3.1) 
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 
SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1
x
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
5
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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 
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.8.8.2.1) (at Week 76, Week 128, Week 
180, Week 232, and End of Year visits only)
x
Urine Tests (refer to Table 9.8.8.2.1) (at Week 76, Week 128, Week 180, Week 232, and End of Year visits 
only)
x
Vital Signs
x
AAV5 TAb Assay
x
AAV5 TI Assay
x
FVIII antibody titer
x
Haemo-QoL-A assessment (at End of Year visits only)
x
EQ-5D-5L (at End of Year visits only)
x
HAL (at End of Year visits only)
x
WPAI+CIQ:HS (at End of Year visits only)
x
Exploratory biomarker assessments
x
PBMC collection
x
VWF:Ag
x
Direct Thrombin test 
x
TGA Assay
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
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Section No./Title
Revision
Rationale
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).
15/DRB
The Data Review Board (DRB) will consist of the 2 Principal Investigators and Sponsor’s Medical Monitor, as well as 
hemophilia expert advisors experienced in the conduct and evaluation of safety and efficacy parameters from 270-201.
28
Appendix 1/ 
Sampson’s 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):
1
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Section No./Title
Revision
Rationale
a.
Infants and children: low systolic blood pressure (age specific) or greater than 30% decrease is 
systolic BP
b.
Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that person’s baseline.
Source: Sampson, 2006.
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4 October 2019 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment 2 
Date: 4 October 2019 
RATIONALE AND SUMMARY OF CHANGES 
A summary of major changes covered by Amendment 2 to the 270-203 protocol is provided 
below: 
1. Prophylactic corticosteroids starting on Day 1 (day of BMN 270 infusion) have been 
added for all subjects. 
Rationale: Preliminary data from the 270-201 and 270-301 studies suggest that earlier 
initiation of corticosteroid treatment decreases the number and severity of ALT elevations 
and concomitant decreases in FVIII activity following BMN 270 infusion. Prophylactic 
corticosteroid treatment, in a regimen similar to what was used in 270-201, is therefore being 
instituted in this protocol in an effort to increase subject safety in patients with detectable 
pre-existing immunity to the vector capsid and maximize treatment response.  
2. The threshold for considering the additional use of therapeutic oral corticosteroids has 
been lowered. 
Rationale: 7KH SUHYLRXV WKUHVKROG ZDV $/7  [ 8/1 RU $/7 ! 8/1 	 ! [ EDVHOLQH
WKH QHZ WKUHVKROG LV $/7  8/1 RU  [ EDVHOLQH 7KLV FKDQJH ZLOO HQFRXUDJH HDUOLHU
treatment with corticosteroids, which could help decrease the extent of increases in ALT and 
better preserve FVIII expression. 
3. Subjects considered to be treatment failures (ie, those who either fail to achieve FVIII 
DFWLYLW\ !  ,8G/ E\ WKH FKURPRJHQLF VXEVWUDWH DVVD\ RU DUH XQDEOH WR PDLQWDLQ
independence from prophylactic FVIII replacement therapy due to joint bleeding 
episodes) may now start following an abbreviated visit schedule only after Week 52, 
not after Week 26. 
Rationale: Emerging data demonstrate that ALT elevations or increases in FVIII activity 
PD\ RFFXU EHWZHHQ :HHNV  DQG  therefore, it is important to maintain the standard visit 
schedule through Week 52. 
4. Vector shedding and contraception use language has been updated to change the 
determination of a “clear” result from negative to below the limit of detection. 
Rationale: The change in language better reflects regulatory guidance documents.  
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5. The Direct Thrombin Assay has been removed. 
Rationale: Based on the lack of correlation observed between FVIII activity levels and the 
Direct Thrombin Assay results in Study 270-201, the test is no longer being collected across 
the BMN 270 clinical development program. 
6. The option to assess an adverse event as related/not related to corticosteroids has been 
added. 
Rationale: With all subjects taking prophylactic corticosteroids, AEs associated with 
corticosteroids are possible and should be noted as such on the eCRF (and for safety 
monitoring and risk:benefit assessment purposes). 
7. A two-step screening process has been introduced. 
Rationale: During step 1 of the screening process, potential subjects may be tested for 
AAV5 TAb titers using a screening assay developed for that purpose. Given that AAV5 TAb 
positivity is required for this study, completing this step first allows subjects who are not 
AAV5 TAb positive to avoid the unnecessary burden of working through additional 
screening steps before finding out they are not eligible to participate in the study. 
8. Language has been added to permit use of mobile nursing (MN) services, provided 
that the site is able to implement them and the subject consents, for certain designated 
study visits. 
Rationale: Allowing for MN services at designated study visits will help alleviate subject 
travel burden. 
9. The period of recommended abstinence from alcohol after BMN 270 infusion was 
increased from 26 weeks to 52 weeks, to support subject liver health and subject 
safety. 
10. The period in the exclusion criteria during which subjects should not have planned 
major surgeries following BMN 270 infusion was increased from 26 to 52 weeks, for 
purposes of aligning with other BMN 270 studies and for the protection of patient 
safety. 
11. Product characteristics and labeling have been updated to reflect the current 
manufacturing process. 
12. The identity of the Medical Monitor has been updated. 
13. The Data Review Board (DRB) has been changed to a independent Data Monitoring 
Committee (DMC). 
14. The vector genome schematic has been updated. 
15. Risk-benefit language has been updated to reflect more current clinical results. 
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16. Inconsistency in the Schedule of Assessments concerning collection of AAV5 TI and 
TAb assay has been clarified. 
17. The proposed number of study sites has been increased. 
18. To reduce subject burden and align with other studies in the BMN 270 clinical 
development program, the every 4 week visits during Year 2 post-infusion have been 
changed to every 6 week visits. 
19. 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 the Amendment 1 (dated 5 October 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 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  
A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus 
Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual 
)9,,, /HYHOV   ,8G/ DQG 3UH-existing Antibodies Against AAV5 
PROTOCOL NUMBER: 
270-203 
STUDY SITES: 
Approximately 5-6 sites globally 
PHASE OF DEVELOPMENT: 
Phase 1/2 
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.   
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived or 
recombinant human FVIII protein (rhFVIII) concentrates, both as prophylaxis 2-3 times per week 
or 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. While infusion 
of FVIII is a major advance in the treatment of HA, severe HA patients continue to have bleeding 
HYHQWV RQ SURSK\ODFWLF WKHUDS\ PHGLDQ $%5V ZHUH -4 with prophylactic treatment in a recently 
published retrospective observational study (Berntorp, 2017) and between 1-2 in 6 prospective 
FVIII interventional studies.  Median ABRs were 4.5-18 and between 20-60 with on-demand-only 
therapy in the same studies, respectively. Continued repeated bleeding events compound 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
debilitating multiple-joint arthropathies as well as the risk of catastrophic events such as 
intracranial hemorrhage and death. 
Extended half-life products created through chemical modification (eg, direct conjugation of 
polyethylene glycol (PEG) polymers) or bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can 
only extend half-life by approximately 50% (half-life 18-19 hours), 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. More recently, 
emicizumab has been approved for the treatment of HA. Emicizumab is a humanized, bispecific 
monoclonal antibody that binds to both activated coagulation factor IX (FIX) and coagulation 
factor X (FX), thereby mimicking the function of activated FVIII. Emicizumab represents an 
incremental improvement in therapeutic burden over replacement FVIII products since it can be 
DGPLQLVWHUHG VXEFXWDQHRXVO\ DV RSSRVHG WR LQWUDYHQRXVO\ KRZHYHU LW LV VWLOO D FKURQLF WUHDWPHQW
that requires repeat administration every 1-4 weeks, and sustained FVIII activity levels above 
5-10 IU/dL have rarely been attained even with extended half-life products. Therefore, there is a 
strong unmet need for a treatment that can alter the fundamental problem for patients with HA, 
namely attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over 
multiple years) without the need for treatment.  
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. 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. Moreover, the circulating FVIII response to gene transduction 
can be assessed using validated quantitative endpoints that are easily assayed using established 
laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 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 (eg serotypes 2, 5, and 8).  
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
over 7 years of stable human factor IX (hFIX) expression at levels sufficient for conversion of their 
bleeding phenotype from severe to moderate or mild, following a single peripheral vein infusion of 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
AAV8-hFIX vector (Nathwani, 2018). Several participants in this trial have been able to 
discontinue factor prophylaxis without suffering spontaneous hemorrhages, even when they 
undertook activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted 
in a substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a hybrid human liver-specific promoter (Figure 1).
Figure 1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein
Legend –1RWH WKDW VFKHPDWLF LV QRW WR VFDOH DD  DPLQR DFLGV ,75  LQYHUWHG WHUPLQDO UHSHDW +/3  KXPDQ
OLYHU SURPRWHU .R]DN  .R]DN FRQFHQVXV VHTXHQFH *&&$&& 6S$  6\QWKHWLF SRO\$ VLJQDO
BMN 270 is delivered by a single IV dose and is designed to achieve stable, durable expression of 
active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose 
escalation study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 
at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201 
explores the relationship of vector dose to the augmentation of residual FVIII activity and whether 
these levels are sufficient to alter the clinical phenotype. Three-year results from 270-201 have 
demonstrated that following gene transfer, mean and median FVIII activity levels above 15% 
(15 IU/dL), as measured by a chromogenic substrate assay, are achievable and sustained following 
a single infusion of 6E13 vg/kg of BMN 270, with administration of prophylactic corticosteroids 
and an acceptable safety profile (Pasi, 2019). In addition, an interim analysis of clinical study 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
270-301, an ongoing phase 3 study designed to assess the efficacy and safety of BMN 270 at a 
dose of 6E13 vg/kg and administration of therapeutic corticosteroids (ie, in response to ALT 
elevations), demonstrated FVIII activity levels that were also well above 15%, albeit lower than 
what was observed for the 6E13 vg/kg cohort in 270-201 at 26 weeks (Pasi, 2019). 
Subjects enrolled and infused in 270-201 screened negative for AAV5 antibodies, as the prevailing 
expectation has been that vector-specific antibodies could interfere with receptor binding and 
effectively neutralize efficient transduction of the target cell population. As this was the first FVIII 
gene therapy with AAV5 in humans, this criterion was adopted out of an abundance of caution. 
These pre-existing vector-specific antibodies are thought to arise from previous exposure to AAV, 
with seroprevalence varying across human populations and across studies. AAV5 has consistently 
been shown to have the lowest seroprevalence among the common AAV serotypes (Boutin, 2010
Hayes, 2019).  
Current data describing the extent of neutralization or inhibited transduction has been inconsistent 
across studies, each employing one of several varying methodologies to evaluate both vector-
specific antibodies and transduction inhibition (TI). Early studies using AAV2 for the treatment of 
hemophilia B described inhibited transduction in patients with neutralizing antibody titers of 2 or 
3 (Manno, 2006), but more recent studies have described successful transduction in patients who, 
in retrospect, were determined to have pre-existing antibody to the vector capsid (Majowicz, 2017).  
Importantly, no drug-related adverse events were described in these patients.  As the sensitivity of 
assays used to detect pre-existing antibody has increased greatly in recent years, the biological 
relevance of any given titer determination, and comparisons across studies using assays with 
differing titer sensitivities, requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of available 
data shows the effect of pre-existing immunogenicity to AAV delivery vectors is not completely 
understood, and indicates that some patients may benefit from AAV5 gene therapy who are 
currently excluded.  
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be enrolled to 
evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate the safety, 
tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing antibodies 
against AAV5 vector capsid at various levels of AAV5 antibody titers. 
 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
OBJECTIVES:  
The primary objective of the study is to: 
 
x 
Assess the safety of a single intravenous administration of BMN 270 in severe HA subjects 
with pre-existing antibody to AAV5 vector capsid, including development of FVIII 
neutralizing antibody 
Secondary objectives of the study are to: 
 
x 
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26 
x 
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy 
x 
Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous 
FVIII therapy 
x 
Evaluate the pharmacodynamics of FVIII expression following IV infusion of BMN 270 
x 
Assess the impact of BMN 270 on patient-reported outcomes (PROs) 
STUDY DESIGN AND PLAN:  
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), with a 
history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with pre-existing 
antibodies to the AAV5 vector capsid as measured by total antibody [TAb] assay. Approximately 
10 subjects may be enrolled at 5-6 sites in 2 cohorts (5 subjects in each cohort) and will receive a 
single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a Screening 
$$9 7$E WLWHU   ZKLOH VXEMHFWV LQ &RKRUW  ZLOO KDYH D 6FUHHQLQJ $$9 7$E WLWHU ! 500.  
Choosing a titer cutoff of 500 reflects the observed distribution of existing titer data with the 
BioMarin titer assay seen to date. 
An independent Data Monitoring Committee (DMC) will consist of experts in clinical trials, 
statistics, and hemophilia. The DMC will review available safety and efficacy data throughout the 
study and provide recommendations based on their review (Figure 2 represents one dosing 
schedule scenario): 
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Figure 2:  270-203 Dosing Schedule (One Possible Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening 
AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a maximum of 
5 subjects have been dosed in Cohort 1 and had their safety and efficacy data (from a minimum of 
6 weeks post-LQIXVLRQ UHYLHZHG )9,,, DFWLYLW\   DIWHU VL[ ZHHNV SRVW-infusion is expected to 
be the earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who 
later achieved normal FVIII activity levels, compared with the one subject who had a slightly 
lower response, based on data from 270-201. Up to 6 weeks post-infusion will provide an 
appropriate timeframe to evaluate the development of any potential delayed hypersensitivity 
reaction (eg, serum sickness).  
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on 
DMC evaluation of safety and efficacy in treated subjects, with the following triggers that may 
potentially pause further enrollment:  
x
DQ\ UHODWHG 6$(
x
DQ\ UHODWHG $( ZLWK D VHYHULW\ ! &7&$( *UDGH  RU
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks post-BMN 270 
infusion.
Following a temporary halt of enrolment, the DMC may approve resumption of enrolment in either 
cohort at a later date at its discretion based on further analysis of accumulating data. 
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 
24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In case of 
suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to physical 
examination and vital signs, will be performed. Additional blood samples will be collected 
(tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory 
testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) will be collected between 8-24 hours after the 
reaction. In addition, a blood sample should be taken 1 week after the hypersensitivity reaction for 
assessment of the cytokine bead array. Exploratory biomarker samples at baseline and at post-
infusion study visits may also be used to assess changes in these biomarkers to better elucidate the 
mechanisms of infusion-related hypersensitivity reactions. Any safety signal may trigger a review 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
of the data and possible additional immunogenicity studies or other diagnostics deemed necessary 
to assess cellular immune responses using collected peripheral blood mononuclear cells (PBMCs).  
The duration of observation may be extended and additional blood samples collected at the 
discretion of the Investigator and Medical Monitor. 
Data from 270- VXJJHVW WKDW DFKLHYHPHQW RI WKHUDSHXWLF )9,,, OHYHOV  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII protection 
ZKLOH VXEMHFWV DUH SURMHFWHG WR UHDFK FOLQLFDOO\ UHOHYDQW )9,,, OHYHOV   ,8G/ SULRU )9,,,
prophylaxis for each subject will be continued at the discretion of the DMC based on individual 
subject status and data review or when FVIII activity has reached at least 5 IU/dL. In subjects who 
experience recurring bleeding episodes, the Investigator and Medical Monitor will discuss whether 
to resume prior FVIII prophylaxis.  
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either 
failure to achieve FVIII activity   ,8G/ 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 by attending 
only the Q12W and End of Year visits during Years 2-5.  
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. After the 
safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, long-term safety and 
efficacy will be assessed in all subjects for up to a total of 5 years post-infusion. During the trial, 
additional subjects may be recruited into each cohort at any time, if deemed necessary by the 
DMC.   
NUMBER OF SUBJECTS PLANNED:  
Approximately 10 subjects  
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
1. 0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as evidenced 
by medical history, at the time of signing the informed consent.  
2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total 
antibody ELISA 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days 
(EDs) 
4. Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior 
to study entry.   
5. 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. 
6. 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)  
7. Sexually active participants must agree to use an acceptable method of effective contraception, 
either double-EDUULHU FRQWUDFHSWLRQ LH FRQGRP  GLDSKUDJP RU FRQGRP RU GLDSKUDJP 
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-LQIXVLRQ DIWHU  ZHHNV VXEMHFWV PD\ VWRS FRQWUDFHSWLRQ XVH RQO\ LI WKH\ KDYH KDG
3 consecutive semen samples with viral vector DNA below the limit of detection. 
8. Willing to abstain from consumption of alcohol for at least the first 52 weeks following 
BMN 270 infusion. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Any evidence of active infection or any immunosuppressive disorder, including HIV infection.  
2. Significant liver dysfunction with any of the following abnormal laboratory results: 
o $/7 DODQLQH DPLQRWUDQVIHUDVH ! [ 8/1 
o A67 DVSDUWDWH DPLQRWUDQVIHUDVH ! [ 8/1 
o GGT (gamma-JOXWDP\OWUDQVIHUDVH ! [ 8/1 
o 7RWDO ELOLUXELQ ! [ 8/1 
o $ONDOLQH SKRVSKDWDVH ! [ 8/1 RU 
o ,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR   
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4 October 2019 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
Subjects 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.  
3. 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 
4. Evidence of any bleeding disorder not related to hemophilia A 
5. Platelet count of < 100 x 109/L 
6. Creatinine   PJG/ 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound  
8. 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 . 
9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy 
10. Active malignancy, except non-melanoma skin cancer 
11. History of hepatic malignancy 
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with 
the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not 
currently ongoing.  
13. .QRZQ LQKHULWHG RU DFTXLUHG WKURPERSKLOLD LQFOXGLQJ FRQGLtions associated with increased 
thromboembolic risk, such as atrial fibrillation. 
14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, vasculitis). 
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational 
product (whichever is longer) prior to the screening period. For subjects who have received a 
prior investigational product, all ongoing adverse events (AEs) experienced while receiving 
that investigational product must have resolved prior to screening for this study 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including possible corticosteroid 
treatment outlined in the protocol) and/or would impact or interfere with evaluation and 
interpretation of subject safety or efficacy result. 
17. Prior treatment with any vector or gene transfer agent 
18. Major surgery planned in the 52-week period following the infusion with BMN 270 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines 
within 30 days before the BMN 270 infusion 
20. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of safety and efficacy of BMN 270 and 
with prior consultation with the Medical Monitor 
21. .QRZQ DOOHUJ\ RU K\SHUVHQVLWLYLW\ WR LQYHVWLJDWLRQDO SURGXFW IRUPXODWLRQ 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single IV infusion of BMN 270 at 6E13 vg/kg. The volume of infusion 
will depend on the subject’s weight. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
No reference therapy will be evaluated in this study. 
DURATION OF TREATMENT:  
BMN 270 is given as a single dose by IV infusion. 
CRITERIA FOR EVALUATION: 
Safety: 
The following safety outcome measurements will be assessed: 
x 
Incidence of adverse events (AEs), including serious AEs (SAEs)  
x 
Change in clinical laboratory tests (serum chemistry and hematology) 
x 
Change in vital signs 
x 
Change in physical examination  
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
x 
Vector shedding (blood, urine, semen, feces, saliva) 
x 
Liver tests (LTs, including ALT, AST, GGT, total bilirubin, and alkaline phosphatase) 
x 
Immune response to FVIII transgene product and AAV5 vector capsid 
No major toxicity is expected based on 270-201 data and non-clinical studies. Each subject will 
have comprehensive surveillance monitoring of LTs (once per week for Weeks 1-26). During the 
long-term safety evaluation, LTs will be monitored every three months for up to 5 years 
post-LQIXVLRQ WKH IUHTXHQF\ DQG GXration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator and review of subject data.  
There will be a detailed assessment of cellular and humoral responses to AAV5 vector capsid and 
FVIII.   
Efficacy:  
The efficacy measure will be to assess plasma FVIII activity. The efficacy goal is to achieve FVIII 
DFWLYLW\   ,8G/ DW  ZHHNV SRVW-BMN 270 administration. Other efficacy measures include 
assessing the impact of BMN 270 on the use of FVIII replacement therapy and on the number of 
bleeding episodes during the study. Subjects will be asked to keep a subject diary, provided by the 
sponsor, to record the relevant details.  
Other efficacy endpoints:   
x 
Change from baseline in the total score of HAEMO-QoL-A at Week 26 of the study post-
BMN 270 infusion 
x 
Change from baseline in the EQ-5D-5L score at Week 26 of the study post-BMN 270 
infusion. 
x 
Change from baseline in the Haemophilia Activities List (HAL) score at Week 26 of the 
study post-BMN 270 infusion. 
x 
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 26 of the 
study post-BMN 270 infusion. 
Pharmacodynamics:  
The FVIII antigen and activity level, as measured by a validated immunoassay and a validated 
)9,,, DFWLYLW\ DVVD\ UHVSHFWLYHO\ ZLOO EH XVHG IRU SODVPD SURILOHV )9,,, DQWLJHQ DQG DFWLYLW\ ZLOO
be used to determine PD parameters.   
STATISTICAL METHODS:  
Approximately 10 subjects may be dosed in the study. The subjects will be followed in a 
longitudinal manner, and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature, but data collected in a longitudinal manner may be analyzed using 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
longitudinal methods, such as a mixed effect model, which take into account the correlation among 
the observations taken at various time points within a subject. Efficacy is a secondary endpoint, 
GHILQHG DV ELRORJLFDOO\ DFWLYH )9,,, DW  5 IU/dL at 26 weeks following study treatment. FVIII 
activity will be assessed weekly during the study period. Assessment of the true steady state of 
FVIII will require that FVIII activity is measured after a minimum of 72 hours (or 5x the known 
half-life of the FVIII replacement therapy administered) has elapsed since the last infusion of FVIII 
concentrates.  
Analysis of neutralizing antibody response, other immunological parameters, and vector shedding 
will be primarily descriptive and involve both inter-subject and intra-subject comparisons across 
cohorts. 
 
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3 TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2 
2 SYNOPSIS ...........................................................................................................................5 
3 TABLE OF CONTENTS ...................................................................................................17 
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 ...................................................................................................29 
7.2 Previous Clinical Studies ..........................................................................................29 
7.3 Study Rationale .........................................................................................................30 
7.4 Summary of Overall Risks and Benefits ...................................................................34 
8 STUDY OBJECTIVES ......................................................................................................36 
9 INVESTIGATIONAL PLAN ............................................................................................37 
9.1 Overall Study Design and Plan .................................................................................37 
9.2 Discussion of Study Design, Including Choice of Control Group ............................55 
9.3 Selection of Study Population ...................................................................................55 
9.3.1 
Inclusion Criteria .........................................................................................55 
9.3.2 
Exclusion Criteria ........................................................................................56 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................58 
9.3.4 
Subject Identification and Replacement of Subjects ...................................60 
9.3.5 
Duration of Subject Participation ................................................................60 
9.4 Treatments .................................................................................................................60 
9.4.1 
Treatments Administered ............................................................................60 
9.4.2 
Identity of Investigational Product ..............................................................60 
9.4.3 
Storage .........................................................................................................61 
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9.4.4 
Directions for Administration .....................................................................61 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................63 
9.4.6 
Selection of Dose Used in the Study ...........................................................63 
9.4.7 
Blinding .......................................................................................................63 
9.4.8 
Prior and Concomitant Medications ............................................................63 
9.4.9 
Treatment Compliance ................................................................................67 
9.5 Investigational Product Accountability .....................................................................67 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................67 
9.6 Dietary or Other Protocol Restrictions......................................................................67 
9.7 Efficacy and Safety Variables ...................................................................................68 
9.7.1 
Efficacy and Safety Measurements Assessed .............................................68 
9.7.2 
Efficacy Variables .......................................................................................68 
9.7.3 
Immunogenicity ...........................................................................................70 
9.7.4 
Pharmacodynamics ......................................................................................70 
9.7.5 
Exploratory Assessments ............................................................................71 
9.7.6 
Safety Variables ..........................................................................................71 
10 REPORTING ADVERSE EVENTS .................................................................................79 
10.1 Safety Parameters and Definitions ............................................................................79 
10.1.1 Adverse Events ............................................................................................79 
10.2 Serious Adverse Events ............................................................................................80 
10.2.1 Events of Special Interest (EOSI) ...............................................................81 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................81 
10.3.1 Adverse Event Reporting Period .................................................................81 
10.3.2 Eliciting Adverse Events .............................................................................81 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................81 
10.4 Procedures for Recording Adverse Events ...............................................................84 
10.4.1 Recording Adverse Events on a eCRF ........................................................84 
10.5 Reporting Requirements ...........................................................................................87 
10.5.1 Expedited Reporting Requirements .............................................................87 
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10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements..............................................................................88 
10.6 Follow-up of Subjects after Adverse Events .............................................................88 
10.7 Post-Study Adverse Events .......................................................................................88 
10.8 Urgent Safety Measures ............................................................................................89 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................90 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................91 
12 STUDY PROCEDURES ...................................................................................................92 
12.1 Prestudy .....................................................................................................................92 
12.2 Screening Visit(s) ......................................................................................................92 
12.2.1 “Smart Rescreening” Visit ..........................................................................93 
12.3 Baseline Visit ............................................................................................................94 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................95 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................96 
12.5.1 Week 1 .........................................................................................................97 
12.5.2 Weeks 2-26 ..................................................................................................98 
12.5.3 Post-Infusion Follow-Up – Weeks 27-52 ..................................................101 
12.6 Post-Infusion Follow-Up – Years 2-5 .....................................................................103 
12.6.1 Years 2-5 – Every 6 Weeks (not required for treatment failure) ...............103 
12.6.2 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)................................................................................................104 
12.7 Early Termination Visit ..........................................................................................106 
12.8 End of Study............................................................................................................107 
13 DATA QUALITY ASSURANCE ...................................................................................108 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................109 
14.1 Statistical and Analytical Plans ...............................................................................109 
14.1.1 Interim Analyses ........................................................................................109 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........109 
14.2 Efficacy Analysis ....................................................................................................109 
14.3 Safety Analysis .......................................................................................................109 
14.4 Determination of Sample Size ................................................................................110 
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14.5 Analysis Populations ...............................................................................................110 
14.6 Changes in the Conduct of the Study or Planned Analyses ....................................110 
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 
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 Subjects.............................................122 
23 SIGNATURE PAGE .......................................................................................................123 
24 APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA .........................................124 
25 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................125 
 
LIST OF TABLES 
Table 9.1.1: Schedule of Activities – Screening/Baseline/Day 1 ............................................40 
Table 9.1.2:  Schedule of Activities – Post-Infusion Follow-Up (Week 1-16) .......................43 
Table 9.1.3:  Schedule of Activities – Post-Infusion Follow-Up (Week 17-32) .....................46 
Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52) .....................49 
Table 9.1.5:  Schedule of Events – Long-Term Follow-Up (Year 2 – Year 5) .......................51 
Table 9.1.6:  Suggested Schedule of Events – Prophylactic Corticosteroids ..........................54 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen .......................................................66 
Table 9.7.6.2.1:  Clinical Laboratory Tests .............................................................................72 
Table 9.7.6.3.1:  Liver Tests ....................................................................................................74 
Table 9.7.6.3.2:  Evaluation of ALT Elevations ......................................................................75 
Table 9.7.6.3.3:  Viral and Autoimmune Hepatitis Testing .....................................................76 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................82 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................83 
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LIST OF FIGURES 
Figure 1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein .........................................7 
Figure 2:  270-203 Dosing Schedule (One Possible Scenario) ................................................10 
Figure 7.3.1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein .................................32 
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario) ........................................................37 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
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 
EC 
ethics 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 
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hFIX 
human coagulation factor IX 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LT 
liver test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
mobile nursing 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
3. 
Pharmacokinetics 
PRO 
patient-reported outcome 
rhFVIII 
recombinant human FVIII protein 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
SoA 
schedule(s) of activities 
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 (EC) 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/EC will be provided to BioMarin Pharmaceutical Inc. (BioMarin) 
or its designee. The Investigator will provide the IRB/EC 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/EC 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/EC 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 
HOLJLEOH VXEMHFWV IRU VWXG\ HQUROOPHQW DGKHULQJ WR DGYHUVH HYHQW UHSRUWLQJ GLDJQRVWLF RU
other procedures as specLILHG LQ WKH SURWRFRO DQG DVVXULQJ DSSURSULDWH FRPSOLDQFH ZLWK VWXG\
treatment administration and accountability. 
This study will be conducted in accordance with the following: 
x European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country 
x US Code of Federal Regulations (CFR) Sections that address clinical research studies, 
and/or other national and local regulations, as applicable 
x ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R2) 
(ICH E6R2) 
x The ethical principles established by the Declaration of Helsinki 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/EC and will be conducted by scientifically and medically qualified persons. The benefits 
of the study are in proportion to the risks. The rights and welfare of the subjects will be 
respected and the investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed informed consent form (ICF), in compliance with ICH E6R2 
(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/EC approval. BioMarin and the 
IRB/EC 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. 
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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. Subjects 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 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.  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 (12-18 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 (.DXIPDQ ). 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 WKXV WKH WKHUDSHXWLF JRDO IRU JHQH
therapy is a modest increase in hFVIII. Finally, the consequences of gene transfer can be 
assessed using validated quantitative endpoints that can be easily assayed in most clinical 
laboratories. 
BMN 270 contains the cDNA for the B-domain-deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs, and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 
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7.1 
Nonclinical Studies 
The nonclinical program supports a single IV 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 
products under EMA Advanced Therapies as well as FDA guidance. The primary 
SKDUPDFRG\QDPLFV 3' SKDUPDFRNLQHWLFV 3. DQG WR[LFLW\ RI ,9 %01 270 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 
PRGHO RI KHPRSKLOLD $ %6-F8tm1Kaz/J x B6.129S6-Rag2tm1Fwa 1 )9,,, .2 [ 5DJ
and normal cynomolgus anG UKHVXV PRQNH\V 6RPH 3' VWXGLHV HYDOXDWHG DGGLWLRQDO 3.
immunogenicity and toxicity endpoints. 
The comparative pharmacodynamics of BMN 270 in cynomolgus monkeys with varying 
pre-existing AAV5 transduction inhibition (TI) titer and AAV5 TAb status was evaluated in 
study BMN270-16-021. BMN 270 was administered to 4 groups of monkeys, a control group 
*URXS  Q  WKDW WHVWHG QHJDWLYH IRU ERWK 7, DQG $$9 7$E *URXS  Q  WKDW ZDV
AAV5 TAb negative, and low TI titer (2- SRVLWLYH *URXS  Q  ZDV DOVR AAV5 TAb 
negative, but had higher TI titers (5- *URXS  Q  WHVWHG SRVLWLYH IRU ERWK $$9 7$E
DQG 7, 7, WLWHUV ZHUH ! $GPLQLVWUDWLRQ RI %01  E\ D VLQJOH LQWUDYHQRXV EROXV
injection was well-tolerated in cynomolgus monkeys regardless of baseline TI titer or TAb 
status. After dosing, all monkeys showed FVIII-SQ levels above the LLOQ, with the 
exception of two monkeys in the group that presented with both positive TI and TAb titers at 
baseline. Though these TAb+ monkeys, regardless of TI titers, showed a significant mean 
reduction in FVIII expression (68% less) compared to TAb negative monkeys, three of five 
monkeys showed detectable levels of FVIII-SQ, with one having levels similar to that 
observed in the TI and TAb negative control group. Monkeys that were TI+ but TAb-at 
baseline had FVIII expression levels that were similar to those of the TI and TAb negative 
control group.  
Results of the nonclinical program to date are detailed in the IB supplied by BioMarin.  
Investigators are to review this document prior to initiating this study. 
7.2 
Previous Clinical Studies 
Ongoing clinical studies for BMN 270 include: 
x 270-201, a phase 1/2, dose-escalation study in patients with severe HA 
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x 270-203, a phase 1/2 study in patients with severe HA who have anti-AAV5 antibody 
titers 
x 270-301, a phase 3 study in patients with severe HA who receive BMN 270 at the 
6E13 vg/kg dose level 
x 270-302, a phase 3 study in patients with severe HA who receive BMN 270 at the 
4E13 vg/kg dose level 
A comprehensive review of safety, efficacy, and immunogenicity results from 270-201 and 
270-301 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.   
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived 
or recombinant human FVIII protein (rhFVIII) concentrates, both as prophylaxis 2-3 times 
per week or 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. While infusion of FVIII is a major advance in the treatment of HA, severe HA 
SDWLHQWV FRQWLQXH WR KDYH EOHHGLQJ HYHQWV RQ SURSK\ODFWLF WKHUDS\ PHGLDQ $%5V ZHUH -4 
with prophylactic treatment in a recently published retrospective observational study 
(Berntorp, 2017) and between 1-2 in 6 prospective FVIII interventional studies.  Median 
ABRs were 4.5-18 and between 20-60 with on-demand-only therapy in the same studies, 
respectively. Continued repeated bleeding events compound debilitating multiple-joint 
arthropathies as well as the risk of catastrophic events such as intracranial hemorrhage and 
death. 
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Extended half-life products created through chemical modification (eg, direct conjugation of 
polyethylene glycol (PEG) polymers) or bioengineering of FVIII (eg, FVIII-Fc fusion 
proteins) can only extend half-life by approximately 50% (half-life 18-19 hours), 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. More recently, emicizumab has been approved for the treatment of 
HA. Emicizumab is a humanized, bispecific monoclonal antibody that binds to both activated 
coagulation factor IX (FIX) and coagulation factor X (FX), thereby mimicking the function 
of activated FVIII. Emicizumab represents an incremental improvement in therapeutic 
burden over replacement FVIII products since it can be administered subcutaneously as 
RSSRVHG WR LQWUDYHQRXVO\ KRZHYHU LW LV VWLOO D FKURQLF WUHDWPHQW WKDW UHTXLUHV UHSHDW
administration every 1-4 weeks, and sustained FVIII activity levels above 5-10 IU/dL have 
rarely been attained even with extended half-life products. Therefore, there is a strong unmet 
need for a treatment that can alter the fundamental problem for patients with HA, namely 
attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over 
multiple years) without the need for treatment.  
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. 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. Moreover, the 
circulating FVIII response to gene transduction can be assessed using validated quantitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 
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 (eg 
serotypes 2, 5, and 8).  Indeed, an ongoing gene therapy clinical trial for a related disorder, 
hemophilia B, has established over 7 years of stable human factor IX (hFIX) expression at 
levels sufficient for conversion of their bleeding phenotype from severe to moderate or mild, 
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following a single peripheral vein infusion of AAV8-hFIX vector (Nathwani, 2018). Several 
participants in this trial have been able to discontinue factor prophylaxis without suffering 
spontaneous hemorrhages, even when they undertook activities that previously resulted in 
bleeding. Thus, gene therapy treatment has resulted in a substantial improvement in their 
quality of life.  
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a hybrid human liver-specific promoter (Figure 7.3.1).
Figure 7.3.1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein
Legend –1RWH WKDW VFKHPDWLF LV QRW WR VFDOH DD  DPLQR DFLGV ,75  LQYHUWHG WHUPLQDO UHSHDW +/3  KXPDQ OLYHU SURPRWHU
.R]DN  .R]DN FRQFHQVXV VHTXHQFH *&&$&& 6S$  6\QWKHWLF SRO\$ VLJQDO
BMN 270 is delivered by a single IV dose and is designed to achieve stable, durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.  
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 
dose escalation study in subjects with severe HA designed to assess the safety and efficacy of 
BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. Three-
year results from 270-201 have demonstrated that following gene transfer, mean and median 
FVIII activity above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are 
achievable and sustained following a single infusion of 6E13 vg/kg of BMN 270, with 
administration of prophylactic corticosteroids and an acceptable safety profile (Pasi, 2019). 
In addition, an interim analysis of clinical study 270-301, an ongoing phase 3 study designed 
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to assess the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg and administration of 
on-demand corticosteroids (ie, in response to ALT elevations), demonstrated FVIII activity 
levels that were also well above 15% at 26 weeks, albeit lower than what was observed for 
the 6E13 vg/kg cohort in 270-201 (Pasi, 2019). For additional information on preliminary 
data in 270-201, refer to the current version of the Investigator’s Brochure. 
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, 
as the prevailing expectation has been that vector-specific antibodies could interfere with 
receptor binding and effectively neutralize efficient transduction of the target cell population. 
As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted 
out of an abundance of caution. These pre-existing vector-specific antibodies are thought to 
arise from previous exposure to AAV, with seroprevalence varying across human 
populations and across studies. AAV5 has consistently been shown to have the lowest 
seroprevalence among the common AAV serotypes (Hayes, 2019 Boutin, 2010).  
Current data describing the extent of neutralization or inhibited transduction has been 
inconsistent across studies, each employing one of several varying methodologies to evaluate 
both vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 
for the treatment of hemophilia B described inhibited transduction in patients with 
neutralizing antibody titers of 2 or 3 (Manno, 2006), but more recent studies have described 
successful transduction in patients who, in retrospect, were determined to have pre-existing 
antibody to the vector capsid (Majowicz, 2017).  Importantly, no drug-related adverse events 
were described in these patients.  As the sensitivity of assays used to detect pre-existing 
antibody has increased greatly in recent years, the biological relevance of any given titer 
determination, and comparisons across studies using assays with differing titer sensitivities, 
requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of 
available data shows the effect of pre-existing immunogenicity to AVV delivery vectors is 
not completely understood, and indicates that some patients may benefit from AAV5 gene 
therapy who are currently excluded.  
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be 
enrolled to evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate 
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the safety, tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing 
antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers. 
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 that have 
reached only slightly above the upper limit of normal (ULN). Subjects in the 6E13 vg/kg 
cohort received corticosteroids, predominantly on a prophylactic basis, starting 2-4 weeks 
following BMN 270 infusion, whereas those in the 4E13 vg/kg cohort received 
FRUWLFRVWHURLGV RQO\ LI WKH\ H[SHULHQFHG DQ HOHYDWLRQ LQ WKHLU $/7  [ 8/1 LH
“therapeutic”). Based on the effectiveness of transient oral corticosteroids used starting 8-10 
weeks after vector infusion to suppress a presumed Class 1 (cytotoxic T-cell) response in 
prior studies with hepatic transduction with AAV vectors (Mingozzi, 2013), subjects were 
treated with 7-32 weeks of oral corticosteroids prophylactically or in response to the 
elevations in ALT to limit hepatotoxicity, ensure preservation of the transduced hepatocytes, 
and minimize any associated impact of such on FVIII levels. Using this approach, no 
sustained loss of FVIII activity has been observed in subjects with ALT elevations. 
Moreover, the rise in ALT levels was not accompanied by significant or lasting abnormalities 
in other liver tests such as AST, bilirubin or albumin, indicating that extent of toxicity is 
limited. At the highest dose tested in 270-201 (6E13 vg/kg), the majority of subjects achieved 
chromogenic FVIII activity levels above 50 IU/dL at 52 weeks post-infusion. Subjects in that 
cohort also reported markedly decreased bleeding compared with pre-study rates and the 
ability to discontinue prophylactic FVIII infusions. Subjects at all dose levels continue to be 
followed. 
In the ongoing 270-301 clinical study, a majority of subjects, all dosed with 6E13 vg/kg 
BMN 270, have experienced asymptomatic elevations in ALT. Subjects received therapeutic 
corticosteroids if they experienced an ALT elevation and/or had a FVIII activity level that 
KDG GHFOLQHG ! IURP SHDN YDOXHV :KLOH VSRUDGLFDOO\ REVHUYHG F\WRWR[LF 7-cell 
responses have not been correlated with ALT elevations, the majority of subjects with 
transient rises in ALT levels had associated declines in their FVIII activity that subsequently 
increase to higher than pre-ALT elevation levels following initiation of therapeutic 
corticosteroids. Similar to 270-201, the rise in ALT levels in 270-301 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. At the time of the 270-301 interim analysis, the 
modified intent-to-WUHDW SRSXODWLRQ Q  ZKR KDG FRPSOHWHG  ZHHNV RQ-study) had 
mean and median chromogenic FVIII activity levels of 36.1 and 33.2 IU/dL at 26 weeks, 
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respectively, which are lower than the corresponding values observed for the 270-201 
6E13 vg/kg cohort. 
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 have been three 
subjects, including one with Gilbert’s syndrome, in the ongoing 270-301 clinical study who 
have 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 beyond Grade 1 to date. Overall, the literature and 
clinical experience with BMN 270 suggests that transient elevations in liver enzymes are 
expected following AAV-based gene therapy for the treatment for hemophilia A or B without 
any long-term concerns of hepatic injury (Manno, 2006 Nathwani, 2011 George, 2016
MLHVEDFK  3DVL ).  
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 
infusion-related hypersensitivity reactions (including anaphylaxis) have been observed 
during dosing of BMN 270 in the 270-301 clinical study (refer to Investigator’s Brochure for 
full details). All of the infusion-related reactions were effectively managed clinically and 
resolved without any clinical sequelae.  
The current data available for BMN 270 has shown an established positive benefit:risk 
profile for BMN 270 at the 6E13 vg/kg dosing level, although impact of prophylactic 
corticosteroids requires further investigation. . Given the monitoring measures in place in the 
clinical protocol(s) to minimize the risk to subjects participating in the existing studies, the 
identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-203 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 from other BMN 270 clinical studies, refer to the 
current version of the IB. 
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8 
STUDY OBJECTIVES 
The primary objective of the study is to: 
x Assess the safety of a single intravenous administration of BMN 270 in severe HA 
subjects with pre-existing antibody to AAV5 vector capsid, including development of 
FVIII neutralizing antibody 
The secondary objectives of the study are to: 
x Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at 
Week 26 
x Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy 
x Assess the impact of BMN 270 on the number of bleeding episodes requiring 
exogenous FVIII therapy 
x Evaluate the pharmacodynamics of FVIII expression following IV infusion of 
BMN 270 
x Assess the impact of BMN 270 on patient-reported outcomes (PROs) 
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), 
with a history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with 
pre-existing antibodies to AAV5 vector capsid as measured by total antibody [TAb] assay. 
Approximately 10 subjects may be enrolled at 5-6 sites globally in 2 cohorts (5 subjects in 
each cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. 
6XEMHFWV LQ &RKRUW  ZLOO KDYH D 6FUHHQLQJ $$9 7$E   ZKLOH VXEMHFWV LQ &RKRUW 2 will 
have a Screening AAV5 TAb ! 500. Choosing a titer cutoff of 500 reflects the observed 
distribution of existing titer data with the BioMarin titer assay seen to date.
An independent Data Monitoring Committee (DMC), consisting of experts in clinical trials, 
statistics, and hemophilia, has been convened.  The DMC will review available safety and 
efficacy data throughout the study and provide recommendations based on their review 
(Figure 9.1.1 represents one dosing schedule scenario):
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their 
Screening AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a 
maximum of 5 subjects have been dosed in Cohort 1 and had their safety and efficacy data 
(from a minimum of 6 weeks post-infusion) reviewed.  Based on data from 270-201, FVIII 
DFWLYLW\   DIWHU six weeks post-infusion is expected to be the earliest differentiating time 
point for the majority of subjects dosed with 6E13 vg/kg who later achieved normal FVIII 
activity levels, compared with the one subject who had a slightly lower response. Up to 
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6 weeks post-infusion will provide an appropriate timeframe to evaluate the development of 
any potential delayed hypersensitivity reaction (eg, serum sickness).   
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC evaluation of safety and efficacy in treated subjects with the following 
triggers that may potentially pause further enrollment:  
x DQ\ UHODWHG 6$( 
x DQ\ UHODWHG $( ZLWK D VHYHULW\ ! &7&$( *UDGH  RU  
x FVIII activity < 5% in at least 2/3 subjects at 6 weeks post-BMN 270 infusion.  
Following a temporary halt of enrolment, the DMC may approve resumption of enrolment in 
either cohort at a later date at its discretion based on further analysis of accumulating data. 
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at 
least 24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In 
case of suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to 
physical examination and vital signs, will be performed. Additional blood samples will be 
collected (tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible 
additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) will be collected 
between 8-24 hours after the reaction. In addition, a blood sample should be taken 1 week 
after the hypersensitivity reaction for assessment of the cytokine bead array. Exploratory 
biomarker samples at baseline and at post-infusion study visits may also be used to assess 
changes in these biomarkers to better elucidate the mechanisms of infusion-related 
hypersensitivity reactions.  Any safety signal may trigger a review of the data and possible 
additional immunogenicity studies or other diagnostics deemed necessary to assess cellular 
immune responses using collected peripheral blood mononuclear cells (PBMCs).  The 
duration of observation may be extended and additional blood samples collected at the 
discretion of the Investigator and Medical Monitor. 
Data from 270- VXJJHVW WKDW DFKLHYHPHQW RI WKHUDSHXWLF )9,,, OHYHOV  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII 
SURWHFWLRQ ZKLOH VXEMHFWV DUH SURMHFWHG WR UHDFK FOLQLFDOO\ UHOHYDQW )9,,, OHYHOV  5 IU/dL, 
prior FVIII prophylaxis for each subject will be continued at the discretion of the DMC based 
on individual subject status and data review or when FVIII activity has reached at least 
5 IU/dL.  
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As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not 
respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve 
FVIII activity   ,8G/ 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 by attending only the Q12W and End of Year visits during Years 2-5.  
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. 
After the safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, 
long-term safety and efficacy will be assessed in all subjects for up to a total of 5 years 
post-infusion. During the trial, additional subjects may be recruited into each cohort at any 
time, if deemed necessary by the DMC.   
A summary of all assessments is provided in the Schedule of Activities (SoA) in Table 9.1.1, 
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5. 
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Table 9.1.1: Schedule of Activities – Screening/Baseline/Day 1 
Assessment 
Prior to BMN 270 Infusion 
BMN 
270 
Infusion 
Visit 
(Day 1)k 
Screening 
Smart 
Rescreeningi  
(Day -28 to 
Day -1) 
Baseline 
(Day -7 
to Day -
1)j 
Screening 
(Day -42 to 
Day -29) 
Screening 
(Day -28 
to Day -1) 
Informed consent 
X 
X 
 
 
 
Demographics (age, sex, race, ethnicity) 
 
X 
 
 
 
Medical History (including hemophilia A history, Hepatitis B, Hepatitis C, and HIV) 
 
X 
 
 
 
Physical Examinationa 
 
X 
 
X 
X 
Height and Weighta 
 
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 useb 
 
X 
 
 
 
Electrocardiogram 
 
X 
 
 
 
Liver Ultrasound 
 
X 
 
 
 
hFVIII Assaysc 
 
X 
Xl 
X 
 
AAV5 TAb Assay (ARUP)d 
X 
 
X 
 
X 
AAV5 TAb Assayse 
 
 
 
X 
 
AAV5 TI Assaye 
 
 
 
X 
X 
Screen for Hepatitis B, Hepatitis C, HIVf 
 
X 
 
 
 
Blood chemistry, hematology, and coagulation testsg 
 
X 
X 
X 
 
Blood fasting lipid panel 
 
 
 
 
X 
Urine Testsg 
 
X 
X 
X 
 
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Assessment 
Prior to BMN 270 Infusion 
BMN 
270 
Infusion 
Visit 
(Day 1)k 
Screening 
Smart 
Rescreeningi  
(Day -28 to 
Day -1) 
Baseline 
(Day -7 
to Day -
1)j 
Screening 
(Day -42 to 
Day -29) 
Screening 
(Day -28 
to Day -1) 
Liver Testsg 
 
X 
X 
X 
 
PBMC collection (for baseline determination of AAV5 and FVIII specific cellular 
immunity) 
 
 
 
X 
 
Von Willebrand Factor Antigen (VWF:Ag)  
 
 
 
X 
 
Thrombin Generation Assay 
 
 
 
X 
 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
 
 
 
X 
Xk 
Biomarker testingh 
 
X 
 
 
 
Exploratory biomarker assessmentsh 
 
 
 
X 
X 
Cytokine bead array assay 
 
 
 
X 
 
Haemo-QOL-A assessment 
 
 
 
X 
 
EQ-5D-5L assessment 
 
 
 
X 
 
HAL assessment 
 
 
 
X 
 
WPAI+CIQ:HS assessment 
 
 
 
X 
 
BMN 270 Infusion 
 
 
 
 
X 
Hypersensitivity blood assessments 
 
 
 
X 
(X)m 
a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit. 
b Diaries should be distributed to subjects who have consented to participate in the study and who have been determined to meet all study eligibility criteria. 
c Includes baseline FVIII activity (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), coagulation exploratory assay, hFVIII inhibitor level (Bethesda 
assay with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen assay. Baseline activity should be assesseG DW WURXJK DW OHDVW ! KRXUV DIWHU ODVW GRVH RI
replacement FVIII therapy, or 5x the known half-life of the FVIII concentrates administered). 
d Screening, Smart Re-screening, and Infusion Day samples will be tested using the ARUP AAV5 TAb assay. During Screening, the ARUP AAV5 TAb assay test may be 
done first, under a standalone informed consent form, before the main ICF for the study is signed and further screening procedures are performed. Sample collection on the 
day of the infusion visit must be performed before the BMN 270 infusion is given.  
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e Baseline and all post-dose samples will be tested in a different AAV5 TAb post-dose immunogenicity monitoring assay. 
f Subjects 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). 
g Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests.  UULQH WHVWV ZLOO EH SHUIRUPHG ORFDOO\ DQG FHQWUDOO\ DOO RWKHU
laboratory assessments will be performed at the central laboratory. ABO blood typing assessment should be performed at Baseline, or at another regularly scheduled visit 
prior to the end of the subject’s participation in the study.   
g Includes HLA genotyping and FVIII genotyping. 
h 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 those evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these 
samples (including those for TGA assay and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
i Smart rescreening should only be performed if a subject 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 (28 + 14 days).  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 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. 
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 a total time of 24 hours during the subject’s stay in the 
clinic. Shedding samples for PCR of vector DNA analysis (blood, saliva, urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been 
completed. 
l Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening. 
m In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will be done and additional blood samples will be 
collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory testing) and 
samples for IgE and cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. In addition, a blood sample should 
be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead array. Exploratory biomarker samples at baseline and at post-infusion study visits 
may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 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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4 October 2019 
Table 9.1.2:  Schedule of Activities – 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 
D2 
D4 
D8 
Study Day* 
2 
4 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
 
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 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, hematology, and 
coagulation testsb 
 
 
 
X 
 
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 
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 
 
X 
 
X 
 
 
 
X 
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolsd 
Xd 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Exploratory biomarker assessmentse 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Haemo-QOL-A assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
EQ-5D-5L assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
HAL assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
WPAI+CIQ:HS assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
AAV5 TAb Assay 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
AAV5 TI Assay 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
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4 October 2019 
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 
D2 
D4 
D8 
Study Day* 
2 
4 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
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 
 
X 
VWF:Ag  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Cytokine bead array assay 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
* Visit windows are ± 24 hours during Week 1 and ± 48 hours starting with the Week 2 visit.   
a Brief physical examination should be done at all weekly visits. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. Urine tests will be performed loFDOO\ DQG FHQWUDOO\ DOO RWKHU
laboratory assessments will be performed at the central laboratory.  LTs may be monitored more or less frequently (and in particular when ALT values are   [ 8/1 RU !
8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice 
ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7   [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH GXULQJ WKH VWXG\ DQG HLWKHU 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 
DERYH 8/1  ,QFUHDVHV LQ $/7 YDOXHV IURP SULRU DVVHVVPHQW DUH DFFRPSDQLHG E\ GHFOLQHV LQ )9,,, DFWLYLW\ OHYHO RU DIWHU D 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 antigen 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-KRXU LQWHUYDO ZLWKRXW )9,,, XVH LV DFKLHYHG WKH -hour wash-out period is only intended for subjects who have acKLHYHG )9,,,  5 IU/dL 
at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in 
which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained.  Collection and testing of semen samples must continue 
through Week 12, even if 3 consecutive results below the limit of detection in that compartment have already been recorded. Separate collection on Day 2 is not required if 
vector shedding samples were collected on Day 1 post-%01  LQIXVLRQ LI FROOHFWLRQ RQ 'D\  LV QHHGHG LW PXVW RFFXU ZLWKLQ  KRXUV RI WKH WLPH RI WKH %01 270 
infusion. 
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4 October 2019 
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes 
that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples 
(including those for TGA assay and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
f Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry, should be 
performed only in subjects who have not received prophylactic oral FRUWLFRVWHURLGV VXEMHFWV ZKR KDYH UHFHLYHG SURSK\ODFWLF oral corticosteroids will have hepatitis B and 
hepatitis C testing at the time points indicated in Table 9.1.6. 
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. 
 
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4 October 2019 
Table 9.1.3:  Schedule of Activities – 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 
30 
31f 
32 
Study Day* 
120 
127 
134 
141 
148 
155 
162 
169 
176 
183 
190 
197 
204 
211 
218 
225 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Assessment of Adverse Events and 
Concomitant Medications  (including 
review of subject diary for bleeding 
and FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, 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 
 
 
 
 
 
 
HAL 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
WPAI+CIQ:HS 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
AAV5 TAb Assay 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
AAV5 TI Assay 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
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4 October 2019 
Assessment 
Follow-Up After BMN 270 Infusion – Weeks* 
17f 
18 
19f 
20 
21f 
22 
23f 
24 
25f 
26 
27f 
28 
29f 
30 
31f 
32 
Study Day* 
120 
127 
134 
141 
148 
155 
162 
169 
176 
183 
190 
197 
204 
211 
218 
225 
PBMC collection (for determination of 
AAV5 and FVIII specific cellular 
immunity) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
VWF:Ag 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Thrombin Generation Assaye 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
Cytokine bead array assay 
 
 
 
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 Week 26. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. 8ULQH WHVWV ZLOO EH SHUIRUPHG ORFDOO\ DQG FHQWUDOO\ DOO RWKHU
laboratory assessments will be performed at the central laboratory.  LTs may be monitored more or less frequently (and in particular when A/7 YDOXHV DUH  [ 8/1 RU !
8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG WKH ,QYHVWLJDWRU DQG UHYLHZ RI VXEMHFW GDWD Eut LTs will be monitored at least twice 
ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  3x ULN.  SubjHFWV ZLWK $/7  [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH GXULQJ WKH VWXG\ DQG HLWKHU DQ DOWHUQDWLYH
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 
DERYH 8/1  ,QFUHDVHV LQ $/7 YDOXHV IURP SULRU DVVHVVPHQW DUH DFFRPSDQLHG E\ GHFOLQHV LQ )9,,, DFWLYLW\ OHYHO RU DIWHU D GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG
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 antigen. 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 aFKLHYHG WKH -hour wash-RXW SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  5 IU/dL 
at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in 
which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism.  
d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained. 
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes 
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4 October 2019 
that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples 
(including those for TGA assay and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
f The scheduled visits at Week 17, Week 19, Week 21, Week 23, Week 25, Week 27, Week 29, 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. 
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Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52) 
Assessment 
Year 1 – Weeks* 
33e 
34 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta 
 
 
 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
 
X 
 
X 
 
X 
 
X 
AAV5 TI Assay 
 
X 
 
X 
 
X 
 
X 
 
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 
 
 
 
X 
VWF:Ag 
 
 
 
X 
 
 
 
 
 
 
 
X 
Thrombin Generation Assayd 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Cytokine bead array assay 
 
 
 
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 
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Assessment 
Year 1 – Weeks* 
33e 
34 
35e 
36 
38e 
40 
42e 
44 
46e 
48 
50e 
52 
WPAI+CIQ:HS 
 
 
 
 
 
 
 
 
 
 
 
X 
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52. 
a &RPSOHWH SK\VLFDO H[DPLQDWLRQ VKRXOG EH SHUIRUPHG DW :HHN  EULHI SK\VLFDO H[DP PD\ EH SHUIRUPHG DW RWKHU VWXG\ YLVLWV :HLght should be recorded at Week 36 and 
every 4 weeks through Week 52. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular 
when ALT values are   [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG WKH ,QYHVWLJDWRU DQG UHYLHZ RI Vubject data, but 
LTs will be monitored aW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7    [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH GXULQJ WKH
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 incUHDVHG WR DERYH 8/1 RU LQFUHDVHG E\ ! 10 8/ IURP SULRU DVVHVVPHQW  ,QFUHDVHV LQ $/7 YDOXHV IURP SULRU DVVHVVPHQW DUH DFFRPSDQLHG E\
GHFOLQHV LQ )9,,, DFWLYLW\ OHYHO RU DIWHU D GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG WKH ,QYHVWLJDWRU EDVHG RQ D UHYiew 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 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-KRXU LQWHUYDO ZLWKRXW )9,,, XVH LV DFKLHYHG WKH -hour wash-RXW SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  5 IU/dL 
at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, 
assessment of FVIII activity may be adjusted based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in 
which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. 
d Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, 
and to develop assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes 
that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples 
(including those for TGA assay and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
e The scheduled visits at Week 33, 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. 
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Table 9.1.5:  Schedule of Events – Long-Term Follow-Up (Year 2 – Year 5) 
Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Q12W 
Q6Wgh 
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 
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 
FVIII assaysc 
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 
Thrombin Generation Assaye 
X 
 
X 
X 
Cytokine bead array assay 
X 
 
X 
X 
PCR of vector DNA in blood, saliva, urine, semen, and stoolsd 
(X)d 
(X)d 
(X)d 
(X)d 
Haemo-QOL-A assessment 
 
 
Xf 
X 
EQ-5D-5L 
 
 
Xf 
X 
HAL 
 
 
Xf 
X 
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Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Q12W 
Q6Wgh 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
W104 
W156 
W208 
W260 
WPAI+CIQ:HS 
 
 
Xf 
X 
* Visit windows are ± 2 weeks for visits in Years 2-5. The Q6W visits during Years 2-5 should restart after each End of Year visit (eg, the first Q6W visit during Year 3 
should be ~6 weeks after the End of Year 2 visit). 
a Brief physical examination should be performed at all visits during Years 2-5. 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 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular 
when ALT values are   [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG WKH ,QYHVWLJDWRU DQG UHYLHZ RI Vubject data, but 
/7V ZLOO EH PRQLWRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7    [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH GXULQJ WKH
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 
LI  WKH $/7 KDV LQFUHDVHG WR DERYH 8/1 RU LQFUHDVHG E\ ! 10 8/ IURP SULRU DVVHVVPHQW  ,QFUHDVHV LQ $/7 YDlues from prior assessment are accompanied by 
GHFOLQHV LQ )9,,, DFWLYLW\ OHYHO RU DIWHU D GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG WKH ,QYHVWLJDWRU EDVHG RQ D UHYLHZ RI 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-KRXU LQWHUYDO ZLWKRXW )9,,, XVH LV DFKLHYHG WKH -hour wash-RXW SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,   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 2-5, 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 below the limit of detection during the Post-Infusion Follow-Up period.  
Subjects who have not had 3 consecutive semen samples below the limit of detection by Week 52 should continue to have PCR testing of semen every 6 weeks during Years 
2-5 until 3 consecutive samples below the limit of detection 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, 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 
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that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples 
(including those for TGA assay and any other exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
f  PRO assessments during Years 2-5 of Long-Term Follow-up should be performed at every End of Year visit. 
g Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 (refer to Section 12.6) may omit the 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 
Q6W during Years 2-5 until vector shedding has been cleared (but do not need to do other scheduled assessments at those visit dates). 
e The scheduled Q6W visits during Years 2-5 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. 
 
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Table 9.1.6:  Suggested Schedule of Events – Prophylactic Corticosteroids 
Assessment 
Corticosteroid Treatment Periodb 
Post-Corticosteroid Periodc 
Day 
1 
Week 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
1 
2 
3 
4 
13 
Prophylactic 
corticosteroid 
dose 
(mg/day) 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
35 
mg 
35 
mg 
30 
mg 
30 
mg 
25 
mg 
25 
mg 
20 
mg 
20 
mg 
15 
mg 
10 
mg 
5 
mg 
 
 
 
 
 
FVIII activity 
testing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hepatitis B 
testingd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HCV Viral 
Loadd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
a This table provides an example of a prophylactic corticosteroid course. Clinical judgment, weighing the potential risks and benefits of corticosteroid treatment, should 
always be exercised when considering adjustment of corticosteroid doses, and discussions between the Investigator and Medical Monitor are advised for any questions or 
concerns. 
b Following initiation or completion of corticosteroid regimen, if a recurrence of ALT values  8/1 RU  [ EDVHOLQH YDOXH LV UHSRUWHG FRUWLFRVWHURLG PDQDJHPHQW GHFisions 
will be based on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for 
the ALT elevation, relationship between increases in ALT and FVIII activity, ALT/FVIII levels post-corticosteroid initiation, and adverse events related to corticosteroid 
dosing. Guidance for tapering oral corticosteroid dosing can be found in Section 9.4.8.2, although a discussion between the PI and Medical Monitor should take place prior 
to tapering the corticosteroid dose. 
c After discontinuation of oral corticosteroids, weekly labs for ALT 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 270-203 is designed to be a Phase 1/2, single-arm, open-label study in hemophilia A 
patients with UHVLGXDO )9,,, OHYHOV   ,8G/ DQG SUH-existing antibodies to the AAV5 vector 
capsid. Hemophilia A patients who provide written informed consent and meet the entry 
criteria will be eligible to enroll in the study. 
Approximately 10 subjects may be enrolled at the 6E13 vg/kg BMN 270 dose.  Subjects will 
be followed for 26 weeks post-BMN 270 infusion during which safety and efficacy 
assessments will be taken. After the final analysis at 26 weeks post-infusion, safety and 
efficacy will then continue to be assessed long-term for approximately a total of 5 years.   
9.3 
Selection of Study Population 
Approximately 10 hemophilia A patients with residual FVIII levels < 1 IU/dL and 
pre-existing antibodies to the AAV5 vector capsid 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 criteria: 
1. 0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as 
evidenced by medical history, at the time of signing the informed consent 
2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by 
AAV5 total antibody ELISA 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs) 
4. Subject must have been on prophylactic FVIII replacement therapy for at least 
12 months prior to study entry.   
5. 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. 
6. 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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7. Sexually active participants must agree to use an acceptable method of effective 
FRQWUDFHSWLRQ HLWKHU GRXEOH EDUULHU FRQWUDFHSWLRQ LH FRQGRP  GLDSKUDJP RU
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-LQIXVLRQ DIWHU  weeks, subjects may 
stop contraception use only if they have had 3 consecutive semen samples with viral 
vector DNA below the level of detection. 
8. Willing to abstain from consumption of alcohol 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. Any evidence of active infection or any immunosuppressive disorder, including HIV 
infection. 
2. Significant liver dysfunction with any of the following abnormal laboratory results: 
o $/7 DODQLQH DPLQRWUDQVIHUDVH ! [ 8/1  
o AST (aspartatH DPLQRWUDQVIHUDVH ! [ 8/1 
o GGT (gamma-JOXWDP\OWUDQVIHUDVH ! [ 8/1 
o 7RWDO ELOLUXELQ ! [ 8/1 
o $ONDOLQH SKRVSKDWDVH ! [ 8/1 RU 
o ,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR   
Subjects whose 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. 
3. 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 
4. Evidence of any bleeding disorder not related to hemophilia A 
5. Platelet count of < 100 x 109/L 
6. Creatinine   PJG/ 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound  
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8. 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. 
9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral 
therapy 
10. Active malignancy, except non-melanoma skin cancer 
11. History of hepatic malignancy 
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial 
embolus), with the exception of catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing.  
13. .QRZQ LQKHULWHG RU DFTXLUHG WKURPERSKLOLD LQFOXGLQJ FRQGLWLRQV DVVRFLDWHG ZLWK
increased thromboembolic risk, such as atrial fibrillation. 
14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, 
vasculitis). 
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the 
investigational product (whichever is longer) prior to the screening period. For 
subjects who have received a prior investigational product, all ongoing adverse events 
(AEs) experienced while receiving that investigational product must have resolved 
prior to screening for this study 
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the 
patient from fully complying with the requirements of the study (including possible 
corticosteroid treatment outlined in the protocol) and/or would impact or interfere 
with evaluation and interpretation of subject safety or efficacy result. 
17. Prior treatment with any vector or gene transfer agent 
18. Major surgery planned in the 52-week period following the infusion with BMN 270 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion 
20. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study that does not interfere with the requirements of the 
current protocol or have the potential to impact the evaluation of safety and efficacy 
of BMN 270 and with prior consultation with the Medical Monitor 
21. .QRZQ DOOHUJ\ RU K\SHUVHQVLWLYLW\ WR LQYHVWLJDWLRQDO SURGXFW IRUPXODWLRQ 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or 
a bleed 
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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: 
x Subject requires medication or medical procedure prohibited by the protocol 
x Subject was erroneously enrolled into the study or does not meet entry criteria and not 
\HW EHHQ GRVHG ZLWK %01  VXEMHFWV ZKR GR QRW PHHW HQWU\ FULWHULD EXW ZKR
erroneously receive BMN 270 should remain in the study for safety monitoring 
x Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/EC It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
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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 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC evaluation of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment:  
x DQ\ UHODWHG 6$( 
x an related AE with D VHYHULW\ ! *UDGH  RU  
x FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.  
Additionally, the DMC should consider whether to restrict dosing to subjects with anti-
AAV5 titers below levels that appear to be causing clinically significant inhibition of 
transduction.  Following a temporary halt of enrolment, the DMC may approve resumption 
of enrolment in either cohort at a later date at its discretion based on further analysis of 
accumulating data. 
If a Grade 4 or Grade 5 adverse event assessed as related to study drug occurs in a study 
subject, further enrollment into the trial will be halted until a full safety review of the data by 
the DMC has taken place. Relevant reporting and discussion with the Sponsor and the DMC 
will take place before resumption of dosing. 
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, further enrollment into the trial will be temporarily put on hold pending prompt 
evaluation by the DMC.   
1. Liver dysfunction (criteria do not apply to ALT elevations with an extra-hepatic 
etiology): 
o $/7 ![ 8/1 IRU PRUH WKDQ  ZHHNV 
o $/7 ![ 8/1 DQG WRWDO ELOLUXELQ ![ 8/1 or ,15 ! 
o $/7 ![ 8/1 ZLWK VLJQV DQG V\PSWRPV RI OLYHU G\VIXQFWLRQ  
2. The occurrence of an AE of hepatic failure. 
3. 7KH GHWHFWLRQ RI KLJK WLWHU QHXWUDOL]LQJ DQWLERGLHV ! BU) to hFVIII following 
BMN 270 infusion in two subjects. 
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4. The occurrence of any cancer (except non-melanoma skin cancer) at any point after 
BMN 270 infusion. 
5. 7KH RFFXUUHQFH RI D WKURPERHPEROLF HYHQW ZLWK )9,,, DFWLYLW\ ! 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, a prompt 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. Acute hypersensitivity assessed as related to BMN 270 
2. The deWHFWLRQ RI KLJK WLWHU QHXWUDOL]LQJ DQWLERGLHV ! %8 WR K)9,,, IROORZLQJ
BMN 270 infusion in one subject 
3. Occurrence of a thromboembolic event 
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. 
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, 26 weeks of Post-Infusion Follow-Up, 
and 234 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 
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 10 mL Crystal Zenith® (CZ) vial. Each CZ vial contains 8.5 mL (extractable volume 
8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 
7.4 phosphate buffer. 
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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 
XQWLO WKH LOOQHVV KDV UHVROYHG VFUHHQLQJ SURFHGXUHV PD\ UHTXLUH UHSHWLWLRQ LI RXWVLGH WKH
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 
therapy will not be given since venipuncture is a minimally invasive procedure in these 
individuals under ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at an 
initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min 
up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an 
increase. Of note, the IP has been shown to be stable at room temperature for approximately 
10 hours following completion of product thaw. Vital signs (pulse, blood pressure, 
respiration rate and temperature) should be monitored at 15 minute (±5 minutes) intervals 
throughout the 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, 
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and anaphylactoid reactions. Additionally, the Investigator should be familiar with 
6DPSVRQ¶V FULWHULD IRU GHILQLQJ DQDSK\OD[LV 6DPSVRQ  $SSHQGL[   
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 (ie, to a slower rate [minimum of 1 mL/min], with 
the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the 
subject’s clinical condition permits such an increase) with careful monitoring of the subject. 
In the event of an infusion rate reaction with more than one dosing interruption, the infusion 
rate would not go beyond 1 mL/min. 
In case of hypersensitivity reactions, safety assessment, including physical examination and 
vital signs, will be done and additional blood samples will be collected within 1 hour of the 
hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as 
well as possible additional exploratory testing) and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) between 8-24 hours after the reaction, if 
possible. In addition, a blood sample should be taken 1 week after the hypersensitivity 
reaction for assessment of the cytokine bead array. Exploratory biomarker samples at 
baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 
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 24 hours to 
REVHUYH IRU DQ\ LPPHGLDWH WR[LFLW\ RI WKH SURFHGXUH LQ-patient observation can be extended 
beyond 24 hours if needed per Investigator discretion. After 24 hours, subjects will be 
discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
Prior to discharging subjects from the clinic, the Investigator or designee should instruct 
subjects how to recognize signs and symptoms of potential (delayed) hypersensitivity 
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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. 
9.4.6 Selection of Dose Used in the Study 
Data from an ongoing first in human 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. The 
6E13 vg/kg dose has been selected for this study to maximize the likelihood of transduction 
in the face of pre-existing AAV5 antibodies. 
9.4.6.1 
Selection of Timing of Dose for Each Subject 
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 as needed (PRN). 
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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: 
x Any investigational therapy 
x Systemic immunosuppressive agents, except for corticosteroids 
x Emicizumab 
x Fitusiran 
x Concizumab 
x Efavirenz 
x Lamivudine 
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their 
participation in 270-203 must have their antiretroviral medication regimen approved by the 
Investigator and Medical Monitor prior to starting antiretroviral treatment. 
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. 
x Alcohol  
x Herbal and natural remedies and dietary supplements 
x Medications which may be hepatotoxic 
x Medications which may reduce or increase the plasma concentration of 
corticosteroids 
Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated. 
The following medications should be avoided during oral corticosteroid therapy: 
x Vaccines 
x 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 
EOHHGLQJ HSLVRGH WKH VXEMHFW PXVW FDUHIXOO\ UHFRUG KLV WUHDWPHQW DQG EOHHGLQJ HSLVRGHV LQ KLV
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diary. Prophylactic FVIII 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 will be 
collected from subjects for the 12-month period immediately preceding study enrollment.   
9.4.8.2 
Therapeutic Corticosteroid Treatment of Elevated Hepatic Transaminases 
All subjects will be started on prophylactic corticosteroids starting on the day of infusion 
(Day 1). Table 9.1.6 provides an example of a possible prophylactic corticosteroid course, 
including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and 
hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and 
benefits of corticosteroid treatment, should always be exercised when considering adjustment 
of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns. 
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels 
EHFRPH LQFUHDVHG HJ  8/1 RU  [ EDVHOLQH YDOXH DQG DOWHUQDWLYH HWLologies have been 
ruled out, prompt institution of therapeutic or on-demand oral corticosteroids (prednisone or 
converted equivalent) should be considered after consultation with the Medical Monitor 
(refer to Table 9.7.6.3.2). 
x Whenever possible, a confirmatory lab draw for ALT should be performed within 
72 hours, along with FVIII activity, prior to initiating oral corticosteroids. 
x Corticosteroids may be delayed if elevations in ALT are clearly not related to 
BMN 270 (eg, elevateG LQ $/7 ZLWK FRQFXUUHQW LQFUHDVH LQ &3. GXH WR LQWHQVLYH
exercise)  
Therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. At minimum, 
the recommended duration of therapeutic corticosteroids is 60 mg/day for 3 weeks, 
40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper thereafter. 
Should a scenario arise in which a deviation from the minimum recommended dose and/or 
duration of therapeutic corticosteroids may be clinically indicated, a discussion should take 
place between the Investigator and Medical Monitor regarding corticosteroid dose 
adjustments. Tapering of corticosteroid dosages should be guided by the following: 
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9.4.9 Treatment Compliance 
Study drug will be administered to subjects at 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 
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 Study Pharmacy Manual. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study.  Alcohol should be avoided 
starting 30 days prior to and for at least the first 52 weeks of the study, and particularly 
within 48 hours prior to lab work. 
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Subjects should be advised to abstain from any blood, organ, or sperm donation after 
BMN 270 infusion, until there is no further evidence of vector shedding from PCR analysis 
of samples. 
9.7 
Efficacy and Safety Variables 
9.7.1 Efficacy and Safety Measurements Assessed 
The SoA (Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5) describe the 
timing of required evaluations. 
9.7.2 Efficacy Variables 
9.7.2.1 
FVIII Activity 
(IILFDF\ UHVSRQVH WR WUHDWPHQW ZLOO EH GHILQHG DV )9,,, DFWLYLW\  5 IU/dL at Week 26 
following BMN 270 infusion. 
Values for FVIII activity will be excluded from analysis 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-KRXU LQWHUYDO ZLWKRXW )9,,, XVH LV DFKLHYHG 7KH -hour wash-out 
SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  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: 
x 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 
x ,I )9,,, DFWLYLW\ KDV GHFOLQHG ! IURP WKH SHDN DQG KDV GHFOLQHG IRU DW OHDVW
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 (ie, treatment failure, manifesting as 
either failure to achieYH )9,,, DFWLYLW\   ,8G/ E\ HLWKHU :HHN  RU :HHN 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 
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discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as 
applicable and at the discretion of the Investigator.  
Details on collecting FVIII activity samples are included in the Laboratory Manual.  
9.7.2.2 
Factor VIII Replacement Therapy/Bleeding Episodes 
Additional efficacy variables are: 
x Change of annualized utilization (IU/kg) of exogenous FVIII replacement therapy 
during Week 5 to Week 26 post BMN 270 infusion from the baseline utilization of 
exogenous FVIII replacement therapy.  
x Change of ABRs requiring exogenous FVIII replacement treatment during Week 5 to 
Week 26 of the study post BMN 270 infusion from the baseline ABR.   
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 
6 weeks post BMN 270 infusion. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. 
9.7.2.3 
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 Study Reference 
Manual. 
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 Study Reference Manual. 
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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 Study 
Reference Manual. 
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 Study 
Reference Manual. 
9.7.3 Immunogenicity 
Immunogenicity assays will be performed on plasma and PBMCs. The assays will include 
detection of anti-AAV5 vector capsid and anti-FVIII total antibodies, as well as 
determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the 
AAV5 vector 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 vector 
capsid-specific cellular immunogenicity. FVIII- and vector capsid-specific cellular immunity 
will be assessed by stimulated cytokine secretion using an ELISpot assay performed on 
collected PBMCs. 
9.7.4 Pharmacodynamics 
The FVIII protein concentration and activity level as measured by a validated immunoassay 
DQG E\ D YDOLGDWHG )9,,, DFWLYLW\ DVVD\ UHVSHFWLYHO\ ZLOO EH XVHG IRU SODVPD SURILOHV )9,,,
protein and activity will be used to determine PD parameters. 
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9.7.5 Exploratory Assessments 
A cytokine bead array assay assessment will be performed at Baseline and then weekly 
through Week 26. 
In addition, 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 AAV5 gene transfer, and to develop assays used for these evaluations. Subject may 
choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research, including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes in this study may be used for exploratory 
research once testing for the primary purpose has been completed.   
9.7.6 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.  
9.7.6.1 
Adverse Events 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. 
9.7.6.2 
Clinical Laboratory Assessments 
The scheduled clinical laboratory tests are listed in Table 9.7.6.2.1. Refer to the Study 
Reference Manual for instructions on obtaining and shipping samples.  Urine tests will be 
SHUIRUPHG ORFDOO\ DQG FHQWUDOO\ DOO RWKHU ODERUDWRU\ DVVHVVPHQWV ZLOO EH SHUIRUPHG DW WKH
central laboratory. In case of a safety concern, additional unscheduled laboratory tests may 
be performed locally (at the Investigator’s discretion) in order to facilitate timely and 
DSSURSULDWH FOLQLFDO PDQDJHPHQW GHFLVLRQV ZKHUH SRVVLEOH D PDWFKHG VDPSOH IRU WHVWLQJ DW
the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same 
time as the local unscheduled sample. 
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 
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within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and 
cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours 
after the reaction. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead array. Exploratory biomarker 
samples at baseline and at post-infusion study visits may also be used to assess changes in 
these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity 
reactions" as described in the rationale of changes. 
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. Potential MN visits are designated in the 
Schedules of Events. 
9.7.6.3 
Liver and Hepatitis Testing 
Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C 
LQIHFWLRQ DW 6FUHHQLQJ KHSDWLWLV % VFUHHQLQJ VKRXOG LQFOXGH +%V$J +%V$E DQG +%F$E
Subjects with documented results showing an absence of active hepatitis B or hepatitis C 
infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to 
repeat those tests during the screening period.   
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with 
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 
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Height will be recorded at Screening only.  Weight will be recorded at Screening and then 
every 4 weeks thereafter through Week 20, at Week 26, every 4 weeks through Week 52, and 
then at the second Q12W visit each year and at every End of Years visit during Years 2-5. 
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. 
9.7.6.6 
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: 
x Blood 
x Saliva 
x Semen 
x Urine 
x Stool 
Vector shedding will also be extensively studied in the present clinical trial, 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.  Testing will 
continue until at least 3 consecutive results below the limit of detection are obtained.  Testing 
of semen will continue at least through Week 12, even if 3 consecutive results below the 
limit of detection have been recorded in that compartment prior to that time point.  Subjects 
who have not had 3 consecutive semen samples below the limit of detection by Week 26 
should continue to have PCR testing in semen every 4 weeks until 3 consecutive samples 
below the limit of detection are documented (or upon consultation between the Investigator 
and Medical Monitor). Subjects who meet the definition of treatment failure and wish to 
follow an abbreviated schedule (refer to Section 12.5.3) but who have not cleared vector 
shedding from all fluids must still provide samples for assessment until vector shedding has 
cleared: at Weeks 32, 36, 40, 44, 48, and 52 (during Year 1) and every 4 weeks during 
Years 2-5. 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 
analysis (saliva, blood, semen, urine, feces).  Alternatively, the vector DNA characterization 
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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 below the limit of detection for vector DNA on at least three 
consecutive visits. 
Contraception use may need to be extended beyond 12 weeks in individual subjects based on 
observed vector shedding in semen.  After 12 weeks, subjects may stop contraception use 
only if they have had 3 consecutive semen samples below the limit of detection (upon 
consultation between the Investigator and Medical Monitor). 
Details for sample collection and storage are provided in the Laboratory Manual. 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEV DQG 6$(V
measurement of protocol-VSHFLILHG KHPDWRORJ\ FOLQLFDO FKHPLVWU\ DQG XULQDO\VLV YDULDEOHV
measurement of protocol-VSHFLILHG YLWDO VLJQV DQG RWKHU SURWRFRO-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: 
x Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Events not meeting the AE definition include: 
x 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. 
x 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. 
x Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x 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: 
x All bleeding events and suspected bleeding events which meet one or more of the 
criteria for being serious (refer to Section 10.1) 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: 
x Results in death 
x 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. 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
o 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. 
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.  
x Results in persistent or significant disability or incapacity 
x Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy 
x Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require medical/surgical intervention to prevent one of the 
other outcomes listed above  (eg, anaphylaxis)  
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10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
x (OHYDWLRQ RI $/7  [ 8/1 RU $/7 ! 8/1 	 ![ EDVHOLQH YDOXH UHJDUGOHVV RI
whether that elevation triggers an initiation or modification of oral corticosteroid 
treatment 
x Thromboembolic event 
x Systemic hypersensitivity, anaphylactic, or anaphylactoid reactions (refer to 
Appendix 1) 
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.  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 10.1.  
10.3.2 Eliciting Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences.  The Investigator will record all relevant AE/SAE/EOSI information in the 
subject’s medical record and AE Case Report Form (eCRF). 
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug and/or corticosteroids, and seriousness 
(refer to Section 10.2 for SAE definitions).  These assessments must be made by a study 
clinician with the training and authority to make a diagnosis (eg, MD/DO, physician’s 
assistant, nurse practitioner, or DDS). 
10.3.3.1 
Seriousness 
The Investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.2.  Seriousness serves as a guide for defining 
regulatory reporting obligations. 
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x Abatement of AE with discontinuation of study drug and/or corticosteroids, and/or 
recurrence of AE with reintroduction of study drug and/or corticosteroids 
The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
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. 
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10.4.1.3 
Persistent or Recurrent Adverse Events 
A persistent AE (duration of adverse event !  GD\V LV RQH WKDW H[WHQGV FRQWLQXRXVO\
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
For example, if a subject has an adverse event of ALT increased that subsequently resolves, 
but 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 (including any local FVIII activity or liver test results) will be 
recorded on the laboratory results pages of the eCRF, or appear on electronically produced 
laboratory reports submitted directly from the central laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF unless associated with an AE that has already been 
reported. 
Any laboratory result abnormality of CTCAE Grade 4 or 5 should be recorded as an SAE in 
the AE eCRF. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met: 
x Accompanied by clinical symptoms 
x Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
x The abnormality suggests a disease and/or organ toxicity 
x The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
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This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
For purposes of this study, laboratory tests showing a decreased level of 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: 
x Perform a protocol-mandated efficacy measurement 
x Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not worsened 
x 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 
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x Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.8 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
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 
6$(V WR UHJXODWRU\ DXWKRULWLHV ZLWKLQ  FDOHQGDU GD\V RI EHLQJ QRWLILHG DERXW WKH HYHQW
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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 
unexpected fatal or life-threatening unexpected suspected adverse reactions (SUSARs) and 
within 15 calendar days for other non-life-threatening SUSARs. 
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 (EC) or Institutional Review Board 
(IRB) will be done in compliance with the standard operating procedures and policies of the 
IRB/EC and with applicable regulatory requirements. Adequate documentation must be 
obtained by BioMarin showing that the IRB/EC 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. 
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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 
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/EC is notified at the same time.”  
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination Visit (ETV). Investigators are required to report any 
events which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
x Lack of study scientific value, or detrimental study conduct or management 
x Discovery that the quality or safety of the IP does not meet established safety 
requirements 
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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. 
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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the subject, the Investigator or designee and witness (if 
required) before any study-related procedures are performed. 
12.2 
Screening Visit(s) 
Screening assessments should be performed within 42 days of BMN 270 infusion, while 
baseline assessments will take place within 7 days prior to BMN 270 infusion (Day 1).  
Should the screening visit occur within 30 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LTs, hematology, urine tests, and coagulation tests do not need 
to be repeated at Baseline.  
During the first part of the Screening Period (Day -42 to Day -29), testing for AAV5 TAb 
titers using the ARUP screening assay may be performed, so that subjects can verify their 
AAV5 TAB status. Subjects who agree to participate in this activity will be asked to sign a 
separate ICF documenting this decision. 
The following procedures will be performed during the Screening Period: 
x Demographics (age, sex, race, ethnicity) 
x 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.  
x Complete Physical Examination  
x Height and weight 
x Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature)  
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) for the previous 12 months 
x Distribution of subject diaries and training in diary completion 
x Electrocardiogram 
x Liver Ultrasound 
x Samples for hFVIII Assays 
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o Baseline FVIII activity – chromogenic substrate FVIII assay 
o Baseline FVIII activity level – one-stage clotting FVIII assay 
o hFVIII coagulation activity exploratory assay (collected but not tested 
prior to enrollment) 
o hFVIII inhibitors (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay (collected but not tested prior to enrollment) 
o hFVIII antigen assay (collected but not tested prior to enrollment) 
x Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested) 
o Hepatitis B screening should include HBsAg, HBsAb, and HBcAb 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
x Blood samples for Biomarker testing (may include 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: 
x Vital signs 
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification)) 
x AAV5 TAb assay (ARUP) 
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x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the infusion visit.  The following 
procedures will be performed during the Baseline Period: 
x Brief physical examination 
x Vital signs 
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x 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 antigen assay 
x Von Willebrand Factor Antigen (VWF:Ag)  
x Blood sample for AAV5 Total Antibody assay 
o Baseline sample will be tested with a AAV5 TAb post-dose 
immunogenicity monitoring assay 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
o ABO blood typing assessment should be performed at Baseline, or at 
another regularly scheduled visit prior to the end of the subject’s 
participation in the study. 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
x PBMC collection for CTL baseline 
x Blood sample for AAV5 TI assay 
x Thrombin Generation Assay 
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x
PCR of vector DNA in blood, saliva, urine, semen, and stools
x
Exploratory biomarker assessments
x
Cytokine bead array assay
x
Hypersensitivity blood assessments
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions:
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one infusion visit for each subject.  Subjects will remain in the clinic for at 
least 24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
AAV5 TAb assay (ARUP) (sample collected pre-infusion for analysis)
x
Blood sample for AAV5 TI assay (sample collected pre-infusion for analysis)
x
Fasting blood sample for future exploratory analysis (sample collected pre-infusion)
x
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.
x
BMN 270 Infusion
x
Vital Signs
o
Vital signs will be recorded prior to BMN 270 infusion and then every
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion,
vital signs will be monitored every 1 hour (± 5 minutes) for at least
8 hours during the subject’s stay in the clinic.
x
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
x
6WDUW SURSK\ODFWLF FRUWLFRVWHURLGV SUHLQIXVLRQ
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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 
within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and 
cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours 
after the reaction, if possible. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead array. 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. Exploratory biomarker samples at 
baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" 
as described in the rationale of changes. 
Subjects should also start prophylactic corticosteroids, prior to BMN 270 infusion, on Study 
Day 1 (refer to Table 9.1.6 for a possible prophylactic corticosteroid regimen, and to 
Section 9.4.8.2 further discussion). Clinical judgment, weighting the potential risks and 
benefits of corticosteroid treatment, should always be exercised when considering adjustment 
of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns. 
12.5 
BMN 270 Infusion Follow-Up Visits 
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. Potential MN visits are designated in the 
Schedules of Events. 
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12.5.1 Week 1 
During Week 1, the subject will be assessed on Study Day 2, Study Day 4, and Study Day 8. 
12.5.1.1 
Week 1, Study Day 2 
On Study Day 2, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.3.1)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Separate collection on Day 2 is not required if vector shedding samples
were collected on Day 1 post-%01  LQIXVLRQ LI FROOHFWion on Day 2 is
needed, it must occur within 24 hours of the time of the BMN 270
infusion.
x
Blood sample for AAV5 TAb Assay
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity
monitoring assay
x
Blood sample for AAV5 TI assay
x
PBMC collection
x
Cytokine bead array assay
12.5.1.2 
Week 1, Study Day 4 
On Study Day 4, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.3.1)
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
12.5.1.3 
Week 1, Study Day 8 
On Study Day 8, the following assessments will be performed: 
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications
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x Vital Signs 
x Liver Tests (refer to Table 9.7.6.3.1) 
x Blood sample for AAV5 TAb Assay 
o Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x Blood sample for AAV5 TI assay 
x Samples for FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o hFVIII antigen assay 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
x Cytokine bead array assay 
12.5.2 Weeks 2-26 
After Week 1 (Day 8), subjects will return to the study site once a week (± 48 hours) during 
Weeks 2-26. 
12.5.2.1 
Once per week (Weeks 2 through 26)  
The following procedures will be performed once per week from Weeks 1 through 26: 
x 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. 
x 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. 
x 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. 
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x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when 
$/7 YDOXHV DUH ![ 8/1 EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO
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.. 
x Samples for FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level 
o hFVIII antigen assay 
12.5.2.2 
Every Other Week (Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26) 
The following procedures will be performed every other week (at Weeks 2, 4, 6, 8, 10, 12, 
14, 16, 18, 20, 22, 24, and 26): 
x Blood sample for AAV5 TAb Assay 
o Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x Blood sample for AAV5 TI assay 
x PBMC collection 
12.5.2.3 
Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26 
The following procedures will be performed at Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26: 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Collection to occur until at least 3 consecutive results below the limit of 
detection are obtained.  Semen samples should continue to be collected and 
tested through Week 12, even if 3 consecutive results below the limit of 
detection in that compartment have been recorded prior to that time point. 
12.5.2.4 
Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 26 
The following procedures will be performed at Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 26: 
x hFVIII total antibody assay 
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12.5.2.5 
Weeks 2, 4, 6, 8, 14, 20, and 26 
The following procedures will be performed at Weeks 2, 4, 6, 8, 14, 20, and 26: 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
12.5.2.6 
Weeks 2, 6, 10, 14, 18, 22, and 26 
The following procedures will be performed at Weeks 2, 6, 10, 14, 18, 22, and 26: 
x Exploratory biomarker assessments 
12.5.2.7 
Weeks 2, 6, 10, 14, 20, 24, and 26 
The following procedures will be performed at Weeks 2, 6, 10, 14, 20, 22, and 26: 
x Cytokine bead array assay 
12.5.2.8 
Weeks 4, 8, 12, 16, 20, and 26 
The following procedures will be performed at Weeks 4, 8, 12, 16, 20, and 26: 
x Weight 
x VWF:Ag  
12.5.2.9 
Weeks 12 and 26 
The following procedures will be performed at Weeks 12 and 26: 
x Urine tests (to be performed locally) 
x Haemo-QoL-A QoL assessment 
x EQ-5D-5L 
x Hemophilia Activities List (HAL) 
x Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire 
12.5.2.10 Week 16 
The following procedure will be performed at Week 16: 
x Testing for reactivation of hepatitis B and hepatitis C (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  UHDFWLYDWLRQ DVVHVVPHQW LQVWHDG WKH\
will be tested for hepatitis B and hepatitis C reactivation at the time points 
listed in Table 9.1.6. 
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12.5.2.11 Weeks 20, 24, and 26 
The following procedure will be performed at Weeks 20, 24, and 26: 
x Thrombin Generation Assay 
12.5.3 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).  At these visits, the following procedures will be completed:  
12.5.3.1 
Every Visit 
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures 
will be performed: 
x Physical examination 
o Brief physical examination should be performed at all weeks except 
Week 52, 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. 
x 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. 
x 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. 
x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are   [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ
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 
VXEMHFW¶V $/7 LV  [ 8/1 
x FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
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o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for FVIII inhibitor level 
o FVIII protein assay  
12.5.3.2 
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: 
x PBMC collection 
12.5.3.3 
Weeks 32, 36, 44, and 52 
At Weeks 32, 36, 44, and 52, the following procedures will be performed: 
x Weight 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.4.8.2.1) 
x FVIII antibody titer 
x Cytokine bead array assay 
12.5.3.4 
Weeks 32, 36, 40, 44, 48, and 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed: 
x Exploratory biomarker assessments 
x TGA Assay 
x AAV5 TAb Assay 
x AAV5 TI Assay 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing to occur until at least 3 consecutive sample below the limit of 
detection results have been obtained.  Subjects who have not had 3 
consecutive semen samples below the limit of detection by Week 52 should 
continue to have PCR testing of semen every 4 weeks until 3 consecutive 
samples below the limit of detection are documented (or upon consultation 
between the Investigator and Medical Monitor). 
o Subjects considered to be treatment failures must continue to provide samples 
for PCR assessment at these timepoints until vector shedding has cleared (in 
such a case, these subjects do not need to perform other assessments except 
for PCR sample delivery scheduled at these timepoints) 
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12.5.3.5 
Week 36 and 52 
At Weeks 36 and 52, the following procedures will be performed: 
x Urine Tests (refer to Table 9.7.6.2.1)  
x VWF:Ag 
12.5.3.6 
Week 52 
At Week 52, the following procedures will be performed: 
x Haemo-QoL-A assessment 
x EQ-5D-5L 
x HAL 
x WPAI+CIQ:HS 
12.6 
Post-Infusion Follow-Up – Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
HLWKHU IDLOXUH WR DFKLHYH )9,,, DFWLYLW\  5 IU/dL by Week 52 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by 
attending only the Q12W and End of Year visits during Years 2-5. 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment every 6 weeks during Years 2-5 until vector shedding has cleared (but do not 
have to perform other scheduled assessments at those study visits). 
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed: 
12.6.1 Years 2-5 – Every 6 Weeks (not required for treatment failure) 
During Years 2-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
x Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
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. 
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x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are   [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ
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 
VXEMHFW¶V $/7 LV  [ 8/1 
x 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 2-5, a fresh sample should be collected within 
4 weeks of the initial visit that had a positive result. 
o FVIII protein assay  
x PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are clear by the end of Year 2.  Subjects who have not had 
3 consecutive semen samples below the limit of detection by the end of Year 1 
should continue to have PCR testing of semen every 6 weeks during Years 2-5 
until 3 consecutive samples below the limit of detection are documented (or 
upon consultation between the Investigator and Medical Monitor). 
o Subjects who meet the definition of treatment failure and wish to follow 
an abbreviated schedule but who have not cleared vector shedding from all 
fluids must still provide samples for assessment every 6 weeks during 
Years 2-5 until vector shedding has cleared (in such a case, these subjects 
do not need to perform other assessments except for PCR sample delivery 
scheduled at these timepoints). 
12.6.2 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects) 
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks ( ± 2 weeks): 
x Year 2 – Week 64, Week 76, Week 88, Week 104 
x Year 3 – Week 116, Week 128, Week 140, Week 156 
x Year 4 – Week 168, Week 180, Week 192, Week 208 
x Year 5 – Week 220, Week 232, Week 244, Week 260 
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For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and 
Week 260) will serve as an End of Year visit. 
At the every 12 week and End of Year visits, the following procedures will be performed: 
x Brief physical examination (at every 12 week visits) or complete physical 
examination (at End of Year visits) 
x Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
x Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use) 
x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
values are   [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ
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 
VXEMHFW¶V $/7 LV  [ 8/1 
x 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 2-5, a fresh sample should be collected within 
4 weeks of the initial visit that had a positive result. 
o FVIII protein assay  
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) (at 
Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
x Urine Tests (refer to Table 9.7.6.2.1 ) (at Week 76, Week 128, Week 180, Week 232, 
and End of Year visits only) 
x Vital Signs 
x AAV5 TAb Assay 
x AAV5 TI Assay 
x FVIII antibody titer 
x Haemo-QoL-A assessment (at End of Year visits only) 
x EQ-5D-5L (at End of Year visits only) 
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x HAL (at End of Year visits only) 
x WPAI+CIQ:HS (at End of Year visits only) 
x Exploratory biomarker assessments 
x PBMC collection 
x VWF:Ag 
x TGA Assay 
x PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are below the limit of detection during the Post-Infusion Follow-Up 
period in Weeks 1-52.  Subjects who have not had 3 consecutive semen 
samples below the limit of detection by Week 52 should continue to have 
PCR testing of semen every 6 weeks during Years 2-5 until 3 consecutive 
samples below the limit of detection are documented (or upon consultation 
between the Investigator and Medical Monitor). 
12.7 
Early Termination Visit 
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
x Complete physical examination 
x Weight 
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x Vital signs 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
x Samples for hFVIII Assays 
o Baseline FVIII activity – chromogenic substrate FVIII assay 
o Baseline FVIII activity level – one-stage clotting FVIII assay 
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o hFVIII coagulation activity exploratory assay 
o hFVIII inhibitors (Bethesda assay with Nijmegen modification) 
o hFVIII antigen assay  
x hFVIII total antibody assay 
x Exploratory biomarker assessments 
x Blood sample for AAV5 Total Antibody assay 
o Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x Blood sample for AAV5 TI assay 
x PBMC collection for CTL baseline 
x VWF:Ag  
x Thrombin Generation Assay 
x Haemo-QoL-A QoL assessment 
x EQ-5D-5L 
x Hemophilia Activities List (HAL) 
x Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire 
x PCR of vector DNA in blood, saliva, urine, semen, and stool 
o Sample testing at the Early Termination Visit is not required if at least 
3 consecutive samples are clear during the period of the subject’s participation 
in the study. 
12.8 
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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DATA QUALITY ASSURANCE 
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications.  
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STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No interim analysis is planned. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data. 
Sensitivity analyses will be conducted to assess the impact of missing data on the primary 
efficacy endpoint analysis. Additional details regarding the handling of missing data will be 
provided in the SAP. 
14.2 
Efficacy Analysis 
The subjects will be followed in a longitudinal manner, and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature, but data collected in a 
longitudinal manner may be analyzed using longitudinal methods, such as mixed effect 
model, which take into account the correlation among the observations taken at various time 
points within a subject. Efficacy is a secondary endpoint, defined as biologically active FVIII 
DW   ,8G/ at 26 weeks following study treatment. FVIII activity will be assessed weekly 
during the study period. We can only assess the true steady state of FVIII produced from 
BMN 270 after a minimum of 72 hours (or 5x the known half-life of the FVIII replacement 
therapy administered) has elapsed since the last infusion of FVIII concentrates. 
14.3 
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), 
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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.  
Analysis of neutralizing antibody response and other immunological parameters as well as 
vector shedding will be primarily descriptive and involve both inter-subject and intra-subject 
comparisons across doses.  
Detailed statistical methods will be provided in the SAP. 
14.4 
Determination of Sample Size 
The sample size is based upon clinical considerations and is sufficient to detect a strong 
clinical efficacy signal. Approximately 10 subjects may be dosed in the study. 
14.5 
Analysis Populations 
The efficacy analysis set will be comprised of all subjects who have received the BMN 270 
infusion. 
The safety population will consist of all subjects who receive BMN 270 infusion during the 
study. 
14.6 
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/EC must be sought, and 
the Investigator should inform BioMarin and the full IRB/EC within 2 working days after the 
emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/EC 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/EC prior to their implementation. 
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When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the IRB/EC, and 
all active subjects must again provide informed consent. 
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DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) will consist of experts in clinical trials, statistics, 
and hemophilia. The DMC will review available safety and efficacy data during the study on 
an ongoing basis to determine, based on emerging data and the benefit/risk profile, whether 
further enrollment should continue.  
Duties of the DMC include: 
x Conducting an ongoing review of individual subject safety and efficacy data during 
WKH VWXG\ 
x Recommending whether to proceed with enrollment of subjects at a different gating 
schedules based on emerging data from 270-203 and the overall risk/benefit analysis 
RI %01  
x If applicable, considering whether to restrict dosing to subjects with anti-AAV5 titers 
below levels that appear to be causing clinically significant inhibition of transduction. 
x Making other recommendations on the conduct and reporting of the trial based on 
their evaluation of clinical data including institution of any pause or stopping stages. 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC determination of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment:  
x DQ\ UHODWHG 6$( 
x DQ\ UHODWHG $( ZLWK D VHYHULW\ ! *UDGH  RU  
x FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.  
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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/EC 
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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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.  
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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 
source data verified.  The Data Manager, or designee, will set the status of the forms, visits, 
and the entire casebook to Locked. The Investigator will then electronically sign the 
casebook, specifying that the information on the eCRFs is accurate and complete. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents. 
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STUDY MONITORING AND AUDITING 
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. 
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files. 
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RETENTION OF RECORDS 
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained. 
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USE OF INFORMATION AND PUBLICATION 
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable, peer-reviewed scientific journals and at 
seminars or conferences. The details of the processes of producing and reviewing reports, 
manuscripts, and presentations based on the data from this study will be described in the 
Clinical Trial Agreement between BioMarin and the Investigator/Institution. Consideration 
for authorship of all publications will be based on compliance with the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) 
of the International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP).  
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21 
REFERENCES 
Angus B, Brook G, Awosusi F, Barker G et al. British HIV Association guidelines for the 
routine investigation and monitoring of adult HIV-1-positive individuals. 2016. Available at 
http://www.bhiva.org/documents/Guidelines/Monitoring/2016-BHIVA-Monitoring-
Guidelines.pdf. Last accessed 12 September 2017. 
%DWWV .3 	 /XGZLJ - &KURQLF KHSDWLWLV DQ XSGDWH RQ WHUPLQRORJ\ DQG UHSRUWLQJ $P -
Surg Pathol 19:1409-1417.  1995. 
Bedossa P, Pynard T, French METAVIR Cooperative Study Group.  An algorithm for 
JUDGLQJ DFWLYLW\ LQ FKURQLF KHSDWLWLV & +HSDWRORJ\ -293.  1996. 
Berntorp E, Dolan G, Hay C, et. al. European retrospective study of real-life haemophilia 
treatment. Haemophilia.  -DQ-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. 
Boutin S, Monteilhet V, Veron P et al. Prevalence of serum IgG and neutralizing factors 
against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: 
LPSOLFDWLRQV IRU JHQH WKHUDS\ XVLQJ $$9 YHFWRUV +XP *HQ 7KHU -712. 
Brooks R. EuroQol: the current state of play. Health Policy. -72. 
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of 
OLIH +HDOWK 3ROLF\ -208. 
George, LA, Sullivan, S, Teitel, J, Cuker, A et al.  Preliminary results of a phase 1/2 trial of 
63.-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. 
+D\HV * $QGUHHYD 7 *UHJJ . .ODPURWK 5 HW DO *OREDO VHURSUHYDOHQFH RI SUH-existing 
immunity against various AAV serotypes in the hemophilia A population. International 
Society on Thrombosis and Haemostasis (ISTH) 2019 XXVII Congress. Presentation. 
Haemo-QoL Study Group.  Scoring Manual.  Available at: http://haemoqol.de/scoring/ 
manual. Last accessed 28 July 2017.   
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.DXIPDQ 5- 3RZHOO -6 0ROHFXODU DSSURDFKHV IRU LPSURYHG FORtting factors for 
hemophilia. Blood 122[22], 3568-3574. 2013. 
Majowicz A, Lampen M, Petry H, Meyer C et al. Pre-existing Anti-AAV5 Neutralizing 
Antibodies Measured Using a Highly Sensitive Assay in Sera of Hemophilia B Patients in a 
Phase I/II Clinical Trial of AMT-060 Do Not Predict Efficacy of AAV5-mediated 
Liver-GLUHFWHG *HQH 7UDQVIHU 5HV 3UDFW 7KURPE +DHPRVWDVLV 6XSSO  
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. 
0LHVEDFK : 7DQJHOGHU 0 .ODPURWK 5 6FKXWJHQV 5 HW DO 8SGDWHG UHVXOWV IURP D GRVH
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016. 
0LQJR]]L ) DQG +LJK .$ ,PPXQH UHVSRQVHV WR $$9 YHFWRUV RYHUFRPLQJ EDUULHUV WR
successful gene therapy.  Blood 122[1], 23-36. 2013. 
Nathwani AC, Reiss U, Tuddenham E, et al. Adeno-Associated Mediated Gene Transfer for 
Hemophilia B:8 Year Follow up and Impact of Removing "Empty Viral Particles" on Safety 
DQG (IILFDF\ RI *HQH 7UDQVIHU %ORRG  
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. 
3DVL .- 5DQJDUDMDQ 6 0LWFKHOO 1 /HVWHU : HW DO )LUVW-in-human Evidence of Durable 
Therapeutic Efficacy and Safety of Durable Therapy Over Three-years with Valoctocogene 
Roxaparvovec for Severe Haemophilia A (BMN 270-201 Study). Res Pract Thromb 
+DHPRVW 6 
3DVL .- 5DQJDUDMDQ 6 .LP % HW DO $FKLHYHPHQt 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. 
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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 
LQ +HDOWK -748. 
Reilly, M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ 
WPAI_Scoring.html. Last accessed 28 July 2017.   
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 
DGXOWV ZLWK KDHPRSKLOLD +DHPRSKLOLD -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 
,PPXQRO -397. 
6ULYDVWDYD $ %UHZHU $. 0DXVHU-%XQVFKRWHQ (3 .H\ 16 HW DO *XLGHOLQHV IRU WKH
management of hemophilia 128. Haemophilia 19[1], e1-47. 2013. 
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010. 
YDQ *HQGHUHQ )5 :HVWHUV 3 +HLMQHQ / GH .OHLMQ 3 HW DO 0HDVXULQJ SDWLHQWV¶ SHUFHSWLRns 
on their functional abilities: validation of the Haemophilia Activities List. Haemophilia. 
-46. 
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22 
INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Subjects  
In accordance with FDA Form 1572 and/or principles of ICH E6 GCP, the Investigator will 
ensure that: 
x He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
x He or she will personally conduct or supervise the study. 
x 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/EC review and 
approval in 21 CFR Part 56 and/or ICH E6 Section 2.6 are met.  
x He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 Section 4.11. 
x He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
x His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
x Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 
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. 
x The IRB/EC complies with the requirements of 21 CFR Part 56, ICH E6 Section 3.0, 
and other applicable regulations, and conducts initial and ongoing reviews and 
approvals of the study. He or she will also ensure that any change in research activity 
and all problems involving risks to human subjects or others are reported to the 
IRB/EC. Additionally, he or she will not make any changes in the research without 
IRB/EC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects. 
x He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6. 
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APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA 
According to the National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network (NIAID/FAAN) Second Symposium on the definition and 
management of anaphylaxis, anaphylaxis is highly likely when any one of the following 3 
criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) 
2. 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) 
3. 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) 
4. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a. Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease is systolic BP 
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline. 
Source: Sampson, 2006. 
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25 
PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to Protocol Amendment 1 and relates the changes to the appropriate rationale (see 
pages 2-4). Added text is indicated by underlined font and deleted text is indicated by strikethrough font. 
Section No./Title 
Revision 
Rationale 
Synopsis/Study Sites 
Approximately 2-35-6 sites LQ WKH 8QLWHG .LQJGRPglobally 
17 
Synopsis/Study Rationale 
Treatment of severe HA presently mainly consists of intravenous injection…. 
19 
Synopsis/Study Rationale 
Extended half-life products created through chemical modification (eg, direct conjugation of polyethylene glycol 
(PEG) polymers) andor bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can only extend half-life to 
maximum of by approximately 50% (half-life 18-19 hours, leaving critical periods when FVIII ), and thus, show 
promise in reduced dosing and maintaining activity levels are below the therapeutic range and leavingabove a 1% 
trough for a greater proportion of the dosing interval. However, patients vulnerable to bleeding and concomitant 
sequelae. As such, despite currently available with severe HA who are treated with extended half-life FVIII 
remain dependent on multiple infusions to maintain critical levels of FVIII activity. More recently, emicizumab 
has been approved for the treatment of HA. Emicizumab is a humanized, bispecific monoclonal antibody that 
binds to both activated coagulation factor IX (FIX) and coagulation factor X (FX), thereby mimicking the 
function of activated FVIII. Emicizumab represents an incremental improvement in therapeutic burden over 
replacement therapies, a highFVIII products since it can be administered subcutaneously as opposed to 
LQWUDYHQRXVO\ KRZHYHU LW LV VWLOO D FKURQLF WUHDWPHQW WKDW Uequires repeat administration every 1-4 weeks, and 
sustained FVIII activity levels above 5-10 IU/dL have rarely been attained even with extended half-life products. 
Therefore, there is a strong unmet need remains for maintenance of a sustained, consistent FVIII level compatible 
with a normal and hemorrhage-free lifefor a treatment that can alter the fundamental problem for patients with 
HA, namely attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over multiple 
years) without the need for treatment.  
19 
Synopsis/Study Rationale 
…. bleeding phenotype from severe to moderate or mild, following a single peripheral vein infusion of AAV8-
hFIX vector (Nathwani, 20142018). 
19 
Synopsis/Study Rationale 
The vector schematic figure and notes have been updated. 
 
BMN 270 is delivered by a single IV dose and is designed to achieve stable, potentially life longdurable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.  
14, 19 
Synopsis/Study Rationale 
PreliminaryThree-year results from 270-201 have demonstrated that following gene transfer, sustained mean and 
median FVIII activity levels above 15% (15 IU/dL) up to ), as measured by a year’s observation ischromogenic 
substrate assay, are achievable withand sustained following a dosesingle infusion of 4 6E13 vg/kg withof BMN 
15 
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270, with administration of prophylactic corticosteroids and an acceptable safety profile (Pasi, 2017). 2019). In 
addition, an interim analysis of clinical study 270-301, an ongoing phase 3 study designed to assess the efficacy 
and safety of BMN 270 at a dose of 6E13 vg/kg and administration of therapeutic corticosteroids (ie, in response 
to ALT elevations), demonstrated FVIII activity levels that were also well above 15%, albeit lower than what was 
observed for the 6E13 vg/kg cohort in 270-201 at 26 weeks (Pasi, 2019). 
Synopsis/Study Rationale 
AAV5 has consistently been shown to have the lowest seroprevalence among the common AAV serotypes. 
%RXWLQ  +D\HV  
19 
Synopsis/Study Design and 
Plan 
Approximately 10 subjects may be enrolled at 2 35-6 sites in 2 cohorts (5 subjects in each cohort) and will 
receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. 
17 
Synopsis/Study Design and 
Plan 
The An independent Data Review Board (DRBMonitoring Committee (DMC) will consist of the Principal 
Investigatorsexperts in clinical trials, statistics, and Sponsor’s Medical Monitor, as well as hemophilia expert 
advisors experienced in the conduct and evaluation of safety and efficacy parameters from 270 201.  The DRB. 
The DMC will review available safety and efficacy data throughout the study and provide recommendations 
based on their review (Figure 2 represents one dosing schedule scenario): 
 
13 
Synopsis/Study Design and 
Plan 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on DRBDMC 
evaluation of safety and efficacy in treated subjects 
13 
Synopsis/Study Design and 
Plan 
Following a temporary halt of enrolment, the DRBDMC may approve resumption of enrolment in…. 
13 
Synopsis/Study Design and 
Plan 
… prior FVIII prophylaxis for each subject will be continued at the discretion of the DRBDMC based on 
individual subject status… 
13 
Synopsis/Study Design and 
Plan 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve 
)9,,, DFWLYLW\   ,8G/ E\ either Week 26 or 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 either Week 26 or Week 52, as applicable by attending only the Q12W 
and at the discretionEnd of the InvestigatorYear visits during Years 2-5. 
3 
Synopsis/Study Design and 
Plan 
… additional subjects may be recruited into each cohort at any time, if deemed necessary by the DRBDMC. 
13 
Synopsis/Diagnosis and all 
criteria for inclusion and 
exclusion 
… after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with 
no detectable viral vector DNA below the limit of detection 
Willing to abstain from consumption of alcohol for at least the first 2652 weeks following BMN 270 infusion 
4, 9, 10 
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Major surgery planned in the 2652-week period following the infusion with BMN 270 
7.2/Previous Clinical Studies 
Study Ongoing clinical studies for BMN 270 include: 
270-201 is an ongoing, a 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 HA 
270 infusion and are to be followed for safety and efficacy for up to 5 years.  A total of 15 subjects have been 
enrolled and dosed-203, a phase 1/2 study in patients with a single IV infusion ofsevere HA who have anti-AAV5 
antibody titers 
270-301, a phase 3 study in patients with severe HA who receive BMN 270 at the 6E13 vg/kg dose level 
270-302, a phase 3 study in patients with severe HA who receive BMN 270 at one of 4 dose levels (6E12, 2E13, 
the 4E13 , and 6E13 vg/kg). dose level 
A comprehensive review of safety, efficacy, and immunogenicity results from 270-201 and 270-301 as of the 
latest data cut…. 
19 
7.3/Study Rationale 
Treatment of severe HA presently mainly consists of intravenous injection…. 
19 
7.3/Study Rationale 
Extended half-life products created through chemical modification (eg, direct conjugation of polyethylene glycol 
(PEG) polymers) andor bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can only extend half -life to 
maximum ofby approximately 50% (half-life 18-19 hours, leaving critical periods when FVIII ), and thus, show 
promise in reduced dosing and maintaining activity levels are below the therapeutic range and leavingabove a 1% 
trough for a greater proportion of the dosing interval. However, patients vulnerable to bleeding and concomitant 
sequelae. As such, despite currently available with severe HA who are treated with extended half-life FVIII 
remain dependent on multiple infusions to maintain critical levels of FVIII activity. More recently, emicizumab 
has been approved for the treatment of HA. Emicizumab is a humanized, bispecific monoclonal antibody that 
binds to both activated coagulation factor IX (FIX) and coagulation factor X (FX), thereby mimicking the 
function of activated FVIII. Emicizumab represents an incremental improvement in therapeutic burden over 
replacement therapies, a highFVIII products since it can be administered subcutaneously as opposed to 
LQWUDYHQRXVO\ KRZHYHU LW LV VWLOO D FKURQLF WUHDWPHQW WKDW UHTXLUHV UHSHDW DGPLQLVWUDWion every 1-4 weeks, and 
sustained FVIII activity levels above 5-10 IU/dL have rarely been attained even with extended half-life products. 
Therefore, there is a strong unmet need remains for maintenance of a sustained, consistent FVIII level compatible 
with a normal and hemorrhage free lifefor a treatment that can alter the fundamental problem for patients with 
HA, namely attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over multiple 
years) without the need for treatment. 
19 
7.3/Study Rationale 
… following a single peripheral vein infusion of AAV8-hFIX vector (Nathwani, 20142018). 
19 
7.3/Study Rationale 
The vector schematic figure and notes have been updated. 
 
14 
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7.3/Study Rationale 
BMN 270 is delivered by a single IV dose and is designed to achieve stable, potentially life longdurable 
expression…. 
19 
7.3/Study Rationale 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. PreliminaryThree-year 
results from 270-201 have demonstrated that following gene transfer, sustained mean and median FVIII activity 
above 15% (15 IU/dL) up to ), as measured by a year’s observation ischromogenic substrate assay, are achievable 
withand sustained following a dosesingle infusion of 4 6E13 vg/kg withof BMN 270, with administration of 
prophylactic corticosteroids and an acceptable safety profile (Pasi, 2017 2019). In addition, an interim analysis of 
clinical study 270-301, an ongoing phase 3 study designed to assess the efficacy and safety of BMN 270 at a dose 
of 6E13 vg/kg and administration of on-demand corticosteroids (ie, in response to ALT elevations), demonstrated 
FVIII activity levels that were also well above 15% at 26 weeks, albeit lower than what was observed for the 
6E13 vg/kg cohort in 270-201 (Pasi, 2019). 
19 
7.3/Study Rationale 
AAV5 has consistently been shown to have the lowest seroprevalence among the common AAV serotypes. 
+D\HV  %RXWLQ  
19 
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 that have reached 
only slightly above the upper limit of normal (ULN). Subjects in the 6E13 vg/kg cohort received corticosteroids, 
predominantly on a prophylactic basis, starting 2-4 weeks following BMN 270 infusion, whereas those in the 
( YJNJ FRKRUW UHFHLYHG FRUWLFRVWHURLGV RQO\ LI WKH\ H[SHULHQFHG DQ HOHYDWLRQ LQ WKHLU $/7  [ 8/1 LH
“therapeutic”). Based on the effectiveness of transient oral corticosteroidcorticosteroids used starting 8-10 weeks 
after vector infusion to suppress a presumed Class 1 (cytotoxic T-cell) response in prior studies with hepatic 
transduction with AAV vectors (Mingozzi, 2013), subjects were treated with 7-32 weeks of oral corticosteroids 
prophylactically or in response to the elevations in ALT to limit hepatotoxicity, ensure preservation of the 
transduced hepatocytes, and minimize any associated impact of such on FVIII levels. 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. Moreover, the rise in ALT levels was not 
accompanied by significant or lasting abnormalities in other liver tests such as AST, bilirubin or albumin, 
indicating that extent of toxicity is limited. At the highest dose tested in 270-201 (6E13 vg/kg), the majority of 
subjects achieved chromogenic FVIII activity levels above 50 IU/dL at 52 weeks post-infusion. Subjects in that 
cohort also reported markedly decreased bleeding compared with pre-study rates and the ability to discontinue 
prophylactic FVIII infusions. Subjects at all dose levels continue to be followed. 
In the ongoing 270-301 clinical study, a majority of subjects, all dosed with 6E13 vg/kg BMN 270, have 
experienced asymptomatic elevations in ALT. Subjects received therapeutic corticosteroids if they experienced 
DQ $/7 HOHYDWLRQ DQGRU KDG D )9,,, DFWLYLW\ OHYHO WKDW KDG GHFOLQHG ! IURP SHDN YDOXHV :KLOH VSRUDGLFDOO\
observed cytotoxic T-cell responses have not been correlated with ALT elevations, the majority of subjects with 
transient rises in ALT levels had associated declines in their FVIII activity that subsequently increase to higher 
15 
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than pre-ALT elevation levels following initiation of therapeutic corticosteroids. Similar to 270-201, the rise in 
ALT levels in 270-301 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. At the time of the 270-301 interim 
analysis, the modified intent-to-WUHDW SRSXODWLRQ Q  ZKR KDG FRPSOHWHG  ZHHNV RQ-study) had mean and 
median chromogenic FVIII activity levels of 36.1 and 33.2 IU/dL at 26 weeks, respectively, which are lower than 
the corresponding values observed for the 270-201 6E13 vg/kg cohort. 
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 hashave been three subjects, including one subject with Gilbert’s syndrome, in the ongoing 270-301 clinical 
study who hashave 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 beyond Grade 1 to date. Overall, the literature and clinical experience with 
BMN 270 suggests that transient elevations in liver enzymes are expected following AAV-based gene therapy for 
the treatment for hemophilia A or B without any long-WHUP FRQFHUQV RI KHSDWLF LQMXU\ 0DQQR  1DWKZDQL
 *HRUJH  0LHVEDFK  3DVL   
At the highest dose evaluated in 270 201 (6E13 vg/kg), the majority of subjects achieved FVIII levels above 50 
IU/dL at 52 weeks post infusion.  Subjects in that cohort also reported markedly decreased bleeding episodes 
compared with pre study rates and the ability to discontinue prophylactic FVIII infusions. Subjects at all dose 
levels continue to be followed. Subjects in 270 203, who have pre existing immunity to the AAV5 vector capsid, 
may get no benefit from the study (in terms of increased FVIII activity) while possibly creating cross reactive 
antibodies that may potentially preclude dosing with other serotypes. 
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 hypersensitivity reactions,  
(including allergic reaction, maculopapular rash, and presyncope,anaphylaxis) have been reported from ongoing, 
activelyobserved during dosing clinical studies of BMN 270, including this  in the 270-301 clinical study. (refer 
to Investigator’s Brochure for full details). 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 comprehensive assessment of the has shown an 
established positive benefit:risk profile of this investigational drugfor BMN 270 at the 6E13 vg/kg dosing level, 
although impact of prophylactic corticosteroids requires further investigation. . Given the monitoring measures in 
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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 270-203 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 201from other BMN 270 clinical studies, refer to the current 
version of the IB. 
9.1/Overall Study Design 
and Plan 
Approximately 10 subjects may be enrolled at 2 35-6 sites globally in 2 cohorts (5 subjects in each cohort) and 
will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a Screening 
$$9 7$E   ZKLOH VXEMHFWV LQ &RKRUW 2 will have a Screening AAV5 TAb ! 500. Choosing a titer cutoff of 
500 reflects the observed distribution of existing titer data with the BioMarin titer assay seen to date. 
The Data Review Board (DRB) will consist of the Principal Investigators and Sponsor’s Medical Monitor, as well 
as hemophilia expert advisors experienced in the conduct and evaluation of safety and efficacy parameters from 
270 201.  The DRBAn independent Data Monitoring Committee (DMC), consisting of experts in clinical trials, 
statistics, and hemophilia, has been convened.  The DMC will review available safety and efficacy data… 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on DRBDMC 
evaluation of safety and efficacy…. 
Following a temporary halt of enrolment, the DRBDMC may approve resumption of enrolment in either 
cohort…. 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not respond to BMN 270 
WUHDWPHQW LH WUHDWPHQW IDLOXUH PDQLIHVWLQJ DV HLWKHU IDLOXUH WR DFKLHYH )9,,, DFWLYLW\   ,8G/ E\ either Week 
26 or 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 either 
Week 26 or Week 52, as applicable by attending only the Q12W and at the discretionEnd of the InvestigatorYear 
visits during Years 2-5.  
During the trial, additional subjects may be recruited into each cohort at any time, if deemed necessary by the 
DRBDMC.   
3, 13, 17, 
19 
Table 9.1.1, Table 9.1.2, 
Table 9.1.3, Table 9.1.4, 
Table 9.1.5, Table 9.1.6 
Updates were made to the tables and associated footnotes to be consistent with the changes in the protocol 
1, 2, 3, 4, 
5, 7, 8, 
16, 18, 19 
9.3.1/Inclusion Criteria 
Participants must agree to contraception use for at least 12 weeks post-LQIXVLRQ DIWHU  ZHHNV VXEMHFWV PD\ VWRS
contraception use only if they have had 3 consecutive semen samples with no detectable viral vector DNA below 
the level of detection. 
4, 9 
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Willing to abstain from consumption of alcohol for at least the first 2652 weeks following BMN 270 infusion. 
9.3.2/Exclusion Criteria 
Major surgery planned in the 2652-week period following the infusion with BMN 270 
 
10 
9.3.3.1/Study Safety 
Evaluation Criteria 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on DRBDMC 
evaluation of safety and efficacy…. 
Additionally, the DRBDMC should consider whether to restrict dosing to subjects with anti-AAV5 titers below 
levels that appear to be causing clinically significant inhibition of transduction.  Following a temporary halt of 
enrolment, the DRBDMC may approve… 
If a Grade 4 or Grade 5 adverse event assessed as related to study drug occurs in a study subject, further 
enrollment into the trial will be halted until a full safety review of the data by the DRBDMC has taken place. 
Relevant reporting and discussion with the Sponsor and the DRBDMC will take place before resumption of 
dosing. 
If any of the following events occur in a subject in the study who has received BMN 270 infusion, further 
enrollment into the trial will be temporarily put on hold pending prompt evaluation by the DRBDMC. 
If any of the following events occurs in a subject in the study who has received BMN 270 infusion, a prompt 
evaluation by the DRBDMC will be required.  Further enrollment into the trial will continue while DRBDMC 
evaluation is ongoing, unless deemed otherwise by the DRBDMC. 
13 
9.4.2.1/Product 
Characteristics and Labeling 
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 210 mL 
polypropylene cryovial.Crystal Zenith® (CZ) vial. Each CZ vial contains 1.1 8.5 mL (extractable volume 8 mL) 
of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. 
11 
9.4.4/Directions for 
Administration 
Of note, the IP has been shown to be stable at room temperature for 7.5approximately 10 hours following 
completion of product thaw. 
In the event of an infusion rate reaction with more than one dosing interruption, the infusion rate would not go 
beyond 1 mL/min. 
In case of hypersensitivity or adverse drug reactionreactions, safety assessment, including physical examination 
and vital signs, will be done and additional blood samples…. 
19 
9.4.8/Prior and Concomitant 
Medications 
The following medications should be avoided, starting 30 days prior to and for at least 2652 weeks after BMN 
270 infusion and minimized throughout the remaining duration of the study. 
x 
Medications which may reduce or increase the plasma concentration of corticosteroids 
1 
9.4.8.2/ Therapeutic 
GlucocorticoidCorticosteroid 
All subjects will be started on prophylactic corticosteroids starting on the day of infusion (Day 1). 
Table 9.1.6Therapeutic provides an example of a possible prophylactic corticosteroid course, including taper and 
post-corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical 
1 
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Treatment forof Elevated 
Hepatic Transaminases 
judgment, weighting the potential risks and benefits of corticosteroid treatment, should always be exercised when 
considering adjustment of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns. 
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased 
HJ  8/1 RU  [ EDVHOLQH YDOXH DQG DOWHUQDWLYH HWLRORJLHV KDYH EHHQ UXOHG RXW SURPSW LQVWLWXWLRQ RI
therapeutic or on-demand oral corticosteroids (prednisone or converted equivalent) should be initiated when 
either of the following occurs post BMN 270 infusion in any subject and considered after consultation with the 
Medical Monitor: 
$/7  [ 8/1 RU $/7 ! 8/1 	 ! [ EDVHOLQH YDOXH LQ  FRQVHFXWLYH DVVHVVPHQWV ZLWKLQ  hours and 
alternative etiologies KDYH EHHQ UXOHG RXW RU $/7  [ 8/1 LQ  consecutive assessments within 48 hours (refer 
to )Table 9.7.6.3.2). 
x 
Whenever possible, a confirmatory lab draw for ALT should be performed within 72 hours, along with 
FVIII activity, prior to initiating oral corticosteroids. 
x 
Corticosteroids may be delayed if elevations in ALT are clearly not related to BMN 270 (eg, elevated in 
$/7 ZLWK FRQFXUUHQW LQFUHDVH LQ &3. GXH WR LQWHQVLYH H[HUFLVH  
The prescribed regimen for therapeutic oral corticosteroids is detailed in . Changes to the corticosteroid regimen 
should be made as follows: 
Therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. At minimum, the recommended 
duration of therapeutic corticosteroids is 60 mg/day for 3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 
weeks, followed by a gradual taper thereafter. Should a scenario arise in which a deviation from the minimum 
recommended dose and/or duration of therapeutic corticosteroids may be clinically indicated, a discussion should 
take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments. Tapering of 
corticosteroid dosages should be guided by the following: 
Following initiation or completion of therapeutic oral corticosteroids, if increased ALT HOHYDWLRQ [ levels (eg, 
 ULN or ALT    8/1 	    2x baseline value is) are reported, corticosteroid management decisions will be 
based on discussions between the Investigator and Medical Monitor. 
Subjects on corticosteroids should receive appropriate counselling and support regarding side effects from the 
Investigator or the treating institution (eg, listings of side effects and when to notify carers, wallet card for 
emergencies if on steroids, etc.). 
Table 9.4.8.2.1/Adjustments 
to Corticosteroid Regimens 
The table has been updated to reflect changes made elsewhere in the body of the protocol. 
1, 2 
9.6/Dietary or Other 
Protocol Restrictions 
There are no dietary or other protocol restrictions for this study.  Alcohol should be avoided starting 30 days prior 
to and for at least the first 2652 weeks of the study, and particularly within 48 hours prior to lab work. 
9, 19 
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Subjects should be advised to abstain from any blood, organ, or sperm donation after BMN 270 infusion, until 
there is no further evidence of vector shedding from PCR analysis of samples. 
9.7.2.1/FVIII Activity 
… discussion with the Medical Monitor, follow an abbreviated visit schedule after either Week 26 or Week 52, as 
applicable and at the discretion of the Investigator. 
3 
Table 9.7.6.2.1 
* 
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).. 
19 
9.7.6.2/Clinical Laboratory 
Assessments 
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. Potential MN visits are designated in 
the Schedules of Events. 
8 
9.7.6.3/Liver and Hepatitis 
Testing 
Subjects with documented results showing an absence of active hepatitis B or hepatitis C infection (as measured 
by positivenegative surface antigen or DNA for hepatitis B or positivenegative RNA testing for hepatitis C)…. 
19 
Table 9.7.6.3.2/Evaluation of 
ALT Elevations 
The table has been updated to reflect changes made elsewhere in the body of the protocol. 
2, 19 
9.7.6.5/Vital Signs 
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. 
Vector shedding will also be extensively studied in the present clinical trial, 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.  Testing will continue until at least 3 
negativeconsecutive results below the limit of detection are obtained.  Testing of semen will continue at least 
through Week 12, even if 3 consecutive negative results below the limit of detection have been recorded in that 
compartment prior to that time point.  Subjects who have not had 3 consecutive negative semen samples below 
the limit of detection by Week 26 should continue to have PCR testing in semen every 4 weeks until 
3 consecutive negative samples below the limit of detection are documented (or upon consultation between the 
Investigator and Medical Monitor). Subjects who meet the definition of treatment failure and wish to follow an 
abbreviated schedule (refer to Section 12.5.3) but who have not cleared vector shedding from all fluids must still 
provide samples for assessment until vector shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 (during 
Year 1),) and every 4 weeks (during Year 2), or every 6 weeks (during Years 32-5).. Such subjects may provide 
samples on the designated study visit dates either at the sites or through use of a MN professional. 
3, 4, 8, 
18, 19 
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 2 7 0- 2 0 3
 
A me n d me nt
 
1
  
 
 
 
 
 Pa ge
 
1 3 4
 
 
Pr o prietar y a n d C o nfi de ntial 
4 Oct o ber 2 0 1 9 
Secti o n N o./ Title 
Re visi o n 
R ati o n ale 
… s per m teste d p ositi ve f or vect or D N A o n at least t hree visits, or if p urifie d s per m teste d ne gati ve bel o w t he 
li mit of detecti o n f or vect or D N A o n at least t hree c o nsec uti ve visits. 
C o ntrace pti o n use ma y nee d t o be e xte n de d be y o n d 2 6 1 2 wee ks i n i n di vi d ual s u bj ects base d o n o bser ve d vect or 
s he d di n g i n se me n.  After 2 6 1 2 wee ks, s u bj ects ma y st o p c o ntrace pti o n use o nl y if t he y ha ve ha d 3 c o nsec uti ve 
ne gati ve se me n sa m ples bel o w t he li mit of detecti o n ( u p o n c o ns ultati o n bet wee n t he I n vesti gat or a n d Me dical 
M o nit or). 
1 0. 3. 3/ Assess me nt of 
Seri o us ness, Se verit y, a n d 
Ca usalit y 
T he I n vesti gat or res p o nsi ble f or t he care of t he s u bj ect or me dicall y q ualifie d desi g nee will assess A Es f or 
se verit y, relati o ns hi p t o st u d y dr u g a n d/ or c ortic oster oi ds, a n d seri o us ness (refer t o Secti o n 1 0. 2 f or S A E 
defi niti o ns). 
6 
1 0. 3. 3. 3/ Ca usalit y 
T he I n vesti gat or will deter mi ne t he relati o ns hi p of a n A E t o t he st u d y dr u g a n d/ or c ortic oster oi ds a n d will rec or d 
it o n t he s o urce d oc u me nts a n d A E e C R F. 
Fact ors s u g gesti ve of a ca usal relati o ns hi p c o ul d i ncl u de ( b ut are n ot li mite d t o): 
 
Pla usi ble te m p oral relati o ns hi p 
 
A bse nce of alter nati ve e x pla nati o ns 
 
Rarit y of e ve nt i n a gi ve n pati e nt or disease state 
 
A bse nce of e ve nt pri or t o st u d y dr u g a n d/ or c ortic oster oi d e x p os ure 
 
C o nsiste nc y wit h st u d y pr o d uct p har mac ol o g y 
 
derl yi n g mec ha nis m of st u d y dr u g a n d/ or c ortic oster oi d acti o n 
 
Si milarit y t o a d verse reacti o ns see n wit h relate d dr u g pr o d ucts 
 
A bate me nt of A E wit h disc o nti n uati o n of st u d y dr u g a n d/ or c ortic oster oi ds, a n d/ or rec urre nce of A E 
wit h rei ntr o d ucti o n of st u d y dr u g a n d/ or c ortic oster oi ds 
 
6 
T a ble 1 0. 3. 3. 3. 1/ Ca usalit y 
Attri b uti o n G ui da nce 
T he ta ble has bee n u p date d t o reflect c ha n ges ma de else w here i n t he b o d y of t he pr ot oc ol. 
6 
1 0. 4. 1. 4/ A b n or mal 
La b orat or y Val ues 
A n y la b orat or y res ult a b n or malit y f ulfilli n g t he criteria f or a S A E or E O SI s h o ul d be re p orte d as s uc h, a n d 
rec or de d i n t he A E e C R F u nless ass ociate d wit h a n A E t hat has alrea d y bee n re p orte d. 
1 9 
1 0. 9/ Bi o Mari n 
P har mac o vi gila nce C o ntact 
I nf or mati o n 
, M A M B B C hir 
c h M D P h D 
Bi o mari n 
P har mace utical I nc. 
1 0 Bl o o ms b ur y Wa y 
L o n d o n W C 1 A 2 S L 
1 2 
D o c u Si g n E n v el o p e I D: 9 0 B B 4 7 E 5- D 2 8 6- 4 A 3 0- 9 6 A 8- F A 7 4 2 7 7 6 2 9 8 9
PI
PI

 
 
270-203 Amendment 1  
 
 
 
 
 
Page 136 
 
Proprietary and Confidential 
4 October 2019 
Section No./Title 
Revision 
Rationale 
considering adjustment of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns. 
12.5/BMN 270 Infusion 
Follow-Up Visits 
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. Potential MN visits are designated in 
the Schedules of Events. 
8 
12.5.2.1/Once per week 
x 
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. 
x 
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. 
x 
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. 
8 
12.5.2.3/ Weeks 2, 3, 4, 6, 8, 
12, 16, 20, 24, and 26 
Collection to occur until at least 3 consecutive negative results below the limit of detection are obtained.  Semen 
samples should continue to be collected and tested through Week 12, even if 3 consecutive negative results below 
the limit of detection in that compartment have been recorded prior to that time point. 
4 
 
Weeks 13 and 26 
The following procedure will be performed at Weeks 13 and 26: 
x 
Direct thrombin activity test 
 
5 
12.5.3/Post-Infusion Follow-
Up 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve 
)9,,, DFWLYLW\   ,8G/ E\ :HHN  RU LQDELOLW\ WR PDLQWDLQ LQGHSHQGHQFH IURP SURSK\ODFWLF )9,,, UHSODFHPHQW
therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion 
and after discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 26 of the study by 
3 
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Proprietary and Confidential 
4 October 2019 
Section No./Title 
Revision 
Rationale 
attending only the Week 36, 44, and 52 visits during the remainder of Year 1.  Such subjects following the 
abbreviated schedule who have not yet cleared vector shedding in all fluids must still provide samples at Week 
32, Week 40, and Week 48, if necessary (but do not need to do other scheduled assessments on that date). 
12.5.3.1/Every Visit 
x 
Physical examination 
o 
Brief physical examination should be performed at all weeks except Week 52, 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. 
x 
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. 
x 
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. 
3 
12.5.3.3/ Weeks 32, 36, 44, 
and 52 
x 
Weight 
x 
Blood chemistry, hematology, and coagulation tests (refer to Table 9.4.8.2.1) 
x 
FVIII antibody titer 
x 
AAV5 TAb Assay 
x 
AAV5 TI Assay 
16 
12.5.3.4/ Weeks 32, 36, 40, 
44, 48, and 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed: 
x 
AAV5 TAb Assay 
x 
AAV5 TI Assay 
x 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
o 
Sample testing to occur until at least 3 consecutive negative sample below the limit of detection 
results have been obtained.  Subjects who have not had 3 consecutive negative semen samples 
below the limit of detection by Week 52 should continue to have PCR testing of semen every 
4 weeks until 3 consecutive negative samples below the limit of detection are documented (or 
upon consultation between the Investigator and Medical Monitor). 
4, 16 
12.5.3.5/ Week 36 and 52 
At Weeks 36 and 52, the following procedures will be performed: 
5 
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Section No./Title 
Revision 
Rationale 
x 
Direct Thrombin test 
12.6/ Post-Infusion Follow-
Up – 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 32-5) until vector shedding has cleared (but do not have to perform other 
scheduled assessments at those study visits). 
18 
12.6/ Post-Infusion Follow-
Up – Years 2-5 
Year 2  Every 4 Weeks (not required for treatment failure) 
During Year 2, every 4 weeks ( ± 2 weeks), the following procedures will be performed: 
x 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for 
bleeding and FVIII use) 
x 
Liver Tests (refer to ) 
o 
LTs may be monitored more or less frequently (and in particular when ALT values are   1.5x 
8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG
the Investigator and review of subject data, but LTs will be monitored at least twice weekly 
during periods when a subject’s ALT LV  [ 8/1 
x 
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  
x 
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o 
Sample testing during Year 2 is not required if at least 3 consecutive samples are negative 
during the Post Infusion Follow Up period in Weeks 1 52.  Subjects who have not had 
3 consecutive negative semen samples by Week 52 should continue to have PCR testing of 
semen every 4 weeks during 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 (in such a case, 
these subjects do not need to perform other assessments except for PCR sample delivery 
scheduled at these timepoints). 
Years 3 5  Every 6 Weeks (not required for treatment failure) 
3, 4, 5, 8, 
18, 19 
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Section No./Title 
Revision 
Rationale 
Years 2-5 – Every 6 Weeks (not required for treatment failure) 
During Years 32-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
x 
Assessment of Adverse Events and Concomitant Medications (including review of subject diary for 
bleeding and FVIII use) 
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. 
x 
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o 
Sample testing during Years 32-5 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 below the 
limit of detection by the end of Year 21 should continue to have PCR testing of semen every 6 
weeks during Years 32-5 until 3 consecutive negative samples below the limit of detection are 
documented (or upon consultation between the Investigator and Medical Monitor). 
o 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from all fluids must still provide samples 
for assessment every 6 weeks during Years 32-5 until vector shedding has cleared (in such a 
case, these subjects do not need to perform other assessments except for PCR sample delivery 
scheduled at these timepoints). 
x 
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 
 
If a subject tests positive in the Bethesda assay (with Nijmegen modification) during 
Years 32-5, a fresh sample should be collected within 4 weeks of the initial visit that 
had a positive result. 
x 
VWF:Ag 
x 
Direct Thrombin test  
x 
TGA Assay 
x 
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o 
Sample testing during Years 2-5 is not required if at least 3 consecutive samples are 
negativebelow the limit of detection during the Post-Infusion Follow-Up period in Weeks 1-52.  
Subjects who have not had 3 consecutive negative semen samples below the limit of detection 
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Section No./Title 
Revision 
Rationale 
by Week 52 should continue to have PCR testing of semen every 4 weeks (during Year 2) or 
every 6 weeks (during Years 32-5) until 3 consecutive negative samples below the limit of 
detection are documented (or upon consultation between the Investigator and Medical 
Monitor). 
12.7/Early Termination Visit 
x 
Direct Thrombin test 
5 
Section 15 
Data REVIEW BOARDmonitoring committee 
The Data Review Board (DRBMonitoring Committee (DMC) will consist of the Principal Investigatorsexperts in 
clinical trials, statistics, and Sponsor’s Medical Monitor, as well as hemophilia expert advisors experienced in the 
conduct and evaluation of safety and efficacy parameters from 270-201. . The DRBDMC will review available 
safety and efficacy data during the study on an ongoing basis to determine, based on emerging data and the 
benefit/risk profile, whether further enrollment should continue. The DRB will meet weekly until all subjects 
have completed Week 26, and then monthly thereafter. 
Duties of the DRBDMC include:… 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on DRBDMC 
determination of safety and efficacy…. 
13 
Section 17/Case Report 
Forms and Source 
Documents 
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 source data verified.  The Data Manager, 
or designee, will set the status of the forms, visits, and the entire casebook to Locked. 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. 
19 
21/References 
Boutin S, Monteilhet V, Veron P et al. Prevalence of serum IgG and neutralizing factors against adeno-associated 
virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. 
+XP *HQ 7KHU -712. 
Hayes G, AndrHHYD 7 *UHJJ . .ODPURWK 5 HW DO *OREDO VHURSUHYDOHQFH RI SUH-existing immunity against 
various AAV serotypes in the hemophilia A population. International Society on Thrombosis and Haemostasis 
(ISTH) 2019 XXVII Congress. Presentation. 
Nathwani AC, Reiss U, Tuddenham E, et al. Adeno-Associated Mediated Gene Transfer for Hemophilia B:8 
Year Follow up and Impact of Removing "Empty Viral Particles" on Safety and Efficacy of Gene Transfer. 
%ORRG  
19 
 
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270-203 Amendment 3 
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Proprietary and Confidential 
24 August 2020 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY 
Amendment 3 
Date: 24 August 2020 
RATIONALE AND SUMMARY OF CHANGES 
A summary of major changes covered by Amendment 3 to the 270-203 protocol is provided 
below: 
1. Screening testing for COVID-19 has been added. 
Rationale: Exclusion criteria for the study already included a provision excluding subjects 
with an active infection. In light of the emergence of the novel coronavirus SARS-CoV-2, the 
criterion has been modified to specify that this includes testing for active COVID-19 
infection, which has been added to the Screening visit in the Schedule of Activities.  
2. Complement panel details have been updated. 
Rationale: Current protocol language says that blood samples will be tested for C3, C3a, C4, 
C5, and C5a complement levels in case of suspected hypersensitivity or adverse drug 
reaction. The revised language adds Bb and substitutes sC5b-9 for C5 and C5a, which brings 
the 270-203 protocol into harmony with more recent BMN 270 study protocols. The breadth 
of additional complement markers allows delineation of the classical and alternative/lectin 
mediated pathways of activation.  
3. Additional complement panel assessments have been added during the first 12 weeks 
post-BMN 270 infusion. 
Rationale: This change both aligns with more recent BMN 270 study protocols and is of 
particular importance in the seropositive subjects being treated in this study. Complement 
panel assessments will be done on the infusion day (within 2 hours after infusion), Day 2, 4, 
and 8, and then every other week between Week 2 and Week 12. This change permits 
assessment of potential innate immune responses at earlier timepoints post-BMN 270 
infusion, which is of particular relevance to the AAV5+ population being evaluated in this 
study. The breadth of markers is the revised panel is designed to delineate between the 
classical and alternative or lectin-based pathways of complement activation. 
4. The occurrence of events of Hy’s law has been added as an event of special interest 
(EOSI) for purposes of expedited safety reporting, and additional safety monitoring in 
the event of a case potentially meeting Hy’s law criteria has been added. 
Rationale: Events potentially meeting the criteria for Hy’s law involve combined assessment 
of elevations in aminotransferases and total bilirubin levels, while the current list of EOSI 
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focuses on elevations in aminotransferases. To date, no events meeting the criteria for Hy’s 
law have been reported in any BMN 270 study. While monitoring for events of Hy’s law has 
been ongoing as part of routine pharmacovigilance in all BMN 270 studies, this change 
ensures that the occurrence of any events in the future will be reported in an expedited 
manner. In addition, expanded laboratory monitoring (to include albumin and PT/INR) has 
been added to the guidelines for evaluating potential Hy’s law cases. 
5. Language has been added concerning the use of liver biopsy sample information for 
biopsies performed for safety-related reasons. 
Rationale: Where a biopsy has been taken for safety-related reasons or was available from a 
past procedure, the Sponsor may want to see that biopsy information to help evaluate the 
impact of BMN 270 on the liver. The Sponsor may request that slides from a liver biopsy be 
made available for additional histopathological review. 
6. FibroScan has been added as an alternative to liver ultrasound at Screening, and a 
fasting FibroTest has been added to the Day 1 (infusion day) assessments. 
Rationale: This change aligns baseline liver health assessments with more recent BMN 270 
study protocols. 
7. Clarifying language has been provided for circumstances where a positive vector 
shedding sample occurs after 3 consecutive tests below the limit of detection have 
already been obtained. 
Rationale: The protocol did not previously specify whether testing should be restarted after a 
positive result occurs after 3 consecutive results below the limit of detection in a matrix have 
been obtained. While this situation would be expected to be rare, and usually subjects remain 
below the limit of detection after having achieved 3 results below the limit of detection in a 
row, in the instance where a positive test occurs then testing should restart and continue until 
an additional 3 consecutive results below the limit of detection have been obtained. The 
purpose of the testing is to declare vector clearance, and in the instance where a positive test 
occurs even after 3 tests below the limit of detection, clearance cannot be confirmed without 
further testing. 
8. The prohibition on the use of non-corticosteroid systemic immunosuppressive agents 
following BMN 270 dosing has been removed. 
Rationale: The intention of the language was to prohibit use of non-steroidal systemic 
immunosuppressive agents within 30 days before the BMN 270 infusion, in line with the 
study exclusion criteria. Following dosing with BMN 270, non-steroidal systemic 
immunosuppressive agents may be used, following a discussion between the Investigator and 
the Medical Monitor, if corticosteroid use for the treatment of elevated hepatic transaminases 
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has been clinically deemed to be ineffective, not tolerated, and/or contraindicated by the 
Investigator.  
9. Guidance for the monitoring and management of elevated hepatic transaminases has 
been modified. 
Rationale: To reflect observations and data gathered from this study and other BMN 270 
studies, the threshold for suggested increase in monitoring of hepatic transaminases and for 
UHSRUWLQJ DV DQ (26, KDV EHHQ FKDQJHG IURP  [ 8/1 RU ! 8/1 	 ! [ EDVHOLQH YDOXH WR
! 8/1 RU  [ EDVHOLQH YDOXH $ VLPLODU FKange has been made to the definition of an 
event of special interest related to elevated transaminases. Guidance has also been added for 
investigators to provide counselling and support to study subjects regarding the side effects 
of corticosteroids. This change should also encourage earlier treatment with corticosteroids, 
which could help decrease the extent of increases in ALT and better preserve FVIII 
expression. 
10. An optional monthly phone check-in has been added during Years 2-5 for subjects 
who are returning to the site only every 12 weeks due to poor FVIII response 
following BMN 270 infusion. 
Rationale: To ensure timely safety monitoring and promote subject retention, subjects who 
are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-
up telephone call from the site to ask about adverse events, concomitant medications, and 
bleeding events/FVIII replacement usage. 
11. The option to assess an adverse event as related/not related to corticosteroids or 
other systemic immunosuppressive agents has been added. 
Rationale: AEs associated with corticosteroids or other systemic immunosuppressive agents 
(if used) are possible and should be noted as such on the eCRF (and for safety monitoring 
and risk:benefit assessment purposes). 
12. Lamivudine has been removed as a prohibited medication. 
Rationale: Lamivudine was added as a prohibited medication after an HIV-positive subject 
in a BMN 270 study developed severe ALT elevations while receiving anti-retroviral therapy 
that included lamivudine as one of its components (and out of concern that lamivudine might 
be interacting with BMN 270 to exacerbate ALT elevations). However, after discussion with 
a liver health advisory board, lamivudine is not viewed as a likely medication that would 
interact with BMN 270 and, as such, should no longer be listed as a prohibited medication. 
13. The requirements around the use of mobile nursing (MN) services to conduct 
unscheduled visits for assessment of FVIII levels or liver tests (LTs) have been 
clarified. 
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Rationale: In instances where a subject’s LTs have been elevated, assessment and workup of 
those elevations may require additional laboratory work (FVIII and LT levels) to be collected 
at unscheduled visits. At sites where MN services have been approved, these unscheduled 
laboratory tests may be performed by a MN professional, rather than requiring a site visit. 
14. Updates have been made to incorporate changes previously communicated to sites 
through protocol clarification letters. These changes include: 
x Corrections to the timing of weight assessment footnotes in the Schedules of 
Activities 
x Clarification of the visit window for AAV5 TAb testing during Screening 
x Update to Section 9.7.6.6 to clarify that vector shedding should be performed 
every 6 weeks during Years 2-5 
x Update Section 12 to include FVIII antibody titer at Week 24 (as is reflected in 
the Schedule of Activities) 
x Update Section 12.5.2.7 to state that the cytokine bead array assay should be 
performed at Week 24 (rather than Week 22) 
x Add the cytokine bead array assay to the Early Termination Visit in Section 12 (as 
is reflected in the Schedule of Activities) 
x Add AAV5 TAb and TI assays to Weeks 28, 30, and 34 in the Schedule of 
Activities and in Section 12 
15. Guidance concerning how to determine whether a subject has been lost to follow-up 
has been added. 
16. The costs and compensation language has been updated to clarify which study-
related costs will be covered by the Sponsor. 
17. The summary of risks and benefits has been updated. 
18. The required timepoints for vector shedding sample collection during Years 2-5 (if 
required) have been clarified. 
19. The identity of the medical monitor has been updated. 
20. Additional minor changes have been made for consistency and clarity. 
Refer to Section 25 for a summary of revisions to Amendment 2 (dated 4 October 2019). 
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2 
SYNOPSIS 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
TITLE OF STUDY:  
A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus 
Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual 
)9,,, /HYHOV   ,8G/ DQG 3UH-existing Antibodies Against AAV5 
PROTOCOL NUMBER: 
270-203 
STUDY SITES: 
Approximately 5-6 sites globally 
PHASE OF DEVELOPMENT: 
Phase 1/2 
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.   
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived or 
recombinant human FVIII protein (rhFVIII) concentrates, both as prophylaxis 2-3 times per week 
or 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. While infusion 
of FVIII is a major advance in the treatment of HA, severe HA patients continue to have bleeding 
events on prophylactic therapy; median ABRs were 1-4 with prophylactic treatment in a recently 
published retrospective observational study (Berntorp, 2017) and between 1-2 in 6 prospective 
FVIII interventional studies.  Median ABRs were 4.5-18 and between 20-60 with on-demand-only 
therapy in the same studies, respectively. Continued repeated bleeding events compound 
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24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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FOR NATIONAL 
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debilitating multiple-joint arthropathies as well as the risk of catastrophic events such as 
intracranial hemorrhage and death. 
Extended half-life products created through chemical modification (eg, direct conjugation of 
polyethylene glycol (PEG) polymers) or bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can 
only extend half-life by approximately 50% (half-life 18-19 hours), 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. More recently, 
emicizumab has been approved for the treatment of HA. Emicizumab is a humanized, bispecific 
monoclonal antibody that binds to both activated coagulation factor IX (FIX) and coagulation 
factor X (FX), thereby mimicking the function of activated FVIII. Emicizumab represents an 
incremental improvement in therapeutic burden over replacement FVIII products since it can be 
administered subcutaneously as opposed to intravenously; however, it is still a chronic treatment 
that requires repeat administration every 1-4 weeks, and sustained FVIII activity levels above 
5-10 IU/dL have rarely been attained even with extended half-life products. Therefore, there is a 
strong unmet need for a treatment that can alter the fundamental problem for patients with HA, 
namely attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over 
multiple years) without the need for treatment.  
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. 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. Moreover, the circulating FVIII response to gene transduction 
can be assessed using validated quantitative endpoints that are easily assayed using established 
laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 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 (eg serotypes 2, 5, and 8).  
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
over 7 years of stable human factor IX (hFIX) expression at levels sufficient for conversion of their 
bleeding phenotype from severe to moderate or mild, following a single peripheral vein infusion of 
AAV8-hFIX vector (Nathwani, 2018). Several participants in this trial have been able to 
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24 August 2020 
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 270 
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page:   
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discontinue factor prophylaxis without suffering spontaneous hemorrhages, even when they 
undertook activities that previously resulted in bleeding. Thus, gene therapy treatment has resulted 
in a substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a hybrid human liver-specific promoter (Figure 1).
Figure 1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein
Legend –Note that schematic is not to scale; aa = amino acids; ITR = inverted terminal repeat; HLP = human 
liver promoter; Kozak = Kozak concensus sequence (GCCACC); SpA = Synthetic poly(A) signal
BMN 270 is delivered by a single IV dose and is designed to achieve stable, durable expression of 
active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose 
escalation study in subjects with severe HA designed to assess the safety and efficacy of BMN 270 
at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201 
explores the relationship of vector dose to the augmentation of residual FVIII activity and whether 
these levels are sufficient to alter the clinical phenotype. Three-year results from 270-201 have 
demonstrated that following gene transfer, mean and median FVIII activity levels above 15% 
(15 IU/dL), as measured by a chromogenic substrate assay, are achievable and sustained following 
a single infusion of 6E13 vg/kg of BMN 270, with administration of prophylactic corticosteroids 
and an acceptable safety profile (Pasi, 2019). In addition, an interim analysis of clinical study 
270-301, an ongoing phase 3 study designed to assess the efficacy and safety of BMN 270 at a 
dose of 6E13 vg/kg and administration of therapeutic corticosteroids (ie, in response to ALT 
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24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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elevations), demonstrated FVIII activity levels that were also well above 15%, albeit lower than 
what was observed for the 6E13 vg/kg cohort in 270-201 at 26 weeks (Pasi, 2019). 
Subjects enrolled and infused in 270-201 screened negative for AAV5 antibodies, as the prevailing 
expectation has been that vector-specific antibodies could interfere with receptor binding and 
effectively neutralize efficient transduction of the target cell population. As this was the first FVIII 
gene therapy with AAV5 in humans, this criterion was adopted out of an abundance of caution. 
These pre-existing vector-specific antibodies are thought to arise from previous exposure to AAV, 
with seroprevalence varying across human populations and across studies. AAV5 has consistently 
been shown to have the lowest seroprevalence among the common AAV serotypes (Boutin, 2010; 
Hayes, 2019).  
Current data describing the extent of neutralization or inhibited transduction has been inconsistent 
across studies, each employing one of several varying methodologies to evaluate both vector-
specific antibodies and transduction inhibition (TI). Early studies using AAV2 for the treatment of 
hemophilia B described inhibited transduction in patients with neutralizing antibody titers of 2 or 3 
(Manno, 2006), but more recent studies have described successful transduction in patients who, in 
retrospect, were determined to have pre-existing antibody to the vector capsid (Majowicz, 2017).  
Importantly, no drug-related adverse events were described in these patients.  As the sensitivity of 
assays used to detect pre-existing antibody has increased greatly in recent years, the biological 
relevance of any given titer determination, and comparisons across studies using assays with 
differing titer sensitivities, requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of available 
data shows the effect of pre-existing immunogenicity to AAV delivery vectors is not completely 
understood, and indicates that some patients may benefit from AAV5 gene therapy who are 
currently excluded.  
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be enrolled to 
evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate the safety, 
tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing antibodies 
against AAV5 vector capsid at various levels of AAV5 antibody titers. 
 
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protocol.pdf Page 698

 
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Proprietary and Confidential 
24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
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ONLY: 
OBJECTIVES:  
The primary objective of the study is to: 
x 
Assess the safety of a single intravenous administration of BMN 270 in severe HA 
subjects with pre-existing antibody to AAV5 vector capsid, including development of 
FVIII neutralizing antibody 
Secondary objectives of the study are to: 
x 
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at 
Week 26 
x 
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy 
x 
Assess the impact of BMN 270 on the number of bleeding episodes requiring 
exogenous FVIII therapy 
x 
Evaluate the pharmacodynamics of FVIII expression following IV infusion of 
BMN 270 
x 
Assess the impact of BMN 270 on patient-reported outcomes (PROs) 
STUDY DESIGN AND PLAN:  
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), with a 
history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with pre-existing 
antibodies to the AAV5 vector capsid as measured by total antibody [TAb] assay. Approximately 
10 subjects may be enrolled at 5-6 sites in 2 cohorts (5 subjects in each cohort) and will receive a 
single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a Screening 
$$9 7$E WLWHU   ZKLOH VXEMHFWV LQ &RKRUW  ZLOO KDYH D 6FUHHQLQJ $$9 7$E WLWHU ! 500.  
Choosing a titer cutoff of 500 reflects the observed distribution of existing titer data with the 
BioMarin titer assay seen to date. 
An independent Data Monitoring Committee (DMC) will consist of experts in clinical trials, 
statistics, and hemophilia. The DMC will review available safety and efficacy data throughout the 
study and provide recommendations based on their review (Figure 2 represents one dosing 
schedule scenario): 
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24 August 2020 
Figure 2:  270-203 Dosing Schedule (One Possible Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening 
AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a maximum of 
5 subjects have been dosed in Cohort 1 and had their safety and efficacy data (from a minimum of 
6 weeks post-LQIXVLRQ UHYLHZHG )9,,, DFWLYLW\   DIWHU VL[ ZHHNV SRVW-infusion is expected to 
be the earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who 
later achieved normal FVIII activity levels, compared with the one subject who had a slightly 
lower response, based on data from 270-201. Up to 6 weeks post-infusion will provide an 
appropriate timeframe to evaluate the development of any potential delayed hypersensitivity 
reaction (eg, serum sickness).  
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on 
DMC evaluation of safety and efficacy in treated subjects, with the following triggers that may 
potentially pause further enrollment:  
x
any related SAE;  
x
any relDWHG $( ZLWK D VHYHULW\ ! &7&$( *UDGH  RU
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks post-BMN 270 
infusion.
Following a temporary halt of enrolment, the DMC may approve resumption of enrolment in either 
cohort at a later date at its discretion based on further analysis of accumulating data. 
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 
24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In case of 
suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to physical 
examination and vital signs, will be performed. Additional blood samples will be collected 
(tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine bead array, as well as possible additional 
exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine 
bead array (and possible additional exploratory testing) will be collected between 8-24 hours after 
the reaction. In addition, a blood sample should be taken 1 week after the hypersensitivity reaction 
for assessment of the cytokine bead array. Exploratory biomarker samples at baseline and at post-
infusion study visits may also be used to assess changes in these biomarkers to better elucidate the 
mechanisms of infusion-related hypersensitivity reactions. Any safety signal may trigger a review 
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Proprietary and Confidential 
24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
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of the data and possible additional immunogenicity studies or other diagnostics deemed necessary 
to assess cellular immune responses using collected peripheral blood mononuclear cells (PBMCs).  
The duration of observation may be extended and additional blood samples collected at the 
discretion of the Investigator and Medical Monitor. 
Data from 270-201 suggest that achievement of therapeutic FV,,, OHYHOV  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII protection 
while subjects are projected to reach clinicaOO\ UHOHYDQW )9,,, OHYHOV   ,8G/ SULRU )9,,,
prophylaxis for each subject will be continued at the discretion of the DMC based on individual 
subject status and data review or when FVIII activity has reached at least 5 IU/dL. In subjects who 
experience recurring bleeding episodes, the Investigator and Medical Monitor will discuss whether 
to resume prior FVIII prophylaxis.  
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either 
IDLOXUH WR DFKLHYH )9,,, DFWLYLW\   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 by attending 
only the Q12W and End of Year visits during Years 2-5. Subjects who are not attending the Q6W 
visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the site to 
ask about adverse events, concomitant medications, and bleeding events/FVIII replacement usage. 
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. After the 
safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, long-term safety and 
efficacy will be assessed in all subjects for up to a total of 5 years post-infusion. During the trial, 
additional subjects may be recruited into each cohort at any time, if deemed necessary by the 
DMC.   
NUMBER OF SUBJECTS PLANNED:  
Approximately 10 subjects  
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
 
1. 0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as evidenced 
by medical history, at the time of signing the informed consent.  
2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total 
antibody ELISA 
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Proprietary and Confidential 
24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
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3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days 
(EDs) 
4. Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior 
to study entry.   
5. 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. 
6. 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)  
7. Sexually active participants must agree to use an acceptable method of effective contraception, 
either double-barrier contraception (ie, condom + diaphragm; or condom or diaphragm + 
spermicidal gel or foam) or their female partner either using hormonal contraceptives or having 
an intrauterine device. Participants must agree to contraception use for at least 12 weeks 
post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 
3 consecutive semen samples with viral vector DNA below the limit of detection. 
8. Willing to abstain from consumption of alcohol for at least the first 52 weeks following 
BMN 270 infusion. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, 
including HIV infection.  
2. Significant liver dysfunction with any of the following abnormal laboratory results: 
o $/7 DODQLQH DPLQRWUDQVIHUDVH ! [ 8/1 
o $67 DVSDUWDWH DPLQRWUDQVIHUDVH ! [ 8/1 
o GGT (gamma-JOXWDP\OWUDQVIHUDVH ! [ 8/1 
o 7RWDO ELOLUXELQ ! [ 8/1 
o $ONDOLQH SKRVSKDWDVH ! 25x ULN; or 
o ,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR   
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protocol.pdf Page 702

 
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24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
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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.  
3. Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated on a 
scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, 
or an equivalent grade of fibrosis if an alternative scale is used. 
4. Evidence of any bleeding disorder not related to hemophilia A 
5. Platelet count of < 100 x 109/L 
6. Creatinine   PJG/ 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan.  
8. 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 . 
9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy 
10. Active malignancy, except non-melanoma skin cancer 
11. History of hepatic malignancy 
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with 
the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not 
currently ongoing.  
13. Known inherited or acquired thrombophilia, including conditions associated with increased 
thromboembolic risk, such as atrial fibrillation. 
14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, 
vasculitis). 
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the 
investigational product (whichever is longer) prior to the screening period. For subjects who 
have received a prior investigational product, all ongoing adverse events (AEs) experienced 
while receiving that investigational product must have resolved prior to screening for this 
study 
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24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
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16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including corticosteroid treatment 
and/or the use of alternative immunosuppressive agents outlined in the protocol) and/or 
would impact or interfere with evaluation and interpretation of subject safety or efficacy 
result. 
17. Prior treatment with any vector or gene transfer agent 
18. Major surgery planned in the 52-week period following the infusion with BMN 270 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion 
20. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of safety and efficacy of BMN 270 
and with prior consultation with the Medical Monitor 
21. Known allergy or hypersensitivity to investigational product formulation 
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed 
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
Each subject will receive a single IV infusion of BMN 270 at 6E13 vg/kg. The volume of infusion 
will depend on the subject’s weight. 
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:  
No reference therapy will be evaluated in this study. 
DURATION OF TREATMENT:  
BMN 270 is given as a single dose by IV infusion. 
CRITERIA FOR EVALUATION: 
Safety: 
The following safety outcome measurements will be assessed: 
x 
Incidence of adverse events (AEs), including serious AEs (SAEs) 
x 
Change in clinical laboratory tests (serum chemistry and hematology) 
x 
Change in vital signs 
x 
Change in physical examination  
x 
Vector shedding (blood, urine, semen, feces, saliva) 
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Proprietary and Confidential 
24 August 2020 
NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
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x 
Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline 
phosphatase) 
x 
Immune response to FVIII transgene product and AAV5 vector capsid 
No major toxicity is expected based on 270-201 data and non-clinical studies. Each subject will 
have comprehensive surveillance monitoring of LTs (once per week for Weeks 1-26). During the 
long-term safety evaluation, LTs will be monitored every three months for up to 5 years 
post-infusion; the frequency and duration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator and review of subject data.  
There will be a detailed assessment of cellular and humoral responses to AAV5 vector capsid and 
FVIII.   
Efficacy:  
The efficacy measure will be to assess plasma FVIII activity. The efficacy goal is to achieve FVIII 
DFWLYLW\   ,8/dL at 26 weeks post-BMN 270 administration. Other efficacy measures include 
assessing the impact of BMN 270 on the use of FVIII replacement therapy and on the number of 
bleeding episodes during the study. Subjects will be asked to keep a subject diary, provided by the 
sponsor, to record the relevant details.  
Other efficacy endpoints:   
x 
Change from baseline in the total score of HAEMO-QoL-A at Week 26 of the study post-
BMN 270 infusion 
x 
Change from baseline in the EQ-5D-5L score at Week 26 of the study post-BMN 270 
infusion. 
x 
Change from baseline in the Haemophilia Activities List (HAL) score at Week 26 of the 
study post-BMN 270 infusion. 
x 
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 26 of the 
study post-BMN 270 infusion. 
Pharmacodynamics:  
The FVIII antigen and activity level, as measured by a validated immunoassay and a validated 
FVIII activity assay, respectively, will be used for plasma profiles; FVIII antigen and activity will 
be used to determine PD parameters.   
STATISTICAL METHODS:  
Approximately 10 subjects may be dosed in the study. The subjects will be followed in a 
longitudinal manner, and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature, but data collected in a longitudinal manner may be analyzed using 
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NAME OF COMPANY 
BioMarin Pharmaceutical Inc. 
105 Digital Drive 
Novato, CA 94949 
 
NAME OF FINISHED PRODUCT: 
BMN 270 
 
NAME OF ACTIVE INGREDIENT: 
AAV5-hFVIII-SQ 
SUMMARY TABLE 
Referring to Part of the 
Dossier: 
 
Volume:  
 
Page:   
 
Reference:  
FOR NATIONAL 
AUTHORITY USE 
ONLY: 
longitudinal methods, such as a mixed effect model, which take into account the correlation among 
the observations taken at various time points within a subject. Efficacy is a secondary endpoint, 
GHILQHG DV ELRORJLFDOO\ DFWLYH )9,,, DW  5 IU/dL at 26 weeks following study treatment. FVIII 
activity will be assessed weekly during the study period. Assessment of the true steady state of 
FVIII will require that FVIII activity is measured after a minimum of 72 hours (or 5x the known 
half-life of the FVIII replacement therapy administered) has elapsed since the last infusion of FVIII 
concentrates.  
Analysis of neutralizing antibody response, other immunological parameters, and vector shedding 
will be primarily descriptive and involve both inter-subject and intra-subject comparisons across 
cohorts. 
 
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3 TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY ............................................2 
2 SYNOPSIS ...........................................................................................................................6 
3 TABLE OF CONTENTS ...................................................................................................18 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................23 
5 ETHICS..............................................................................................................................26 
5.1 Institutional Review Board or Independent Ethics Committee ................................26 
5.2 Ethical Conduct of Study ..........................................................................................26 
5.3 Subject Information and Informed Consent ..............................................................27 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................28 
7 INTRODUCTION .............................................................................................................29 
7.1 Nonclinical Studies ...................................................................................................30 
7.2 Previous Clinical Studies ..........................................................................................30 
7.3 Study Rationale .........................................................................................................31 
7.4 Summary of Overall Risks and Benefits ...................................................................35 
8 STUDY OBJECTIVES ......................................................................................................37 
9 INVESTIGATIONAL PLAN ............................................................................................38 
9.1 Overall Study Design and Plan .................................................................................38 
9.2 Discussion of Study Design, Including Choice of Control Group ............................55 
9.3 Selection of Study Population ...................................................................................55 
9.3.1 
Inclusion Criteria .........................................................................................55 
9.3.2 
Exclusion Criteria ........................................................................................56 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................58 
9.3.4 
Subject Identification and Replacement of Subjects ...................................60 
9.3.5 
Duration of Subject Participation ................................................................60 
9.4 Treatments .................................................................................................................60 
9.4.1 
Treatments Administered ............................................................................60 
9.4.2 
Identity of Investigational Product ..............................................................61 
9.4.3 
Storage .........................................................................................................61 
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9.4.4 
Directions for Administration .....................................................................61 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................63 
9.4.6 
Selection of Dose Used in the Study ...........................................................63 
9.4.7 
Blinding .......................................................................................................63 
9.4.8 
Prior and Concomitant Medications ............................................................63 
9.4.9 
Treatment Compliance ................................................................................67 
9.5 Investigational Product Accountability .....................................................................67 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................67 
9.6 Dietary or Other Protocol Restrictions......................................................................68 
9.7 Efficacy and Safety Variables ...................................................................................68 
9.7.1 
Efficacy and Safety Measurements Assessed .............................................68 
9.7.2 
Efficacy Variables .......................................................................................68 
9.7.3 
Immunogenicity ...........................................................................................71 
9.7.4 
Pharmacodynamics ......................................................................................71 
9.7.5 
Exploratory Assessments ............................................................................71 
9.7.6 
Safety Variables ..........................................................................................71 
10 REPORTING ADVERSE EVENTS .................................................................................80 
10.1 Safety Parameters and Definitions ............................................................................80 
10.1.1 Adverse Events ............................................................................................80 
10.2 Serious Adverse Events ............................................................................................81 
10.2.1 Events of Special Interest (EOSI) ...............................................................82 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters .....................82 
10.3.1 Adverse Event Reporting Period .................................................................82 
10.3.2 Eliciting Adverse Events .............................................................................82 
10.3.3 Assessment of Seriousness, Severity, and Causality ...................................82 
10.4 Procedures for Recording Adverse Events ...............................................................85 
10.4.1 Recording Adverse Events on a eCRF ........................................................85 
10.5 Reporting Requirements ...........................................................................................88 
10.5.1 Expedited Reporting Requirements .............................................................88 
10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements..............................................................................89 
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10.6 Follow-up of Subjects after Adverse Events .............................................................89 
10.7 Post-Study Adverse Events .......................................................................................89 
10.8 Urgent Safety Measures ............................................................................................90 
10.9 BioMarin Pharmacovigilance Contact Information ..................................................90 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................92 
12 STUDY PROCEDURES ...................................................................................................93 
12.1 Prestudy .....................................................................................................................93 
12.2 Screening Visit(s) ......................................................................................................93 
12.2.1 “Smart Rescreening” Visit ..........................................................................94 
12.3 Baseline Visit ............................................................................................................95 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1) ....................................................96 
12.5 BMN 270 Infusion Follow-Up Visits .......................................................................98 
12.5.1 Week 1 .........................................................................................................98 
12.5.2 Weeks 2-26 ................................................................................................100 
12.5.3 Post-Infusion Follow-Up – Weeks 27-52 ..................................................102 
12.6 Post-Infusion Follow-Up – Years 2-5 .....................................................................105 
12.6.1 Years 2-5 – Every 6 Weeks (not required for treatment failure) ...............105 
12.6.2 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)................................................................................................106 
12.7 Early Termination Visit ..........................................................................................108 
12.8 End of Study............................................................................................................109 
13 DATA QUALITY ASSURANCE ...................................................................................110 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................111 
14.1 Statistical and Analytical Plans ...............................................................................111 
14.1.1 Interim Analyses ........................................................................................111 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data ........111 
14.2 Efficacy Analysis ....................................................................................................111 
14.3 Safety Analysis .......................................................................................................111 
14.4 Determination of Sample Size ................................................................................112 
14.5 Analysis Populations ...............................................................................................112 
14.6 Changes in the Conduct of the Study or Planned Analyses ....................................112 
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15 DATA MONITORING COMMITTEE ...........................................................................113 
16 COSTS, COMPENSATION, AND SUBJECT INJURY ................................................114 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................115 
18 STUDY MONITORING AND AUDITING ...................................................................117 
19 RETENTION OF RECORDS .........................................................................................118 
20 USE OF INFORMATION AND PUBLICATION .........................................................119 
21 REFERENCES ................................................................................................................120 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................123 
22.1 Conduct of Study and Protection of Human Subjects.............................................123 
23 SIGNATURE PAGE .......................................................................................................124 
24 APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA .........................................125 
25 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................126 
 
LIST OF TABLES 
Table 9.1.1: Schedule of Activities – Screening/Baseline/Day 1 ............................................41 
Table 9.1.2:  Schedule of Activities – Post-Infusion Follow-Up (Week 1-16) .......................44 
Table 9.1.3:  Schedule of Activities – Post-Infusion Follow-Up (Week 17-32) .....................47 
Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52) .....................49 
Table 9.1.5:  Schedule of Activities – Long-Term Follow-Up (Year 2 – Year 5) ...................51 
Table 9.1.6:  Suggested Schedule of Activities – Prophylactic Corticosteroids ......................54 
Table 9.4.8.2.1:  Adjustments to Corticosteroid Regimen .......................................................66 
Table 9.7.6.2.1:  Clinical Laboratory Tests .............................................................................73 
Table 9.7.6.3.1:  Liver Tests ....................................................................................................75 
Table 9.7.6.3.2:  Evaluation of ALT Elevations ......................................................................76 
Table 9.7.6.3.3:  Viral and Autoimmune Hepatitis Testing .....................................................77 
Table 10.3.3.2.1:  Adverse Event Grading (Severity) Scale ....................................................83 
Table 10.3.3.3.1:  Causality Attribution Guidance ..................................................................84 
 
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LIST OF FIGURES 
Figure 1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein .........................................8 
Figure 2:  270-203 Dosing Schedule (One Possible Scenario) ................................................11 
Figure 7.3.1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein .................................33 
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario) ........................................................38 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
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 
EC 
ethics 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 
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hFIX 
human coagulation factor IX 
hFVIII 
human coagulation factor VIII 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 [R2] 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
LT 
liver test 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source data verification 
SoA 
schedule(s) of activities 
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 (EC) 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/EC will be provided to BioMarin Pharmaceutical Inc. (BioMarin) 
or its designee. The Investigator will provide the IRB/EC 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/EC 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/EC and BioMarin by the Investigator in accordance with applicable guidance documents 
and governmental regulations. 
5.2 
Ethical Conduct of Study 
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
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eligible subjects for study enrollment; adhering to adverse event reporting, diagnostic, or 
other procedures as specified in the protocol; and assuring appropriate compliance with study 
treatment administration and accountability. 
This study will be conducted in accordance with the following: 
x European Clinical Trial Directive 2001/20/EC and Good Clinical Practice 
Directive 2005/28/EC, for studies conducted within any European country 
x US Code of Federal Regulations (CFR) Sections that address clinical research 
studies, and/or other national and local regulations, as applicable 
x ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice 
E6(R2) (ICH E6R2) 
x The ethical principles established by the Declaration of Helsinki 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/EC and will be conducted by scientifically and medically qualified persons. The benefits 
of the study are in proportion to the risks. The rights and welfare of the subjects will be 
respected and the investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each subject will provide written, informed consent before any 
study-related tests or evaluations are performed. 
5.3 
Subject Information and Informed Consent 
A properly written and executed informed consent form (ICF), in compliance with ICH E6R2 
(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/EC approval. BioMarin and the 
IRB/EC 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. 
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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. Subjects 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 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.  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 (12-18 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 validated quantitative endpoints that can be easily assayed in most clinical 
laboratories. 
BMN 270 contains the cDNA for the B-domain-deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs, and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study. 
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7.1 
Nonclinical Studies 
The nonclinical program supports a single IV 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 
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. 
The comparative pharmacodynamics of BMN 270 in cynomolgus monkeys with varying 
pre-existing AAV5 transduction inhibition (TI) titer and AAV5 TAb status was evaluated in 
study BMN270-16-021. BMN 270 was administered to 4 groups of monkeys, a control group 
(Group 1, n=3) that tested negative for both TI and AAV5 TAb, Group 2 (n=4) that was 
AAV5 TAb negative, and low TI titer (2-5) positive. Group 3 (n=4) was also AAV5 TAb 
negative, but had higher TI titers (5-10). Group 4 (n=5) tested positive for both AAV5 TAb 
DQG 7, 7, WLWHUV ZHUH ! $GPLQLVWUDWLRQ RI %01  E\ D VLQJOH LQWUDYHQRXV EROXV
injection was well-tolerated in cynomolgus monkeys regardless of baseline TI titer or TAb 
status. After dosing, all monkeys showed FVIII-SQ levels above the LLOQ, with the 
exception of two monkeys in the group that presented with both positive TI and TAb titers at 
baseline. Though these TAb+ monkeys, regardless of TI titers, showed a significant mean 
reduction in FVIII expression (68% less) compared to TAb negative monkeys, three of five 
monkeys showed detectable levels of FVIII-SQ, with one having levels similar to that 
observed in the TI and TAb negative control group. Monkeys that were TI+ but TAb-at 
baseline had FVIII expression levels that were similar to those of the TI and TAb negative 
control group.  
Results of the nonclinical program to date are detailed in the IB supplied by BioMarin.  
Investigators are to review this document prior to initiating this study. 
7.2 
Previous Clinical Studies 
Ongoing clinical studies for BMN 270 include: 
x 270-201, a phase 1/2, dose-escalation study in patients with severe HA 
x 270-203, a phase 1/2 study in patients with severe HA who have anti-AAV5 antibody 
titers 
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x 270-301, a phase 3 study in patients with severe HA who receive BMN 270 at the 
6E13 vg/kg dose level 
x 270-302, a phase 3 study in patients with severe HA who receive BMN 270 at the 
4E13 vg/kg dose level 
A comprehensive review of safety, efficacy, and immunogenicity results from 270-201 and 
270-301 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.   
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived 
or recombinant human FVIII protein (rhFVIII) concentrates, both as prophylaxis 2-3 times 
per week or 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. While infusion of FVIII is a major advance in the treatment of HA, severe HA 
patients continue to have bleeding events on prophylactic therapy; median ABRs were 1-4 
with prophylactic treatment in a recently published retrospective observational study 
(Berntorp, 2017) and between 1-2 in 6 prospective FVIII interventional studies.  Median 
ABRs were 4.5-18 and between 20-60 with on-demand-only therapy in the same studies, 
respectively. Continued repeated bleeding events compound debilitating multiple-joint 
arthropathies as well as the risk of catastrophic events such as intracranial hemorrhage and 
death. 
Extended half-life products created through chemical modification (eg, direct conjugation of 
polyethylene glycol (PEG) polymers) or bioengineering of FVIII (eg, FVIII-Fc fusion 
proteins) can only extend half-life by approximately 50% (half-life 18-19 hours), and thus, 
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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. More recently, emicizumab has been approved for the treatment of 
HA. Emicizumab is a humanized, bispecific monoclonal antibody that binds to both activated 
coagulation factor IX (FIX) and coagulation factor X (FX), thereby mimicking the function 
of activated FVIII. Emicizumab represents an incremental improvement in therapeutic 
burden over replacement FVIII products since it can be administered subcutaneously as 
opposed to intravenously; however, it is still a chronic treatment that requires repeat 
administration every 1-4 weeks, and sustained FVIII activity levels above 5-10 IU/dL have 
rarely been attained even with extended half-life products. Therefore, there is a strong unmet 
need for a treatment that can alter the fundamental problem for patients with HA, namely 
attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over 
multiple years) without the need for treatment.  
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. 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. Moreover, the 
circulating FVIII response to gene transduction can be assessed using validated quantitative 
endpoints that are easily assayed using established laboratory techniques. 
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 
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 
(eg serotypes 2, 5, and 8).  Indeed, an ongoing gene therapy clinical trial for a related 
disorder, hemophilia B, has established over 7 years of stable human factor IX (hFIX) 
expression at levels sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild, following a single peripheral vein infusion of AAV8-hFIX vector 
(Nathwani, 2018). Several participants in this trial have been able to discontinue factor 
prophylaxis without suffering spontaneous hemorrhages, even when they undertook activities 
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that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a hybrid human liver-specific promoter (Figure 7.3.1).
Figure 7.3.1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein
Legend –Note that schematic is not to scale; aa = amino acids; ITR = inverted terminal repeat; HLP = human liver promoter; 
Kozak = Kozak concensus sequence (GCCACC); SpA = Synthetic poly(A) signal
BMN 270 is delivered by a single IV dose and is designed to achieve stable, durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.  
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 
dose escalation study in subjects with severe HA designed to assess the safety and efficacy of 
BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. Three-
year results from 270-201 have demonstrated that following gene transfer, mean and median 
FVIII activity above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are 
achievable and sustained following a single infusion of 6E13 vg/kg of BMN 270, with 
administration of prophylactic corticosteroids and an acceptable safety profile (Pasi, 2019). 
In addition, an interim analysis of clinical study 270-301, an ongoing phase 3 study designed 
to assess the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg and administration of 
on-demand corticosteroids (ie, in response to ALT elevations), demonstrated FVIII activity 
levels that were also well above 15% at 26 weeks, albeit lower than what was observed for 
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the 6E13 vg/kg cohort in 270-201 (Pasi, 2019). For additional information on preliminary 
data in 270-201, refer to the current version of the Investigator’s Brochure. 
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, 
as the prevailing expectation has been that vector-specific antibodies could interfere with 
receptor binding and effectively neutralize efficient transduction of the target cell population. 
As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted 
out of an abundance of caution. These pre-existing vector-specific antibodies are thought to 
arise from previous exposure to AAV, with seroprevalence varying across human 
populations and across studies. AAV5 has consistently been shown to have the lowest 
seroprevalence among the common AAV serotypes (Hayes, 2019; Boutin, 2010).  
Current data describing the extent of neutralization or inhibited transduction has been 
inconsistent across studies, each employing one of several varying methodologies to evaluate 
both vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 
for the treatment of hemophilia B described inhibited transduction in patients with 
neutralizing antibody titers of 2 or 3 (Manno, 2006), but more recent studies have described 
successful transduction in patients who, in retrospect, were determined to have pre-existing 
antibody to the vector capsid (Majowicz, 2017).  Importantly, no drug-related adverse events 
were described in these patients.  As the sensitivity of assays used to detect pre-existing 
antibody has increased greatly in recent years, the biological relevance of any given titer 
determination, and comparisons across studies using assays with differing titer sensitivities, 
requires additional study.  
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of 
available data shows the effect of pre-existing immunogenicity to AVV delivery vectors is 
not completely understood, and indicates that some patients may benefit from AAV5 gene 
therapy who are currently excluded.  
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be 
enrolled to evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate 
the safety, tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing 
antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers. 
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7.4 
Summary of Overall Risks and Benefits 
Overall, 151 subjects have received a BMN 270 infusion at one of 4 dose levels (6E12 vg/kg, 
2E13 vg/kg, 4E13 vg/kg, or 6E13 vg/kg) in one of the four ongoing BMN 270 clinical 
studies (270-201, 270-301, 270-302, 270-203). Single infusions have been generally well-
tolerated across all investigated doses. All subjects have successfully completed their full-
dose infusion of BMN 270, with no discontinuation of dosing due to adverse events observed 
during the infusion. No deaths have been reported in any of the BMN 270 studies, and no 
participants have discontinued from studies as a result of an adverse event.  
Transient ALT elevation (Grade 1 to 3 in severity) has been observed in most subjects 
administered BMN 270 shortly after dosing, with no evidence for major impacts upon liver 
function; no events meeting the Hy’s Law criteria have been identified. Liver function has 
remained stable over time. ALT elevations have been reported as events of interest in 
13 subjects in 270-201, 1 subject in 270-302, and 91 subjects in 270-301. Although the 
majority of events have been Grade 1 or Grade 2 in severity, 11 subjects (1 in 270-302 and 
10 in 270-301) had a reported Grade 3 ALT elevation. Only one serious event of ALT 
increased has been reported by investigators (in addition to one event that BioMarin 
conservatively assessed as serious based on the details of the case). While the majority of 
ALT elevations responded rapidly to corticosteroids, given current interest in the field of 
AAV gene therapy for the use of non-steroidal approaches to managing or preventing ALT 
elevations, alternate non-steroidal systemic immunosuppressive agents have also been used 
to manage hepatic reactions where corticosteroids have proven to be ineffective or where 
high doses/and or prolonged exposure to corticosteroids have led to unwanted side effects. 
Overall, the literature and clinical experience with BMN 270 suggests that transient 
elevations in liver enzymes are expected following AAV-based gene therapy for the 
treatment for hemophilia A or B without any long-term concerns of hepatic injury 
(Manno, 2006; Nathwani, 2011; George, 2016; Miesbach, 2016; Pasi, 2017).  
Short-lived infusion reactions associated with one-time BMN 270 administration have 
included symptoms such as nausea, maculopapular rash, urticaria, diarrhea, watery eyes, 
rigors, chills, myalgia, fever, tachycardia and hypotension emerging within 24 hours of 
receiving BMN 270. Most infusion-related reactions were Grade 1 or Grade 2 in severity, 
and all events resolved, typically within 48 hours following medical management. Three of 
these cases required temporary interruption of the infusion, followed by re-initiation at a 
slower rate. All subjects completed their infusions. The reactions with onset during or within 
approximately 5 hours after the end of infusion responded to treatment with systemic 
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antihistamines and/or corticosteroids, where administered. Infusion-related reactions were 
effectively mitigated by managing infusion rate and medications.  
No subjects have experienced thromboembolic events or developed inhibitors to FVIII 
following BMN 270 infusion. 
At the highest dose tested in 270-201 (6E13 vg/kg), the majority of subjects achieved FVIII 
levels above 50 IU/dL at 52 weeks post-infusion.  Subjects in that cohort also reported 
markedly decreased bleeding compared with pre-study rates and the ability to discontinue 
prophylactic FVIII infusions. Subjects at all dose levels continue to be followed.  
In 270-301, an interim analysis has shown increased FVIII activity in the majority of subjects 
to mild HA or normal levels at 26 weeks post-infusion, also with markedly decreased 
bleeding compared with pre-study rates and the ability to discontinue prophylactic FVIII 
infusions. All subjects who will be included in the final analysis have been dosed with 
6E13 vg/kg and continue to be followed. 
The current data available for BMN 270 has shown an established positive benefit:risk 
profile for BMN 270 at the 6E13 vg/kg dosing level, although impact of prophylactic 
corticosteroids requires further investigation. Given the monitoring measures in place in the 
clinical protocol(s) to minimize the risk to subjects participating in the existing studies, the 
identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-203 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 from other BMN 270 clinical studies, refer to the 
current version of the IB. 
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8 
STUDY OBJECTIVES 
The primary objective of the study is to: 
x Assess the safety of a single intravenous administration of BMN 270 in severe 
HA subjects with pre-existing antibody to AAV5 vector capsid, including 
development of FVIII neutralizing antibody 
The secondary objectives of the study are to: 
x Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at 
Week 26 
x Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy 
x Assess the impact of BMN 270 on the number of bleeding episodes requiring 
exogenous FVIII therapy 
x Evaluate the pharmacodynamics of FVIII expression following IV infusion of 
BMN 270 
x Assess the impact of BMN 270 on patient-reported outcomes (PROs) 
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a Phase 1/2, single-arm, open-ODEHO VWXG\ LQ VHYHUH +$ SDWLHQWV )9,,,  1 IU/dL), 
with a history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with 
pre-existing antibodies to AAV5 vector capsid as measured by total antibody [TAb] assay. 
Approximately 10 subjects may be enrolled at 5-6 sites globally in 2 cohorts (5 subjects in 
each cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. 
6XEMHFWV LQ &RKRUW  ZLOO KDYH D 6FUHHQLQJ $$9 7$E   ZKLOH VXEMHFWV LQ &RKRUW 2 will 
have a Screening AAV5 TAb ! 500. Choosing a titer cutoff of 500 reflects the observed 
distribution of existing titer data with the BioMarin titer assay seen to date.
An independent Data Monitoring Committee (DMC), consisting of experts in clinical trials, 
statistics, and hemophilia, has been convened.  The DMC will review available safety and 
efficacy data throughout the study and provide recommendations based on their review 
(Figure 9.1.1 represents one dosing schedule scenario): 
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their 
Screening AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a 
maximum of 5 subjects have been dosed in Cohort 1 and had their safety and efficacy data 
(from a minimum of 6 weeks post-infusion) reviewed.  Based on data from 270-201, FVIII 
DFWLYLW\   DIWHU VL[ ZHHNV SRVW-infusion is expected to be the earliest differentiating time 
point for the majority of subjects dosed with 6E13 vg/kg who later achieved normal FVIII 
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activity levels, compared with the one subject who had a slightly lower response. Up to 
6 weeks post-infusion will provide an appropriate timeframe to evaluate the development of 
any potential delayed hypersensitivity reaction (eg, serum sickness).   
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC evaluation of safety and efficacy in treated subjects with the following 
triggers that may potentially pause further enrollment:  
x any related SAE; 
x DQ\ UHODWHG $( ZLWK D VHYHULW\ ! &7&$( *UDGH  RU  
x FVIII activity < 5% in at least 2/3 subjects at 6 weeks post-BMN 270 infusion.  
Following a temporary halt of enrolment, the DMC may approve resumption of enrolment in 
either cohort at a later date at its discretion based on further analysis of accumulating data. 
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at 
least 24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In 
case of suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to 
physical examination and vital signs, will be performed. Additional blood samples will be 
collected (tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine bead array, as well as possible 
additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) will be collected 
between 8-24 hours after the reaction. In addition, a blood sample should be taken 1 week 
after the hypersensitivity reaction for assessment of the cytokine bead array. Exploratory 
biomarker samples at baseline and at post-infusion study visits may also be used to assess 
changes in these biomarkers to better elucidate the mechanisms of infusion-related 
hypersensitivity reactions.  Any safety signal may trigger a review of the data and possible 
additional immunogenicity studies or other diagnostics deemed necessary to assess cellular 
immune responses using collected peripheral blood mononuclear cells (PBMCs).  The 
duration of observation may be extended and additional blood samples collected at the 
discretion of the Investigator and Medical Monitor. 
Data from 270- VXJJHVW WKDW DFKLHYHPHQW RI WKHUDSHXWLF )9,,, OHYHOV  5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII 
SURWHFWLRQ ZKLOH VXEMHFWV DUH SURMHFWHG WR UHDFK FOLQLFDOO\ UHOHYDQW )9,,, OHYHOV  5 IU/dL, 
prior FVIII prophylaxis for each subject will be continued at the discretion of the DMC based 
on individual subject status and data review or when FVIII activity has reached at least 
5 IU/dL.  
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As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not 
respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve 
)9,,, DFWLYLW\   ,8G/ E\ :HHN  RU LQDELOLW\ WR PDLQWDLQ LQGHSHQGHQFH IURP SURSK\ODFWLF
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 by attending only the Q12W and End of Year visits during Years 2-5. Subjects who 
are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly 
follow-up telephone call from the site to ask about adverse events, concomitant medications, 
and bleeding events/FVIII replacement usage. 
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. 
After the safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, 
long-term safety and efficacy will be assessed in all subjects for up to a total of 5 years 
post-infusion. During the trial, additional subjects may be recruited into each cohort at any 
time, if deemed necessary by the DMC.   
A summary of all assessments is provided in the Schedule of Activities (SoA) in Table 9.1.1, 
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5. 
 
 
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Table 9.1.1: Schedule of Activities – Screening/Baseline/Day 1 
Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion 
Visit 
(Day 1)m 
Screening 
Smart 
Rescreeningk  
(Day -28 to 
Day -1) 
Baseline 
(Day -7 to 
Day -1)l 
Screening 
(Day -42 to 
Day -29) 
Screening 
(Day -28 to 
Day -1) 
Informed consent 
X 
X 
 
 
 
Demographics (age, sex, race, ethnicity) 
 
X 
 
 
 
Medical History (including hemophilia A history, Hepatitis B, Hepatitis C, and HIV) 
 
X 
 
 
 
Physical Examinationa 
 
X 
 
X 
X 
Height and Weighta 
 
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 useb 
 
X 
 
 
 
Electrocardiogram 
 
X 
 
 
 
Liver Ultrasound/FibroScan 
 
X 
 
 
 
hFVIII Assaysc 
 
X 
Xn 
X 
 
AAV5 TAb Assay (ARUP)d 
X 
Xd 
X 
 
X 
AAV5 TAb Assayse 
 
 
 
X 
 
AAV5 TI Assaye 
 
 
 
X 
X 
Screen for Hepatitis B, Hepatitis C, HIVf 
 
X 
 
 
 
Screen for COVID-19 (local or central)g 
 
X 
X 
 
 
Blood chemistry, hematology, and coagulation testsh 
 
X 
X 
X 
 
Blood fasting lipid panel 
 
 
 
 
X 
Fasting FibroTest 
 
 
 
 
X 
Urine Testsh 
 
X 
X 
X 
 
Liver Testsh 
 
X 
X 
X 
 
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Assessment 
Prior to BMN 270 Infusion 
BMN 270 
Infusion 
Visit 
(Day 1)m 
Screening 
Smart 
Rescreeningk  
(Day -28 to 
Day -1) 
Baseline 
(Day -7 to 
Day -1)l 
Screening 
(Day -42 to 
Day -29) 
Screening 
(Day -28 to 
Day -1) 
PBMC collection (for baseline determination of AAV5 and FVIII specific cellular 
immunity) 
 
 
 
X 
 
Von Willebrand Factor Antigen (VWF:Ag)  
 
 
 
X 
 
Thrombin Generation Assay 
 
 
 
X 
 
PCR of vector DNA in blood, saliva, urine, semen, and stools 
 
 
 
X 
Xm 
Biomarker testingi 
 
X 
 
 
 
Exploratory biomarker assessmentsj 
 
 
 
X 
X 
Cytokine bead array assay 
 
 
 
X 
 
Haemo-QOL-A assessment 
 
 
 
X 
 
EQ-5D-5L assessment 
 
 
 
X 
 
HAL assessment 
 
 
 
X 
 
WPAI+CIQ:HS assessment 
 
 
 
X 
 
BMN 270 Infusion 
 
 
 
 
X 
Complement panel 
 
 
 
 
Xo 
Hypersensitivity blood assessments 
 
 
 
X 
(X)p 
a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit. 
b Diaries should be distributed to subjects who have consented to participate in the study and who have been determined to meet all study eligibility criteria. 
c Includes baseline FVIII activity (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), coagulation exploratory assay, hFVIII inhibitor level (Bethesda assay with 
Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen assay. Baseline activity should be assessed at trough DW OHDVW ! KRXUV DIWHr last dose of replacement FVIII 
therapy, or 5x the known half-life of the FVIII concentrates administered). 
d Screening, Smart Re-screening, and Infusion Day samples will be tested using the ARUP AAV5 TAb assay. During Screening, the ARUP AAV5 TAb assay test may be done first, under a 
standalone informed consent form, before the main ICF for the study is signed and further screening procedures are performed. Sample collection on the day of the infusion visit must be 
performed before the BMN 270 infusion is given. If the ARUP AAV5 TAb assay test is done first with the standalone consent, it does not need to be repeated as part of regular Screening. 
e Baseline and all post-dose samples will be tested in a different AAV5 TAb post-dose immunogenicity monitoring assay. 
f Subjects 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). 
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24 August 2020 
g COVID-19 RT-PCR testing is required during Screening, and all subjects must have at least one negative test result prior to dosing. If the test is performed locally an additional 2nd test is 
recommended, but negative results from the 2nd test must be received prior to dosing. 
h Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests.  Urine tests will be performed locally and centrally; all other laboratory assessments 
will be performed at the central laboratory. ABO blood typing assessment should be performed at Baseline, or at another regularly scheduled visit prior to the end of the subject’s 
participation in the study.   
i Includes HLA genotyping and FVIII genotyping. 
j 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 those 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. 
k Smart rescreening should only be performed if a subject 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 (28 + 14 days). COVID-19 RT-PCR testing is required as part of smart rescreening, and all subjects must have at least one negative test result 
prior to dosing. If the test is performed locally an additional 2nd test is recommended, but negative results from the 2nd test must be received prior to dosing. Subjects who undergo smart 
rescreening must complete the rescreening assessments and receive the infusion within 90 days of signing the original consent.  Subjects who do not complete dosing within 90 days will 
be required to re-consent and undergo all screening procedures.  Subjects may not undergo smart rescreening more than once. 
l 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. 
m 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 
analysis (blood, saliva, urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been completed. 
n Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening. 
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and should be collected within 2 hours post-infusion. 
p In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will be done and additional blood samples will be collected within 1 hour 
of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE and cytokine bead 
array (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. In addition, a blood sample should be taken 1 week after the hypersensitivity reaction 
for assessment of the cytokine bead array. Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these biomarkers to better 
elucidate the mechanisms of infusion-related hypersensitivity reactions. 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 Activities – 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 
D2 
D4 
D8 
Study Day* 
2 
4 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
 
 
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 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, hematology, and coagulation 
testsb 
 
 
 
X 
 
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 
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 
 
X 
 
X 
 
 
 
X 
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolsd 
Xd 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Exploratory biomarker assessmentse 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Haemo-QOL-A assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
EQ-5D-5L assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
HAL assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
WPAI+CIQ:HS assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
AAV5 TAb Assay 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
AAV5 TI Assay 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
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24 August 2020 
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 
D2 
D4 
D8 
Study Day* 
2 
4 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
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 
 
X 
Complement panelh 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
VWF:Ag  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Cytokine bead array assay 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
* Visit windows are ± 24 hours during Week 1 and ± 48 hours starting with the Week 2 visit.   
a Brief physical examination should be done at all weekly visits. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. Urine tests will be performed locally and centrally; all other laboratory assessments 
will be performed at the central laboratory.  /7V PD\ EH PRQLWRUHG PRUH RU OHVV IUHTXHQWO\ DQG LQ SDUWLFXODU ZKHQ $/7 YDOXHV DUH ! 8/1 RU  [ EDVHOLQH YDOXH EDVHG RQ discussion 
between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during perioGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV
ZLWK $/7 ! 8/1 RU  [ EDVHOLQH YDOXH GXULQJ WKH VWXG\ DQG HLWKHU DQ DOWHUQDWLYH Htiology 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 antigen 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-RXW SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  5 IU/dL at 16 weeks after BMN 270 infusion and who 
have not resumed FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion 
between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if 
there is a concern for a venous thromboembolism.  
d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained.  Collection and testing of semen samples must continue through Week 12, 
even if 3 consecutive results below the limit of detection in that compartment have already been recorded. Separate collection on Day 2 is not required if vector shedding samples were 
collected on Day 1 post-BMN 270 infusion; if collection on Day 2 is needed, it must occur within 24 hours of the time of the BMN 270 infusion. 
   
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270-203 Amendment 3 
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Proprietary and Confidential 
24 August 2020 
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for TGA assay and any other 
exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
f Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry, should be performed only in 
subjects who have not received prophylactic oral corticosteroids; subjects who have received prophylactic oral corticosteroids will have hepatitis B and hepatitis C testing at the time points 
indicated in Table 9.1.6. 
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 Activities will not 
be performed at these MN or lab draw-only visits. 
h Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
   
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protocol.pdf Page 735

 
270-203 Amendment 3 
Page 47 
 
Proprietary and Confidential 
24 August 2020 
Table 9.1.3:  Schedule of Activities – 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 
30 
31f 
32 
Study Day* 
120 
127 
134 
141 
148 
155 
162 
169 
176 
183 
190 
197 
204 
211 
218 
225 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Assessment of Adverse Events and 
Concomitant Medications  (including 
review of subject diary for bleeding and 
FVIII use) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry, 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 
 
 
 
 
 
 
HAL 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
WPAI+CIQ:HS 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
AAV5 TAb Assay 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
AAV5 TI Assay 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PBMC collection (for determination of 
AAV5 and FVIII specific cellular 
immunity) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
VWF:Ag 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Thrombin Generation Assaye 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
   
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270-203 Amendment 3 
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Proprietary and Confidential 
24 August 2020 
Assessment 
Follow-Up After BMN 270 Infusion – Weeks* 
17f 
18 
19f 
20 
21f 
22 
23f 
24 
25f 
26 
27f 
28 
29f 
30 
31f 
32 
Study Day* 
120 
127 
134 
141 
148 
155 
162 
169 
176 
183 
190 
197 
204 
211 
218 
225 
Cytokine bead array assay 
 
 
 
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, 
Week 26, and Week 32. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. Urine tests will be performed locally and centrally; all other laboratory assessments 
will be performed at the central laboratory.  /7V PD\ EH PRQLWRUHG PRUH RU OHVV IUHTXHQWO\ DQG LQ SDUWLFXODU ZKHQ $/7 YDOXHV DUH ! 8/1 RU  [ EDVHOLQH YDOXH) based on discussion 
between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  3x ULN.  Subjects 
ZLWK $/7 ! 8/1 RU  [ EDVHOLQH YDOXH GXULQJ WKH 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 antigen. 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 ZKR KDYH DFKLHYHG )9,,,  5 IU/dL at 16 weeks after BMN 270 infusion and who have 
not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between 
the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a 
concern for a venous thromboembolism.  
d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained. 
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for TGA assay and any other 
exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
f The scheduled visits at Week 17, Week 19, Week 21, Week 23, Week 25, Week 27, Week 29, 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 Activities will not be performed at these MN or lab draw-only visits. 
   
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
	
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protocol.pdf Page 737

 
270-203 Amendment 3 
Page 49 
 
Proprietary and Confidential 
24 August 2020 
Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52) 
Assessment 
Year 1 – Weeks* 
33e 
34 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighta 
 
 
 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
 
X 
 
X 
 
X 
 
X 
AAV5 TI Assay 
 
X 
 
X 
 
X 
 
X 
 
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 
 
 
 
X 
VWF:Ag 
 
 
 
X 
 
 
 
 
 
 
 
X 
Thrombin Generation Assayd 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Cytokine bead array assay 
 
 
 
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 
   
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protocol.pdf Page 738

 
270-203 Amendment 3 
Page 50 
 
Proprietary and Confidential 
24 August 2020 
Assessment 
Year 1 – Weeks* 
33e 
34 
35e 
36 
38e 
40 
42e 
44 
46e 
48 
50e 
52 
WPAI+CIQ:HS 
 
 
 
 
 
 
 
 
 
 
 
X 
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52. 
a Complete physical examination should be performed at Week 52; brief physical exam may be performed at other study visits. Weight should be recorded at Week 36, Week 44, and 
Week 52. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular when ALT values 
DUH ! 8/1 RU  [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLtor and the Investigator and review of subject data, but LTs will be monitored at least twice weekly 
GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7 ! 8/1 RU  [ EDVHOLQH YDOXH GXULQJ WKH VWXG\ DQG HLWKHU 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 /7V GXULQJ DQ\ VWXG\ ZHHN PD\ EH SHUIRUPHG LI  WKH $/7 KDV LQFUHDVHG WR DERYH 8/1 RU LQFUHDVHG E\ ! 10 U/L from prior assessment; 
(2) Increases in ALT values from prior assessment are accompanied by declines in FVIII activity level; or after a discussion between the Medical Monitor and the Investigator based on a 
review of subject data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion 
between the Medical Monitor and the Investigator.  
c Includes 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 suEMHFWV ZKR KDYH DFKLHYHG )9,,,  5 IU/dL at 16 weeks after BMN 270 infusion and who 
have not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion 
between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels are above the normal physiological range and/or if 
there is a concern for a venous thromboembolism. 
d Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop 
assays used for these evaluations.  Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be 
associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of these samples (including those for TGA assay and any other 
exploratory assessments) will be performed only as deemed necessary by the Sponsor. 
e The scheduled visits at Week 33, 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 Activities will not 
be performed at these MN or lab draw-only visits. 
   


	
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protocol.pdf Page 739

 
270-203 Amendment 3 
Page 51 
 
Proprietary and Confidential 
24 August 2020 
Table 9.1.5:  Schedule of Activities – Long-Term Follow-Up (Year 2 – Year 5) 
Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Q12W 
Q6Wgh 
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 
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 
FVIII assaysc 
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 
Thrombin Generation Assaye 
X 
 
X 
X 
Cytokine bead array assay 
X 
 
X 
X 
PCR of vector DNA in semend 
(X)d 
(X)d 
(X)d 
(X)d 
PCR of vector DNA in blood, saliva, urine, and stoolsd 
(X)d 
 
(X)d 
(X)d 
Haemo-QOL-A assessment 
 
 
Xf 
X 
EQ-5D-5L 
 
 
Xf 
X 
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Assessment 
Years 2-5* 
End of Year Visit 
ETV 
Q12W 
Q6Wgh 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week* 
W104 
W156 
W208 
W260 
HAL 
 
 
Xf 
X 
WPAI+CIQ:HS 
 
 
Xf 
X 
* Visit windows are ± 2 weeks for visits in Years 2-5. The Q6W visits during Years 2-5 should restart after each End of Year visit (eg, the first Q6W visit during Year 3 should be ~6 weeks 
after the End of Year 2 visit). 
a Brief physical examination should be performed at all visits during Years 2-5. 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 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored more or less frequently (and in particular when ALT values 
DUH ! 8/1 RU  [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH 0HGLFDO 0RQLWRU DQG WKH ,QYHVWLJDWRU DQG UHYLHZ RI VXEMHFt data, but LTs will be monitored at least twice weekly 
during periods when a subject’s $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7 ! 8/1 RU  [ EDVHOLQH YDOXH GXULQJ WKH VWXG\ DQG HLWKHU DQ DOWHUQDWLYH HWLRORJ\ FRQVLGHred 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 aboYH 8/1 RU LQFUHDVHG E\ ! 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-RXW SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,   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 2-5, 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 below the limit of detection during the Post-Infusion Follow-Up period.  Subjects who 
have not had 3 consecutive semen samples below the limit of detection by Week 52 should continue to have PCR testing of semen every 6 weeks during Years 2-5 until 3 consecutive 
samples below the limit of detection 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, 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 every End of Year visit. 
g Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 (refer to Section 12.6) may omit the Q6W visits during Years 2-5, and must attend only the Q12W 
and End of Year visits. Subjects who are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the site to ask about adverse 
events, concomitant medications, and bleeding events/FVIII replacement usage. Such subjects following the abbreviated schedule who have not yet cleared vector shedding in semen must 
still provide samples Q6W during Years 2-5 until vector shedding has been cleared (but do not need to do other scheduled assessments at those visit dates). 
e The scheduled Q6W visits during Years 2-5 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 Activities will not be performed at these MN or lab draw-only visits. 
 
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Table 9.1.6:  Suggested Schedule of Activities – Prophylactic Corticosteroids 
Assessment 
Corticosteroid Treatment Periodb 
Post-Corticosteroid Periodc 
Day 
1 
Week 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
1 
2 
3 
4 
13 
Prophylactic 
corticosteroid 
dose (mg/day) 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
40 
mg 
35 
mg 
35 
mg 
30 
mg 
30 
mg 
25 
mg 
25 
mg 
20 
mg 
20 
mg 
15 
mg 
10 
mg 
5 
mg 
 
 
 
 
 
FVIII activity 
testing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hepatitis B 
testingd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HCV Viral 
Loadd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
a This table provides an example of a prophylactic corticosteroid course. Clinical judgment, weighing the potential risks and benefits of corticosteroid treatment, should always be exercised 
when considering adjustment of corticosteroid doses, and discussions between the Investigator and Medical Monitor are advised for any questions or concerns. 
b Following initiation or completion of corticosteroid regimen, if a recurrence of ALT values  8/1 RU  [ EDVHOLQH YDOXH LV UHSRUWHG FRUWLFRVWHURLG PDQDJHPHQW GHFisions will be based on 
discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation, relationship 
between increases in ALT and FVIII activity, ALT/FVIII levels post-corticosteroid initiation, and adverse events related to corticosteroid dosing. Guidance for tapering oral corticosteroid 
dosing can be found in Section 9.4.8.2, although a discussion between the PI and Medical Monitor should take place prior to tapering the corticosteroid dose. 
c After discontinuation of oral corticosteroids, weekly labs for ALT 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 270-203 is designed to be a Phase 1/2, single-arm, open-label study in hemophilia A 
patients with UHVLGXDO )9,,, OHYHOV   ,8G/ DQG SUH-existing antibodies to the AAV5 vector 
capsid. Hemophilia A patients who provide written informed consent and meet the entry 
criteria will be eligible to enroll in the study. 
Approximately 10 subjects may be enrolled at the 6E13 vg/kg BMN 270 dose.  Subjects will 
be followed for 26 weeks post-BMN 270 infusion during which safety and efficacy 
assessments will be taken. After the final analysis at 26 weeks post-infusion, safety and 
efficacy will then continue to be assessed long-term for approximately a total of 5 years.  
9.3 
Selection of Study Population 
Approximately 10 hemophilia A patients with residual FVIII levels < 1 IU/dL and 
pre-existing antibodies to the AAV5 vector capsid 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 criteria: 
1. 0DOHV   \HDUV RI DJH ZLWK KHPRSKLOLD $ DQG UHVLGXDO )9,,, OHYHOV   IU/dL as 
evidenced by medical history, at the time of signing the informed consent 
2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by 
AAV5 total antibody ELISA 
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs) 
4. Subject must have been on prophylactic FVIII replacement therapy for at least 
12 months prior to study entry.   
5. 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. 
6. 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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7. Sexually active participants must agree to use an acceptable method of effective 
contraception, either double barrier contraception (ie, condom + diaphragm; or 
condom or diaphragm + spermicidal gel or foam) or their female partner either using 
hormonal contraceptives or having an intrauterine device. Participants must agree to 
contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may 
stop contraception use only if they have had 3 consecutive semen samples with viral 
vector DNA below the limit of detection. 
8. Willing to abstain from consumption of alcohol 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. Any evidence of active infection, including COVID-19, or any immunosuppressive 
disorder, including HIV infection. 
2. Significant liver dysfunction with any of the following abnormal laboratory results: 
o $/7 DODQLQH DPLQRWUDQVIHUDVH ! [ 8/1  
o $67 DVSDUWDWH DPLQRWUDQVIHUDVH ! 5x ULN; 
o GGT (gamma-JOXWDP\OWUDQVIHUDVH ! [ 8/1 
o 7RWDO ELOLUXELQ ! [ 8/1 
o $ONDOLQH SKRVSKDWDVH ! [ 8/1 RU 
o ,15 LQWHUQDWLRQDO QRUPDOL]HG UDWLR   
Subjects whose 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. 
3. Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as 
rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR 
(Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative 
scale is used. 
4. Evidence of any bleeding disorder not related to hemophilia A 
5. Platelet count of < 100 x 109/L 
6. Creatinine   PJG/ 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan.  
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8. 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. 
9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral 
therapy 
10. Active malignancy, except non-melanoma skin cancer 
11. History of hepatic malignancy 
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial 
embolus), with the exception of catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing.  
13. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation. 
14. A history of known inflammatory, connective tissue, or autoimmune disorders 
(eg, vasculitis). 
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the 
investigational product (whichever is longer) prior to the screening period. For 
subjects who have received a prior investigational product, all ongoing adverse 
events (AEs) experienced while receiving that investigational product must have 
resolved prior to screening for this study 
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the 
patient from fully complying with the requirements of the study (including 
corticosteroid treatment and/or use of alternative immunosuppressive agents 
outlined in the protocol) and/or would impact or interfere with evaluation and 
interpretation of subject safety or efficacy result. 
17. Prior treatment with any vector or gene transfer agent 
18. Major surgery planned in the 52-week period following the infusion with BMN 270 
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion 
20. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study that does not interfere with the requirements of 
the current protocol or have the potential to impact the evaluation of safety and 
efficacy of BMN 270 and with prior consultation with the Medical Monitor 
21. Known allergy or hypersensitivity to investigational product formulation 
22. Unwilling to receive blood or blood products for treatment of an adverse event 
and/or a bleed 
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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: 
x Subject requires medication or medical procedure prohibited by the protocol 
x 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 
x Subject is lost to follow-up 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records.  
Subjects may be considered lost to follow-up if the subject has missed 3 consecutive visits in 
the study and has failed to communicate a reason for this to the site. In addition, the site has 
documented at least 4 attempted contacts by key research personnel to reach the subject 
without success in the following manner: 
x 2 attempts by telephone or email (if possible); then 
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x If telephone/email contacts are unsuccessful, 2 attempts must be made by certified 
letter or by appropriate local process. 
Where communication has been made by phone, this should be documented in the subject 
source notes. 
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/EC It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study. 
9.3.3.1 
Study Safety Evaluation Criteria 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC evaluation of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment:  
x any related SAE; 
x DQ UHODWHG $( ZLWK D VHYHULW\ ! *UDGH  RU  
x FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.  
Additionally, the DMC should consider whether to restrict dosing to subjects with anti-
AAV5 titers below levels that appear to be causing clinically significant inhibition of 
transduction.  Following a temporary halt of enrolment, the DMC may approve resumption 
of enrolment in either cohort at a later date at its discretion based on further analysis of 
accumulating data. 
If a Grade 4 or Grade 5 adverse event assessed as related to study drug occurs in a study 
subject, further enrollment into the trial will be halted until a full safety review of the data by 
the DMC has taken place. Relevant reporting and discussion with the Sponsor and the DMC 
will take place before resumption of dosing. 
If any of the following events occur in a subject in the study who has received BMN 270 
infusion, further enrollment into the trial will be temporarily put on hold pending prompt 
evaluation by the DMC.   
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1. Liver dysfunction (criteria do not apply to ALT elevations with an extra-hepatic 
etiology): 
o $/7 ![ 8/1 IRU PRUH WKDQ  ZHHNV 
o $/7 ![ 8/1 DQG WRWDO ELOLUXELQ ![ 8/1 or ,15 ! 
o $/7 !3x ULN with signs and symptoms of liver dysfunction  
2. The occurrence of an AE of hepatic failure. 
3. 7KH GHWHFWLRQ RI KLJK WLWHU QHXWUDOL]LQJ DQWLERGLHV ! BU) to hFVIII following 
BMN 270 infusion in two subjects. 
4. The occurrence of any cancer (except non-melanoma skin cancer) at any point after 
BMN 270 infusion. 
5. 7KH RFFXUUHQFH RI D WKURPERHPEROLF HYHQW ZLWK )9,,, DFWLYLW\ ! 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, a prompt 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. Acute hypersensitivity assessed as related to BMN 270 
2. 7KH GHWHFWLRQ RI KLJK WLWHU QHXWUDOL]LQJ DQWLERGLHV ! %8 WR K)9,,, IROORZLQJ
BMN 270 infusion in one subject 
3. Occurrence of a thromboembolic event 
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. 
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, 26 weeks of Post-Infusion Follow-Up, 
and 234 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. 
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9.4.2 Identity of Investigational Product 
9.4.2.1 
Product Characteristics and Labeling 
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 10 mL Crystal Zenith® (CZ) vial. Each CZ vial contains 8.5 mL (extractable volume 
8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 
7.4 phosphate buffer. 
The 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 
therapy will not be given since venipuncture is a minimally invasive procedure in these 
individuals under ordinary conditions. 
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at an 
initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min 
up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an 
increase. Of note, the IP has been shown to be stable at room temperature for approximately 
10 hours following completion of product thaw. Vital signs (pulse, blood pressure, 
respiration rate and temperature) should be monitored at 15 minute (±5 minutes) intervals 
throughout the period of the infusion.  
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As with any infused biological product, there is a potential risk of acute, systemic 
hypersensitivity reactions (including anaphylaxis) with BMN 270. Dosing will be 
administered at a qualified infusion site, with appropriate resuscitation equipment and 
medication available and easily accessible. 
Clinical staff administering BMN 270 should be trained appropriately in recognizing and 
managing the signs and symptoms associated with potential hypersensitivity, anaphylactic, 
and anaphylactoid reactions. Additionally, the Investigator should be familiar with 
Sampson’s criteria for defining anaphylaxis (Sampson, 2006; Appendix 1).   
Should symptoms of potential hypersensitivity occur, the infusion may be slowed or halted at 
the Investigator’s discretion, with consideration of the subject’s clinical condition. If the 
infusion is halted, it should only be restarted if the Investigator considers it safe and 
appropriate to do so. Antihistamines, anti-pyretic, and/or corticosteroid administration is 
permitted prior to restarting an interrupted infusion by an infusion-related reaction. At the 
restart, the infusion rate may be adjusted (ie, to a slower rate [minimum of 1 mL/min], with 
the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the 
subject’s clinical condition permits such an increase) with careful monitoring of the subject. 
In the event of an infusion rate reaction with more than one dosing interruption, the infusion 
rate would not go beyond 1 mL/min. 
In case of hypersensitivity reactions, safety assessment, including physical examination and 
vital signs, will be done and additional blood samples will be collected within 1 hour of the 
hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine bead array, as 
well as possible additional exploratory testing) and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) between 8-24 hours after the reaction, if 
possible. In addition, a blood sample should be taken 1 week after the hypersensitivity 
reaction for assessment of the cytokine bead array. Exploratory biomarker samples at 
baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 
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 24 hours to 
observe for any immediate toxicity of the procedure; in-patient observation can be extended 
beyond 24 hours if needed per Investigator discretion. After 24 hours, subjects will be 
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discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor. 
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. 
9.4.6 Selection of Dose Used in the Study 
Data from an ongoing first in human 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. The 
6E13 vg/kg dose has been selected for this study to maximize the likelihood of transduction 
in the face of pre-existing AAV5 antibodies. 
9.4.6.1 
Selection of Timing of Dose for Each Subject 
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 
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concomitant medications added or discontinued during the study should be recorded on the 
eCRF. Medications should, whenever possible, not be recorded in the electronic database 
with a frequency of as needed (PRN). 
The following medications are prohibited starting 30 days before Screening and through the 
end of the study, and the Sponsor must be notified if a subject receives any of these during 
the study: 
x Any investigational therapy 
x Emicizumab 
x Fitusiran 
x Concizumab 
x Efavirenz 
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their 
participation in 270-203 must have their antiretroviral medication regimen approved by the 
Investigator and Medical Monitor prior to starting antiretroviral treatment. 
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. 
x Alcohol  
x Herbal and natural remedies and dietary supplements 
x Medications which may be hepatotoxic, including isotretinoin and 
dextroamphetamine/amphetamine 
x Medications which may reduce or increase the plasma concentration of 
corticosteroids 
Subjects should be counseled to avoid starting potentially hepatotoxic therapies and to inform 
the Investigator of any new medications prescribed by other physicians. Investigators should 
carefully consider both the mechanism of action and potential hepatotoxicity of any new 
medication prior to initiation. If a potentially concerning new medication is started, 
Investigators should closely monitor both FVIII activity and ALT levels (eg, weekly to every 
2 weeks for the first month) in order to determine if any detrimental effects on the efficacy or 
safety of BMN 270 have occurred. If co-medications are required during the course of the 
study, where possible, please check the National Center for Biotechnology Information 
LiverTox website for potential hepatotoxicity issues prior to prescribing (NCBI, 2020). 
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Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated. 
The following medications should be avoided during oral corticosteroid therapy: 
x Vaccines 
x 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 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 will be 
collected from subjects for the 12-month period immediately preceding study enrollment.   
9.4.8.2 
Therapeutic Corticosteroid Treatment and/or Immunosuppressive Agent 
Treatment of Elevated Hepatic Transaminases 
Refer to corticosteroid prescription guidelines for recommended monitoring for, and 
management of, potential side effects of corticosteroids, including guidance on medications 
that should be avoided during corticosteroid treatment.  
All subjects will be started on prophylactic corticosteroids starting on the day of infusion 
(Day 1). Table 9.1.6 provides an example of a possible prophylactic corticosteroid course, 
including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and 
hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and 
benefits of corticosteroid treatment, should always be exercised when considering adjustment 
of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns. 
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels 
EHFRPH LQFUHDVHG HJ ! 8/1 RU  [ EDVHOLQH YDOXH DQG DOWHUQDWLYH HWLRORJLHV KDYH EHHQ
ruled out, prompt institution of therapeutic or on-demand oral corticosteroids (prednisone or 
converted equivalent) should be considered after consultation with the Medical Monitor 
(refer to Table 9.7.6.3.2). 
x Whenever possible, a confirmatory lab draw for ALT should be performed within 
72 hours, along with FVIII activity, prior to initiating oral corticosteroids. 
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monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not 
contraindicated during corticosteroid treatment, should be limited, if possible.  Practical 
management to prevent complications related to oral corticosteroid therapy may be 
undertaken at the discretion of the Investigator (eg, evaluation of glucose intolerance, 
hyperlipidemia). Alternative, non-steroidal systemic immunosuppressive agents may be used, 
following a discussion between the Investigator and the Medical Monitor, should 
corticosteroid use be deemed by an Investigator to be clinically ineffective, not tolerated, 
and/or contraindicated. Hepatitis B status and HCV viral load will be rechecked 6 weeks 
after the start of oral corticosteroid/immunosuppressive agent treatment and then 1 week and 
13 weeks after the completion of oral corticosteroid/immunosuppressive agent treatment in 
subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse 
events suspected to be caused by or related to corticosteroid/immunousuppressive agent use) 
should be reported as outlined in Section 10 of the protocol. 
Subjects on corticosteroids should receive appropriate counselling and support regarding side 
effects from the Investigator or the treating institution (eg, listings of side effects and when to 
notify carers, wallet card for emergencies if on steroids, etc.). Additional management, 
including the co prescription of additional medications to prevent complications related to 
corticosteroid therapy, may be undertaken at the discretion of the investigator, including, but 
not limited to, prophylaxis against the occurrence of gastric ulcers, osteoporosis, and 
infections. The above guidance should also be followed in the event that an alternative 
immunosuppressive agent is used, as applicable. 
9.4.9 Treatment Compliance 
Study drug will be administered to subjects at 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 
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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 
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 Study Pharmacy Manual. 
9.6 
Dietary or Other Protocol Restrictions 
There are no dietary or other protocol restrictions for this study.  Alcohol should be avoided 
starting 30 days prior to and for at least the first 52 weeks of the study, and particularly 
within 48 hours prior to lab work. Alcohol use should be minimized throughout the 
remaining duration of the study. 
Subjects should be advised to abstain from any blood, organ, or sperm donation after 
BMN 270 infusion, until there is no further evidence of vector shedding from PCR analysis 
of samples. 
9.7 
Efficacy and Safety Variables 
9.7.1 Efficacy and Safety Measurements Assessed 
The SoA (Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5) describe the 
timing of required evaluations. 
9.7.2 Efficacy Variables 
9.7.2.1 
FVIII Activity 
Efficacy (response to treatment) will be defined as FVIII aFWLYLW\  5 IU/dL at Week 26 
following BMN 270 infusion. 
Values for FVIII activity will be excluded from analysis 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 
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measurements when a 72-hour interval without FVIII use is achieved; The 72-hour wash-out 
SHULRG LV RQO\ LQWHQGHG IRU VXEMHFWV ZKR KDYH DFKLHYHG )9,,,  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: 
x 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 
x ,I )9,,, DFWLYLW\ KDV GHFOLQHG ! IURP WKH SHDN DQG KDV GHFOLQHG IRU DW OHDVW
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 (ie, treatment failure, manifesting as 
eiWKHU IDLOXUH WR DFKLHYH )9,,, DFWLYLW\   ,8G/ E\ HLWKHU :HHN  RU :HHN 52 or inability 
to maintain independence from prophylactic FVIII replacement therapy due to joint bleeding 
episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after 
discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as 
applicable and at the discretion of the Investigator. Subjects who are not attending the Q6W 
visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the 
site to ask about adverse events, concomitant medications, and bleeding events/FVIII 
replacement usage.   
Details on collecting FVIII activity samples are included in the Laboratory Manual.  
9.7.2.2 
Factor VIII Replacement Therapy/Bleeding Episodes 
Additional efficacy variables are: 
x Change of annualized utilization (IU/kg) of exogenous FVIII replacement therapy 
during Week 5 to Week 26 post BMN 270 infusion from the baseline utilization 
of exogenous FVIII replacement therapy.  
x Change of ABRs requiring exogenous FVIII replacement treatment during 
Week 5 to Week 26 of the study post BMN 270 infusion from the baseline ABR.   
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.  
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Subjects are strongly encouraged to immediately consult Investigator for guidance regarding 
exogenous FVIII administration for suspected bleeds or bleeding episodes within the first 
6 weeks post BMN 270 infusion. 
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. 
9.7.2.3 
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 Study Reference 
Manual. 
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 Study Reference Manual.
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 Study 
Reference Manual. 
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).   
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$ sample copy of the WPAI+CIQ:HS and additional information are provided in the Study 
Reference Manual. 
9.7.3 Immunogenicity 
Immunogenicity assays will be performed on plasma and PBMCs. The assays will include 
detection of anti-AAV5 vector capsid and anti-FVIII total antibodies, as well as 
determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the 
AAV5 vector 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 vector 
capsid-specific cellular immunogenicity. FVIII- and vector capsid-specific cellular immunity 
will be assessed by stimulated cytokine secretion using an ELISpot assay performed on 
collected PBMCs. 
9.7.4 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. 
9.7.5 Exploratory Assessments 
A cytokine bead array assay assessment will be performed at Baseline and then at the 
timepoints listed in the Schedule of Activities. 
In addition, 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 AAV5 gene transfer, and to develop assays used for these evaluations. Subject may 
choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. 
All biomarker samples collected in this study may be used for exploratory biomarker 
research, including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes in this study may be used for exploratory 
research once testing for the primary purpose has been completed. 
9.7.6 Safety Variables 
Safety in this study will be determined from evaluation of AEs, clinical laboratory 
assessments with a particular attention to the liver function, vital signs assessments, physical 
examinations, and immunogenicity.  
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9.7.6.1 
Adverse Events 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. 
9.7.6.2 
Clinical Laboratory Assessments 
The scheduled clinical laboratory tests are listed in Table 9.7.6.2.1. Refer to the Study 
Reference Manual for instructions on obtaining and shipping samples.  Urine tests will be 
performed locally and centrally; all other laboratory assessments will be performed at the 
central laboratory. In case of a safety concern, additional unscheduled laboratory tests may 
be performed locally (at the Investigator’s discretion) in order to facilitate timely and 
appropriate clinical management decisions; where possible, a matched sample for testing at 
the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same 
time as the local unscheduled sample. 
Any 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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Table 9.7.6.2.1:  Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urine Tests 
Coagulation Screen 
including: 
Albumin 
Hemoglobin 
Appearance 
APTT 
BUN 
Hematocrit 
Color 
PT/INR 
Calcium 
WBC count 
pH 
TT 
Chloride 
RBC count 
Specific gravity 
 
Total cholesterol 
Platelet count 
Ketones 
 
CPK 
Differential cell count 
Protein 
 
Creatinine 
RBC indices  
(MCV and MCH) 
Glucose 
 
CRP 
 
Bilirubin 
Other Tests: 
Glucose 
 
Nitrite 
ABO blood typing* 
Phosphorus 
 
Urobilinogen 
 
Potassium 
 
Hemoglobin 
 
Total protein 
 
 
 
Sodium 
 
 
 
Uric Acid 
 
 
 
BUN, blood urea nitrogen; CPK, creatinine phosphokinase; CRP, C-reactive protein; PT, prothrombin time; APTT, 
activated partial thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; INR, international 
normalized ratio; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin. 
* ABO blood typing assessment should be performed at Baseline, or at another regularly scheduled visit prior to the end of 
the subject’s participation in the study. 
 
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel 
(including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) and fasting 
FibroTest will be assessed at the BMN 270 infusion visit. Subjects will fast for at least 
8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. 
In case of hypersensitivity or adverse drug reaction, safety assessment, including physical 
examination and vital signs, will be done and additional blood samples will be collected 
within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and 
cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours 
after the reaction. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead array. Exploratory biomarker 
samples at baseline and at post-infusion study visits may also be used to assess changes in 
these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity 
reactions" as described in the rationale of changes. 
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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. Potential MN visits are designated in the 
Schedules of Events. 
9.7.6.3 
Liver and Hepatitis Testing 
Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C 
infection at Screening; hepatitis B screening should include HBsAg, HBsAb, and HBcAb.   
Subjects with documented results showing an absence of active hepatitis B or hepatitis C 
infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to 
repeat those tests during the screening period.   
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with 
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. 
A liver ultrasound/FibroScan and liver tests (LTs) during Screening will identify any 
significant hepatic dysfunction.   
Where a biopsy has been taken for safety-related reasons or was available from a past 
procedure, the Sponsor may request the biopsy information to help evaluate the impact of 
BMN 270 on the liver. The Sponsor may request that slides from a liver biopsy be made 
available for additional histopathological review. 
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Height will be recorded at Screening only.  Weight will be recorded at Screening and then 
every 4 weeks thereafter through Week 20, at Week 26, Week 32, Week 36, Week 44, and 
Week 52, and then at the second Q12W visit each year and at every End of Year visit during 
Years 2-5. 
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 
Activities will not be performed. 
9.7.6.6 
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: 
x Blood 
x Saliva 
x Semen 
x Urine 
x Stool 
Vector shedding will also be extensively studied in the present clinical trial, 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. Testing will 
continue until at least 3 consecutive results below the limit of detection are obtained. If a 
positive result is obtained in a matrix after 3 consecutive results below the limit of detection 
have already been recorded, testing in that matrix should restart and continue until an 
additional 3 consecutive results below the limit of detection have been obtained in order to 
confirm clearance. 
Testing of semen will continue at least through Week 12, even if 3 consecutive results below 
the limit of detection have been recorded in that compartment prior to that time point. 
Subjects who have not had 3 consecutive semen samples below the limit of detection by 
Week 26 should continue to have PCR testing in semen at the timepoints designated in the 
SoA until 3 consecutive samples below the limit of detection are documented (or upon 
consultation between the Investigator and Medical Monitor). Subjects who meet the 
definition of treatment failure and wish to follow an abbreviated schedule (refer to 
Section 12.5.3) but who have not cleared vector shedding from a matrix must still provide 
samples for assessment until vector shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 
(during Year 1) and every 6 weeks (for semen samples) or every 12 weeks (for all uncleared 
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matrices) during Years 2-5. 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 
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 below the limit of detection for vector DNA on at least three 
consecutive visits. 
Contraception use may need to be extended beyond 12 weeks in individual subjects based on 
observed vector shedding in semen.  After 12 weeks, subjects may stop contraception use 
only if they have had 3 consecutive semen samples below the limit of detection (upon 
consultation between the Investigator and Medical Monitor). 
Details for sample collection and storage are provided in the Laboratory Manual. 
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10 
REPORTING ADVERSE EVENTS 
10.1 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug. 
10.1.1 Adverse Events 
For this protocol, an adverse event (AE) is any untoward medical occurrence in a subject, 
temporally associated with the use of study intervention, whether or not considered related to 
the study intervention.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention.  
Events meeting the AE definition include: 
x Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Events not meeting the AE definition include: 
x 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. 
x 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. 
x Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x 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: 
x All bleeding events and suspected bleeding events which meet one or more of the 
criteria for being serious (refer to Section 10.1) 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: 
x Results in death 
x 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. 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
o 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. 
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.  
x Results in persistent or significant disability or incapacity 
x Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to 
IP prior to conception or during pregnancy 
x Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require medical/surgical intervention to prevent one of 
the other outcomes listed above  (eg, anaphylaxis)  
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10.2.1 Events of Special Interest (EOSI)  
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality:  
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elevation triggers an initiation or modification of oral corticosteroid treatment 
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x Thromboembolic event 
x Systemic hypersensitivity, anaphylactic, or anaphylactoid reactions (refer to 
Appendix 1) 
x 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. 
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 10.1.  
10.3.2 Eliciting Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences.  The Investigator will record all relevant AE/SAE/EOSI information in the 
subject’s medical record and AE Case Report Form (eCRF). 
10.3.3 Assessment of Seriousness, Severity, and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug and/or corticosteroids and/or other 
immunosuppressive agents, and seriousness (refer to Section 10.2 for SAE definitions).  
These assessments must be made by a study clinician with the training and authority to make 
a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or DDS). 
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x Known relationship to underlying mechanism of study drug and/or corticosteroid 
and/or other immunosuppressive agent action 
x Similarity to adverse reactions seen with related drug products 
x Abatement of AE with discontinuation of study drug and/or corticosteroids and/or 
other immunosuppressive agents, and/or recurrence of AE with reintroduction of 
study drug and/or corticosteroids and/or other immunosuppressive agents 
The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators and applicable regulatory authorities. 
10.4 
Procedures for Recording Adverse Events 
10.4.1 Recording Adverse Events on a eCRF 
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations. 
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries). 
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology. 
10.4.1.1 
Diagnosis versus Signs and Symptoms 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. Using accepted medical terminology, 
enter the diagnosis (if known).  If not known, enter sign(s) and/or symptom(s).  If a diagnosis 
subsequently becomes available, then this diagnosis should be entered on the AE (or SAE, as 
appropriate) eCRF, replacing the original entries where appropriate. 
10.4.1.2 
Persistent or Recurrent Adverse Events 
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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.   
10.4.1.3 
Abnormal Laboratory Values 
Laboratory test results (including any local FVIII activity or liver test results) will be 
recorded on the laboratory results pages of the eCRF, or appear on electronically produced 
laboratory reports submitted directly from the central laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF unless associated with an AE that has already been 
reported. 
Any laboratory result abnormality of CTCAE Grade 4 or 5 should be recorded as an SAE in 
the AE eCRF unless associated with an AE that has already been reported. 
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met: 
x Accompanied by clinical symptoms 
x Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
x The abnormality suggests a disease and/or organ toxicity 
x The abnormality is of a degree that requires active management (eg, change of 
dose, discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.) 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.  
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For purposes of this study, laboratory tests showing a decreased level of FVIII activity 
should not be reported as adverse events unless there is an impact to clinical outcomes (eg, 
increased rate of bleeding, worsening of joint disease). 
10.4.1.4 
Pre-existing Conditions 
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches). 
10.4.1.5 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.5).  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. 
10.4.1.6 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2). 
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to: 
x Perform a protocol-mandated efficacy measurement 
x Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not worsened 
x 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 
x Receive scheduled therapy (study drug or otherwise) for the study indication 
10.4.1.7 
Deaths 
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE. 
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When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF. 
10.4.1.8 
Pregnancy 
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion. 
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to 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 
unexpected fatal or life-threatening unexpected suspected adverse reactions (SUSARs) and 
within 15 calendar days for other non-life-threatening SUSARs. 
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. 
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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 (EC) or Institutional Review Board 
(IRB) will be done in compliance with the standard operating procedures and policies of the 
IRB/EC and with applicable regulatory requirements. Adequate documentation must be 
obtained by BioMarin showing that the IRB/EC 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 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study.  
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2 7 0- 2 0 3 A me n d me nt 3 
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Pr o prietar y a n d C o nfi de ntial  
2 4 A u g ust 2 0 2 0 
1 0. 8  
Ur ge nt S afet y Me as ures 
T he re g ulati o ns g o ver ni n g cli nical  trials state t hat t he S p o ns or a n d I n vesti g at or are re q uire d 
t o ta ke a p pr o pri ate ur gent safet y meas ures t o pr otect s u bjects a gai nst a n y i m me diate hazar ds 
t hat ma y aff ect t he saf et y of s u bjects, a n d t hat t he a p pr o priate re g ul at or y b o dies s h o ul d be 
n otifie d acc or di n g t o t heir res pecti ve re g ul ati o ns. Acc or di n g t o t he E ur o p ea n U ni o n ( E U) 
Cli nical Trial Directi ve 2 0 0 1/ 2 0/ E C, “ …i n t h e li g ht of t he circ u msta nces, n ota bl y t he 
occ urr e nce of a n y n e w e ve nt relati n g t o t he c o n d u ct of t he trial or t he d e vel o p me nt of t he 
i n vesti gati o nal me dici nal pr o d uct w here t hat ne w e ve nt is li kel y t o affect t he safet y of t h e 
patie nts, t he S p o ns or a n d t he I n v esti gat or s hall ta k e a p pr o pri ate ur ge nt s afet y meas ures t o 
pr otect t he patie nts a g ai nst a n y i m me diate hazar d. T he S p o ns or s hall f ort h wit h i nf or m t he 
c o m pete nt a ut h orities of t h ose ne w e ve nts a n d t he meas ures ta k e n a n d s hall e ns ure t hat t he 
I R B/ E C is n otifie d at t he sa me ti me.”  
T he re p orti n g peri o d f or t hese e ve nts w hi c h ma y re q uire t he i m ple me ntati on of ur ge nt safet y 
meas ures is t he peri o d fr o m t he ti me of si g ni n g of t he I C F t hr o u g h t he c o m pleti o n of t he last 
st u d y visit or at t he Earl y Ter mi nati o n Visit ( ET V). I n vesti gat ors are re q uire d t o re p ort a n y 
e ve nts w hic h ma y re q uire t he i m ple me ntati o n of ur ge nt safet y meas ures  t o Bi o Mari n wit hi n 
2 4 h o urs. 
E xa m ples of sit uati o ns t hat ma y re q uire ur ge nt safet y meas ures i ncl u d e disc o ver y of t h e 
f oll o wi n g: 
 Lac k of st u d y scie ntific v al ue, or detri me nt al st u d y c o n d uct or ma na g e me nt 
 Disc o ver y t hat t he q u alit y or safet y of t h e I P d oes n ot meet esta blis he d safet y 
re q uire me nts 
1 0. 9  
Bi o M ari n P h ar m ac o vi gil a nce C o nt act I nf or m ati o n 
C o ntact i nf or mati o n f or Bi o Mari n P har mac o vi gila nce is as f oll o ws: 
Bi o Mari n P har mace utical I nc. 
A d dress  
1 0 5 Di gital Dri ve 
 
 N o vat o,
 
C A
 
9 4 9 4 9
 
P h o ne:  
 
Fa x:
 
 
 
E- mail:
 dr u gsafet y @ b mr n. c o m
 
T he I n vesti gat or is e n c o ura ge d t o disc uss w it h t he me dical m o nit or a n y A Es f or w hic h t he 
iss ue of seri o us ness is u n clear or q uesti o ne d. Co ntact i nf or mati o n f or t h e me dical m o nit or is 
as f oll o ws: 
PI
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11 
APPROPRIATENESS OF MEASUREMENTS 
The measures of efficacy to be used in this study are standard, ie, widely used and generally 
recognized as reliable, accurate, and relevant (able to discriminate between effective and 
ineffective agents). The measures of safety used in this study are routine clinical and 
laboratory procedures. 
The chromogenic substrate FVIII assay and the one-stage clotting FVIII assay are both 
validated and utilize CE marked reagents. 
 
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12 
STUDY PROCEDURES 
12.1 
Prestudy 
An ICF must be signed and dated by the subject, the Investigator or designee and witness 
(if required) before any study-related procedures are performed. 
12.2 
Screening Visit(s) 
Screening assessments should be performed within 42 days of BMN 270 infusion, while 
baseline assessments will take place within 7 days prior to BMN 270 infusion (Day 1).  
Should the screening visit occur within 30 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LTs, hematology, urine tests, and coagulation tests do not need 
to be repeated at Baseline.  
During the first part of the Screening Period (Day -42 to Day -29), testing for AAV5 TAb 
titers using the ARUP screening assay may be performed, so that subjects can verify their 
AAV5 TAb status. Subjects who agree to participate in this activity will be asked to sign a 
separate ICF documenting this decision. Subjects who do not agree will have the ARUP 
AAV5 TAb screening assay performed along with other assessments during the regular 
Screening period. 
The following procedures will be performed during the Screening Period (Day -28 to 
Day -1): 
x Demographics (age, sex, race, ethnicity) 
x 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.  
x Complete Physical Examination  
x Height and weight 
x Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature)  
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) for the previous 12 months 
x Distribution of subject diaries and training in diary completion 
x Electrocardiogram 
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x Liver Ultrasound/FibroScan 
x Samples for hFVIII Assays 
o Baseline FVIII activity – chromogenic substrate FVIII assay 
o Baseline FVIII activity level – one-stage clotting FVIII assay 
o hFVIII coagulation activity exploratory assay (collected but not tested 
prior to enrollment) 
o hFVIII inhibitors (Bethesda assay with Nijmegen modification) 
o hFVIII total antibody assay (collected but not tested prior to 
enrollment) 
o hFVIII antigen assay (collected but not tested prior to enrollment) 
x Blood sample for ARUP AAV5 TAb assay 
o Subjects who underwent the ARUP AAV5 TAb assay test earlier in 
the Screening period with the standalone consent do not need to repeat 
the test as part of regular Screening. 
x Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with 
documented negative results 30 days prior to informed consent being obtained do 
not need to be retested) 
o Hepatitis B screening should include HBsAg, HBsAb, and HBcAb 
x Screen for COVID-19 (local or central testing) 
o COVID-19 RT-PCR testing is required during Screening, and all 
subjects must have at least one negative test result prior to dosing. If 
the test is performed locally an additional 2nd test is recommended, but 
negative results from the 2nd test must be received prior to dosing. 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
x Blood samples for Biomarker testing (may include 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. 
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If a patient has to be screened again because the original assessments have fallen out of the 
28 + 14 day period allowed for Screening (refer to Section 12.2), then only the following 
assessments need to be performed (rather than the full list indicated in Section 12.2) for the 
patient to be successfully re-screened for the study: 
x Vital signs 
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification)) 
x AAV5 TAb assay (ARUP) 
x Screen for COVID-19 (local or central testing) 
o COVID-19 RT-PCR testing is required during smart rescreening, and 
all subjects must have at least one negative test result prior to dosing. 
If the test is performed locally an additional 2nd test is recommended, 
but negative results from the 2nd test must be received prior to dosing. 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
12.3 
Baseline Visit 
Baseline values will be recorded from 1 to 7 days prior to the infusion visit.  The following 
procedures will be performed during the Baseline Period: 
x Brief physical examination 
x Vital signs 
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x 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) 
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o hFVIII total antibody assay 
o hFVIII antigen assay 
x Von Willebrand Factor Antigen (VWF:Ag)  
x Blood sample for AAV5 Total Antibody assay 
o Baseline sample will be tested with a AAV5 TAb post-dose 
immunogenicity monitoring assay 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
o ABO blood typing assessment should be performed at Baseline, or at 
another regularly scheduled visit prior to the end of the subject’s 
participation in the study. 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
x PBMC collection for CTL baseline 
x Blood sample for AAV5 TI assay 
x Thrombin Generation Assay 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
x Exploratory biomarker assessments 
x Cytokine bead array assay 
x Hypersensitivity blood assessments 
x Haemo-QoL-A assessment 
x EQ-5D-5L 
x Hemophilia Activities List (HAL) 
x Work Productivity and Activity Impairment plus Classroom Impairment 
Questions: Hemophilia Specific (WPAI+CIQ:HS) questionnaire 
12.4 
Treatment Visit/BMN 270 Infusion Visit (Day 1) 
There will be one infusion visit for each subject.  Subjects will remain in the clinic for at 
least 24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit: 
x Brief physical examination 
x Start prophylactic corticosteroids (pre-infusion) 
x Assessment of Adverse Events and Concomitant Medications 
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x AAV5 TAb assay (ARUP) (sample collected pre-infusion for analysis) 
x Blood sample for AAV5 TI assay (sample collected pre-infusion for analysis) 
x Fasting blood sample for future exploratory analysis (sample collected 
pre-infusion) 
x 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. 
x Fasting FibroTest 
x BMN 270 Infusion 
x Complement panel 
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and 
should be collected within 2 hours post-BMN 270 infusion. 
x Vital Signs 
o Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following 
infusion, vital signs will be monitored every 1 hour (± 5 minutes) for 
at least 8 hours during the subject’s stay in the clinic. 
x 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 
within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and 
cytokine bead array, as well as possible additional exploratory testing) and samples for IgE 
and cytokine bead array (and possible additional exploratory testing) between 8-24 hours 
after the reaction, if possible. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead array. 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. Exploratory biomarker samples at 
baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" 
as described in the rationale of changes. 
Subjects should also start prophylactic corticosteroids, prior to BMN 270 infusion, on Study 
Day 1 (refer to Table 9.1.6 for a possible prophylactic corticosteroid regimen, and to 
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Section 9.4.8.2 further discussion). Clinical judgment, weighting the potential risks and 
benefits of corticosteroid treatment, should always be exercised when considering adjustment 
of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns. 
12.5 
BMN 270 Infusion Follow-Up Visits 
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. Potential MN visits are designated in the 
Schedules of Events. 
12.5.1 Week 1 
During Week 1, the subject will be assessed on Study Day 2, Study Day 4, and Study Day 8. 
12.5.1.1 
Week 1, Study Day 2 
On Study Day 2, the following assessments will be performed: 
x Brief physical examination 
x Assessment of Adverse Events and Concomitant Medications 
x Vital Signs 
x Liver Tests (refer to Table 9.7.6.3.1) 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Separate collection on Day 2 is not required if vector shedding 
samples were collected on Day 1 post-BMN 270 infusion; if collection 
on Day 2 is needed, it must occur within 24 hours of the time of the 
BMN 270 infusion. 
x Blood sample for AAV5 TAb Assay 
o Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x Blood sample for AAV5 TI assay 
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x PBMC collection 
x Complement panel 
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
x Cytokine bead array assay 
12.5.1.2 
Week 1, Study Day 4 
On Study Day 4, the following assessments will be performed: 
x Brief physical examination 
x Assessment of Adverse Events and Concomitant Medications 
x Vital Signs 
x Liver Tests (refer to Table 9.7.6.3.1) 
x Complement panel 
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
12.5.1.3 
Week 1, Study Day 8 
On Study Day 8, the following assessments will be performed: 
x Brief physical examination 
x Assessment of Adverse Events and Concomitant Medications 
x Vital Signs 
x Liver Tests (refer to Table 9.7.6.3.1) 
x Blood sample for AAV5 TAb Assay 
o Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x Blood sample for AAV5 TI assay 
x Samples for FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor 
level 
o hFVIII antigen assay 
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x Complement panel 
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
x Cytokine bead array assay 
12.5.2 Weeks 2-26 
After Week 1 (Day 8), subjects will return to the study site once a week (± 48 hours) during 
Weeks 2-26. 
12.5.2.1 
Once per week (Weeks 2 through 26)  
The following procedures will be performed once per week from Weeks 1 through 26: 
x 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. 
x 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. 
x 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. 
x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when 
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subject data, but LTs will be monitored at least twice weekly during 
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x Samples for FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
o FVIII activity level (one-stage clotting FVIII assay) 
o FVIII coagulation activity exploratory assay 
o Bethesda assay (with Nijmegen modification) for hFVIII inhibitor 
level 
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o hFVIII antigen assay 
12.5.2.2 
Every Other Week (Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26) 
The following procedures will be performed every other week (at Weeks 2, 4, 6, 8, 10, 12, 
14, 16, 18, 20, 22, 24, and 26): 
x Blood sample for AAV5 TAb Assay 
o Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x Blood sample for AAV5 TI assay 
x PBMC collection 
12.5.2.3 
Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26 
The following procedure will be performed at Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26: 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Collection to occur until at least 3 consecutive results below the limit of 
detection are obtained.  Semen samples should continue to be collected and 
tested through Week 12, even if 3 consecutive results below the limit of 
detection in that compartment have been recorded prior to that time point. 
12.5.2.4 
Weeks 2, 4, 6, 8, 10, and 12 
The following procedure will be performed at Weeks 2, 4, 6, 8, 10, and 12: 
x Complement panel 
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
12.5.2.5 
Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26 
The following procedure will be performed at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 26: 
x hFVIII total antibody assay 
12.5.2.6 
Weeks 2, 4, 6, 8, 14, 20, and 26 
The following procedure will be performed at Weeks 2, 4, 6, 8, 14, 20, and 26: 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
12.5.2.7 
Weeks 2, 6, 10, 14, 18, 22, and 26 
The following procedure will be performed at Weeks 2, 6, 10, 14, 18, 22, and 26: 
x Exploratory biomarker assessments 
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12.5.2.8 
Weeks 2, 6, 10, 14, 20, 24, and 26 
The following procedure will be performed at Weeks 2, 6, 10, 14, 20, 24, and 26: 
x Cytokine bead array assay 
12.5.2.9 
Weeks 4, 8, 12, 16, 20, and 26 
The following procedures will be performed at Weeks 4, 8, 12, 16, 20, and 26: 
x Weight 
x VWF:Ag  
12.5.2.10 Weeks 12 and 26 
The following procedures will be performed at Weeks 12 and 26: 
x Urine tests (to be performed locally) 
x Haemo-QoL-A QoL assessment 
x EQ-5D-5L 
x Hemophilia Activities List (HAL) 
x Work Productivity and Activity Impairment plus Classroom Impairment 
Questions: Hemophilia Specific (WPAI+CIQ:HS) questionnaire 
12.5.2.11 Week 16 
The following procedure will be performed at Week 16: 
x Testing for reactivation of hepatitis B and hepatitis C (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. 
12.5.2.12 Weeks 20, 24, and 26 
The following procedure will be performed at Weeks 20, 24, and 26: 
x Thrombin Generation Assay 
12.5.3 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).  At these visits, the following procedures will be completed:  
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12.5.3.1 
Every Visit 
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures 
will be performed: 
x Physical examination 
o Brief physical examination should be performed at all weeks except 
Week 52, 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. 
x 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. 
x 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. 
x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
valueV DUH ! 8/1 RU  [ EDVHOLQH YDOXH EDVHG RQ GLVFXVVLRQ EHWZHHQ WKH
Medical Monitor and the Investigator and review of subject data, but LTs will 
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3x ULN. 
x 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  
12.5.3.2 
Weeks 28, 30, 32, 34, 36, 40, 44, 48, and 52 
At Weeks 28, 30, 32, 34, 36, 40, 44, 48, and 52, the following procedures will be performed: 
x AAV5 TAb Assay 
x AAV5 TI Assay 
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12.5.3.3 
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: 
x PBMC collection 
12.5.3.4 
Weeks 32, 36, 44, and 52 
At Weeks 32, 36, 44, and 52, the following procedures will be performed: 
x Weight 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.4.8.2.1) 
x FVIII antibody titer 
x Cytokine bead array assay 
12.5.3.5 
Weeks 32, 36, 40, 44, 48, and 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed: 
x Exploratory biomarker assessments 
x TGA Assay 
x PCR of vector DNA in blood, saliva, urine, semen, and stools 
o Sample testing to occur until at least 3 consecutive sample below the limit of 
detection results have been obtained.  Subjects who have not had 
3 consecutive semen samples below the limit of detection by Week 52 should 
continue to have PCR testing of semen every 6 weeks until 3 consecutive 
samples below the limit of detection are documented (or upon consultation 
between the Investigator and Medical Monitor). 
o Subjects considered to be treatment failures must continue to provide samples 
for PCR assessment at these timepoints until vector shedding has cleared (in 
such a case, these subjects do not need to perform other assessments except 
for PCR sample delivery scheduled at these timepoints) 
12.5.3.6 
Week 36 and 52 
At Weeks 36 and 52, the following procedures will be performed: 
x Urine Tests (refer to Table 9.7.6.2.1)  
x VWF:Ag 
12.5.3.7 
Week 52 
At Week 52, the following procedures will be performed: 
x Haemo-QoL-A assessment 
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x EQ-5D-5L 
x HAL 
x WPAI+CIQ:HS 
12.6 
Post-Infusion Follow-Up – Years 2-5 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
either failure to achieve )9,,, DFWLYLW\  5 IU/dL by Week 52 or inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by 
attending only the Q12W and End of Year visits during Years 2-5. 
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from semen must still provide semen 
samples for assessment every 6 weeks during Years 2-5 until vector shedding has cleared 
(but do not have to perform other scheduled assessments at those study visits). Subjects who 
are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-
up telephone call from the site to ask about adverse events, concomitant medications, and 
bleeding events/FVIII replacement usage.   
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed: 
12.6.1 Years 2-5 – Every 6 Weeks (not required for treatment failure) 
During Years 2-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
x Assessment of Adverse Events and Concomitant Medications (including review 
of subject diary for bleeding and FVIII use) 
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. 
x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
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3x ULN. 
x FVIII Assays 
o FVIII activity level (chromogenic substrate FVIII assay) 
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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 2-5, a fresh sample should be collected 
within 4 weeks of the initial visit that had a positive result. 
o FVIII protein assay  
x PCR of vector DNA in semen (if required) 
o Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are clear by the end of Year 1.  Subjects who have not had 
3 consecutive semen samples below the limit of detection by the end of Year 1 
should continue to have PCR testing of semen every 6 weeks during Years 2-5 
until 3 consecutive samples below the limit of detection are documented (or 
upon consultation between the Investigator and Medical Monitor). 
o Subjects who meet the definition of treatment failure and wish to 
follow an abbreviated schedule but who have not cleared vector 
shedding from semen must still provide semen samples for assessment 
every 6 weeks during Years 2-5 until vector shedding has cleared (in 
such a case, these subjects do not need to perform other assessments 
except for PCR sample delivery scheduled at these timepoints). 
12.6.2 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects) 
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks ( ± 2 weeks): 
x Year 2 – Week 64, Week 76, Week 88, Week 104 
x Year 3 – Week 116, Week 128, Week 140, Week 156 
x Year 4 – Week 168, Week 180, Week 192, Week 208 
x Year 5 – Week 220, Week 232, Week 244, Week 260 
For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and 
Week 260) will serve as an End of Year visit. 
At the every 12 week and End of Year visits, the following procedures will be performed: 
x Brief physical examination (at every 12 week visits) or complete physical 
examination (at End of Year visits) 
x Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits 
only) 
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x Assessment of Adverse Events and Concomitant Medications (including review 
of subject diary for bleeding and FVIII use) 
x Liver Tests (refer to Table 9.7.6.3.1) 
o LTs may be monitored more or less frequently (and in particular when ALT 
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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. 
x 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 2-5, a fresh sample should be collected 
within 4 weeks of the initial visit that had a positive result. 
o FVIII protein assay  
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
(at Week 76, Week 128, Week 180, Week 232, and End of Year visits only) 
x Urine Tests (refer to Table 9.7.6.2.1 ) (at Week 76, Week 128, Week 180, 
Week 232, and End of Year visits only) 
x Vital Signs 
x AAV5 TAb Assay 
x AAV5 TI Assay 
x FVIII antibody titer 
x Haemo-QoL-A assessment (at End of Year visits only) 
x EQ-5D-5L (at End of Year visits only) 
x HAL (at End of Year visits only) 
x WPAI+CIQ:HS (at End of Year visits only) 
x Exploratory biomarker assessments 
x PBMC collection 
x VWF:Ag 
x TGA Assay 
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x PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are below the limit of detection during the Post-Infusion Follow-Up 
period in Weeks 1-52. 
12.7 
Early Termination Visit 
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit. 
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit.  At the Early Termination visit, as 
many of the following assessments as possible should be done: 
x Complete physical examination 
x Weight 
x Assessment of Adverse Events and Concomitant Medications 
x Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) 
x Vital signs 
x Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1) 
x Urine Tests (refer to Table 9.7.6.2.1) 
x Liver Tests (refer to Table 9.7.6.3.1) 
x 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 antigen assay  
x hFVIII total antibody assay 
x Exploratory biomarker assessments 
x Blood sample for AAV5 Total Antibody assay 
o Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay 
x Blood sample for AAV5 TI assay 
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x Cytokine bead array assay 
x PBMC collection for CTL baseline 
x VWF:Ag  
x Thrombin Generation Assay 
x Haemo-QoL-A QoL assessment 
x EQ-5D-5L 
x Hemophilia Activities List (HAL) 
x Work Productivity and Activity Impairment plus Classroom Impairment 
Questions: Hemophilia Specific (WPAI+CIQ:HS) questionnaire 
x PCR of vector DNA in blood, saliva, urine, semen, and stool 
o Sample testing at the Early Termination Visit is not required if at least 
3 consecutive samples are clear during the period of the subject’s participation 
in the study. 
12.8 
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, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records.  
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications.  
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14 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 
Statistical and Analytical Plans 
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS. 
14.1.1 Interim Analyses 
No interim analysis is planned. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data. 
Sensitivity analyses will be conducted to assess the impact of missing data on the primary 
efficacy endpoint analysis. Additional details regarding the handling of missing data will be 
provided in the SAP. 
14.2 
Efficacy Analysis 
The subjects will be followed in a longitudinal manner, and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature, but data collected in a 
longitudinal manner may be analyzed using longitudinal methods, such as mixed effect 
model, which take into account the correlation among the observations taken at various time 
points within a subject. Efficacy is a secondary endpoint, defined as biologically active FVIII 
DW   ,8G/ DW  ZHHNV IROOowing study treatment. FVIII activity will be assessed weekly 
during the study period. We can only assess the true steady state of FVIII produced from 
BMN 270 after a minimum of 72 hours (or 5x the known half-life of the FVIII replacement 
therapy administered) has elapsed since the last infusion of FVIII concentrates. 
14.3 
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.  
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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.  
Analysis of neutralizing antibody response and other immunological parameters as well as 
vector shedding will be primarily descriptive and involve both inter-subject and intra-subject 
comparisons across doses.  
Detailed statistical methods will be provided in the SAP. 
14.4 
Determination of Sample Size 
The sample size is based upon clinical considerations and is sufficient to detect a strong 
clinical efficacy signal. Approximately 10 subjects may be dosed in the study. 
14.5 
Analysis Populations 
The efficacy analysis set will be comprised of all subjects who have received the BMN 270 
infusion. 
The safety population will consist of all subjects who receive BMN 270 infusion during the 
study. 
14.6 
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/EC must be sought, and 
the Investigator should inform BioMarin and the full IRB/EC within 2 working days after the 
emergency occurs.  
With the exception of minor administrative or typographical changes, the IRB/EC 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/EC 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/EC, and 
all active subjects must again provide informed consent. 
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15 
DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) will consist of experts in clinical trials, statistics, 
and hemophilia. The DMC will review available safety and efficacy data during the study on 
an ongoing basis to determine, based on emerging data and the benefit/risk profile, whether 
further enrollment should continue.  
Duties of the DMC include: 
x Conducting an ongoing review of individual subject safety and efficacy data 
during the study; 
x Recommending whether to proceed with enrollment of subjects at a different 
gating schedules based on emerging data from 270-203 and the overall 
risk/benefit analysis of BMN 270; 
x If applicable, considering whether to restrict dosing to subjects with anti-AAV5 
titers below levels that appear to be causing clinically significant inhibition of 
transduction. 
x Making other recommendations on the conduct and reporting of the trial based on 
their evaluation of clinical data including institution of any pause or stopping 
stages. 
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC determination of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment:  
x any related SAE; 
x DQ\ UHODWHG $( ZLWK D VHYHULW\ ! *UDGH  RU  
x FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.  
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COSTS, COMPENSATION, AND SUBJECT INJURY 
BioMarin will pay the full costs of the study-related tests, procedures, and treatments set 
forth in the protocol. In addition, after IRB/EC approval, BioMarin may reimburse the 
reasonable cost of travel for study-related visits in accordance with BioMarin’s travel and 
reimbursement policy. 
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the study drug or by procedures performed as part of the study. Any 
subject who experiences a study-related injury should be instructed by the Investigator to 
seek immediate medical treatment at a pre-specified medical institution if possible, or at the 
closest medical treatment facility if necessary. The subject should be given the name of a 
person to contact to seek further information about, and assistance with, treatment for 
study-related injuries. BioMarin or the institution may pay for reasonable and necessary 
medical services to treat the injuries caused by the study drug or study procedures. In some 
jurisdictions, BioMarin is obligated by law to pay for study-related injuries. If this is the case, 
BioMarin will comply with the law. BioMarin will not pay for any hospitalizations, tests, or 
treatments for medical problems of any sort related solely to the study subject’s primary 
disease or any concurrent disease that are unrelated to this study. 
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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 Data Manager, or designee, will set the status of the forms, visits, 
and the entire casebook to Locked. The Investigator will then electronically sign the 
casebook, specifying that the information on the eCRFs is accurate and complete. 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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21 
REFERENCES 
%DWWV .3 	 /XGZLJ - &KURQLF KHSDWLWLV DQ XSGDWH RQ WHUPLQRORJ\ DQG UHSRUWLQJ $P -
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, et. al. European retrospective study of real-life haemophilia 
treatment. Haemophilia. 2017 Jan;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. 
Boutin S, Monteilhet V, Veron P et al. Prevalence of serum IgG and neutralizing factors 
against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: 
implications for gene therapy using AAV vectors. Hum Gen Ther. 2010;21:704-712. 
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37:53-72. 
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of 
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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.  
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Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: 
a randomized dose comparison. Blood 119[6], 1335-1344. 2012. 
Hayes G, Andreeva T, Gregg K, Klamroth R et al. Global seroprevalence of pre-existing 
immunity against various AAV serotypes in the hemophilia A population. International 
Society on Thrombosis and Haemostasis (ISTH) 2019 XXVII Congress. Presentation. 
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. 
Majowicz A, Lampen M, Petry H, Meyer C et al. Pre-existing Anti-AAV5 Neutralizing 
Antibodies Measured Using a Highly Sensitive Assay in Sera of Hemophilia B Patients in a 
Phase I/II Clinical Trial of AMT-060 Do Not Predict Efficacy of AAV5-mediated 
Liver-directed Gene Transfer. Res Pract Thromb Haemostasis. 2017;1(Suppl. 1):766. 
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Manno, CS, Pierce, GF, Arruda, VR, Glader, B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med 12[3], 342-347. 2006. 
Miesbach, W, Tangelder, M, Klamroth, R, Schutgens, R et al.  Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy.  Haemophilia 22[Suppl. 4], 151-152. 2016. 
Mingozzi, F and High, KA.  Immune responses to AAV vectors: overcoming barriers to 
successful gene therapy.  Blood 122[1], 23-36. 2013. 
Nathwani AC, Reiss U, Tuddenham E, et al. Adeno-Associated Mediated Gene Transfer for 
Hemophilia B:8 Year Follow up and Impact of Removing "Empty Viral Particles" on Safety 
and Efficacy of Gene Transfer. Blood. 2018;132:491. 
Nathwani, AC, Reiss, UM, Tuddenham, EG, Rosales, C et. al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 371[21], 1994-2004. 2014. 
Nathwani, AC, Rosales, C, McIntosh, J, Rastegarlari, G et. al. Long-term safety and efficacy 
following systemic administration of a self-complementary AAV vector encoding human 
FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19[5], 876-885. 2011. 
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992. 
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Pasi KJ, Rangarajan S, Mitchell N, Lester W et al. First-in-human Evidence of Durable 
Therapeutic Efficacy and Safety of Durable Therapy Over Three-years with Valoctocogene 
Roxaparvovec for Severe Haemophilia A (BMN 270-201 Study). Res Pract Thromb 
Haemost. 2019;3(S2):2. 
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. 
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. 
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Reilly, M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ 
WPAI_Scoring.html. Last accessed 28 July 2017.   
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. 
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. 
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. 
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22 
INVESTIGATOR RESPONSIBILITIES 
22.1 
Conduct of Study and Protection of Human Subjects  
In accordance with FDA Form 1572 and/or principles of ICH E6 GCP, the Investigator will 
ensure that: 
x He or she will conduct the study in accordance with the relevant, current protocol 
and will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
x He or she will personally conduct or supervise the study. 
x 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/EC review and approval in 21 CFR Part 56 and/or ICH E6 Section 2.6 are 
met.  
x He or she will report to the sponsor adverse experiences that occur in the course 
of the investigation in accordance with 21 CFR 312.64 and/or ICH E6 
Section 4.11. 
x He or she has read and understands the information in the Investigator’s 
Brochure, including potential risks and side effects of the drug. 
x His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments 
x Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 
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. 
x The IRB/EC complies with the requirements of 21 CFR Part 56, ICH E6 Section 
3.0, and other applicable regulations, and conducts initial and ongoing reviews 
and approvals of the study. He or she will also ensure that any change in research 
activity and all problems involving risks to human subjects or others are reported 
to the IRB/EC. Additionally, he or she will not make any changes in the research 
without IRB/EC approval, except where necessary to eliminate apparent 
immediate hazards to human subjects. 
x He or she agrees to comply with all other requirements regarding the obligations 
of clinical Investigators and all other pertinent requirements in 21 CFR Part 312 
and/or ICH E6. 
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APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA 
According to the National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network (NIAID/FAAN) Second Symposium on the definition and 
management of anaphylaxis, anaphylaxis is highly likely when any one of the following 3 
criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) 
2. 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) 
3. 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) 
4. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a. Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease is systolic BP 
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline. 
Source: Sampson, 2006. 
 
 
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PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to Protocol Amendment 1 and relates the changes to the appropriate rationale (refer to 
pages 2-4). Added text is indicated by underlined font and deleted text is indicated by strikethrough font. 
Section No./Title 
Revision 
Rationale 
2/Synopsis (Study 
Design and Plan) 
Additional blood samples will be collected (tryptase, C3, C3a, C4, C5, C5aBb, sC5b-9, and cytokine bead array, as well as 
possible additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) will be collected between 8-24 hours after the reaction. 
... 
Subjects who are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-up telephone call 
from the site to ask about adverse events, concomitant medications, and bleeding events/FVIII replacement usage. 
2, 10 
2/Synopsis (Exclusion 
Criteria) 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
1. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, including HIV infection.  
3. PriorMost recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the 
Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative 
scale is used. 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan.  
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the 
requirements of the study (including possible corticosteroid treatment and/or the use of alternative immunosuppressive agents 
outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result. 
1, 6, 8 
2/Synopsis (Criteria 
for Evaluation) 
Safety: 
x 
Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline phosphatase) 
20 
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 that have reached only slightly above the upper limit of normal (ULN). Subjects 
in the 6E13 vg/kg cohort received corticosteroids, predominantly on a prophylactic basis, starting 2-4 weeks following BMN 
270 infusion, whereas those in the 4E13 vg/kg cohort received corticosteroids only if they experienced an elevation in their 
$/7  1.5x ULN (ie, “therapeutic”). Based on the effectiveness of transient oral corticosteroids used starting 8 10 weeks after 
vector infusion to suppress a presumed Class 1 (cytotoxic T-cell) response in prior studies with hepatic transduction with AAV 
vectors (Mingozzi, 2013), subjects were treated with 7 32 weeks of oral corticosteroids prophylactically or in response to the 
elevations in ALT to limit hepatotoxicity, ensure preservation of the transduced hepatocytes, and minimize any associated 
17 
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impact of such on FVIII levels. Using this approach, no sustained loss of FVIII activity has been observed in subjects with ALT 
elevations. Moreover, the rise in ALT levels was not accompanied by significant or lasting abnormalities in other liver tests 
such as AST, bilirubin or albumin, indicating that extent of toxicity is limited. At the highest dose tested in 270-201 
(6E13 vg/kg), the majority of subjects achieved chromogenic FVIII activity levels above 50 IU/dL at 52 weeks post infusion. 
Subjects in that cohort also reported markedly decreased bleeding compared with pre-study rates and the ability to discontinue 
prophylactic FVIII infusions. Subjects at all dose levels continue to be followed. 
In the ongoing 270 301 clinical study, a majority of subjects, all dosed with 6E13 vg/kg BMN 270, have experienced 
asymptomatic elevations in ALT. Subjects received therapeutic corticosteroids if they experienced an ALT elevation and/or had 
D )9,,, DFWLYLW\ OHYHO WKDW KDG GHFOLQHG ! IURP SHDN YDOXHV :KLOH VSRUDGLFDOO\ REVHUYed cytotoxic T cell responses have 
not been correlated with ALT elevations, the majority of subjects with transient rises in ALT levels had associated declines in 
their FVIII activity that subsequently increase to higher than pre ALT elevation levels following initiation of therapeutic 
corticosteroids. Similar to 270-201, the rise in ALT levels in 270-301 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. At the time of the 
270 301 interim analysis, the modified intent to WUHDW SRSXODWLRQ Q  ZKR KDG FRPSOHWHG  ZHHNV RQ study) had mean and 
median chromogenic FVIII activity levels of 36.1 and 33.2 IU/dL at 26 weeks, respectively, which are lower than the 
corresponding values observed for the 270 201 6E13 vg/kg cohort. 
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 have been three subjects, 
including one with Gilbert’s syndrome, in the ongoing 270-301 clinical study who have 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 beyond Grade 1 to date.Overall, 151 subjects have received a BMN 270 
infusion at one of 4 dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, or 6E13 vg/kg) in one of the four ongoing BMN 270 
clinical studies (270-201, 270-301, 270-302, 270-203). Single infusions have been generally well-tolerated across all 
investigated doses. All subjects have successfully completed their full-dose infusion of BMN 270, with no discontinuation of 
dosing due to adverse events observed during the infusion. No deaths have been reported in any of the BMN 270 studies, and 
no participants have discontinued from studies as a result of an adverse event.  
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Transient ALT elevation (Grade 1 to 3 in severity) has been observed in most subjects administered BMN 270 shortly after 
dosing, with no evidence for major impacts upon liver function; no events meeting the Hy’s Law criteria have been identified. 
Liver function has remained stable over time. ALT elevations have been reported as events of interest in 13 subjects in 270-201, 
1 subject in 270-302, and 91 subjects in 270-301. Although the majority of events have been Grade 1 or Grade 2 in severity, 11 
subjects (1 in 270-302 and 10 in 270-301) had a reported Grade 3 ALT elevation. Only one serious event of ALT increased has 
been reported by investigators (in addition to one event that BioMarin conservatively assessed as serious based on the details of 
the case). While the majority of ALT elevations responded rapidly to corticosteroids, given current interest in the field of AAV 
gene therapy for the use of non-steroidal approaches to managing or preventing ALT elevations, alternate non-steroidal 
systemic immunosuppressive agents have also been used to manage hepatic reactions where corticosteroids have proven to be 
ineffective or where high doses/and or prolonged exposure to corticosteroids have led to unwanted side effects. Overall, the 
literature and clinical experience with BMN 270 suggests that transient elevations in liver enzymes are expected following 
AAV-based gene therapy for the treatment for hemophilia A or B without any long-term concerns of hepatic injury (Manno, 
2006; Nathwani, 2011; George, 2016; Miesbach, 2016; Pasi, 2017).  
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 infusion related hypersensitivity reactions (including anaphylaxis) have been observed during dosing of BMN 
270 in the 270-301 clinical study (refer to Investigator’s Brochure for full details). All of the infusion-related reactions were 
effectively managed clinically and resolved without any clinical sequelae.  
Short-lived infusion reactions associated with one-time BMN 270 administration have included symptoms such as nausea, 
maculopapular rash, urticaria, diarrhea, watery eyes, rigors, chills, myalgia, fever, tachycardia and hypotension emerging within 
24 hours of receiving BMN 270. Most infusion-related reactions were Grade 1 or Grade 2 in severity, and all events resolved, 
typically within 48 hours following medical management. Three of these cases required temporary interruption of the infusion, 
followed by re-initiation at a slower rate. All subjects completed their infusions. The reactions with onset during or within 
approximately 5 hours after the end of infusion responded to treatment with systemic antihistamines and/or corticosteroids, 
where administered. Infusion-related reactions were effectively mitigated by managing infusion rate and medications.  
No subjects have experienced thromboembolic events or developed inhibitors to FVIII following BMN 270 infusion. 
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At the highest dose tested in 270-201 (6E13 vg/kg), the majority of subjects achieved FVIII levels above 50 IU/dL at 52 weeks 
post-infusion.  Subjects in that cohort also reported markedly decreased bleeding compared with pre-study rates and the ability 
to discontinue prophylactic FVIII infusions. Subjects at all dose levels continue to be followed.  
In 270-301, an interim analysis has shown increased FVIII activity in the majority of subjects to mild HA or normal levels at 26 
weeks post-infusion, also with markedly decreased bleeding compared with pre-study rates and the ability to discontinue 
prophylactic FVIII infusions. All subjects who will be included in the final analysis have been dosed with 6E13 vg/kg and 
continue to be followed. 
9.1/Overall Study 
Design and Plan 
Additional blood samples will be collected (tryptase, C3, C3a, C4, C5, C5aBb, sC5b-9, and cytokine bead array, as well as 
possible additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) will be collected between 8-24 hours after the reaction. 
... 
Subjects who are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-up telephone call 
from the site to ask about adverse events, concomitant medications, and bleeding events/FVIII replacement usage. 
2, 10 
Schedules of Activities 
(Table 9.1.1 through 
Table 9.1.5) 
Updates have been made in Table 9.1.1 through Table 9.1.5 consistent with changes made to the table notes and elsewhere in 
the protocol. 
1, 2, 3, 6, 
9, 14, 18, 
20 
Table 9.1.1 (notes) 
d Screening, Smart Re-screening, and Infusion Day samples will be tested using the ARUP AAV5 TAb assay. During Screening, the ARUP 
AAV5 TAb assay test may be done first, under a standalone informed consent form, before the main ICF for the study is signed and further 
screening procedures are performed. Sample collection on the day of the infusion visit must be performed before the BMN 270 infusion is 
given. If the ARUP AAV5 TAb assay test is done first with the standalone consent, it does not need to be repeated as part of regular 
Screening. 
g COVID-19 RT-PCR testing is required during Screening, and all subjects must have at least one negative test result prior to 
dosing. If the test is performed locally an additional 2nd test is recommended, but negative results from the 2nd test must be 
received prior to dosing. 
k Smart rescreening should only be performed if a subject 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 (28 + 14 days). COVID-
19 RT-PCR testing is required as part of smart rescreening, and all subjects must have at least one negative test result prior to 
dosing. If the test is performed locally an additional 2nd test is recommended, but negative results from the 2nd test must be 
received prior to dosing... 
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and should be collected within 2 hours post-infusion. 
1, 2, 3 
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p In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will be 
done and additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, 
C5, C5aBb, sC5b-9, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE and 
cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible... 
Table 9.1.2 (notes) 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. Urine tests will be 
performed locally and centrally; all other laboratory assessments will be performed at the central laboratory.  LTs may be 
monitored more or less frequently (and in particular when ALT values are   1.5x! ULN or ! 8/1 	 ! [ [ baseline 
value) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be 
PRQLWRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7   1.5x! ULN or !
8/1 	 ! [ 5x baseline value during the study and either an alternative etiology considered or for further evaluation of the 
lab abnormality may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, 
and/or liver biopsy) at the discretion of the Investigator... 
h Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
3, 9 
Table 9.1.3 (notes) 
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, Week 26, and Week 2632. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. Urine tests will be 
performed locally and centrally; all other laboratory assessments will be performed at the central laboratory.  LTs may be 
monitored more or less frequently (and in particular when ALT values are  1.5x! ULN or ! 8/1 	 ! [ [ baseline 
value) based on discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be 
PRQLWRUHG DW OHDVW WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  3x ULN.  Subjects with ALT  1.5x! ULN or !
8/1 	 ! x [ 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... 
9, 14 
Table 9.1.4 (notes) 
a Complete physical examination should be performed at Week 52; brief physical exam may be performed at other study visits. 
Weight should be recorded at Week 36, Week 44, and every 4 weeks through Week 52. 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored 
more or less frequently (and in particular when ALT values are   1.5x! ULN or ! 8/1 	 ! [ [ baseline value) based on 
discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least 
WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7    1.5x! ULN or ! 8/1 	 ! x [ 
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... 
9, 14 
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Table 9.1.5 (notes) 
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.3.1 for liver tests. LTs may be monitored 
more or less frequently (and in particular when ALT values are   1.5x! ULN or ! 8/1 	 ! [ [ baseline value) based on 
discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be monitored at least 
WZLFH ZHHNO\ GXULQJ SHULRGV ZKHQ D VXEMHFW¶V $/7 LV  [ 8/1 6XEMHFWV ZLWK $/7    1.5x! ULN or ! 8/1 	 ! [ [ 
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... 
g Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 (refer to Section 12.6) may omit the 
Q6W visits during Years 2-5, and must attend only the Q12W and End of Year visits. Subjects who are not attending the Q6W 
visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the site to ask about adverse events, 
concomitant medications, and bleeding events/FVIII replacement usage. Such subjects following the abbreviated schedule 
who have not yet cleared vector shedding in all fluidssemen must still provide samples Q6W during Years 2-5 until vector 
shedding has been cleared (but do not need to do other scheduled assessments at those visit dates). 
9, 10, 18 
9.3.1/Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
7. Sexually active participants must agree to use an acceptable method of effective contraception, either double barrier 
contraception (ie, condom + diaphragm; or condom or diaphragm + spermicidal gel or foam) or their female partner either using 
hormonal contraceptives or having an intrauterine device. Participants must agree to contraception use for at least 12 weeks 
post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with viral 
vector DNA below the levellimit of detection. 
20 
9.3.2/Exclusion 
Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 
1. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, including HIV infection. 
3. PriorMost recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-
Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is 
used. 
7. Liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan.  
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the 
requirements of the study (including possible corticosteroid treatment and/or use of alternative immunosuppressive agents 
outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result. 
1, 6, 8 
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9.3.3/Removal of 
Subjects from 
Treatment or 
Assessment 
Subjects may be considered lost to follow-up if the subject has missed 3 consecutive visits in the study and has failed to 
communicate a reason for this to the site. In addition, the site has documented at least 4 attempted contacts by key research 
personnel to reach the subject without success in the following manner: 
x 
2 attempts by telephone or email (if possible); then 
x 
If telephone/email contacts are unsuccessful, 2 attempts must be made by certified letter or by appropriate local 
process. 
Where communication has been made by phone, this should be documented in the subject source notes. 
15 
9.4.4/Directions for 
Administration 
In case of hypersensitivity reactions, safety assessment, including physical examination and vital signs, will be done and 
additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5aBb, 
sC5b-9, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE and cytokine bead array 
(and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. 
2 
9.4.8/Prior and 
Concomitant 
Medications 
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: 
x 
Systemic immunosuppressive agents, except for corticosteroids 
x 
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. 
x 
Medications which may be hepatotoxic, including isotretinoin and dextroamphetamine/amphetamine 
Subjects should be counseled to avoid starting potentially hepatotoxic therapies and to inform the Investigator of any new 
medications prescribed by other physicians. Investigators should carefully consider both the mechanism of action and potential 
hepatotoxicity of any new medication prior to initiation. If a potentially concerning new medication is started, Investigators 
should closely monitor both FVIII activity and ALT levels (eg, weekly to every 2 weeks for the first month) in order to 
determine if any detrimental effects on the efficacy or safety of BMN 270 have occurred. If co-medications are required during 
the course of the study, where possible, please check the National Center for Biotechnology Information LiverTox website for 
potential hepatotoxicity issues prior to prescribing (NCBI, 2020). 
8, 12, 20 
9.4.8.2/Therapeutic 
Corticosteroid and/or 
Immunosuppressive 
Refer to corticosteroid prescription guidelines for recommended monitoring for, and management of, potential side effects of 
corticosteroids, including guidance on medications that should be avoided during corticosteroid treatment.  
8, 9, 20 
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Agent Treatment of 
Elevated Hepatic 
Transaminases 
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased (eg, ! ULN or 
 2x1.5x baseline value) and alternative etiologies have been ruled out, prompt institution of therapeutic or on-demand oral 
corticosteroids (prednisone or converted equivalent) should be considered after consultation with the Medical Monitor (refer to 
Table 9.7.6.3.2). 
x 
Alternative immunosuppressive agents may also be considered for use on a case-by-case basis and following 
consultation with the Medical Monitor (eg, if prolonged corticosteroid use is contraindicated). 
... 
Following initiation or completion of therapeutic oral corticosteroids, if increased ALT levels (eg, ! 8/1 RU  2x1.5x baseline 
value) are reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical 
Monitor... 
Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in 
consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid 
treatment and specific monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not contraindicated 
during corticosteroid treatment, should be limited, if possible.  Practical management to prevent complications related to oral 
corticosteroid therapy may be undertaken at the discretion of the Investigator (eg, evaluation of glucose intolerance, 
hyperlipidemia etc.).). Alternative, non-steroidal systemic immunosuppressive agents may be used, following a discussion 
between the Investigator and the Medical Monitor, should corticosteroid use be deemed by an Investigator to be clinically 
ineffective, not tolerated, and/or contraindicated. Hepatitis B status and HCV viral load will be rechecked 6 weeks after the start 
of oral corticosteroid/immunosuppressive agent treatment and then 1 week and 13 weeks after the completion of oral 
corticosteroid/immunosuppressive agent treatment in 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/immunousuppressive agent use) should be 
reported as outlined in Section 10 of the protocol. 
Subjects on corticosteroids should receive appropriate counselling and support regarding side effects from the Investigator or 
the treating institution (eg, listings of side effects and when to notify carers, wallet card for emergencies if on steroids, etc.). 
Additional management, including the co prescription of additional medications to prevent complications related to 
corticosteroid therapy, may be undertaken at the discretion of the investigator, including, but not limited to, prophylaxis against 
the occurrence of gastric ulcers, osteoporosis, and infections. The above guidance should also be followed in the event that an 
alternative immunosuppressive agent is used, as applicable. 
9.6/Dietary or Other 
Protocol Restrictions 
Alcohol should be avoided starting 30 days prior to and for at least the first 52 weeks of the study, and particularly within 48 
hours prior to lab work. Alcohol use should be minimized throughout the remaining duration of the study. 
20 
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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 
  ,8G/ E\ HLWKHU :HHN  RU :HHN 52 or inability to maintain independence from prophylactic FVIII replacement therapy 
due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the discretion of the 
Investigator. Subjects who are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-up 
telephone call from the site to ask about adverse events, concomitant medications, and bleeding events/FVIII replacement 
usage.   
10 
9.7.5/Exploratory 
Assessments 
A cytokine bead array assay assessment will be performed at Baseline and then weekly through Week 26at the timepoints listed 
in the Schedule of Activities. 
20 
9.7.6.2/Clinical 
Laboratory 
Assessments 
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel (including triglycerides, total cholesterol, 
HDL cholesterol, and LDL cholesterol) and fasting FibroTest will be assessed at the BMN 270 infusion visit. Subjects will fast 
for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. 
In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination and vital signs, will be 
done and additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, 
C5, C5aBb, sC5b-9, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE and 
cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction. 
2, 6 
Table 9.7.6.2.1 
The ABO blood typing assessment has been listed as an “other test” rather than as part of the Hematology assessment panel. 
20 
9.7.6.3/Liver and 
Hepatitis Testing 
A liver ultrasound/FibroScan and liver tests (LTs) during Screening will identify any significant hepatic dysfunction.   
Where a biopsy has been taken for safety-related reasons or was available from a past procedure, the Sponsor may request the 
biopsy information to help evaluate the impact of BMN 270 on the liver. The Sponsor may request that slides from a liver 
biopsy be made available for additional histopathological review... 
Elevated ALT levels should be evaluated according to the following plan: (note that these evaluations may indicate additional 
testing of LTs and FVIII levels at unscheduled visits; these unscheduled laboratory tests may be completed by a mobile nursing 
professional at sites where the use of MN services has been approved): 
5, 6, 13 
Table 9.7.6.3.2 
)RU $/7 [ 8/1 
x 
,Q WKH HYHQW WKDW $/7 RU $67 LV [ 8/1 DQG WRWDO ELOLUXELQ LV [ 8/1 DOEXPLQ DQG 37,15 VKRXOG DOVR EH
obtained. 
4 
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9.7.6.5/Vital Signs, 
Physical 
Examinations, and 
Other Observations 
Related to Safety 
Height will be recorded at Screening only.  Weight will be recorded at Screening and then every 4 weeks thereafter through 
Week 20, at Week 26, every 4 weeks throughWeek 32, Week 36, Week 44, and Week 52, and then at the second Q12W visit 
each year and at every End of YearsYear visit during Years 2-5. 
14, 20 
9.7.6.6/Vector 
Shedding 
Vector shedding will also be extensively studied in the present clinical trial, 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.  Testing will continue until at least 3 consecutive results below the limit 
of detection are obtained. If a positive result is obtained in a matrix after 3 consecutive results below the limit of detection have 
already been recorded, testing in that matrix should restart and continue until an additional 3 consecutive results below the limit 
of detection have been obtained in order to confirm clearance. 
Testing of semen will continue at least through Week 12, even if 3 consecutive results below the limit of detection have been 
recorded in that compartment prior to that time point.  Subjects who have not had 3 consecutive semen samples below the limit 
of detection by Week 26 should continue to have PCR testing in semen every 4 weeksat the timepoints designated in the SoA 
until 3 consecutive samples below the limit of detection are documented (or upon consultation between the Investigator and 
Medical Monitor). Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule (refer to 
Section 12.5.3) but who have not cleared vector shedding from all fluidsa matrix must still provide samples for assessment until 
vector shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 (during Year 1) and every 46 weeks (for semen samples) or 
every 12 weeks (for all uncleared matrices) during Years 2-5. Such subjects may provide samples on the designated study visit 
dates either at the sites or through use of a MN professional. 
7, 18, 20 
10.2.1/Events of 
Special Interest (EOSI) 
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, irrespective of seriousness, severity 
or causality:  
x 
Elevation of ALT  1.5x! ULN or $/7 ! 8/1 	 ![[ baseline value, regardless of whether that elevation 
triggers an initiation or modification of oral corticosteroid treatment 
x 
(YHQWV SRWHQWLDOO\ PHHWLQJ WKH FULWHULD IRU +\¶V ODZ $/7 RU $67 HOHYDWLRQ  [ 8/1 SOXV WRWDO ELOLUXELQ  [
ULN) 
x 
Development of anti-FVIII inhibitory antibodies (inhibitors) 
4, 9, 20 
10.3.3/Assessment of 
Seriousness, Severity, 
and Causality 
The Investigator responsible for the care of the subject or medically qualified designee will assess AEs for severity, relationship 
to study drug and/or corticosteroids and/or other immunosuppressive agents, and seriousness (refer to Section 10.2 for SAE 
definitions)... 
 
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2 7 0- 2 0 3 A me n d me nt 3 
Pa ge 1 3 6 
 
Pr o prietar y a n d C o nfi de ntial 
2 4 A u g ust 2 0 2 0 
Secti o n N o./ Title 
Re visi o n 
R ati o n ale 
1 0. 3. 3. 3/ Ca usalit y 
T he I n vesti gat or will deter mi ne t he relati o ns hi p of a n A E t o t he st u d y dr u g a n d/ or c ortic oster oi ds a n d/ or ot her 
i m m u n os u p pressi ve a ge nts a n d will rec or d it o n t he s o urce d oc u me nts a n d A E e C R F.  T o e ns ure c o nsiste nc y of ca usalit y 
assess me nts, I n vesti gat ors s h o ul d a p pl y t he g ui da nce i n Ta ble 1 0. 3. 3. 3. 1. 
Fact ors s u g gesti ve of a ca usal relati o ns hi p c o ul d i ncl u de ( b ut are n ot li mite d t o): 
 
A bse nce of e ve nt pri or t o st u d y dr u g a n d/ or c ortic oster oi d a n d/ or ot her i m m u n os u p pressi ve a ge nt e x p os ure 
 
K n o w n relati o ns hi p t o u n derl yi n g mec ha nis m of st u d y dr u g a n d/ or c ortic oster oi d a n d/ or ot her i m m u n os u p pressi ve 
a ge nt acti o n 
 
A bate me nt of A E wit h disc o nti n uati o n of st u d y dr u g a n d/ or c ortic oster oi ds a n d/ or ot her i m m u n os u p pressi ve 
a ge nts, a n d/ or rec urre nce of A E wit h rei ntr o d ucti o n of st u d y dr u g a n d/ or c ortic oster oi ds a n d/ or ot her 
i m m u n os u p pressi ve a ge nts 
1 1 
Ta ble 1 0. 3. 3. 3. 1  
Ta ble 1 0. 3. 3. 3. 1 has bee n u p date d t o i ncl u de assess me nt of ca usalit y a gai nst alter na ti ve i m m u n os u p pressi ve a gents
 1 1
 
1 0. 4. 1. 2/ A d verse 
E ve nts Occ urri n g 
Sec o n dar y t o Ot her 
E ve nts 
I n ge neral, A Es occ urri n g sec o n dar y t o ot her e ve nts (e g, casca de e ve nts) s h o ul d be i de ntifie d b y t heir pri mar y ca use.  F or 
e xa m ple, if se vere diarr hea is k n o w n t o ha ve res ulte d i n de h y drati o n, it is s ufficie nt t o rec or d o nl y diarr hea as a n A E or S A E o n 
t he A E e C R F.  H o we ver, me dicall y i m p orta nt e ve nts t hat ma y be li n ke d a n d/ or se parate d i n ti me s h o ul d be rec or de d as 
i n de pe n de nt e ve nts o n t he A E e C R F.  F or e xa m ple, if se vere he m orr ha ge lea ds t o re nal fail ure, b ot h e ve nts s h o ul d be rec or de d 
se paratel y o n t he A E e C R F. 
2 0 
1 0. 4. 1. 4/ A b n or mal 
La b orat or y Val ues 
A n y la b orat or y res ult a b n or malit y of C T C A E Gra de 4 or 5 s h o ul d be rec or de d as a n S A E i n t h e A E e C R F u nless ass ociate d 
wit h a n A E t hat has alrea d y bee n re p orte d. 
2 0 
1 0. 9/ B P V C o ntact 
I nf or mati o n 
T he I n vesti gat or is e nc o ura ge d t o disc uss wit h t he me dical m o nit or a n y A Es f or w hic h t he iss ue of seri o us ness is u nclear or 
q uesti o ne d. C o ntact i nf or mati o n f or t he me dical m o nit or is as f oll o ws: 
Na me: 
 M D P h D
M A M B B C hir M Sc 
A d dress: Bi o Mari n P har mace utical I nc. ( U K) Lt d. 
1 0 5 Di gital Dri ve 1 0 Bl o o ms b ur y Wa y 
N o vat o, C A  9 4 9 4 9 L o n d o n W C 1 A 2 S L 
P h o ne: 
( office) 
( m o bile) 
E- mail:
1 9 
PI
PI
PI
PI
PI

 
270-203 Amendment 3 
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Section No./Title 
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Rationale 
12.2/Screening Visit(s) 
During the first part of the Screening Period (Day -42 to Day -29), testing for AAV5 TAb titers using the ARUP screening 
assay may be performed, so that subjects can verify their AAV5 TAB status. Subjects who agree to participate in this activity 
will be asked to sign a separate ICF documenting this decision. Subjects who do not agree will have the ARUP AAV5 TAb 
screening assay performed along with other assessments during the regular Screening period. 
The following procedures will be performed during the Screening Period: (Day -28 to Day -1): 
x 
Liver Ultrasound/FibroScan 
x 
Blood sample for ARUP AAV5 TAb assay 
o 
Subjects who underwent the ARUP AAV5 TAb assay test earlier in the Screening period with the 
standalone consent do not need to repeat the test as part of regular Screening. 
x 
Screen for COVID-19 (local or central testing) 
o 
COVID-19 RT-PCR testing is required during Screening, and all subjects must have at least one 
negative test result prior to dosing. If the test is performed locally an additional 2nd test is 
recommended, but negative results from the 2nd test must be received prior to dosing. 
1, 6, 14 
12.2.1/”Smart 
Rescreening” Visit 
If a patient has to be screened again because the original assessments have fallen out of the 28 + 14 day period allowed for 
Screening (refer to Section 12.2), then only the following assessments need to be performed (rather than the full list indicated in 
Section 12.2) for the patient to be successfully re-screened for the study: 
x 
Screen for COVID-19 (local or central testing) 
o 
COVID-19 RT-PCR testing is required during smart rescreening, and all subjects must have at least 
one negative test result prior to dosing. If the test is performed locally an additional 2nd test is 
recommended, but negative results from the 2nd test must be received prior to dosing. 
1 
12.4/Treatment Visit 
(Day 1) 
The following procedures will be performed during the BMN 270 Infusion Visit: 
x 
Fasting FibroTest 
x 
Complement panel 
o 
Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and should be collected within 2 
hours post-BMN 270 infusion. 
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 within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, 
2, 3, 6 
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C5, C5aBb, sC5b-9, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE and 
cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. 
12.5.1.1/Week 1, 
Study Day 2 
On Study Day 2, the following assessments will be performed: 
x 
Complement panel 
o 
Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
3 
12.5.1.2/Week 1, 
Study Day 4 
On Study Day 4, the following assessments will be performed: 
x 
Complement panel 
o 
Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
3 
12.5.1.3/Week 1, 
Study Day 8 
On Study Day 8, the following assessments will be performed: 
x 
Complement panel 
o 
Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
3 
12.5.2.1/Once per 
Week (Weeks 2 
through 26) 
The following procedures will be performed once per week from Weeks 1 through 26: 
x 
Liver Tests (refer to Table 9.7.6.3.1) 
o 
LTs may be monitored more or less frequently (and in particular when ALT YDOXHV DUH ! 8/1 RU 
1.5x ULNbaseline 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 
VXEMHFW¶V $/7 LV  3x ULN. 
9 
12.5.2.4/Weeks 2, 4, 6, 
8, 10, and 12 
The following procedure will be performed at Weeks 2, 4, 6, 8, 10, and 12: 
x 
Complement panel 
o 
Complement panel should include C3, C3a, C4, Bb, and sC5b-9. 
3 
12.5.2.8/Weeks 2, 6, 
10, 14, 20, 24, and 26 
The following procedure will be performed at Weeks 2, 6, 10, 14, 20, 2224, and 26: 
x 
Cytokine bead array assay 
14 
12.5.3.1/Every Visit 
(Weeks 27-52) 
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures will be performed: 
x 
Liver Tests (refer to Table 9.7.6.3.1) 
9 
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o 
LTs may be monitored more or less frequently (and in particular when ALT values are   1.5x! ULN or !
8/1 	 ! [ [ 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 
LV  [ 8/1 
12.5.3.2/Weeks 28, 30, 
32, 34, 36, 40, 44, 48, 
and 52 
At Weeks 28, 30, 32, 34, 36, 40, 44, 48, and 52, the following procedures will be performed: 
x 
AAV5 TAb Assay 
x 
AAV5 TI Assay 
14 
12.5.3.5/Weeks 32, 36, 
40, 44, 48, and 52 
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed: 
x 
AAV5 TAb Assay 
x 
AAV5 TI Assay 
14 
12.6/Post-Infusion 
Follow-Up – 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 fluidssemen must still provide semen samples for assessment every 6 weeks during Years 2-5 until 
vector shedding has cleared (but do not have to perform other scheduled assessments at those study visits). Subjects who are not 
attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the site to ask about 
adverse events, concomitant medications, and bleeding events/FVIII replacement usage. 
10, 18 
12.6.1/Years 2-5 – 
Every 6 Weeks (not 
required for treatment 
failure) 
During Years 2-5, every 6 weeks (± 2 weeks), the following procedures will be performed: 
x 
Liver Tests (refer to Table 9.7.6.3.1) 
o 
LTs may be monitored more or less frequently (and in particular when ALT values are   1.5x! ULN or !
8/1 	 ! [ [ 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 
LV  [ 8/1 
x 
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o 
Sample testing during Years 2-5 is not required if at least 3 consecutive samples are clear by the end of Year 
21.  Subjects who have not had 3 consecutive semen samples below the limit of detection by the end of 
Year 1 should continue to have PCR testing of semen every 6 weeks during Years 2-5 until 3 consecutive 
samples below the limit of detection are documented (or upon consultation between the Investigator and 
Medical Monitor). 
9, 18, 20 
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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 fluidssemen must still provide semen samples for assessment every 
6 weeks during Years 2-5 until vector shedding has cleared (in such a case, these subjects do not need to 
perform other assessments except for PCR sample delivery scheduled at these timepoints). 
12.6.2/Years 2-5 – 
Every 12 Weeks and 
End of Year Visits 
(required for all 
subjects) 
At the every 12 week and End of Year visits, the following procedures will be performed: 
x 
Liver Tests (refer to Table 9.7.6.3.1) 
o 
LTs may be monitored more or less frequently (and in particular when ALT values are   1.5x! ULN or !
8/1 	 ! [ [ 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 
LV  [ 8/1 
x 
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required) 
o 
Sample testing during Years 2-5 is not required if at least 3 consecutive samples are below the limit of 
detection during the Post-Infusion Follow-Up period in Weeks 1-52.  Subjects who have not had 
3 consecutive semen samples below the limit of detection by Week 52 should continue to have PCR testing of 
semen every 6 weeks during Years 2-5 until 3 consecutive samples below the limit of detection are 
documented (or upon consultation between the Investigator and Medical Monitor). 
9, 20 
12.7/Early 
Termination Visit 
At the Early Termination visit, as many of the following assessments as possible should be done: 
x 
Cytokine bead array assay 
14 
16/Costs, 
Compensation, and 
Subject Injury 
There will be no charge to study subjects to be in this study. BioMarin will pay allthe full costs of the study-related tests, 
procedures, and treatments that are part of this studyset forth in the protocol. In addition, after IRB/EC 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 
16 
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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. BioMarin will not pay for any 
hospitalizations, tests, or treatments for medical problems of any sort related solely to the study subject’s primary disease or any 
concurrent disease that are unrelated to this study. 
21/References 
Angus B, Brook G, Awosusi F, Barker G et al. British HIV Association guidelines for the routine investigation and monitoring 
of adult HIV 1 positive individuals. 2016. Available at http://www.bhiva.org/documents/Guidelines/Monitoring/2016 BHIVA
Monitoring-Guidelines.pdf. Last accessed 12 September 2017. 
National Center for Biotechnology Information (NCBI). LiverTox: Clinical and Research Information on Drug-Induced Liver 
Injury. Available at: https://livertox.nih.gov (last accessed 20 August 2020). 
20 
 
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270-203 Amendment 4
Page 2
Proprietary and Confidential
4 August 2021
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY
Amendment 4
Date: 4 August 2021
RATIONALE AND SUMMARY OF CHANGES
A summary of major changes covered by Amendment 4 to the 270-203 protocol is provided 
below:
1. Changes have been made to enhance screening for potential malignancies (including 
hepatic cancers) and establishing baseline liver health during the Screening Period.
Rationale: The changes made include:
x
Clarifying that all patients should undergo a liver ultrasound at Screening to screen 
for clinically significant liver disease and hepatocellular carcinoma (HCC), and that a 
FibroScan can also be performed at the discretion of the Investigator;
x
Moving the fasting FibroTest from Day 1 to Screening for assessment of liver 
fibrosis;
As no current guidelines regarding HCC screening exist for AAV gene therapy recipients, the 
Sponsor engaged experts regarding current and recommended screening for HCC prior to 
administration of gene therapy. Protocol amendments contained herein were made based 
upon expert opinion, literature review, and evaluation of best practices.
2. Changes have been made to enhance screening for potential malignancies (including 
hepatic cancers) after dosing with BMN 270.
Rationale: The changes made include:
x
Including a targeted liver ultrasound at the End of Year visits for Year 1 through 
Year 5 to screen for HCC (additional interim liver ultrasounds may be performed at 
the discretion of the Investigator);
x
Recommending genomic analyses for any malignancy (except non-melanoma skin 
cancer) diagnosed during the course of the study.
Year-end liver ultrasounds are being implemented to assess the theoretical risk of HCC. 
While no cases of HCC have been reported in the Sponsor's AAV gene therapy non-clinical 
or clinical trials (more than 150 patients dosed, with some dosed more than 5 years ago), 
these assessments will further inform this theoretical risk.
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270-203 Amendment 4
Page 3
Proprietary and Confidential
4 August 2021
3. Malignancy (except non-melanoma skin cancer) has been added as an Event of 
Special Interest (EOSI).
Rationale: The occurrence of malignancy (as above) was added as an EOSI for purposes of 
expedited safety reporting and additional safety monitoring.
4. HIV-positive patients (serological evidence of HIV-1 or HIV-2 infection) may now 
enroll in the study, provided their HIV infection is stable and well-controlled with an 
adequate CD4 count (>200/mm3) and an undetectable viral load, respectively, at 
Screening and they are on an antiretroviral therapy (ART) regimen that does not 
contain efavirenz or another potentially hepatotoxic ART.
Rationale: HIV-positive subjects were initially included in prior BMN 270 studies.
However, after an HIV-positive subject in 270-302 developed markedly elevated liver 
enzyme levels after receiving 4E13 vg/kg of BMN 270, out of an abundance of caution for 
the long-term liver health of HIV-positive patients, further enrollment of HIV-positive 
subjects was suspended in 270-301 (Protocol Amendment 3) and 270-302 (Protocol 
Amendment 3). The subject in 270-302 referenced above was receiving efavirenz and 
lamivudine as part of his ART regimen. Following discussion with a liver advisory board and
review of the accumulated 270-301 data, efavirenz and not lamivudine has been implicated 
as the most likely medication that interacted with BMN 270 and contributed to the 270-302
subject's elevated liver enzyme levels. Due to its hepatotoxicity, efavirenz is considered a 
prohibited medication in all BMN 270 studies.
The two HIV-positive subjects on stable, non-efavirenz-containing ART regimens who were 
enrolled in and dosed in 270-301 study prior to Amendment 3 have been monitored closely. 
Following BMN 270 infusion, these subjects continued their ART as prescribed and followed 
routine monitoring of CD4 count and viral load. Results from 270-301 show similar safety 
results for the two HIV-positive subjects compared to those who are HIV-negative. The 
Sponsor believes that HIV infection, in and of itself, is not a contraindication to receive 
BMN 270 and has therefore removed the exclusion of HIV-positive subjects, as long as they 
are not receiving efavirenz or other potentially hepatotoxic ART in their HIV treatment 
regimen.
5. Language has been added concerning the use of the SARS-CoV-2 vaccines.
Rationale: Due to the current worldwide SARS-CoV-2 pandemic and evolving availability 
and types of vaccines, language has been added to assist with timing and planning for vaccine 
administration. The Sponsor's recommendations reflect the risk assessment conducted on the 
currently available vaccines and guidance from multiple health agencies, and include 
information regarding different types of SARS-CoV-2 vaccines.
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6. The reactive corticosteroid regimen for ALT elevation has been updated.
Rationale: The guidance for the reactive corticosteroid regimen, including management of 
ALT elevations and corticosteroid taper, reflects the data gathered from previous BMN 270 
studies. This change attempts to promote the safe and effective use of reactive 
corticosteroids.
7. Thrombin generation assay (TGA) assessment has been removed.
Rationale: Assessment of TGA in other studies in the BMN 270 development program has 
provided sufficient data; additional assessments are not expected to be needed. Removing 
this assessment helps to alleviate patient and site burden. If TGA assessments from 270-203
are needed in the future, backup aliquots from other platelet-poor plasma samples can be 
utilized.
8. The definition of treatment failure has changed.
Rationale: The previous definition required either a failure to achieve FVIII activity 
≥5 IU/dL by Week 52 or an inability to maintain independence from prophylactic FVIII 
replacement therapy due to joint bleeding episodes; the revised definition requires both of 
these conditions to be present before a subject may be considered a treatment failure. The 
revision reflects the data seen as of the 52-week data cut for 270-301, where some subjects 
were still able to remain off of prophylactic FVIII replacement therapy (due to an absence of 
treated bleeding events) despite lower FVIII levels 1 or more years after BMN 270 infusion.
9. Frequency of several laboratory assessments during Years 2-5 has been decreased. 
These changes include:
x
Reducing FVIII Antigen BDD Assay to Q12W for Years 2-5
Rationale: Robust characterization is already available from Year 1 data, and more 
frequent sampling is not needed to understand long-term protein to activity ratios.
x
Reducing AAV5 TAb to End of Year Visits only for Years 3-5
Rationale: Antibody response is high and does not change much over time. Yearly 
testing should be sufficient to understand longer term responses, as little change is 
expected.
x
Reducing FVIII TAb to End of Year Visits only for Years 3-5
Rationale: FVIII Bethesda Inhibitor is the main safety assessment. After 3 years, if 
there is a need in specific instances for data more frequent than once a year, backup 
plasma from another assay may be used for testing.
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x
Reducing AAV5 TI assay to End of Year visits only for Years 2-5
Rationale: Yearly testing is considered to be sufficient to understand longer term 
responses, as little change is expected.
x
Reducing PBMC collection to every other Q12W visit during Years 3-5
Rationale: Cellular immune responses appear to taper off after the first year. After 
Year 2, sampling every 6 months should be sufficient to monitor late or more durable 
responses.
10. The identity of the Medical Monitor has been updated.
11. The option for a legally authorized representative to provide informed consent where 
needed has been added.
12. Additional minor changes have been made for consistency and clarity.
Refer to Section 25 for a summary of revisions to Amendment 3 (dated 24 August 2020).
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2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
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TITLE OF STUDY: 
A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus 
Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual 
FVIII Levels ≤ 1 IU/dL and Pre-existing Antibodies Against AAV5
PROTOCOL NUMBER:
270-203
STUDY SITES:
Approximately 5-14 sites globally
PHASE OF DEVELOPMENT:
Phase 1/2
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.  
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived or 
recombinant human FVIII protein (rhFVIII) concentrates, both as prophylaxis 2-3 times per week 
or 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. While infusion 
of FVIII is a major advance in the treatment of HA, severe HA patients continue to have bleeding 
events on prophylactic therapy; median ABRs were 1-4 with prophylactic treatment in a recently 
published retrospective observational study and between 1-2 in 6 prospective FVIII interventional 
studies.  Median ABRs were 4.5-18 and between 20-60 with episodic (on-demand-only) therapy in 
the same studies, respectively. Continued repeated bleeding events compound debilitating 
multiple-joint arthropathies as well as the risk of catastrophic events such as intracranial 
hemorrhage and death.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
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Extended half-life products created through chemical modification (eg, direct conjugation of 
polyethylene glycol (PEG) polymers) or bioengineering of FVIII (eg, FVIII-Fc fusion proteins) can 
only extend half-life by approximately 50% (half-life 18-19 hours), 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. More recently, 
emicizumab has been approved for the treatment of HA. Emicizumab is a humanized, bispecific 
monoclonal antibody that binds to both activated coagulation factor IX (FIX) and coagulation 
factor X (FX), thereby mimicking the function of activated FVIII. Emicizumab represents an 
incremental improvement in therapeutic burden over replacement FVIII products since it can be 
administered subcutaneously as opposed to intravenously; however, it is still a chronic treatment 
that requires repeat administration every 1-4 weeks, and sustained FVIII activity levels above 
5-10 IU/dL have rarely been attained even with extended half-life products. Therefore, there is a 
strong unmet need for a treatment that can alter the fundamental problem for patients with HA, 
namely attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over 
multiple years) without the need for treatment. 
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. 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. Moreover, the circulating FVIII response to gene transduction 
can be assessed using validated quantitative endpoints that are easily assayed using established 
laboratory techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 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 (eg serotypes 2, 5, and 8).
Indeed, an ongoing gene therapy clinical trial for a related disorder, hemophilia B, has established 
over 7 years of stable human factor IX (hFIX) expression at levels sufficient for conversion of their 
bleeding phenotype from severe to moderate or mild, 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 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
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ONLY:
previously resulted in bleeding. Thus, gene therapy treatment has resulted in a substantial 
improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the 
control of a hybrid human liver-specific promoter (Figure 1).
Figure 1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein
Legend –Note that schematic is not to scale; aa = amino acids; ITR = inverted terminal repeat; HLP = human 
liver promoter; Kozak = Kozak concensus sequence (GCCACC); SpA = Synthetic poly(A) signal
BMN 270 is delivered by a single IV dose and is designed to achieve stable, durable expression of 
active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose 
escalation study in subjects with severe HA designed to assess the safety and efficacy of BMN 270
at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201
explores the relationship of vector dose to the augmentation of residual FVIII activity and whether 
these levels are sufficient to alter the clinical phenotype. An additional study has been undertaken 
at the 6E13 vg/kg dose (270-301 in subjects with severe HA), as well as a study in subjects 
receiving the 4E13 vg/kg dose (270-302).
Four-year results from 270-201 and one-year results from 270-301 have demonstrated that 
following gene transfer, mean and median FVIII activity levels above 15% (15 IU/dL), as 
measured by a chromogenic substrate assay, are achievable and sustained following a single 
infusion of 6E13 vg/kg of BMN 270, with administration of prophylactic corticosteroids and an 
acceptable safety profile. Preliminary results from optional liver biopsies (in subjects receiving 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
lower doses of BMN 270 in 270-201) confirm dose-dependent pan-lobular and otherwise healthy 
liver transduction at 2.7-4.1 years.
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects 
in 270-301; in 270-201, subjects were scheduled to start corticosteroids by Week 3 (either before 
Week 3, in response to an alanine aminotransferase (ALT) elevation, or at Week 3 otherwise, per 
protocol), whereas in 270-301 subjects received corticosteroids only in response to an ALT 
elevation. Possibly as a result of this difference, subjects receiving 6E13 vg/kg in 270-201 started 
corticosteroids at an earlier date in reference to the date of BMN 270 infusion and showed later 
onset of first ALT elevations when compared with subjects in 270-301. Recently published data 
from 270-201 and recent analysis of 270-301 data suggest that corticosteroids may have assisted in 
rescue or protection of FVIII activity levels during elevations of ALT and in resolution of elevated 
ALT levels in some subjects.
Subjects enrolled and infused in 270-201 screened negative for AAV5 antibodies, as the prevailing 
expectation has been that vector-specific antibodies could interfere with receptor binding and 
effectively neutralize efficient transduction of the target cell population. As this was the first FVIII 
gene therapy with AAV5 in humans, this criterion was adopted out of an abundance of caution. 
Subjects enrolled and infused in 270-301 also screened negative for AAV5 antibodies. These 
pre-existing vector-specific antibodies are thought to arise from previous exposure to AAV, with 
seroprevalence varying across human populations and across studies. AAV5 has consistently been 
shown to have the lowest seroprevalence among the common AAV serotypes. 
Current data describing the extent of neutralization or inhibited transduction has been inconsistent 
across studies, each employing one of several varying methodologies to evaluate both 
vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 for the 
treatment of hemophilia B described inhibited transduction in patients with neutralizing antibody 
titers of 2 or 3, but more recent studies have described successful transduction in patients who, in 
retrospect, were determined to have pre-existing antibody to the vector capsid.  Importantly, no 
drug-related adverse events were described in these patients.  As the sensitivity of assays used to 
detect pre-existing antibody has increased greatly in recent years, the biological relevance of any 
given titer determination, and comparisons across studies using assays with differing titer 
sensitivities, requires additional study. 
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of available 
data shows the effect of pre-existing immunogenicity to AAV delivery vectors is not completely 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
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ONLY:
understood, and indicates that some patients may benefit from AAV5 gene therapy who are 
currently excluded. 
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be enrolled to 
evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate the safety, 
tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing antibodies 
against AAV5 vector capsid at various levels of AAV5 antibody titers.
OBJECTIVES: 
The primary objective of the study is to:
x
Assess the safety of a single intravenous administration of BMN 270 in severe HA subjects 
with pre-existing antibody to AAV5 vector capsid, including development of FVIII 
neutralizing antibody
Secondary objectives of the study are to:
x
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26
x
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy
x
Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous 
FVIII therapy
x
Evaluate the pharmacodynamics of FVIII expression following IV infusion of BMN 270
x
Assess the impact of BMN 270 on patient-reported outcomes (PROs)
STUDY DESIGN AND PLAN: 
This is a Phase 1/2, single-arm, open-label study in severe HA patients (FVIII ≤1 IU/dL), with a 
history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with pre-existing 
antibodies to the AAV5 vector capsid as measured by total antibody [TAb] assay. Approximately 
10 subjects may be enrolled at 5-14 sites in 2 cohorts (5 subjects in each cohort) and will receive a
single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a Screening 
AAV5 TAb titer ≤ 500, while subjects in Cohort 2 will have a Screening AAV5 TAb titer > 500.  
Choosing a titer cutoff of 500 reflects the observed distribution of existing titer data with the 
BioMarin titer assay seen to date.
An independent Data Monitoring Committee (DMC) will consist of experts in clinical trials, 
statistics, and hemophilia. The DMC will review available safety and efficacy data throughout the 
study and provide recommendations based on their review (Figure 2 represents one dosing 
schedule scenario):
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Figure 2:  270-203 Dosing Schedule (One Possible Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening 
AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a maximum of 
5 subjects have been dosed in Cohort 1 and had their safety and efficacy data (from 1-6 weeks 
post-infusion) reviewed.  FVIII activity ≥ 5% after six weeks post-infusion is expected to be the 
earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who later 
achieved normal FVIII activity levels, compared with the one subject who had a slightly lower 
response, based on data from 270-201. Between 1 and 6 weeks post-infusion will provide an 
appropriate timeframe to evaluate the development of any potential delayed hypersensitivity 
reaction (eg, serum sickness).  
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be based on 
DMC evaluation of safety and efficacy in treated subjects, with the following triggers that may 
potentially pause further enrollment: 
x
any related SAE; 
x
any related AE with a severity > CTCAE Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks post-BMN 270
infusion.
Following a temporary halt of enrolment, the DMC may approve resumption of enrolment in either 
cohort at a later date at its discretion based on further analysis of accumulating data.
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 
24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In case of 
suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to physical 
examination and vital signs, will be performed. Additional blood samples will be collected 
(tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine profiling, as well as possible additional 
exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE and cytokine 
profiling (and possible additional exploratory testing) will be collected between 8-24 hours after 
the reaction. In addition, a blood sample should be taken 1 week after the hypersensitivity reaction 
for assessment of the cytokine profiling. Exploratory biomarker samples at baseline and at 
post-infusion study visits may also be used to assess changes in these biomarkers to better elucidate 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
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AUTHORITY USE 
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the mechanisms of infusion-related hypersensitivity reactions. Any safety signal may trigger a 
review of the data and possible additional immunogenicity studies or other diagnostics deemed 
necessary to assess cellular immune responses using collected peripheral blood mononuclear cells 
(PBMCs).  The duration of observation may be extended and additional blood samples collected at 
the discretion of the Investigator and Medical Monitor.
Data from 270-201 suggest that achievement of therapeutic FVIII levels ≥5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII protection 
while subjects are projected to reach clinically relevant FVIII levels ≥ 5 IU/dL, prior FVIII 
prophylaxis for each subject will be continued at the discretion of the DMC based on individual 
subject status and data review or when FVIII activity has reached at least 5 IU/dL. In subjects who 
experience recurring bleeding episodes, the Investigator and Medical Monitor will discuss whether 
to resume prior FVIII prophylaxis. 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as failure to 
achieve FVIII activity ≥ 5 IU/dL by Week 52 and inability to maintain independence from 
prophylactic FVIII replacement therapy due to joint bleeding episodes, in the judgment of the 
Investigator) may, at the Investigator’s discretion and after discussion with the Medical Monitor or 
Sponsor-designated Data Monitor, follow an abbreviated visit schedule after Week 52 by attending 
only the Q12W and End of Year visits during Years 2-5. Subjects who are not attending the Q6W 
visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the site to 
ask about adverse events, concomitant medications, and bleeding events/FVIII replacement usage.
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. After the 
safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, long-term safety and 
efficacy will be assessed in all subjects for up to a total of 5 years post-infusion. During the trial, 
additional subjects may be recruited into each cohort at any time, if deemed necessary by the 
DMC.  
NUMBER OF SUBJECTS PLANNED:
Approximately 10 subjects 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following 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. 
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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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2.
Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total 
antibody ELISA
3.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days 
(EDs)
4.
Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior 
to study entry.  
5.
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. If the subject is unable to provide 
consent, a legally authorized representative may provide written informed consent.
6.
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) 
7.
Sexually active participants must agree to use an acceptable method of effective contraception, 
either double-barrier contraception (ie, condom + diaphragm; or condom or diaphragm + 
spermicidal gel or foam) or their female partner either using hormonal contraceptives or having 
an intrauterine device. Participants must agree to contraception use for at least 12 weeks 
post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 
3 consecutive semen samples with viral vector DNA below the limit of detection.
8.
Willing to abstain from consumption of alcohol for at least the first 52 weeks following 
BMN 270 infusion.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study:
1.
Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, 
except for HIV infection. HIV-positive patients who meet all other eligibility criteria may be 
included if they have a CD4 count > 200/mm3 and an undetectable viral load (unquantifiable 
viral load as defined as less than the limit of quantification by the testing laboratory’s assay is 
permitted) while receiving an antiretroviral therapy (ART) regimen that does not contain 
efavirenz or another potentially hepatotoxic ART.
2.
Significant liver dysfunction with any of the following abnormal laboratory results:
o
ALT (alanine aminotransferase) > 1.25x ULN;
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
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o
AST (aspartate aminotransferase) > 1.25x ULN;
o
GGT (gamma-glutamyltransferase) > 1.25x ULN;
o
Total bilirubin > 1.25x ULN;
o
Alkaline phosphatase > 1.25x ULN; or
o
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. 
3.
Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated on a 
scale of 0-4 on the Batts-Ludwig or METAVIR scoring systems, or an equivalent grade of 
fibrosis if an alternative scale is used.
4.
Evidence of any bleeding disorder not related to hemophilia A
5.
Platelet count of < 100 x 109/L
6.
Creatinine ≥ 1.5 mg/dL
7.
Liver cirrhosis or other clinically significant liver disease of any etiology as assessed by liver 
ultrasound/FibroScan. 
8.
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.
9.
Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy
10.
Active malignancy, except non-melanoma skin cancer
11.
History of hepatic malignancy
12.
History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with 
the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not 
currently ongoing. 
13.
Known inherited or acquired thrombophilia, including conditions associated with increased 
thromboembolic risk, such as atrial fibrillation.
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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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14.
A history of known inflammatory, connective tissue, or autoimmune disorders (eg, 
vasculitis).
15.
Treatment with any Investigational Product within 30 days or 5 half-lives of the 
investigational product (whichever is longer) prior to the screening period. For subjects who 
have received a prior investigational product, all ongoing adverse events (AEs) experienced 
while receiving that investigational product must have resolved prior to screening for this 
study
16.
Any condition that, in the opinion of the investigator or Sponsor would prevent the patient 
from fully complying with the requirements of the study (including corticosteroid treatment 
and/or the use of alternative immunosuppressive agents outlined in the protocol) and/or 
would impact or interfere with evaluation and interpretation of subject safety or efficacy 
result.
17.
Prior treatment with any vector or gene transfer agent
18.
Major surgery planned in the 52-week period following the infusion with BMN 270
19.
Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion
20.
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study that does not interfere with the requirements of the current 
protocol or have the potential to impact the evaluation of safety and efficacy of BMN 270
and with prior consultation with the Medical Monitor
21.
Known allergy or hypersensitivity to investigational product formulation
22.
Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Each subject will receive a single IV infusion of BMN 270 at 6E13 vg/kg. The volume of infusion 
will depend on the subject’s weight.
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
No reference therapy will be evaluated in this study.
DURATION OF TREATMENT:
BMN 270 is given as a single dose by IV infusion.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 270
NAME OF ACTIVE INGREDIENT:
AAV5-hFVIII-SQ
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
CRITERIA FOR EVALUATION:
Safety:
The following safety outcome measurements will be assessed:
x
Incidence of adverse events (AEs), including serious AEs (SAEs)
x
Change in clinical laboratory tests (serum chemistry and hematology)
x
Change in vital signs
x
Change in physical examination 
x
Vector shedding (blood, urine, semen, feces, saliva)
x
Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline 
phosphatase)
x
Immune response to FVIII transgene product and AAV5 vector capsid
No major toxicity is expected based on 270-201 data and non-clinical studies. Each subject will 
have comprehensive surveillance monitoring of LTs (once per week for Weeks 1-26). During the 
long-term safety evaluation, LTs will be monitored every three months for up to 5 years 
post-infusion; the frequency and duration of LT testing may be changed based on discussion 
between the Medical Monitor and the Investigator and review of subject data. 
There will be a detailed assessment of cellular and humoral responses to AAV5 vector capsid and 
FVIII.  
Efficacy: 
The efficacy measure will be to assess plasma FVIII activity. The efficacy goal is to achieve FVIII 
activity ≥ 5 IU/dL at 26 weeks post-BMN 270 administration. Other efficacy measures include 
assessing the impact of BMN 270 on the use of FVIII replacement therapy and on the number of 
bleeding episodes during the study. Subjects will be asked to keep a subject diary, provided by the 
sponsor, to record the relevant details. 
Other efficacy endpoints:  
x
Change from baseline in the total score of HAEMO-QoL-A at Week 26 of the study 
post-BMN 270 infusion
x
Change from baseline in the EQ-5D-5L score at Week 26 of the study post-BMN 270
infusion.
x
Change from baseline in the Haemophilia Activities List (HAL) score at Week 26 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
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
x
Change from baseline in the Work Productivity and Activity Impairment plus Classroom 
Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 26 of the 
study post-BMN 270 infusion.
Pharmacodynamics: 
The FVIII antigen and activity level, as measured by a validated immunoassay and a validated 
FVIII activity assay, respectively, will be used for plasma profiles; FVIII antigen and activity will 
be used to determine PD parameters.
STATISTICAL METHODS: 
Approximately 10 subjects may be dosed in the study. The subjects will be followed in a 
longitudinal manner, and all the relevant information will be collected. The analysis of the data will 
be descriptive in nature, but data collected in a longitudinal manner may be analyzed using 
longitudinal methods, such as a mixed effect model, which take into account the correlation among 
the observations taken at various time points within a subject. Efficacy is a secondary endpoint, 
defined as biologically active FVIII at ≥5 IU/dL at 26 weeks following study treatment. 
Assessment of the true steady state of FVIII will require that FVIII activity is measured after a
minimum of 72 hours (or 5x the known half-life of the FVIII replacement therapy administered) 
has elapsed since the last infusion of FVIII concentrates. 
Analysis of neutralizing antibody response, other immunological parameters, and vector shedding 
will be primarily descriptive and involve both inter-subject and intra-subject comparisons across 
cohorts.
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3
TABLE OF CONTENTS
1
TITLE PAGE .....................................................................................................................1
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY............................................2 
2 SYNOPSIS...........................................................................................................................6 
3 TABLE OF CONTENTS...................................................................................................18 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................23 
5 ETHICS..............................................................................................................................26 
5.1 Institutional Review Board or Independent Ethics Committee ................................26 
5.2 Ethical Conduct of Study..........................................................................................26 
5.3 Subject Information and Informed Consent..............................................................27 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................28 
7 INTRODUCTION .............................................................................................................29 
7.1 Nonclinical Studies ...................................................................................................30 
7.2 Ongoing Clinical Studies ..........................................................................................30 
7.3 Study Rationale.........................................................................................................31 
7.4 Summary of Overall Risks and Benefits...................................................................35 
8 STUDY OBJECTIVES......................................................................................................37 
9 INVESTIGATIONAL PLAN............................................................................................38 
9.1 Overall Study Design and Plan.................................................................................38 
9.2 Discussion of Study Design, Including Choice of Control Group............................58 
9.3 Selection of Study Population...................................................................................58 
9.3.1 
Inclusion Criteria.........................................................................................58 
9.3.2 
Exclusion Criteria........................................................................................59 
9.3.3 
Removal of Subjects from Treatment or Assessment .................................61 
9.3.4 
Subject Identification and Replacement of Subjects...................................63 
9.3.5 
Duration of Subject Participation................................................................63 
9.4 Treatments.................................................................................................................64 
9.4.1 
Treatments Administered ............................................................................64 
9.4.2 
Identity of Investigational Product..............................................................64 
9.4.3 
Storage.........................................................................................................64 
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9.4.4 
Directions for Administration .....................................................................64 
9.4.5 
Method of Assigning Subjects to Treatment Groups ..................................66 
9.4.6 
Selection of Dose Used in the Study...........................................................66 
9.4.7 
Blinding.......................................................................................................66 
9.4.8 
Prior and Concomitant Medications............................................................67 
9.4.9 
Treatment Compliance ................................................................................73 
9.5 Investigational Product Accountability.....................................................................73 
9.5.1 
Return and Disposition of Clinical Supplies ...............................................73 
9.6 Dietary or Other Protocol Restrictions......................................................................73 
9.7 Efficacy and Safety Variables...................................................................................74 
9.7.1 
Efficacy and Safety Measurements Assessed .............................................74 
9.7.2 
Efficacy Variables .......................................................................................74 
9.7.3 
Immunogenicity...........................................................................................76 
9.7.4 
Pharmacodynamics......................................................................................76 
9.7.5 
Exploratory Assessments ............................................................................76 
9.7.6 
Safety Variables ..........................................................................................77 
10 REPORTING ADVERSE EVENTS .................................................................................84 
10.1 Safety Parameters and Definitions............................................................................84 
10.1.1 Adverse Events............................................................................................84 
10.2 Serious Adverse Events ............................................................................................85 
10.2.1 Events of Special Interest (EOSI) ...............................................................86 
10.3 Methods and Timing for Capturing and Assessing Safety Parameters.....................86 
10.3.1 Adverse Event Reporting Period.................................................................86 
10.3.2 Eliciting Adverse Events.............................................................................86 
10.3.3 Assessment of Seriousness, Severity, and Causality...................................86 
10.4 Procedures for Recording Adverse Events ...............................................................89 
10.4.1 Recording Adverse Events on a eCRF........................................................89 
10.5 Reporting Requirements ...........................................................................................92 
10.5.1 Expedited Reporting Requirements.............................................................92 
10.5.2 Institutional Review Board or Independent Ethics Committee 
Reporting Requirements..............................................................................93 
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10.6 Follow-up of Subjects after Adverse Events.............................................................93 
10.7 Post-Study Adverse Events.......................................................................................93 
10.8 Urgent Safety Measures............................................................................................94 
10.9 BioMarin Pharmacovigilance Contact Information..................................................94 
11 APPROPRIATENESS OF MEASUREMENTS...............................................................96 
12 STUDY PROCEDURES ...................................................................................................97 
12.1 Prestudy.....................................................................................................................97 
12.2 Screening Visit(s)......................................................................................................97 
12.2.1 “Smart Rescreening” Visit ..........................................................................99 
12.3 Baseline Visit............................................................................................................99 
12.4 Treatment Visit/BMN 270 Infusion Visit (Day 1)..................................................101 
12.5 BMN 270 Infusion Follow-Up Visits .....................................................................102 
12.5.1 Week 1.......................................................................................................102 
12.5.2 Weeks 2-26................................................................................................104 
12.5.3 Post-Infusion Follow-Up – Weeks 27-52..................................................107 
12.6 Post-Infusion Follow-Up – Years 2-5.....................................................................109 
12.6.1 Years 2-5 – Every 6 Weeks (not required for treatment failure)...............109 
12.6.2 Years 2-5 – Every 12 Weeks and End of Year Visits (required for 
all subjects)................................................................................................110 
12.7 Early Termination Visit ..........................................................................................112 
12.8 End of Study............................................................................................................113 
13 DATA QUALITY ASSURANCE...................................................................................114 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE................115 
14.1 Statistical and Analytical Plans...............................................................................115 
14.1.1 Interim Analyses........................................................................................115 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data........115 
14.2 Efficacy Analysis ....................................................................................................115 
14.3 Safety Analysis .......................................................................................................115 
14.4 Determination of Sample Size ................................................................................116 
14.5 Analysis Populations...............................................................................................116 
14.6 Changes in the Conduct of the Study or Planned Analyses....................................116 
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15 DATA MONITORING COMMITTEE...........................................................................117 
16 COSTS, COMPENSATION, AND SUBJECT INJURY................................................118 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS............................................119 
18 STUDY MONITORING AND AUDITING ...................................................................121 
19 RETENTION OF RECORDS .........................................................................................122 
20 USE OF INFORMATION AND PUBLICATION .........................................................123 
21 REFERENCES ................................................................................................................124 
22 INVESTIGATOR RESPONSIBILITIES ........................................................................127 
22.1 Conduct of Study and Protection of Human Subjects.............................................127 
23 SIGNATURE PAGE .......................................................................................................128 
24 APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA .........................................129 
25 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................130 
LIST OF TABLES
Table 9.1.1: Schedule of Activities – Screening/Baseline/Day 1 ............................................41 
Table 9.1.2: Schedule of Activities – Post-Infusion Follow-Up (Week 1-16) .......................45 
Table 9.1.3:  Schedule of Activities – Post-Infusion Follow-Up (Week 17-32) .....................48 
Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52) .....................51 
Table 9.1.5:  Schedule of Activities – Long-Term Follow-Up (Year 2 – Year 5)...................54 
Table 9.1.6:  Suggested Schedule of Activities – Prophylactic Corticosteroids......................57 
Table 9.4.8.2.2.1:  Management of ALT Elevations with Reactive Corticosteroids...............70 
Table 9.4.8.2.2.2:  Viral and Autoimmune Hepatitis Testing..................................................71 
Table 9.7.6.2.1:  Clinical Laboratory Tests .............................................................................78 
Table 9.7.6.4.1:  Liver Tests ....................................................................................................80 
Table 10.3.3.2.1: Adverse Event Grading (Severity) Scale....................................................87 
Table 10.3.3.3.1: Causality Attribution Guidance ..................................................................88 
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LIST OF FIGURES
Figure 1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein.........................................8 
Figure 2:  270-203 Dosing Schedule (One Possible Scenario)................................................11 
Figure 7.3.1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein.................................33 
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario) ........................................................38 
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
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
EC
ethics 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
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hFIX
human coagulation factor IX
hFVIII
human coagulation factor VIII
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICH E6 [R2]
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6
IND
Investigational New Drug (application)
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IV
intravenous
LT
liver test
MedDRA
Medical Dictionary for Regulatory Activities
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
SAE
serious adverse event
SAP
statistical analysis plan
SDV
source data verification
SoA
schedule(s) of activities
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 (EC) 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/EC will be provided to BioMarin Pharmaceutical Inc. (BioMarin) 
or its designee. The Investigator will provide the IRB/EC 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/EC 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/EC and BioMarin by the Investigator in accordance with applicable guidance documents 
and governmental regulations.
5.2
Ethical Conduct of Study
It is expected that Investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, including providing 
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eligible subjects for study enrollment; adhering to adverse event reporting, diagnostic, or 
other procedures as specified in the protocol; and assuring appropriate compliance with study 
treatment administration and accountability.
This study will be conducted in accordance with the following:
x
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country
x
US Code of Federal Regulations (CFR) Sections that address clinical research studies, 
and/or other national and local regulations, as applicable
x
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R2) 
(ICH E6R2)
x
The ethical principles established by the Declaration of Helsinki
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/EC and will be conducted by scientifically and medically qualified persons. The benefits 
of the study are in proportion to the risks. The rights and welfare of the subjects will be 
respected and the investigators conducting the study do not find the hazards to outweigh the 
potential benefits. Each subject (or his legally authorized representative, if required) 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 E6R2 
(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/EC approval. BioMarin and the 
IRB/EC 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.
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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 (and their legally authorized representatives, if required).
Subjects who are not willing and/or are not able to comply with all aspects of the study 
should not be encouraged to participate.
Prior to beginning the study, the Investigator at each site must provide to BioMarin or 
designee a fully executed and signed Statement of Investigator (SOI) form.  A US Food and 
Drug Administration (FDA) Form FDA 1572 serves as an acceptable SOI form.  If Form 
FDA 1572 may not be used in a particular region, the Investigator must provide a fully 
executed SOI on the form provided by the Sponsor.  All Investigators and Sub-Investigators 
must be listed on Form FDA 1572 or its equivalent SOI.  Financial Disclosure Forms must 
also be completed for all Investigators and Sub-Investigators listed on the Form FDA 1572 or 
SOI who will be directly involved in the treatment or evaluation of subjects in this study.
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical Research Associates (CRAs) or trained designees will monitor each site 
on a periodic basis and perform verification of source documentation for each subject as well 
as other required review processes. BioMarin’s Regulatory Affairs Department (or designee) 
will be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required.
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study overview. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
Investigators participating in the study will be provided in the CSR.
Clinical Laboratory assessments will be performed at a nominated central laboratory.
Bioanalytical samples will be sent to the appropriate specialty laboratories for testing. Refer 
to laboratory manual for more details. 
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7
INTRODUCTION
Hemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 
1 in 5,000 males (Iorio 2019). It is caused by 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.  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 (12-18 hours) necessitates frequent infusions and 
makes this treatment prohibitively expensive for the majority of the world’s hemophilia A 
patients. These individuals develop debilitating arthropathy and have a substantially 
increased risk of death from hemorrhage in life (Stonebraker 2010). Chemical modification 
or bioengineering of FVIII may improve half-life to 18-19 hours (Kaufman 2013). However, 
these extended half-life FVIII variants do not eliminate the need for lifelong FVIII protein 
administration (Hay 2012).
Gene therapy offers the potential of disease-modifying therapy by continuous endogenous 
production of human FVIII (hFVIII) following a single administration of vector. Hemophilia 
A is well-suited for this approach because its clinical manifestations are attributable to the 
lack of a single gene product (FVIII) that circulates in low amounts (100-200 ng/ml) in the 
plasma. Tightly regulated control of gene expression is not essential, and a modest increase 
in the level of FVIII (a plasma level of 2 ng/ml protein leads to a 1% expression) can 
ameliorate the severe phenotype (Srivastava 2020); thus, the therapeutic goal for gene 
therapy is a modest increase in hFVIII. Finally, the consequences of gene transfer can be 
assessed using validated quantitative endpoints that can be easily assayed in most clinical 
laboratories.
BMN 270 contains the cDNA for the B-domain-deleted SQ FVIII with a liver-specific HLP 
transcription promoter. The expression cassette is inserted between AAV2 ITRs, and this 
genome is packaged in the AAV5 capsid.  A comprehensive review of BMN 270 is contained 
in the IB supplied by BioMarin. Investigators are to review this document prior to initiating 
this study.
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7.1
Nonclinical Studies
The nonclinical program supports a single IV 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 
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.
The comparative pharmacodynamics of BMN 270 in cynomolgus monkeys with varying 
pre-existing AAV5 transduction inhibition (TI) titer and AAV5 TAb status was evaluated in 
study BMN270-16-021. BMN 270 was administered to 4 groups of monkeys, a control group 
(Group 1, n=3) that tested negative for both TI and AAV5 TAb, Group 2 (n=4) that was 
AAV5 TAb negative, and low TI titer (2-5) positive. Group 3 (n=4) was also AAV5 TAb 
negative, but had higher TI titers (5-10). Group 4 (n=5) tested positive for both AAV5 TAb 
and TI (TI titers were >5). Administration of BMN 270 by a single intravenous bolus 
injection was well-tolerated in cynomolgus monkeys regardless of baseline TI titer or TAb 
status. After dosing, all monkeys showed FVIII-SQ levels above the LLOQ, with the 
exception of two monkeys in the group that presented with both positive TI and TAb titers at 
baseline. Though these TAb+ monkeys, regardless of TI titers, showed a significant mean 
reduction in FVIII expression (68% less) compared to TAb negative monkeys, three of five 
monkeys showed detectable levels of FVIII-SQ, with one having levels similar to that 
observed in the TI and TAb negative control group. Monkeys that were TI+ but TAb-at 
baseline had FVIII expression levels that were similar to those of the TI and TAb negative 
control group. 
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
Ongoing Clinical Studies
Ongoing clinical studies for BMN 270 include:
x
270-201, a phase 1/2, dose-escalation study in patients with severe HA
x
270-205, a phase 1/2 study in patients with severe HA who have active or prior FVIII 
inhibitors
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x
270-301, a phase 3 study in patients with severe HA who receive BMN 270 at the 
6E13 vg/kg dose level
x
270-302, a phase 3 study in patients with severe HA who receive BMN 270 at the 
4E13 vg/kg dose level
x
270-303, a phase 3 study in patients with severe HA who received BMN 270 at the 
6E13 vg/kg dose level along with prophylactic corticosteroids
A comprehensive review of safety, efficacy, and immunogenicity results as of the latest data 
cut is contained in the IB supplied by BioMarin. Investigators are to review this document 
prior to initiating this study.
7.3
Study Rationale
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.  
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived 
or recombinant human FVIII protein (rhFVIII) concentrates, both as prophylaxis 2-3 times 
per week or 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. While infusion of FVIII is a major advance in the treatment of HA, severe HA 
patients continue to have bleeding events on prophylactic therapy; median ABRs were 1-4
with prophylactic treatment in a recently published retrospective observational study 
(Berntorp 2017) and between 1-2 in 6 prospective FVIII interventional studies.  Median 
ABRs were 4.5-18 and between 20-60 with episodic (on-demand-only) therapy in the same 
studies, respectively. Continued repeated bleeding events compound debilitating 
multiple-joint arthropathies as well as the risk of catastrophic events such as intracranial 
hemorrhage and death.
Extended half-life products created through chemical modification (eg, direct conjugation of 
polyethylene glycol (PEG) polymers) or bioengineering of FVIII (eg, FVIII-Fc fusion 
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proteins) can only extend half-life by approximately 50% (half-life 18-19 hours), 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. More recently, emicizumab has been approved for the treatment of 
HA. Emicizumab is a humanized, bispecific monoclonal antibody that binds to both activated 
coagulation factor IX (FIX) and coagulation factor X (FX), thereby mimicking the function 
of activated FVIII. Emicizumab represents an incremental improvement in therapeutic 
burden over replacement FVIII products since it can be administered subcutaneously as
opposed to intravenously; however, it is still a chronic treatment that requires repeat 
administration every 1-4 weeks, and sustained FVIII activity levels above 5-10 IU/dL have 
rarely been attained even with extended half-life products. Therefore, there is a strong unmet 
need for a treatment that can alter the fundamental problem for patients with HA, namely 
attainment of sustained, hemostatically effective FVIII activity levels long-term (ie, over 
multiple years) without the need for treatment. 
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. 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. Moreover, the 
circulating FVIII response to gene transduction can be assessed using validated quantitative 
endpoints that are easily assayed using established laboratory techniques.
Several different gene transfer strategies for FVIII replacement have been evaluated, with 
adeno-associated viral (AAV) vectors used in most hemophilia clinical trials. AAV vectors 
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 
(eg serotypes 2, 5, and 8). Indeed, an ongoing gene therapy clinical trial for a related 
disorder, hemophilia B, has established over 7 years of stable human factor IX (hFIX) 
expression at levels sufficient for conversion of their bleeding phenotype from severe to 
moderate or mild, following a single peripheral vein infusion of AAV8-hFIX vector 
(Nathwani 2018). Several participants in this trial have been able to discontinue factor 
prophylaxis without suffering spontaneous hemorrhages, even when they undertook activities 
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that previously resulted in bleeding. Thus, gene therapy treatment has resulted in a 
substantial improvement in their quality of life. 
BMN 270 is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under 
the control of a hybrid human liver-specific promoter (Figure 7.3.1).
Figure 7.3.1:  AAV5-hFVIII-SQ Vector Genome and Encoded Protein
Legend –Note that schematic is not to scale; aa = amino acids; ITR = inverted terminal repeat; HLP = human 
liver promoter; Kozak = Kozak concensus sequence (GCCACC); SpA = Synthetic poly(A) signal
BMN 270 is delivered by a single IV dose and is designed to achieve stable, durable 
expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. 
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2
dose escalation study in subjects with severe HA designed to assess the safety and efficacy of 
BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). 
Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual 
FVIII activity and whether these levels are sufficient to alter the clinical phenotype. An
additional study has been undertaken at the 6E13 vg/kg dose (270-301 in subjects with severe 
HA), as well as a study in subjects receiving the 4E13 vg/kg dose (270-302).
Four-year results from 270-201 and one-year results from 270-301 have demonstrated that 
following gene transfer, mean and median FVIII activity above 15% (15 IU/dL), as measured 
by a chromogenic substrate assay, are achievable and sustained following a single infusion of 
6E13 vg/kg of BMN 270, with administration of prophylactic corticosteroids and an 
acceptable safety profile. Preliminary results from optional liver biopsies (in subjects 
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receiving lower doses of BMN 270 in 270-201) confirm dose-dependent pan-lobular and 
otherwise healthy liver transduction at 2.7-4.1 years.
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than 
subjects in 270-301; in 270-201, subjects were scheduled to start corticosteroids by Week 3 
(either before Week 3, in response to an alanine aminotransferase (ALT) elevation, or at 
Week 3 otherwise, per protocol), whereas in 270-301 subjects received corticosteroids only 
in response to an ALT elevation. Possibly as a result of this difference, subjects receiving 
6E13 vg/kg in 270-201 started corticosteroids at an earlier date in reference to the date of 
BMN 270 infusion and showed later onset of first ALT elevations when compared with 
subjects in 270-301. Recently published data from 270-201 and recent analysis of 270-301
data suggest that corticosteroids may have assisted in rescue or protection of FVIII activity 
levels during elevations of ALT and in resolution of elevated ALT levels in some subjects.
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, 
as the prevailing expectation has been that vector-specific antibodies could interfere with 
receptor binding and effectively neutralize efficient transduction of the target cell population. 
As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted 
out of an abundance of caution. Subjects enrolled and infused in 270-301 also screened 
negative for AAV5 antibodies. These pre-existing vector-specific antibodies are thought to 
arise from previous exposure to AAV, with seroprevalence varying across human 
populations and across studies. AAV5 has consistently been shown to have the lowest 
seroprevalence among the common AAV serotypes (Hayes 2019; Boutin 2010).
Current data describing the extent of neutralization or inhibited transduction has been 
inconsistent across studies, each employing one of several varying methodologies to evaluate 
both vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 
for the treatment of hemophilia B described inhibited transduction in patients with 
neutralizing antibody titers of 2 or 3 (Manno 2006), but more recent studies have described 
successful transduction in patients who, in retrospect, were determined to have pre-existing 
antibody to the vector capsid (Majowicz 2017).  Importantly, no drug-related adverse events 
were described in these patients.  As the sensitivity of assays used to detect pre-existing 
antibody has increased greatly in recent years, the biological relevance of any given titer 
determination, and comparisons across studies using assays with differing titer sensitivities, 
requires additional study. 
Data from a non-clinical study conducted by BioMarin in cynomolgus monkeys further 
demonstrated that transduction efficiency can vary greatly in the presence of pre-existing 
anti-AAV5 antibody.  In non-human primates, the ability to attain FVIII levels in the face of 
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measurable AAV5 antibody titers without significant safety risks supports the possibility of 
achieving a similar response in patients with AAV5 antibody positivity. The totality of 
available data shows the effect of pre-existing immunogenicity to AVV delivery vectors is 
not completely understood, and indicates that some patients may benefit from AAV5 gene 
therapy who are currently excluded. 
In this study, patients with severe HA and pre-existing antibodies against AAV5 will be 
enrolled to evaluate the clinical response to BMN 270 gene therapy. The aim is to evaluate 
the safety, tolerability, and efficacy of BMN 270 in patients with severe HA and pre-existing 
antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers.
7.4
Summary of Overall Risks and Benefits
Overall, 151 subjects have received a BMN 270 infusion at one of 4 dose levels (6E12 vg/kg, 
2E13 vg/kg, 4E13 vg/kg, or 6E13 vg/kg) in one of the four ongoing BMN 270 clinical 
studies (270-201, 270-301, 270-302, 270-203). Single infusions have been generally 
well-tolerated across all investigated doses. All subjects have successfully completed their 
full-dose infusion of BMN 270, with no discontinuation of dosing due to adverse events 
observed during the infusion. No deaths have been reported in any of the BMN 270 studies, 
and no participants have discontinued from studies as a result of an adverse event. 
Transient ALT elevation (Grade 1 to 3 in severity) has been observed in most subjects 
administered BMN 270 shortly after dosing, with no evidence for major impacts upon liver 
function; no events meeting the Hy’s Law criteria have been identified. Liver function has 
remained stable over time. Across the 6E13 vg/kg cohort of 270-201 and 270-301, subjects 
enrolled in 270-201 developed ALT elevation about 5.5 weeks later than subjects in 270-301,
generally once the first course of corticosteroids was being tapered, and experienced lower 
peak elevations in ALT (75.7 U/L) than subjects in 270-301 (112.5 U/L). The difference in 
the ALT profile seen between the 6E13 vg/kg subjects in 270-201 and the subjects in 
270-301 could be attributed to the difference in the protocol-specified corticosteroid 
regimens in place in those studies, including the early use of corticosteroids (ie, by Week 3 
post-BMN 270 infusion). While the majority of ALT elevations responded rapidly to 
corticosteroids, given current interest in the field of AAV gene therapy for the use of 
non-steroidal approaches to managing or preventing ALT elevations, alternate non-steroidal 
systemic immunosuppressive agents have also been used to manage hepatic reactions where 
corticosteroids have proven to be ineffective or where high doses/and or prolonged exposure 
to corticosteroids have led to unwanted side effects. Overall, the literature and clinical 
experience with BMN 270 suggests that transient elevations in liver enzymes are expected 
following AAV-based gene therapy for the treatment for hemophilia A or B without any 
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long-term concerns of hepatic injury (Manno 2006; Nathwani 2011; George 2016;
Miesbach 2016; Pasi 2020).
Short-lived infusion reactions associated with one-time BMN 270 administration have 
included symptoms such as nausea, maculopapular rash, urticaria, diarrhea, watery eyes, 
rigors, chills, myalgia, fever, tachycardia and hypotension emerging within 24 hours of 
receiving BMN 270. Most infusion-related reactions were Grade 1 or Grade 2 in severity, 
and all events resolved, typically within 48 hours following medical management. While 
some cases required temporary interruption of the infusion, followed by re-initiation at a 
slower rate, all subjects completed their infusions. The reactions with onset during or within 
approximately 5 hours after the end of infusion responded to treatment with systemic 
antihistamines and/or corticosteroids, where administered. Infusion-related reactions were 
effectively mitigated by managing infusion rate and medications. 
No subjects have experienced thromboembolic events or developed inhibitors to FVIII 
following BMN 270 infusion.
Subjects given the 6E13 vg/kg dose in 270-201 and 270-301 have achieved mean FVIII 
activity above 40 IU/dL at 49-52 weeks post-infusion, with markedly decreased bleeding 
compared with pre-study rates and the ability to discontinue prophylactic FVIII infusions. 
Subjects at all dose levels continue to be followed. 
The current data available for BMN 270 has shown an established positive benefit:risk 
profile for BMN 270 at the 6E13 vg/kg dosing level, although impact of prophylactic 
corticosteroids requires further investigation. Given the monitoring measures in place in the 
clinical protocol(s) to minimize the risk to subjects participating in the existing studies, the 
identified risks are justified by the anticipated benefits that may be afforded to subjects.  
Each subject in 270-203 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 from other BMN 270 clinical studies, refer to the 
current version of the IB.
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8
STUDY OBJECTIVES
The primary objective of the study is to:
x
Assess the safety of a single intravenous administration of BMN 270 in severe HA 
subjects with pre-existing antibody to AAV5 vector capsid, including development of 
FVIII neutralizing antibody
The secondary objectives of the study are to:
x
Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at 
Week 26
x
Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy
x
Assess the impact of BMN 270 on the number of bleeding episodes requiring 
exogenous FVIII therapy
x
Evaluate the pharmacodynamics of FVIII expression following IV infusion of 
BMN 270
x
Assess the impact of BMN 270 on patient-reported outcomes (PROs)
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a Phase 1/2, single-arm, open-label study in severe HA patients (FVIII ≤1 IU/dL), 
with a history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with 
pre-existing antibodies to AAV5 vector capsid as measured by total antibody [TAb] assay. 
Approximately 10 subjects may be enrolled at 5-14 sites globally in 2 cohorts (5 subjects in 
each cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. 
Subjects in Cohort 1 will have a Screening AAV5 TAb ≤ 500, while subjects in Cohort 2 will 
have a Screening AAV5 TAb > 500. Choosing a titer cutoff of 500 reflects the observed 
distribution of existing titer data with the BioMarin titer assay seen to date.
An independent Data Monitoring Committee (DMC), consisting of experts in clinical trials, 
statistics, and hemophilia, has been convened.  The DMC will review available safety and 
efficacy data throughout the study and provide recommendations based on their review 
(Figure 9.1.1 represents one dosing schedule scenario):
Figure 9.1.1:  270-203 Dosing Schedule (One Scenario)
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their 
Screening AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a 
maximum of 5 subjects have been dosed in Cohort 1 and had their safety and efficacy data 
(from 1-6 weeks post-infusion) reviewed.  Based on data from 270-201, FVIII activity ≥ 5% 
after six weeks post-infusion is expected to be the earliest differentiating time point for the 
majority of subjects dosed with 6E13 vg/kg who later achieved normal FVIII activity levels, 
compared with the one subject who had a slightly lower response. Between 1 and 6 weeks 
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post-infusion will provide an appropriate timeframe to evaluate the development of any 
potential delayed hypersensitivity reaction (eg, serum sickness).  
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC evaluation of safety and efficacy in treated subjects with the following 
triggers that may potentially pause further enrollment: 
x
any related SAE;
x
any related AE with a severity > CTCAE Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects at 6 weeks post-BMN 270 infusion.
Following a temporary halt of enrolment, the DMC may approve resumption of enrolment in 
either cohort at a later date at its discretion based on further analysis of accumulating data.
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at 
least 24 hours post-infusion for any immediate hypersensitivity or adverse drug reaction. In 
case of suspected hypersensitivity or adverse drug reaction, safety assessments, in addition to 
physical examination and vital signs, will be performed. Additional blood samples will be 
collected (tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine profiling, as well as possible 
additional exploratory testing) within 1 hour of hypersensitivity reaction, and samples for IgE 
and cytokine profiling (and possible additional exploratory testing) will be collected between 
8-24 hours after the reaction. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine profiling. Exploratory biomarker 
samples at baseline and at post-infusion study visits may also be used to assess changes in 
these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity 
reactions. Any safety signal may trigger a review of the data and possible additional 
immunogenicity studies or other diagnostics deemed necessary to assess cellular immune 
responses using collected peripheral blood mononuclear cells (PBMCs).  The duration of 
observation may be extended and additional blood samples collected at the discretion of the 
Investigator and Medical Monitor.
Data from 270-201 suggest that achievement of therapeutic FVIII levels ≥5 IU/dL occurs 
approximately 4 weeks after BMN 270 infusion, although the FVIIII PD in AAV+ subjects is 
unknown and requires close monitoring. As such, in order to provide adequate FVIII 
protection while subjects are projected to reach clinically relevant FVIII levels ≥5 IU/dL, 
prior FVIII prophylaxis for each subject will be continued at the discretion of the DMC based 
on individual subject status and data review or when FVIII activity has reached at least 
5 IU/dL. 
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As the relationship between activity assay results of the BMN 270 gene product and bleeding 
remains to be established, Investigators should strive to minimize bias by avoiding 
consideration of FVIII activity levels by themselves or subjects in the reporting of bleeding 
episodes and FVIII usage.
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not 
respond to BMN 270 treatment (ie, treatment failure, manifesting as failure to achieve FVIII 
activity ≥ 5 IU/dL by Week 52 and inability to maintain independence from prophylactic 
FVIII replacement therapy due to joint bleeding episodes, in the judgment of the 
Investigator) may, at the Investigator’s discretion and after discussion with the Medical 
Monitor or Sponsor-designated Data Monitor, follow an abbreviated visit schedule after 
Week 52 by attending only the Q12W and End of Year visits during Years 2-5. Subjects who 
are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly 
follow-up telephone call from the site to ask about adverse events, concomitant medications, 
and bleeding events/FVIII replacement usage.
The study analysis will be performed after all subjects have been followed for 26 weeks 
post-BMN 270 infusion, with presentation of safety, efficacy, and FVIII PD assessments. 
After the safety, efficacy, and FVIII PD analyses at 26 weeks post-BMN 270 infusion, 
long-term safety and efficacy will be assessed in all subjects for up to a total of 5 years 
post-infusion. During the trial, additional subjects may be recruited into each cohort at any 
time, if deemed necessary by the DMC.  
A summary of all assessments is provided in the Schedule of Activities (SoA) in Table 9.1.1,
Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5.
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Table 9.1.1: Schedule of Activities – Screening/Baseline/Day 1
Assessment
Prior to BMN 270 Infusion
BMN 270 
Infusion 
Visit
(Day 1)o
Screening
Smart 
Rescreeningm
(Day -28 to 
Day -1)
Baseline 
(Day -7 to 
Day -1)n
Screening
(Day -42 to 
Day -29)
Screening
(Day -28 to 
Day -1)
Informed consent
X
X
Demographics (age, sex, race, ethnicity)
X
Medical History (including hemophilia A history, Hepatitis B, Hepatitis C, and HIV)
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 useb
X
Electrocardiogram
X
Liver Ultrasound (and FibroScan at discretion of Investigator)c
X
hFVIII Assaysd
X
Xp
X
AAV5 TAb Assay (ARUP)e
X
Xe
X
X
AAV5 TAb Assaysf
X
AAV5 TI Assayf
X
X
Screen for Hepatitis B, Hepatitis C, HIVg
X
SARS-CoV-2 screening (local or central)h
X
X
Blood chemistry, hematology, and coagulation testsi
X
X
X
Blood fasting lipid panel
X
Fasting FibroTest
X
Urine Testsi
X
X
X
Liver Testsi
X
X
X
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Assessment
Prior to BMN 270 Infusion
BMN 270 
Infusion 
Visit
(Day 1)o
Screening
Smart 
Rescreeningm
(Day -28 to 
Day -1)
Baseline 
(Day -7 to 
Day -1)n
Screening
(Day -42 to 
Day -29)
Screening
(Day -28 to 
Day -1)
PBMC collection (for baseline determination of AAV5 and FVIII specific cellular 
immunity)
X
Von Willebrand Factor Antigen (VWF:Ag) 
X
PCR of vector DNA in blood, saliva, urine, semen, and stools
X
Xo
Biomarker testingj
X
Exploratory biomarker assessmentsk
X
X
Cytokine profiling
X
Haemo-QOL-A assessment
X
EQ-5D-5L assessment
X
HAL assessment
X
WPAI+CIQ:HS assessment
X
BMN 270 Infusion
X
Complement panel and exploratory cytokine profilingl
Xl
Hypersensitivity blood assessments
X
(X)q
a Complete physical examination should be done at Screening.  Brief physical examination may be done at Baseline and at the BMN 270 Infusion Visit.
b Diaries should be distributed to subjects who have consented to participate in the study and who have been determined to meet all study eligibility criteria.
c All patients must have a liver ultrasound performed during the Screening period to screen for significant liver disease and hepatocellular carcinoma. A FibroScan may 
also be performed at the discretion of the Investigator.
d Includes baseline FVIII activity (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), coagulation exploratory assay, hFVIII inhibitor level (Bethesda 
assay with Nijmegen modification), hFVIII total antibody titer, and hFVIII antigen assay. Baseline activity should be assessed at trough (at least >72 hours after last 
dose of replacement FVIII therapy, or 5x the known half-life of the FVIII concentrates administered).
e Screening, Smart Re-screening, and Infusion Day samples will be tested using the ARUP AAV5 TAb assay. During Screening, the ARUP AAV5 TAb assay test may be 
done first, under a standalone informed consent form, before the main ICF for the study is signed and further screening procedures are performed. Sample collection on 
the day of the infusion visit must be performed before the BMN 270 infusion is given. If the ARUP AAV5 TAb assay test is done first with the standalone consent, it 
does not need to be repeated as part of regular Screening.
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f Baseline and all post-dose samples will be tested in a different AAV5 TAb post-dose immunogenicity monitoring assay.
g Subjects 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).
hSARS-CoV-2 RT-PCR testing is required during Screening, and all subjects must have at least one negative test result prior to dosing. If the test is performed locally an 
additional 2nd test is recommended, but negative results from the 2nd test must be received prior to dosing. A SARS-CoV-2 vaccine is recommended for subjects if 
indicated and if available. If a two-step SARS-CoV-2 vaccine is being used, sites should consider using the flexible re-screen option to allow subjects to receive both 
doses at least 14 days prior to treatment with BMN 270 (or at least 30 days prior to treatment with BMN 270 for any live-virus vaccines). It is preferable for 
SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. Investigators should use clinical judgment, taking into consideration local factors, individual risk factors, 
and benefit/risk related to timing of vaccine administration.
i Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests.  Urine tests will be performed locally and centrally; all other 
laboratory assessments will be performed at the central laboratory. ABO blood typing assessment should be performed at Baseline, or at another regularly scheduled 
visit prior to the end of the subject’s participation in the study. 
j Includes HLA genotyping and FVIII genotyping.
k 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 those evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or 
try to discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing 
of these samples (including those for any exploratory assessments) will be performed only as deemed necessary by the Sponsor.
l Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and should be collected within 2 hours post-infusion. While exploratory samples for cytokine profiling 
will be collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the Sponsor.
m Smart rescreening should only be performed if a subject 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 (28 + 14 days). SARS-CoV-2 RT-PCR testing is required as part of smart rescreening, and all subjects 
must have at least one negative test result prior to dosing. If the test is performed locally an additional 2nd test is recommended, but negative results from the 2nd test must 
be received prior to dosing. Subjects who undergo smart rescreening must complete the rescreening assessments and receive the infusion within 90 days of signing the 
original consent.  Subjects who do not complete dosing within 90 days will be required to re-consent and undergo all screening procedures.  Subjects may not undergo 
smart rescreening more than once.
n 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.
o With the exception of the collection of samples for PCR vector DNA analysis and the collection of the complement panel/exploratory cytokine profiling sample,
assessments on the day of infusion must be performed prior to the infusion. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of 
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the infusion visit. On the day of the BMN 270 Infusion, vital signs will be monitored prior to the infusion, during the infusion every 15 minutes (± 5 minutes), and 
following the infusion hourly (± 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Shedding samples for PCR of vector DNA analysis (blood, saliva, 
urine, semen, stool) should be collected between 2 and 24 hours after the infusion has been completed.
p Only the hFVIII inhibitor level (Bethesda assay with Nijmegen modification) assay must be done at smart rescreening.
q In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will be done and additional blood samples will be 
collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine profiling, as well as possible additional exploratory testing) 
and samples for IgE and cytokine profiling (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. In addition, a blood sample 
should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine profiling. Exploratory biomarker samples at baseline and at post-infusion study 
visits may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 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 Activities – 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
D2
D4
D8
Study Day*
2
4
8
15
22
29
36
43
50
57
64
71
78
85
92
99
106
113
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
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
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, hematology, and coagulation 
testsb
X
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
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
X
X
X
PCR of vector DNA in blood, saliva, urine, 
semen, and stoolsd
Xd
X
X
X
X
X
X
X
X
X
Exploratory biomarker assessmentse
X
X
X
X
Haemo-QOL-A assessment
X
EQ-5D-5L assessment
X
HAL assessment
X
WPAI+CIQ:HS assessment
X
AAV5 TAb Assay
X
X
X
X
X
X
X
X
X
X
AAV5 TI Assay
X
X
X
X
X
X
X
X
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
D2
D4
D8
Study Day*
2
4
8
15
22
29
36
43
50
57
64
71
78
85
92
99
106
113
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
X
Complement panelh
X
X
X
X
X
X
X
X
X
VWF:Ag 
X
X
X
X
Cytokine profiling
X
X
X
X
X
X
* Visit windows are ± 24 hours during Week 1 and ± 48 hours starting with the Week 2 visit.  
a Brief physical examination should be done at all weekly visits.
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. Urine tests will be performed locally and centrally; all other 
laboratory assessments will be performed at the central laboratory. LTs assessment is weekly, but may be checked more frequently when ALT values are > ULN or ≥ 
1.5x baseline value or based upon discussion between the Medical Monitor and the Investigator.  Subjects with ALT > ULN or ≥ 1.5x baseline value during the study 
and either an alternative etiology considered or for further evaluation of the lab abnormality may undergo additional evaluations (eg, imaging studies including MRI or 
ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the Investigator. Additional testing of FVIII and LTs during any study week may be performed 
if: the ALT has increased to above ULN; or after a discussion between the Medical Monitor and the Investigator based on a review of subject data.  If ALT values are 
stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical Monitor and the 
Investigator. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely 
and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit 
lab kit) at the same time as the local unscheduled sample.
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 antigen assay. Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by 
the Sponsor. If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed FVIII replacement therapy.  If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
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based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels are above the 
normal physiological range and/or if there is a concern for a venous thromboembolism. 
d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained.  Collection and testing of semen samples must continue 
through Week 12, even if 3 consecutive results below the limit of detection in that compartment have already been recorded. Separate collection on Day 2 is not required 
if vector shedding samples were collected on Day 1 post-BMN 270 infusion; if collection on Day 2 is needed, it must occur within 24 hours of the time of the BMN 270
infusion.
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for any exploratory assessments) will be performed only as deemed necessary by the Sponsor.
f Testing for reactivation of hepatitis B and hepatitis C at Week 16, for subjects with a past medical history of hepatitis B or hepatitis C prior to study entry, should be 
performed only in subjects who have not received prophylactic oral corticosteroids; subjects who have received prophylactic oral corticosteroids will have hepatitis B 
and hepatitis C testing at the time points indicated in Table 9.1.6.
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 [or his legally authorized representative, if required] 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 Activities will not be performed at these MN or lab draw-only 
visits.
h Complement panel should include C3, C3a, C4, Bb, and sC5b-9. While exploratory samples for cytokine profiling will be collected at the time points indicated above, 
testing of these samples will be performed only as deemed necessary by the Sponsor.
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Table 9.1.3:  Schedule of Activities – 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
30
31f
32
Study Day*
120
127
134
141
148
155
162
169
176
183
190
197
204
211
218
225
Physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weighta
X
X
X
Assessment of Adverse Events and 
Concomitant Medications  (including 
review of subject diary for bleeding and 
FVIII use)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry, 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
HAL
X
WPAI+CIQ:HS
X
AAV5 TAb Assay
X
X
X
X
X
X
X
X
AAV5 TI Assay
X
X
X
X
X
X
X
X
PBMC collection (for determination of 
AAV5 and FVIII specific cellular 
immunity)
X
X
X
X
X
X
X
X
VWF:Ag
X
X
Cytokine profilingg
X
X
X
X
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* 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, Week 26, and Week 32.
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. Urine tests will be performed locally and centrally; all other 
laboratory assessments will be performed at the central laboratory. LTs assessment may be checked more frequently when ALT values are > ULN or ≥ 1.5x baseline 
value or based upon discussion between the Medical Monitor and the Investigator.  Subjects with ALT > ULN or ≥ 1.5x baseline value during the study and either an 
alternative etiology considered or for further evaluation of the lab abnormality may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, 
additional blood tests, and/or liver biopsy) at the discretion of the Investigator.  Additional testing of FVIII and LTs during any study week may be performed if: the 
ALT has increased to above ULN;; or after a discussion between the Medical Monitor and the Investigator based on a review of subject data.  If FVIII levels and/or ALT 
values are stable over the course of several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical Monitor and 
the Investigator. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate 
timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled 
Visit lab kit) at the same time as the local unscheduled sample
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 antigen assay. Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by 
the Sponsor. If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels are above the 
normal physiological range and/or if there is a concern for a venous thromboembolism. 
d Collection for each matrix to occur until at least 3 consecutive results below the limit of detection are obtained.
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for any 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, and Week 31 may be performed by a mobile nursing (MN) professional at 
the subject’s home or another suitable location (if the subject [or his legally authorized representative, if required] 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 
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MN visits, the service will collect this information. The physical examination and vital signs assessments listed in the Schedule of Activities will not be performed at 
these MN or lab draw-only visits.
g While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples will be performed only as deemed 
necessary by the Sponsor.
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Table 9.1.4:  Schedule of Activities – Post-Infusion Follow-Up (Week 33-52)
Assessment
Year 1 – Weeks*
33e
34
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
X
X
X
X
X
X
X
X
X
X
X
X
Weighta
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
X
X
X
X
X
X
X
X
X
X
X
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
X
X
X
X
AAV5 TI Assay
X
X
X
X
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
X
VWF:Ag
X
X
Cytokine profilingf
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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Assessment
Year 1 – Weeks*
33e
34
35e
36
38e
40
42e
44
46e
48
50e
52
Liver ultrasoundg
X
* Visit windows are ± 48 hours through Week 36, then ±1 week until Week 52.
a Complete physical examination should be performed at Week 52; brief physical exam may be performed at other study visits. Weight should be recorded at Week 36, 
Week 44, and Week 52.
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. LTs assessment may be checked more frequently when ALT 
values are > ULN or ≥ 1.5x baseline value or based upon discussion between the Medical Monitor and the Investigator. Subjects with ALT > ULN or ≥ 1.5x baseline 
value during the study and either an alternative etiology considered or for further evaluation of the lab abnormality  may undergo additional evaluations (eg, imaging 
studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the Investigator. Additional testing of FVIII and LTs during any 
study week may be performed if: the ALT has increased to above ULN or increased by > 10 U/L from prior assessment; or after a discussion between the Medical 
Monitor and the Investigator based on a review of subject data. If FVIII levels and/or ALT values are stable over the course of several weeks, assessment of FVIII 
activity and ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator. In case of a safety concern, additional unscheduled 
laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where possible, a 
matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample.
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor 
level, coagulation exploratory assay, and hFVIII antigen assay. Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by 
the Sponsor. If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval 
without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥5 IU/dL at 16 weeks after BMN 270 infusion and 
who have not resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted 
based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels are above the 
normal physiological range and/or if there is a concern for a venous thromboembolism.
d Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for any exploratory assessments) will be performed only as deemed necessary by the Sponsor.
e The scheduled visits at Week 33, 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 [or his legally authorized representative, if required] 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 
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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 Activities will not be performed at these MN or lab 
draw-only visits.
f While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples will be performed only as deemed 
necessary by the Sponsor.
g Additional liver ultrasounds may be performed prior to Week 52 at the discretion of the Investigator.
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Table 9.1.5:  Schedule of Activities – Long-Term Follow-Up (Year 2 – Year 5)
Assessment
Years 2-5* 
End of Year Visit 
ETV 
Q12W
Q6Wgh 
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
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
FVIII assaysc
X
X
X
X
FVIII antigen assay
X
X
X
AAV5 TAb Assay
X (Year 2 only)
X
X
AAV5 TI Assay
X
X
FVIII antibody titer
X (Year 2 only)
X
X
Exploratory biomarker assessmentse
X
X
X
PBMC Collection 
(for determination of FVIII and Capsid specific cellular immunity)
Xk
X
X
VWF:Ag
X
X
X
Cytokine profilingi
X
X
X
PCR of vector DNA in semend
(X)d
(X)d
(X)d
(X)d
PCR of vector DNA in blood, saliva, urine, and stoolsd
(X)d
(X)d
(X)d
Haemo-QOL-A assessment
Xf
X
EQ-5D-5L
Xf
X
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Assessment
Years 2-5* 
End of Year Visit 
ETV 
Q12W
Q6Wgh 
Year 2 
Year 3 
Year 4 
Year 5 
Study Week*
W104
W156
W208
W260
HAL
Xf
X
WPAI+CIQ:HS
Xf
X
Liver Ultrasoundj
X
X
ETV: Early Termination Visit
* Visit windows are ± 2 weeks for visits in Years 2-5. The Q6W visits during Years 2-5 should restart after each End of Year visit (eg, the first Q6W visit during Year 3 
should be ~6 weeks after the End of Year 2 visit).
a Complete physical examination should be performed at the End of Year visits (genitourinary examination may be deferred); brief physical examination may be 
performed at Q12W 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 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. LT assessment may be checked more frequently when ALT 
values are > ULN or ≥ 1.5x baseline value or based upon discussion between the Medical Monitor and the Investigator. Subjects with ALT > ULN or ≥ 1.5x baseline 
value during the study and either an alternative etiology considered or for further evaluation of the lab abnormality  may undergo additional evaluations (eg, imaging 
studies including MRI or ultrasound, additional blood tests, and/or liver biopsy) at the discretion of the Investigator. Additional testing of FVIII and LTs during any 
study week may be performed if: (1) the ALT has increased to above ULN or increased by > 10 U/L from prior assessment; or (2) after a discussion between the Medical 
Monitor and the Investigator based on a review of subject data. If ALT values are stable over the course of several weeks, assessment of FVIII activity and ALT levels 
may be adjusted based on discussion between the Medical Monitor and the Investigator. During Years 2-5 of the Post-Infusion Follow-Up period, urine tests and blood, 
chemistry, and coagulation tests should be performed at the second Q12W visit each year and at every End of Year visit.
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with Nijmegen modification) for hFVIII inhibitor 
level, and coagulation exploratory assay. Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. If a 
subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII 
use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 5 IU/dL at 16 weeks after BMN 270 infusion and who have not 
resumed FVIII replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on 
discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels are above the normal 
physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests positive in the Bethesda assay (with Nijmegen modification) during 
Years 2-5, a fresh sample should be collected within 4 weeks of the initial visit that had a positive result.
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d Sample testing during Long-Term Follow-Up is not required if at least 3 consecutive samples were below the limit of detection during the Post-Infusion Follow-Up 
period.  Subjects who have not had 3 consecutive semen samples below the limit of detection by Week 52 should continue to have PCR testing of semen every 6 weeks 
during Years 2-5 until 3 consecutive samples below the limit of detection 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, coagulation, and/or AAV gene 
transfer, and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for any exploratory assessments) will be performed only as deemed necessary by the Sponsor.
f PRO assessments during Years 2-5 of Long-Term Follow-up should be performed at every End of Year visit.
g Subjects who meet the definition of treatment failure to BMN 270 therapy after Week 52 (refer to Section 12.6) may omit the Q6W visits during Years 2-5, and must 
attend only the Q12W and End of Year visits. Subjects who are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly follow-up telephone call 
from the site to ask about adverse events, concomitant medications, and bleeding events/FVIII replacement usage. Such subjects following the abbreviated schedule who 
have not yet cleared vector shedding in semen must still provide samples Q6W during Years 2-5 until vector shedding has been cleared (but do not need to do other 
scheduled assessments at those visit dates).
h The scheduled Q6W visits during Years 2-5 may be performed by a mobile nursing (MN) professional at the subject’s home or another suitable location (if the subject
[or his legally authorized representative, if required] 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 Activities will not be performed at these MN or lab draw-only visits.
i While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples will be performed only as deemed 
necessary by the Sponsor.
j Additional liver ultrasounds may be performed at interim timepoints (ie, between the End of Year visits) at the discretion of the Investigator.
k PBMC collection should occur at each Q12W visit during Year 2, then at every other Q12W visit during Years 3-5, as well as at all End of Year Visits for Years 2-5.
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Table 9.1.6:  Suggested Schedule of Activities – Prophylactic Corticosteroids
Assessment
Corticosteroid Treatment Periodb
Post-Corticosteroid Periodc
Day 
1
Week
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
4
13
Prophylactic 
corticosteroid 
dose (mg/day)
40
mg
40
mg
40
mg
40
mg
40
mg
35
mg
35
mg
30
mg
30
mg
25
mg
25
mg
20
mg
20
mg
15
mg
10
mg
5
mg
FVIII activity 
testing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis B 
testingd
X
X
X
HCV Viral 
Loadd
X
X
X
a This table provides an example of a prophylactic corticosteroid course. Clinical judgment, weighing the potential risks and benefits of corticosteroid treatment, should 
always be exercised when considering adjustment of corticosteroid doses, and discussions between the Investigator and Medical Monitor are advised for any questions 
or concerns.
b Following initiation or completion of corticosteroid regimen, if a recurrence of ALT values ≥ ULN or ≥ 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 timing of 
ALT elevation (prior to or after Week 52), as well as possible confounders for the ALT elevation and adverse events related to corticosteroid dosing. Guidance for 
tapering oral corticosteroid dosing can be found in Section 9.4.8.2, although a discussion between the PI and Medical Monitor should take place prior to tapering the 
corticosteroid dose.
c After discontinuation of oral corticosteroids, weekly labs for ALT 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 270-203 is designed to be a Phase 1/2, single-arm, open-label study in hemophilia A 
patients with residual FVIII levels ≤ 1 IU/dL and pre-existing antibodies to the AAV5 vector 
capsid. Hemophilia A patients who provide written informed consent (or who have a legally 
authorized representative provide consent, if required) and meet the entry criteria will be 
eligible to enroll in the study.
Approximately 10 subjects may be enrolled at the 6E13 vg/kg BMN 270 dose.  Subjects will 
be followed for 26 weeks post-BMN 270 infusion during which safety and efficacy 
assessments will be taken. After the final analysis at 26 weeks post-infusion, safety and 
efficacy will then continue to be assessed long-term for approximately a total of 5 years. 
9.3
Selection of Study Population
Approximately 10 hemophilia A patients with residual FVIII levels < 1 IU/dL and 
pre-existing antibodies to the AAV5 vector capsid 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 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. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by 
AAV5 total antibody ELISA
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 
150 exposure days (EDs)
4. Subject must have been on prophylactic FVIII replacement therapy for at least 
12 months prior to study entry.  
5. 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. If the subject is 
unable to provide consent, a legally authorized representative may provide written 
informed consent.
6. 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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7. Sexually active participants must agree to use an acceptable method of effective 
contraception, either double barrier contraception (ie, condom + diaphragm; or 
condom or diaphragm + spermicidal gel or foam) or their female partner either using 
hormonal contraceptives or having an intrauterine device. Participants must agree to 
contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may 
stop contraception use only if they have had 3 consecutive semen samples with viral 
vector DNA below the limit of detection.
8. Willing to abstain from consumption of alcohol 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. Any evidence of active infection, including COVID-19, or any immunosuppressive 
disorder except for HIV infection. HIV-positive patients who meet all other eligibility 
criteria may be included if they have a CD4 count > 200/mm3 and an undetectable 
viral load (unquantifiable viral load as defined as less than the limit of quantification 
by the testing laboratory’s assay is permitted) while receiving an antiretroviral 
therapy (ART) regimen that does not contain efavirenz or another potentially 
hepatotoxic ART.
2. Significant liver dysfunction with any of the following abnormal laboratory results:
x
ALT (alanine aminotransferase) > 1.25x ULN; 
x
AST (aspartate aminotransferase) > 1.25x ULN;
x
GGT (gamma-glutamyltransferase) > 1.25x ULN;
x
Total bilirubin > 1.25x ULN;
x
Alkaline phosphatase > 1.25x ULN; or
x
INR (international normalized ratio) ≥ 1.4
Subjects whose 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.
3. Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as 
rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR 
(Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative 
scale is used.
4. Evidence of any bleeding disorder not related to hemophilia A
5. Platelet count of < 100 x 109/L
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6. Creatinine ≥ 1.5 mg/dL
7. Liver cirrhosis or other clinically significant liver disease of any etiology as assessed
by liver ultrasound/FibroScan. 
8. 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.
9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral 
therapy
10. Active malignancy, except non-melanoma skin cancer
11. History of hepatic malignancy
12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, 
non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial 
embolus), with the exception of catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing. 
13. Known inherited or acquired thrombophilia, including conditions associated with 
increased thromboembolic risk, such as atrial fibrillation.
14. A history of known inflammatory, connective tissue, or autoimmune disorders 
(eg, vasculitis).
15. Treatment with any Investigational Product within 30 days or 5 half-lives of the 
investigational product (whichever is longer) prior to the screening period. For 
subjects who have received a prior investigational product, all ongoing adverse 
events (AEs) experienced while receiving that investigational product must have 
resolved prior to screening for this study
16. Any condition that, in the opinion of the investigator or Sponsor would prevent the 
patient from fully complying with the requirements of the study (including 
corticosteroid treatment and/or use of alternative immunosuppressive agents 
outlined in the protocol) and/or would impact or interfere with evaluation and 
interpretation of subject safety or efficacy result.
17. Prior treatment with any vector or gene transfer agent
18. Major surgery planned in the 52-week period following the infusion with BMN 270
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live 
vaccines within 30 days before the BMN 270 infusion
20. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study that does not interfere with the requirements of 
the current protocol or have the potential to impact the evaluation of safety and 
efficacy of BMN 270 and with prior consultation with the Medical Monitor
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21. Known allergy or hypersensitivity to investigational product formulation
22. Unwilling to receive blood or blood products for treatment of an adverse event 
and/or a bleed
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:
x
Subject requires medication or medical procedure prohibited by the protocol
x
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
x
Subject is lost to follow-up
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, a certified letter should 
be sent to the subject requesting contact with the Investigator. This information should be 
recorded in the study records. 
Subjects may be considered lost to follow-up if the subject has missed 3 consecutive visits in 
the study and has failed to communicate a reason for this to the site. In addition, the site has 
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documented at least 4 attempted contacts by key research personnel to reach the subject 
without success in the following manner:
x
2 attempts by telephone or email (if possible); then
x
If telephone/email contacts are unsuccessful, 2 attempts must be made by certified 
letter or by appropriate local process.
Where communication has been made by phone, this should be documented in the subject 
source notes.
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/EC It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will 
be removed from the study.
9.3.3.1
Study Safety Evaluation Criteria
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC evaluation of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment: 
x
any related SAE;
x
an related AE with a severity > Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.
Additionally, the DMC should consider whether to restrict dosing to subjects with 
anti-AAV5 titers below levels that appear to be causing clinically significant inhibition of 
transduction.  Following a temporary halt of enrolment, the DMC may approve resumption 
of enrolment in either cohort at a later date at its discretion based on further analysis of 
accumulating data.
If a Grade 4 or Grade 5 adverse event assessed as related to study drug occurs in a study 
subject, further enrollment into the trial will be halted until a full safety review of the data by 
the DMC has taken place. Relevant reporting and discussion with the Sponsor and the DMC
will take place before resumption of dosing.
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If any of the following events occur in a subject in the study who has received BMN 270
infusion, further enrollment into the trial will be temporarily put on hold pending prompt 
evaluation by the DMC.  
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 an AE of hepatic failure.
3. The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following
BMN 270 infusion in two subjects.
4. The occurrence of any cancer (except non-melanoma skin cancer) at any point after 
BMN 270 infusion.
5. 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, a prompt 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. Acute hypersensitivity assessed as related to BMN 270
2. The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following 
BMN 270 infusion in one subject
3. Occurrence of a thromboembolic event
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.
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, 26 weeks of Post-Infusion Follow-Up,
and 234 weeks of Long-Term Follow-Up.
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9.4
Treatments
9.4.1
Treatments Administered
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study.  BioMarin is responsible for shipping study drug to clinical sites.
9.4.2
Identity of Investigational Product
9.4.2.1
Product Characteristics and Labeling
BMN 270 is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied 
in a 10 mL Crystal Zenith® (CZ) vial. Each CZ vial contains 8.5 mL (extractable volume 
8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 
7.4 phosphate buffer.
The 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 
therapy will not be given since venipuncture is a minimally invasive procedure in these 
individuals under ordinary conditions.
BMN 270 will be prepared and infused as a pure solution over a dose-dependent time. 
Prepared drug will be kept at room temperature prior to administration. An electric syringe 
pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. 
BMN 270 will be infused through the catheter using an appropriate infusion pump at an 
initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min 
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up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an 
increase. Of note, the IP has been shown to be stable at room temperature for approximately 
10 hours following completion of product thaw. Vital signs (pulse, blood pressure, 
respiration rate and temperature) should be monitored at 15 minute (±5 minutes) intervals 
throughout the 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 (ie, to a slower rate [minimum of 1 mL/min], with 
the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the 
subject’s clinical condition permits such an increase) with careful monitoring of the subject. 
In the event of an infusion rate reaction with more than one dosing interruption, the infusion 
rate would not go beyond 1 mL/min.
In case of hypersensitivity reactions, safety assessment, including physical examination and 
vital signs, will be done and additional blood samples will be collected within 1 hour of the 
hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine profiling, as 
well as possible additional exploratory testing) and samples for IgE and cytokine profiling
(and possible additional exploratory testing) between 8-24 hours after the reaction, if 
possible. In addition, a blood sample should be taken 1 week after the hypersensitivity 
reaction for assessment of the cytokine profiling. Exploratory biomarker samples at baseline 
and at post-infusion study visits may also be used to assess changes in these biomarkers to 
better elucidate the mechanisms of infusion-related hypersensitivity reactions. 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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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 24 hours to 
observe for any immediate toxicity of the procedure; in-patient observation can be extended 
beyond 24 hours if needed per Investigator discretion. After 24 hours, subjects will be 
discharged from the clinic unless toxicity has been observed in which case the stay in the 
clinic may be extended or the subject may transfer to a separate facility based on the 
evaluation and judgment of the Principal Investigator after consultation with the Medical 
Monitor.
Prior to discharging subjects from the clinic, the Investigator or designee should instruct 
subjects how to recognize signs and symptoms of potential (delayed) hypersensitivity 
reactions and anaphylaxis, and to contact a medical practitioner or seek emergency care in 
case of such an event.
9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects who meet all eligibility criteria (refer to Section 9.3.1 and Section 9.3.2) may be 
enrolled into the study. Approval by the Medical Monitor will be required prior to enrollment 
of each study subject. Upon their enrollment into the study, subjects will be assigned a 
unique subject number.
9.4.6
Selection of Dose Used in the Study
Data from an ongoing first in human 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. The 
6E13 vg/kg dose has been selected for this study to maximize the likelihood of transduction 
in the face of pre-existing AAV5 antibodies.
9.4.6.1
Selection of Timing of Dose for Each Subject
9.4.7
Blinding
This is an open-label study.
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9.4.8
Prior and Concomitant Medications
All prescription and over-the-counter medications (including dietary and herbal supplements) 
taken by a subject for 30 days before Screening will be recorded on the designated eCRF. For 
HIV-positive patients, prior to enrollment, the Medical Monitor will review the patient’s 
ART regimen to assess that it does not contain efavirenz or another potentially hepatotoxic 
ART. The Investigator may prescribe additional medications, deemed necessary to provide 
adequate prophylactic or supportive care, during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the Medical Monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
eCRF. Medications should, whenever possible, not be recorded in the electronic database 
with a frequency of as needed (PRN).
The following medications are prohibited starting 30 days before Screening and through the 
end of the study, and the Sponsor must be notified if a subject receives any of these during 
the study:
x
Any investigational therapy other than BMN 270
x
Emicizumab
x
Fitusiran
x
Concizumab
x
Efavirenz
Subjects who begin antiretroviral therapy following BMN 270 infusion and during their 
participation in 270-203 must have their antiretroviral medication regimen approved by the 
Investigator and Medical Monitor prior to starting antiretroviral treatment.
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.
x
Alcohol 
x
Herbal and natural remedies and dietary supplements
x
Medications which may be hepatotoxic, including isotretinoin and 
dextroamphetamine/amphetamine
x
Medications which may reduce or increase the plasma concentration of 
corticosteroids
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Subjects should be counseled to avoid starting potentially hepatotoxic therapies and to inform 
the Investigator of any new medications prescribed by other physicians. Investigators should 
carefully consider both the mechanism of action and potential hepatotoxicity of any new 
medication prior to initiation. If a potentially concerning new medication is started, 
Investigators should closely monitor both FVIII activity and ALT levels (eg, weekly to every 
2 weeks for the first month) in order to determine if any detrimental effects on the efficacy or 
safety of BMN 270 have occurred. If co-medications are required during the course of the 
study, where possible, please check the National Center for Biotechnology Information 
LiverTox website for potential hepatotoxicity issues prior to prescribing (NCBI, 2020).
Vaccines should also be avoided during this period, but in particular during the first 26 weeks 
unless clinically indicated.
It is preferable for SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. If a 
two-step SARS-CoV-2 vaccine is being used, sites should consider using the flexible 
re-screen option to allow subjects to receive both doses at least 14 days prior to treatment 
with BMN 270. If a live-virus SARS-CoV-2 vaccine is being used, subjects should wait at 
least 30 days after vaccination to receive a BMN 270 infusion. Investigators should use 
clinical judgment, taking into consideration local factors, individual risk factors, and the 
benefit/risk related to timing of vaccine administration. Administration of SARS-CoV-2
vaccine after BMN 270 infusion may occur after consultation between Investigator and 
Medical Monitor. 
The following medications should be avoided during oral corticosteroid therapy:
x
Vaccines
x
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 episodic (or “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 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 will be 
collected from subjects for the 12-month period immediately preceding study enrollment.  
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9.4.8.2
Corticosteroid and/or Immunosuppressive Agent Treatment of Elevated 
Hepatic Transaminases
Refer to corticosteroid prescription guidelines for recommended monitoring for, and 
management of, potential side effects of corticosteroids, including guidance on medications 
that should be avoided during corticosteroid treatment. 
9.4.8.2.1
Prophylactic Corticosteroids
All subjects will be started on prophylactic corticosteroids starting on the day of infusion 
(Day 1). Table 9.1.6 provides an example of the recommended prophylactic corticosteroid 
course, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, 
and hepatitis B/hepatitis C reactivation. Clinical judgment, weighing the potential risks and 
benefits of corticosteroid treatment, should always be exercised when considering adjustment 
of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns.
9.4.8.2.2
Reactive Corticosteroids
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels 
become increased (eg, > ULN or ≥ 1.5x baseline value) and alternative etiologies have been 
ruled out, prompt institution of newly administrated or an increased dose of reactive (ie, 
started in response to an ALT elevation) oral corticosteroids (prednisone or converted 
equivalent) should be considered after consultation with the Medical Monitor (refer to 
Error! Unknown switch argument.).
x
Whenever possible, a confirmatory lab draw for ALT should be performed within 
72 hours, along with FVIII activity, prior to initiating reactive oral corticosteroids.
x
Newly administered corticosteroids or dose increases are not indicated if elevations in 
ALT are clearly not related to BMN 270 (eg, elevated ALT with concurrent increase 
in CPK due to intensive exercise) although this should be discussed with the Medical 
Monitor (in particular, for elevations occurring at least 52 weeks after the BMN 270 
infusion).
x
Alternative immunosuppressive agents may also be considered for use on a 
case-by-case basis and following consultation with the Medical Monitor (eg, if 
prolonged corticosteroid use is contraindicated).
Unless otherwise indicated, reactive corticosteroid treatment should be initiated at a dose of 
60 mg/day. If the ALT level remains stable or declines after 2 weeks, consider gradual taper 
of corticosteroids: 40 mg/day for 4 weeks, 30 mg/day for 1 week, 20 mg/day for 1 week, and 
10 mg/day for 1 week. Should a scenario arise in which a deviation from the minimum 
recommended dose and/or duration of reactive corticosteroids may be clinically indicated, a 
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subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse 
events suspected to be caused by or related to corticosteroid/immunosuppressive agent use) 
should be reported as outlined in Section 10 of the protocol.
Subjects on corticosteroids should receive appropriate counselling and support regarding side 
effects from the Investigator or the treating institution (eg, listings of side effects and when to 
notify carers, wallet card for emergencies if on steroids, etc.). Additional management, 
including the co prescription of additional medications to prevent complications related to 
corticosteroid therapy, may be undertaken at the discretion of the investigator, including, but 
not limited to, prophylaxis against the occurrence of gastric ulcers, osteoporosis, and 
infections. The above guidance should also be followed in the event that an alternative 
immunosuppressive agent is used, as applicable.
9.4.8.3
Monitoring of HIV-Positive Subjects
HIV-positive subjects may be enrolled in 270-203 if the subject is well controlled on an ART 
regimen that does not contain efavirenz or another potentially hepatotoxic ART, has a CD4 
count > 200/mm3, and has an undetectable viral load (unquantifiable viral load as defined as 
less than the limit of quantification by the testing laboratory’s assay is permitted).
HIV-positive subjects were initially included in prior BMN 270 studies. However, after an 
HIV-positive subject in 270-302 developed markedly elevated liver enzyme levels after 
receiving 4E13 vg/kg of BMN 270, out of an abundance of caution for the long-term liver 
health of HIV-positive patients, further enrollment of HIV-positive subjects was suspended 
in 270-301 (Protocol Amendment 3) and 270-302 (Protocol Amendment 3). The subject in 
270-302 referenced above was receiving efavirenz and lamivudine as part of his ART 
regimen. Following discussion with a liver advisory board and review of the accumulated 
270-301 data, efavirenz and not lamivudine has been implicated as the most likely 
medication that interacted with BMN 270 and contributed to the 270-302 subject's elevated 
liver enzyme levels. Due to its hepatotoxicity, efavirenz is a prohibited medication in all 
BMN 270 studies.
The two HIV-positive subjects on stable, non-efavirenz-containing ART regimens who were 
enrolled in and dosed in 270-301 study prior to Amendment 3 have been monitored closely. 
Following BMN 270 infusion, these subjects continued their ART as prescribed and followed 
routine monitoring of CD4 count and viral load. Results from 270-301 show similar safety 
results for the two HIV-positive subjects compared to those who are HIV-negative. The 
Sponsor believes that HIV infection, in and of itself, is not a contraindication to receive 
BMN 270 and has therefore removed the exclusion of HIV-positive subjects.
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Subjects should continue ART as prescribed and follow routine monitoring of CD4 count and 
viral load (US Dept Health Human Services 2019). Investigators will continue to monitor 
HIV-positive subjects per routine standard of care.
9.4.9
Treatment Compliance
Study drug will be administered to subjects at 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 
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 Study Pharmacy Manual.
9.6
Dietary or Other Protocol Restrictions
There are no dietary or other protocol restrictions for this study.  Alcohol should be avoided 
starting 30 days prior to and for at least the first 52 weeks of the study, and particularly 
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within 48 hours prior to lab work. Alcohol use should be minimized throughout the 
remaining duration of the study.
Subjects should be advised to abstain from any blood, organ, or sperm donation after 
BMN 270 infusion, until there is no further evidence of vector shedding from PCR analysis 
of samples.
9.7
Efficacy and Safety Variables
9.7.1
Efficacy and Safety Measurements Assessed
The SoA (Table 9.1.1, Table 9.1.2, Table 9.1.3, Table 9.1.4, and Table 9.1.5) describe the 
timing of required evaluations.
9.7.2
Efficacy Variables
9.7.2.1
FVIII Activity
Efficacy (response to treatment) will be defined as FVIII activity ≥5 IU/dL at Week 26
following BMN 270 infusion.
Values for FVIII activity will be excluded from analysis 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.
Note that fluctuations in FVIII activity after gene therapy are common, and more frequent 
monitoring of FVIII activity levels is not needed in the absence of a concurrent or recent 
ALT elevation or upon consultation between the Investigator and the Medical Monitor. 
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
failure to achieve FVIII activity ≥ 5 IU/dL by either Week 26 or Week 52 and inability to 
maintain independence from prophylactic FVIII replacement therapy due to joint bleeding 
episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after 
discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as 
applicable and at the discretion of the Investigator. Subjects who are not attending the Q6W 
visits during Years 2-5 may receive a scheduled monthly follow-up telephone call from the 
site to ask about adverse events, concomitant medications, and bleeding events/FVIII 
replacement usage.  
Details on collecting FVIII activity samples are included in the Laboratory Manual. 
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9.7.2.2
Factor VIII Replacement Therapy/Bleeding Episodes
Additional efficacy variables are:
x
Change of annualized utilization (IU/kg) of exogenous FVIII replacement therapy 
during Week 5 to Week 26 post BMN 270 infusion from the baseline utilization of 
exogenous FVIII replacement therapy. 
x
Change of ABRs requiring exogenous FVIII replacement treatment during Week 5 to 
Week 26 of the study post BMN 270 infusion from the baseline ABR.  
During the study, subjects will be asked at each study visit to report the use of factor 
replacement therapy and the number of bleeding episodes since the previous visit. This 
information will be captured on the subject’s diary or other subject records. Subjects will be 
encouraged to discuss any bleeding episodes with the Investigator and attempt to objectively 
assess any reported bleeds through use of ultrasound or non-invasive imaging.
Subjects are strongly encouraged to immediately consult the Investigator for guidance 
regarding exogenous FVIII administration for suspected bleeds or bleeding episodes within 
the first 6 weeks post BMN 270 infusion.
In subjects who experience recurrent bleeding episodes, the Investigator and Medical 
Monitor will discuss whether to resume prior FVIII prophylaxis.
9.7.2.3
Patient-Reported Outcome (PRO) Measures
The Haemo-QoL-A questionnaire is a validated hemophilia-specific health-related quality of 
life questionnaire for adults (Rentz 2008). It consists of 41 questions covering six domains 
(Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional 
Impact and Treatment Concerns). Items are answered on a 6-point Likert-type scale, ranging 
from 0 (None of the time) to 5 (All of the time).  Higher scores mean better health-related 
quality of life or less impairment for a particular subscale (Haemo-QoL Study Group 2017).
Details regarding the Haemo-QoL-A assessment will be included in the Study Reference 
Manual.
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 Study Reference Manual.
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 
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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 Study 
Reference Manual.
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 Study 
Reference Manual.
9.7.3
Immunogenicity
Immunogenicity assays will be performed on plasma and PBMCs. The assays will include 
detection of anti-AAV5 vector capsid and anti-FVIII total antibodies, as well as 
determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the 
AAV5 vector 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 vector 
capsid-specific cellular immunogenicity. FVIII- and vector capsid-specific cellular immunity 
will be assessed by stimulated cytokine secretion using an ELISpot assay performed on 
collected PBMCs.
9.7.4
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.
9.7.5
Exploratory Assessments
A cytokine profiling assessment will be performed at Baseline and then at the timepoints 
listed in the Schedule of Activities.
In addition, 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, 
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molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, 
and/or AAV5 gene transfer, and to develop assays used for these evaluations. Subject may 
choose to opt out of the exploratory genetic/genomic research being done to study or try to 
discover genes that are not yet known to be associated with hemophilia A.
All biomarker samples collected in this study may be used for exploratory biomarker 
research, including evaluation of additional biomarkers not specifically listed in the protocol.  
In addition, samples collected for other purposes in this study may be used for exploratory 
research once testing for the primary purpose has been completed.
9.7.6
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.
9.7.6.1
Adverse Events
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10.
9.7.6.2
Clinical Laboratory Assessments
The scheduled clinical laboratory tests are listed in Table 9.7.6.2.1. Refer to the Study 
Reference Manual for instructions on obtaining and shipping samples.  Urine tests will be 
performed locally and centrally; all other laboratory assessments will be performed at the 
central laboratory. In case of a safety concern, additional unscheduled laboratory tests may 
be performed locally (at the Investigator’s discretion) in order to facilitate timely and 
appropriate clinical management decisions; where possible, a matched sample for testing at 
the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same 
time as the local unscheduled sample.
Any 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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Table 9.7.6.2.1:  Clinical Laboratory Tests
Blood Chemistry
Hematology
Urine Tests
Coagulation Screen 
including:
Albumin
Hemoglobin
Appearance
APTT
BUN
Hematocrit
Color
PT/INR
Calcium
WBC count
pH
TT
Chloride
RBC count
Specific gravity
Total cholesterol
Platelet count
Ketones
CPK
Differential cell count
Protein
Creatinine
RBC indices 
(MCV and MCH)
Glucose
CRP
Bilirubin
Other Tests:
Glucose
Nitrite
ABO blood typing*
Phosphorus
Urobilinogen
Potassium
Hemoglobin
Total protein
Sodium
Uric Acid
BUN, blood urea nitrogen; CPK, creatinine phosphokinase; CRP, C-reactive protein; PT, prothrombin time; 
APTT, activated partial thromboplastin time; RBC, red blood cell; WBC, white blood cell; TT, thrombin time; 
INR, international normalized ratio; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin.
*ABO blood typing assessment should be performed at Baseline, or at another regularly scheduled visit prior to 
the end of the subject’s participation in the study.
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel 
(including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) will be 
assessed at the BMN 270 infusion visit. Subjects will fast for at least 8 hours prior to 
pre-infusion laboratory sampling on the day of the infusion visit.
In case of hypersensitivity or adverse drug reaction, safety assessment, including physical 
examination and vital signs, will be done and additional blood samples will be collected 
within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and 
cytokine profiling, as well as possible additional exploratory testing) and samples for IgE and 
cytokine profiling (and possible additional exploratory testing) between 8-24 hours after the 
reaction. In addition, a blood sample should be taken 1 week after the hypersensitivity 
reaction for assessment of the cytokine profiling. Exploratory biomarker samples at baseline 
and at post-infusion study visits may also be used to assess changes in these biomarkers to 
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better elucidate the mechanisms of infusion-related hypersensitivity reactions" as described 
in the rationale of changes.
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 (or
his legally authorized representative, if required) gives written informed consent to 
participate in MN visits, the MN network will communicate with the patient and the patient’s 
site. Potential MN visits are designated in the Schedules of Events.
9.7.6.3
Malignancies
A liver ultrasound (and FibroScan, at the discretion of the Investigator) will be performed at 
Screening to screen for HCC. Thereafter, liver ultrasounds will be performed annually at 
each End of Year visit starting at Year 1 (Week 52) through the end of the study to screen for 
HCC. Additional liver ultrasounds may be performed prior to Week 52 and/or between the 
End of Year visits at the discretion of the Investigator.
Any development of a malignancy (except non-melanoma skin cancers) during the course of 
the study will be considered an EOSI (refer to Section 10.2.1) and is subject to expedited 
reporting. In addition, it is recommended that genomic analyses be performed on any 
malignancy (except non-melanoma skin cancers) diagnosed during the course of the study. 
The study site will coordinate sending samples from the malignancy for genomic analyses, if 
available.
9.7.6.4
Liver and Hepatitis Testing
Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C 
infection at Screening; hepatitis B screening should include HBsAg, HBsAb, and HBcAb.   
Subjects with documented results showing an absence of active hepatitis B or hepatitis C 
infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA 
testing for hepatitis C) 30 days prior to providing signed informed consent do not need to 
repeat those tests during the screening period.  
Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with 
history of hepatitis B or hepatitis C infection prior to study entry will be tested for hepatitis B 
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9.7.6.6
Vital Signs, Physical Examinations and Other Observations Related to Safety
Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration 
rate, and temperature. Any clinically significant change in vital signs will be recorded as an 
AE.
Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature 
will be assessed at Screening, Baseline, and at the beginning of each visit during the 
Post-Infusion Follow-Up and 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 should be performed at Screening, Week 26, Week 52, and 
at the End of Year visits. A complete physical examination will include general appearance 
(head, eyes, ears, nose, and throat), cardiovascular, dermatologic, lymphatic, respiratory, 
gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. The genitourinary 
examination may be deferred for visits after Year 1 unless the subject has 
genitourinary-related complaints.
At other visits, brief physical examinations may be performed at the discretion of the 
Investigator based on the subject’s clinical condition. A brief physical examination will 
include general appearance, cardiovascular, dermatologic, respiratory, gastrointestinal, 
musculoskeletal, and neurologic assessments. Particular attention should be given to signs of 
bleeding, as well as assessing possible hemarthroses.
Height will be recorded at Screening only.  Weight will be recorded at Screening and then 
every 4 weeks thereafter through Week 20, at Week 26, Week 32, Week 36, Week 44, and 
Week 52, and then at the second Q12W visit each year and at every End of Year visit during 
Years 2-5.
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 
Activities will not be performed.
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9.7.6.7
Vector Shedding
During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily 
samples to look for evidence of vector shedding for possible viral transmission.  Bodily 
fluids will be tested by polymerase chain reaction (PCR).  Fluids tested will include:
x
Blood
x
Saliva
x
Semen
x
Urine
x
Stool
Vector shedding will also be extensively studied in the present clinical trial, 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. Testing will 
continue until at least 3 consecutive results below the limit of detection are obtained. If a 
positive result is obtained in a matrix after 3 consecutive results below the limit of detection 
have already been recorded, testing in that matrix should restart and continue until an 
additional 3 consecutive results below the limit of detection have been obtained in order to 
confirm clearance.
Testing of semen will continue at least through Week 12, even if 3 consecutive results below 
the limit of detection have been recorded in that compartment prior to that time point.
Subjects who have not had 3 consecutive semen samples below the limit of detection by 
Week 26 should continue to have PCR testing in semen at the timepoints designated in the 
SoA until 3 consecutive samples below the limit of detection are documented (or upon 
consultation between the Investigator and Medical Monitor). Subjects who meet the
definition of treatment failure and wish to follow an abbreviated schedule (refer to 
Section 12.5.3) but who have not cleared vector shedding from a matrix must still provide 
samples for assessment until vector shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 
(during Year 1) and every 6 weeks (for semen samples) or every 12 weeks (for all uncleared 
matrices) during Years 2-5. 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 
analysis (saliva, blood, semen, urine, feces).  Alternatively, the vector DNA characterization 
during shedding analysis may utilize already fractionated exploratory samples obtained from 
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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 below the limit of detection for vector DNA on at least three 
consecutive visits.
Contraception use may need to be extended beyond 12 weeks in individual subjects based on 
observed vector shedding in semen.  After 12 weeks, subjects may stop contraception use 
only if they have had 3 consecutive semen samples below the limit of detection (upon 
consultation between the Investigator and Medical Monitor).
Details for sample collection and storage are provided in the Laboratory Manual.
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10
REPORTING ADVERSE EVENTS
10.1
Safety Parameters and Definitions
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug.
10.1.1 Adverse Events
For this protocol, an adverse event (AE) is any untoward medical occurrence in a subject, 
temporally associated with the use of study intervention, whether or not considered related to 
the study intervention. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention. 
Events meeting the AE definition include:
x
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
x
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
x
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Events not meeting the AE definition include:
x
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.
x
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.
x
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
x
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
x
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:
x
All bleeding events and suspected bleeding events which meet one or more of the 
criteria for being serious (refer to Section 10.1) 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:
x
Results in death
x
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.
x
Requires inpatient hospitalization or prolongation of existing hospitalization
o
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. 
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. 
x
Results in persistent or significant disability or incapacity
x
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy
x
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require medical/surgical intervention to prevent one of the 
other outcomes listed above  (eg, anaphylaxis)
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10.2.1 Events of Special Interest (EOSI)
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, 
irrespective of seriousness, severity or causality: 
x
Elevation of ALT > ULN or ≥1.5x baseline value, regardless of whether that 
elevation triggers an initiation or modification of oral corticosteroid treatment
x
Events potentially meeting the criteria for Hy’s law (ALT or AST elevation ≥ 3x 
ULN plus total bilirubin ≥ 2x ULN)
x
Thromboembolic event
x
Systemic hypersensitivity, anaphylactic, or anaphylactoid reactions (refer to 
Appendix 1)
x
Development of anti-FVIII inhibitory antibodies (inhibitors)
x
Any new diagnosis of malignancy (except non-melanoma skin cancer)
10.3
Methods and Timing for Capturing and Assessing Safety Parameters
10.3.1 Adverse Event Reporting Period
The study AE reporting period is as follows: After informed consent but prior to initiation of 
study drug, only SAEs associated with any protocol-imposed interventions will be collected.
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 10.1.
10.3.2 Eliciting Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences.  The Investigator will record all relevant AE/SAE/EOSI information in the 
subject’s medical record and AE Case Report Form (eCRF).
10.3.3 Assessment of Seriousness, Severity, and Causality
The Investigator responsible for the care of the subject or medically qualified designee will 
assess AEs for severity, relationship to study drug and/or corticosteroids and/or other 
immunosuppressive agents, and seriousness (refer to Section 10.2 for SAE definitions).  
These assessments must be made by a study clinician with the training and authority to make 
a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or DDS).
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x
Similarity to adverse reactions seen with related drug products
x
Abatement of AE with discontinuation of study drug and/or corticosteroids and/or 
other immunosuppressive agents, and/or recurrence of AE with reintroduction of 
study drug and/or corticosteroids and/or other immunosuppressive agents
The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the Investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators and applicable regulatory authorities.
10.4
Procedures for Recording Adverse Events
10.4.1 Recording Adverse Events on a eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on the 
AE eCRF.  Avoid colloquialisms and abbreviations.
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries).
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the AE eCRF, using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology.
10.4.1.1
Diagnosis versus Signs and Symptoms
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. Using accepted medical terminology, 
enter the diagnosis (if known).  If not known, enter sign(s) and/or symptom(s).  If a diagnosis 
subsequently becomes available, then this diagnosis should be entered on the AE (or SAE, as 
appropriate) eCRF, replacing the original entries where appropriate.
10.4.1.2
Persistent or Recurrent Adverse Events
A persistent AE (duration of adverse event > 7 days) is one that extends continuously, 
without resolution, between subject evaluation time points.  Events that change in severity 
necessitate the recording of an additional AE.  AEs that do not have a change in severity 
should be recorded only once on the eCRF.
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs.  All recurrences of the AE should be recorded on the AE eCRF. 
For example, if a subject has an adverse event of ALT increased that subsequently resolves,
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but the subject’s ALT increases again, that should be reported as two adverse events – the
initial ALT increase, and the second ALT increase.  
10.4.1.3
Abnormal Laboratory Values
Laboratory test results (including any local FVIII activity or liver test results) will be 
recorded on the laboratory results pages of the eCRF, or appear on electronically produced 
laboratory reports submitted directly from the central laboratory, if applicable.
Any laboratory result abnormality fulfilling the criteria for a SAE or EOSI should be reported 
as such, and recorded in the AE eCRF unless associated with an AE that has already been 
reported.
Any laboratory result abnormality of CTCAE Grade 4 or 5 should be recorded as an SAE in 
the AE eCRF unless associated with an AE that has already been reported.
A clinical laboratory abnormality is considered clinically significant and should be 
documented as an AE if not refuted by a repeat test to confirm the abnormality and any one 
or more of the following conditions is met:
x
Accompanied by clinical symptoms
x
Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).
x
The abnormality suggests a disease and/or organ toxicity
x
The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc.)
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.
For purposes of this study, laboratory tests showing a decreased level of 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).
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10.4.1.4
Pre-existing Conditions
A pre-existing condition is one that is present prior to administration of BMN 270.  Such 
conditions should be recorded as medical history on the appropriate eCRF.
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period.  It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches).
10.4.1.5
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.4.1.4).  During the study, any new clinically significant 
findings and/or abnormalities discovered on physical examination that meet the definition of 
an AE (or an SAE) must be recorded and documented as an AE or SAE on the AE eCRF.
10.4.1.6
Hospitalization, Prolonged Hospitalization, or Surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.2).
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE.  These scenarios include planned hospitalizations or prolonged 
hospitalizations to:
x
Perform a protocol-mandated efficacy measurement
x
Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not worsened
x
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
x
Receive scheduled therapy (study drug or otherwise) for the study indication
10.4.1.7
Deaths
All deaths that occur during the AE reporting period (refer to Section 10.3.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause of death 
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is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the AE eCRF.
10.4.1.8
Pregnancy
Although not an AE per se, pregnancy in the partner of a subject taking trial medication 
should be reported expeditiously to the Sponsor to facilitate outcome monitoring by the 
Sponsor.  Pregnancy in partner should be reported during the period up to 5 years after viral 
infusion.
Pregnancy in a partner should be reported within 24 hours of the site becoming aware of the 
pregnancy by entering the information on the Pregnancy eCRF and submitting to 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 
unexpected fatal or life-threatening unexpected suspected adverse reactions (SUSARs) and 
within 15 calendar days for other non-life-threatening SUSARs.
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.
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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 (EC) or Institutional Review Board 
(IRB) will be done in compliance with the standard operating procedures and policies of the 
IRB/EC and with applicable regulatory requirements. Adequate documentation must be 
obtained by BioMarin showing that the IRB/EC 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 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study. 
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2 7 0- 2 0 3 A me n d me nt 4
Pa ge 9 4
Pr o prietar y a n d C o nfi de ntial
4 A u g ust 2 0 2 1
1 0. 8  
Ur ge nt S af et y Me as ures
T he re g ulati o ns g o ver ni n g cli nic al trials state t hat t he S p o ns or a n d I n vesti gat or are re q uir e d 
t o ta ke a p pr o pri ate ur ge nt safet y meas ur es t o pr otect s u bjects a gai nst a n y i m me diate hazar ds 
t hat ma y affect t he safet y of s u bjects, a n d t hat t he a p pr o priate re g ulat or y b o dies s h o ul d be 
n otifie d acc or di n g t o t heir res pecti ve re g ul ati o ns. Acc or di n g t o t he E ur o p ea n U ni o n ( E U) 
Cli nical Trial Directi ve 2 0 0 1/ 2 0/ E C, “ …i n t he li g ht of t h e circ u msta nces, n ota bl y t he 
occ urre nce of a n y n e w e ve nt relati n g t o t he c o n d u ct of t he trial or t he d e vel o p me nt of t he 
i n vesti gati o nal me dici nal pr o d uct w here t hat ne w e ve nt is li kel y t o affect t he safet y of t h e 
patie nts, t he S p o ns or a n d t he I n v esti gat or s hall ta k e a p pr o pri ate ur ge nt s afet y me as ures t o 
pr otect t he patie nts a gai nst a n y i m me diate h azar d. T he S p o ns or s hall f ort h wit h i nf or m t he 
c o m pete nt a ut h orities of t h ose ne w e ve nts a n d t he meas ures ta k e n a n d s hall e ns ure t hat t he 
I R B/ E C is n otifie d at t he sa me ti me.” 
T he re p orti n g peri o d f or t hese e ve nts w hi c h ma y re q uire t he i m ple me ntati o n of ur ge nt safet y 
meas ures is t he peri o d fr o m t he ti me of si g ni n g of t he I C F t hr o u g h t he c o m pleti o n of t he last 
st u d y visit or at t he Earl y Ter mi nati o n Visit ( E T V). I n vesti gat ors are re q uir e d t o re p ort a n y 
e ve nts w hic h ma y re q uir e t he i m ple me ntati o n of ur ge nt safet y me as ures t o Bi o Mari n wit hi n 
2 4 h o urs of bec o mi n g a w are of t h e e ve nt.
E x a m ples of sit uati o ns t hat ma y re q uir e ur ge nt safet y me as ures i ncl u d e disc o ver y of t h e 
f oll o wi n g:
Lac k of st u d y scie ntific v al ue, or detri me nt al st u d y c o n d uct or ma na ge me nt
Disc o ver y t hat t he q u alit y or s afet y of t h e I P d oes n ot meet esta blis he d safet y 
re q uire me nts
1 0. 9 
Bi o M ari n P h ar m ac o vi gil a nce C o nt act I nf or m ati o n
C o ntact i nf or mati o n f or Bi o Mari n P har mac o vi gila nce is as f oll o ws:
Bi o Mari n P har mace utical I nc.
A d dress 
1 0 5 Di gital Dri ve
N o vat o, C A 9 4 9 4 9
P h o ne:
Fa x:
E- mail: 
dr u gs afet y @ b mr n. c o m
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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.
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12
STUDY PROCEDURES
12.1
Prestudy
An ICF must be signed and dated by the subject (or the subject’s legally authorized 
representative), the Investigator or designee and witness (if required) before any 
study-related procedures are performed.
12.2
Screening Visit(s)
Screening assessments should be performed within 42 days of BMN 270 infusion, while 
baseline assessments will take place within 7 days prior to BMN 270 infusion (Day 1).
Should the screening visit occur within 30 days of the drug infusion, physical examination, 
vital signs, blood chemistry, LTs, hematology, urine tests, and coagulation tests do not need 
to be repeated at Baseline.
During the first part of the Screening Period (Day -42 to Day -29), testing for AAV5 TAb 
titers using the ARUP screening assay may be performed, so that subjects can verify their 
AAV5 TAb status. Subjects who agree to participate in this activity (or their legally 
authorized representative) will be asked to sign a separate ICF documenting this decision.
Subjects who do not agree will have the ARUP AAV5 TAb screening assay performed along 
with other assessments during the regular Screening period.
The following procedures will be performed during the Screening Period (Day -28 to 
Day -1):
x
Demographics (age, sex, race, ethnicity)
x
Full medical history, including hemophilia A history, Hepatitis B, Hepatitis C, and 
HIV. Subjects with a history of hepatitis B, hepatitis C, or HIV will be asked for 
information about the treatments received. Any prior pharmacokinetics information 
obtained while the subject was receiving prophylactic or episodic FVIII therapy prior 
to the study should also be collected.
x
Complete Physical Examination 
x
Height and weight
x
Vital Signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature) 
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information) for the previous 12 months
x
Distribution of subject diaries and training in diary completion
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x
Electrocardiogram
x
Liver ultrasound to screen for hepatocellular carcinoma and clinically significant liver 
disease (FibroScan can be performed additionally at the discretion of the Investigator)
x
Samples for hFVIII Assays
o
Baseline FVIII activity – chromogenic substrate FVIII assay
o
Baseline FVIII activity level – one-stage clotting FVIII assay
o
hFVIII coagulation activity exploratory assay (collected but not tested 
prior to enrollment)
o
hFVIII inhibitors (Bethesda assay with Nijmegen modification)
o
hFVIII total antibody assay (collected but not tested prior to enrollment)
o
hFVIII antigen assay (collected but not tested prior to enrollment)
x
Blood sample for ARUP AAV5 TAb assay
o
Subjects who underwent the ARUP AAV5 TAb assay test earlier in the 
Screening period with the standalone consent do not need to repeat the test 
as part of regular Screening.
x
Screen for Hepatitis B, Hepatitis C, and HIV if required (subjects with documented 
negative results 30 days prior to informed consent being obtained do not need to be 
retested)
o
Hepatitis B screening should include HBsAg, HBsAb, and HBcAb
x
SARS-CoV-2 screening (local or central testing)
o
SARS-CoV-2 RT-PCR testing is required during Screening, and all 
subjects must have at least one negative test result prior to dosing. If the 
test is performed locally an additional 2nd test is recommended, but 
negative results from the 2nd test must be received prior to dosing. A
SARS-CoV-2 vaccine is recommended for subjects if indicated and if 
available (refer to Section 9.4.8 for vaccine guidance).
x
Fasting FibroTest
o
Subjects will fast for at least 8 hours prior to sampling on the day of the 
FibroTest Screening visit. Fasting FibroTest results must be available prior 
to BMN 270 infusion.
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1)
x
Urine Tests (refer to Table 9.7.6.2.1)
x
Liver Tests (refer to Table 9.7.6.4.1)
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x
Blood samples for Biomarker testing (may include 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:
x
Vital signs
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
x
hFVIII Assays (only the hFVIII inhibitor level (Bethesda assay with Nijmegen 
modification))
x
AAV5 TAb assay (ARUP)
x
SARS-CoV-2 screening (local or central testing)
o
SARS-CoV-2 RT-PCR testing is required during smart rescreening, and 
all subjects must have at least one negative test result prior to dosing. If 
the test is performed locally an additional 2nd test is recommended, but 
negative results from the 2nd test must be received prior to dosing. A
SARS-CoV-2 vaccine is recommended for subjects if indicated and if 
available (refer to Section 9.4.8 for vaccine guidance).
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1)
x
Urine Tests (refer to Table 9.7.6.2.1)
x
Liver Tests (refer to Table 9.7.6.4.1)
12.3
Baseline Visit
Baseline values will be recorded from 1 to 7 days prior to the infusion visit.  The following 
procedures will be performed during the Baseline Period:
x
Brief physical examination
x
Vital signs
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x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
x
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 antigen assay
x
Von Willebrand Factor Antigen (VWF:Ag) 
x
Blood sample for AAV5 Total Antibody assay
o
Baseline sample will be tested with a AAV5 TAb post-dose 
immunogenicity monitoring assay
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1)
o
ABO blood typing assessment should be performed at Baseline, or at 
another regularly scheduled visit prior to the end of the subject’s 
participation in the study.
x
Urine Tests (refer to Table 9.7.6.2.1)
x
Liver Tests (refer to Table 9.7.6.4.1)
x
PBMC collection for CTL baseline
x
Blood sample for AAV5 TI assay
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
x
Exploratory biomarker assessments
x
Cytokine profiling
x
Hypersensitivity blood assessments
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
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12.4
Treatment Visit/BMN 270 Infusion Visit (Day 1)
There will be one infusion visit for each subject.  Subjects will remain in the clinic for at 
least 24 hours for the BMN 270 Infusion Visit.  The following procedures will be performed 
during the BMN 270 Infusion Visit:
x
Brief physical examination (pre-infusion)
x
Start prophylactic corticosteroids (pre-infusion)
x
Assessment of Adverse Events and Concomitant Medications (pre-infusion)
x
AAV5 TAb assay (ARUP) (sample collected pre-infusion for analysis)
x
Blood sample for AAV5 TI assay (sample collected pre-infusion for analysis)
x
Fasting blood sample for future exploratory analysis (sample collected pre-infusion)
x
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.
x
BMN 270 Infusion
x
Complement panel and exploratory cytokine profiling
o
Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and 
should be collected within 2 hours post-BMN 270 infusion.
x
Vital Signs
o
Vital signs will be recorded prior to BMN 270 infusion and then every 
15 minutes (± 5 minutes) during BMN 270 infusion.  Following infusion, 
vital signs will be monitored every 1 hour (± 5 minutes) for at least 
8 hours during the subject’s stay in the clinic.
x
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 
within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9, and 
cytokine profiling, as well as possible additional exploratory testing) and samples for IgE and 
cytokine profiling (and possible additional exploratory testing) between 8-24 hours after the 
reaction, if possible. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine profiling . In-patient observation can 
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be extended and additional blood samples can be collected if deemed necessary at the 
discretion of the Investigator and Medical Monitor. Exploratory biomarker samples at 
baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" 
as described in the rationale of changes.
Subjects should also start prophylactic corticosteroids, prior to BMN 270 infusion, on Study 
Day 1 (refer to Table 9.1.6 for a possible prophylactic corticosteroid regimen, and to 
Section 9.4.8.2 further discussion). Clinical judgment, weighting the potential risks and 
benefits of corticosteroid treatment, should always be exercised when considering adjustment 
of corticosteroid doses. Discussions between the Investigator and Medical Monitor are 
advised for any questions or concerns.
12.5
BMN 270 Infusion Follow-Up Visits
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 (or
his legally authorized representative, if required) gives written informed consent to 
participate in MN visits, the MN network will communicate with the patient and the patient’s 
site. Potential MN visits are designated in the Schedules of Events.
12.5.1 Week 1
During Week 1, the subject will be assessed on Study Day 2, Study Day 4, and Study Day 8.
12.5.1.1
Week 1, Study Day 2
On Study Day 2, the following assessments will be performed:
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.4.1)
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x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Separate collection on Day 2 is not required if vector shedding samples 
were collected on Day 1 post-BMN 270 infusion; if collection on Day 2 is 
needed, it must occur within 24 hours of the time of the BMN 270
infusion.
x
Blood sample for AAV5 TAb Assay
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay
x
Blood sample for AAV5 TI assay
x
PBMC collection
x
Complement panel
o
Complement panel should include C3, C3a, C4, Bb, and sC5b-9.
x
Cytokine profiling
12.5.1.2
Week 1, Study Day 4
On Study Day 4, the following assessments will be performed:
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.4.1)
x
Complement panel
o
Complement panel should include C3, C3a, C4, Bb, and sC5b-9.
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
12.5.1.3
Week 1, Study Day 8
On Study Day 8, the following assessments will be performed:
x
Brief physical examination
x
Assessment of Adverse Events and Concomitant Medications
x
Vital Signs
x
Liver Tests (refer to Table 9.7.6.4.1)
x
Blood sample for AAV5 TAb Assay
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay
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x
Blood sample for AAV5 TI assay
x
Samples for FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
hFVIII antigen assay
x
Complement panel
o
Complement panel should include C3, C3a, C4, Bb, and sC5b-9.
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
x
Cytokine profiling
12.5.2 Weeks 2-26
After Week 1 (Day 8), subjects will return to the study site once a week (± 48 hours) during 
Weeks 2-26.
12.5.2.1
Once per week (Weeks 2 through 26)
The following procedures will be performed once per week from Weeks 2 through 26:
x
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.
x
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.
x
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.
x
Liver Tests (refer to Table 9.7.6.4.1)
o
LT assessment may be checked more frequently when ALT values are > 
ULN or ≥ 1.5x baseline value or based upon discussion between the 
Medical Monitor and the Investigator.
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x
Samples for FVIII Assays
o
FVIII activity level (chromogenic substrate FVIII assay)
o
FVIII activity level (one-stage clotting FVIII assay)
o
FVIII coagulation activity exploratory assay
o
Bethesda assay (with Nijmegen modification) for hFVIII inhibitor level
o
hFVIII antigen assay
12.5.2.2
Every Other Week (Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26)
The following procedures will be performed every other week (at Weeks 2, 4, 6, 8, 10, 12, 
14, 16, 18, 20, 22, 24, and 26):
x
Blood sample for AAV5 TAb Assay
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay
x
Blood sample for AAV5 TI assay
x
PBMC collection
12.5.2.3
Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26
The following procedure will be performed at Weeks 2, 3, 4, 6, 8, 12, 16, 20, 24, and 26:
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Collection to occur until at least 3 consecutive results below the limit of 
detection are obtained.  Semen samples should continue to be collected and 
tested through Week 12, even if 3 consecutive results below the limit of 
detection in that compartment have been recorded prior to that time point.
12.5.2.4
Weeks 2, 4, 6, 8, 10, and 12
The following procedure will be performed at Weeks 2, 4, 6, 8, 10, and 12:
x
Complement panel
o
Complement panel should include C3, C3a, C4, Bb, and sC5b-9.
12.5.2.5
Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 26
The following procedure will be performed at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 26:
x
hFVIII total antibody assay
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12.5.2.6
Weeks 2, 4, 6, 8, 14, 20, and 26
The following procedure will be performed at Weeks 2, 4, 6, 8, 14, 20, and 26:
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1)
12.5.2.7
Weeks 2, 6, 10, 14, 18, 22, and 26
The following procedure will be performed at Weeks 2, 6, 10, 14, 18, 22, and 26:
x
Exploratory biomarker assessments
12.5.2.8
Weeks 2, 6, 10, 14, 20, 24, and 26
The following procedure will be performed at Weeks 2, 6, 10, 14, 20, 24, and 26:
x
Cytokine profiling
12.5.2.9
Weeks 4, 8, 12, 16, 20, and 26
The following procedures will be performed at Weeks 4, 8, 12, 16, 20, and 26:
x
Weight
x
VWF:Ag 
12.5.2.10 Weeks 12 and 26
The following procedures will be performed at Weeks 12 and 26:
x
Urine tests (to be performed locally)
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
12.5.2.11 Week 16
The following procedure will be performed at Week 16:
x
Testing for reactivation of hepatitis B and hepatitis C (only in subjects with evidence 
of prior exposure to hepatitis B and/or hepatitis C)
o
Subjects who receive reactive 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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12.5.3 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).  At these visits, the following procedures will be completed: 
12.5.3.1
Every Visit
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures 
will be performed:
x
Physical examination
o
Brief physical examination should be performed at all weeks except 
Week 52, 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.
x
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.
x
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.
x
Liver Tests (refer to Table 9.7.6.4.1)
o
LT assessment may be checked more frequently when ALT values are > 
ULN or ≥ 1.5x baseline value or based upon discussion between the 
Medical Monitor and the Investigator.
x
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 antigen assay 
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12.5.3.2
Weeks 28, 30, 32, 34, 36, 40, 44, 48, and 52
At Weeks 28, 30, 32, 34, 36, 40, 44, 48, and 52, the following procedures will be performed:
x
AAV5 TAb Assay
x
AAV5 TI Assay
12.5.3.3
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:
x
PBMC collection
12.5.3.4
Weeks 32, 36, 44, and 52
At Weeks 32, 36, 44, and 52, the following procedures will be performed:
x
Weight
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1)
x
FVIII antibody titer
x
Cytokine profiling
12.5.3.5
Weeks 32, 36, 40, 44, 48, and 52
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed:
x
Exploratory biomarker assessments
x
PCR of vector DNA in blood, saliva, urine, semen, and stools
o
Sample testing to occur until at least 3 consecutive sample below the limit of 
detection results have been obtained. Subjects who have not had 
3 consecutive semen samples below the limit of detection by Week 52 should 
continue to have PCR testing of semen every 6 weeks until 3 consecutive 
samples below the limit of detection are documented (or upon consultation 
between the Investigator and Medical Monitor).
o
Subjects considered to be treatment failures must continue to provide samples 
for PCR assessment at these timepoints until vector shedding has cleared (in 
such a case, these subjects do not need to perform other assessments except 
for PCR sample delivery scheduled at these timepoints)
12.5.3.6
Week 36 and 52
At Weeks 36 and 52, the following procedures will be performed:
x
Urine Tests (refer to Table 9.7.6.2.1)
x
VWF:Ag
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12.5.3.7
Week 52
At Week 52, the following procedures will be performed:
x
Liver ultrasound
o
Additional liver ultrasounds may be performed prior to Week 52 at the 
discretion of the Investigator.
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
HAL
x
WPAI+CIQ:HS
12.6
Post-Infusion Follow-Up – Years 2-5
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as 
failure to achieve FVIII activity ≥5 IU/dL by Week 52 and inability to maintain 
independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in 
the judgment of the Investigator) may, at the Investigator’s discretion and after discussion 
with the Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by 
attending only the Q12W and End of Year visits during Years 2-5.
Subjects who meet the definition of treatment failure and wish to follow an abbreviated 
schedule but who have not cleared vector shedding from semen must still provide semen 
samples for assessment every 6 weeks during Years 2-5 until vector shedding has cleared 
(but do not have to perform other scheduled assessments at those study visits). Subjects who 
are not attending the Q6W visits during Years 2-5 may receive a scheduled monthly 
follow-up telephone call from the site to ask about adverse events, concomitant medications, 
and bleeding events/FVIII replacement usage.  
During Years 2-5 of Post-Infusion Follow-up, the following procedures will be completed:
12.6.1 Years 2-5 – Every 6 Weeks (not required for treatment failure)
During Years 2-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
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.
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x
Liver Tests (refer to Table 9.7.6.4.1)
o
LT assessment may be checked more frequently when ALT values are > 
ULN or ≥ 1.5x baseline value or based upon discussion between the 
Medical Monitor and the Investigator.
x
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 2-5, a fresh sample should be collected within 
4 weeks of the initial visit that had a positive result.
x
PCR of vector DNA in semen (if required)
o
Sample testing during Years 2-5 is not required if at least 3 consecutive 
samples are clear by the end of Year 1.  Subjects who have not had 
3 consecutive semen samples below the limit of detection by the end of Year 1
should continue to have PCR testing of semen every 6 weeks during Years 2-5
until 3 consecutive samples below the limit of detection are documented (or 
upon consultation between the Investigator and Medical Monitor).
o
Subjects who meet the definition of treatment failure and wish to follow 
an abbreviated schedule but who have not cleared vector shedding from 
semen must still provide semen samples for assessment every 6 weeks 
during Years 2-5 until vector shedding has cleared (in such a case, these 
subjects do not need to perform other assessments except for PCR sample 
delivery scheduled at these timepoints).
12.6.2 Years 2-5 – Every 12 Weeks and End of Year Visits (required for all subjects)
During Years 2-5, subjects will be asked to return to the study site for visits at the following 
study weeks (±2 weeks):
x
Year 2 – Week 64, Week 76, Week 88, Week 104
x
Year 3 – Week 116, Week 128, Week 140, Week 156
x
Year 4 – Week 168, Week 180, Week 192, Week 208
x
Year 5 – Week 220, Week 232, Week 244, Week 260
For each of these years, the last study visit listed (Week 104, Week 156, Week 208, and 
Week 260) will serve as an End of Year visit.
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At the every 12 week and End of Year visits, the following procedures will be performed:
x
Brief physical examination (at every 12 week visits) or complete physical 
examination (at End of Year visits; genitourinary examination may be deferred)
x
Weight (at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
x
Assessment of Adverse Events and Concomitant Medications (including review of 
subject diary for bleeding and FVIII use)
x
Liver Tests (refer to Table 9.7.6.4.1)
o
LT assessment may be checked more frequently when ALT values are > 
ULN or ≥ 1.5x baseline value or based upon discussion between the 
Medical Monitor and the Investigator.
x
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 2-5, a fresh sample should be collected within 
4 weeks of the initial visit that had a positive result.
x
FVIII antigen assay 
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1)
(at Week 76, Week 128, Week 180, Week 232, and End of Year visits only)
x
Urine Tests (refer to Table 9.7.6.2.1 ) (at Week 76, Week 128, Week 180, Week 232,
and End of Year visits only)
x
Vital Signs
x
AAV5 TAb Assay (at Week 64, Week 76, Week 88, Week 104, then at End of Year 
visit for Years 3-5)
x
AAV5 TI Assay (at End of Year visit for Years 2-5 only)
x
FVIII antibody titer (at Week 64, Week 76, Week 88, Week 104, then at End of Year 
visit for Years 3-5)
x
Haemo-QoL-A assessment (at End of Year visits only)
x
EQ-5D-5L (at End of Year visits only)
x
HAL (at End of Year visits only)
x
WPAI+CIQ:HS (at End of Year visits only)
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x
Exploratory biomarker assessments
x
Cytokine profiling
x
PBMC collection (at Week 64, Week 76, Week 88, Week 104, Week 128, Week 156, 
Week 180, Week 208, Week 232, and Week 260)
x
VWF:Ag
x
Liver ultrasound (at End of Year visits only)
o
Additional liver ultrasounds may be performed at interim time points (ie, 
between the End of Year visits) at the discretion of the Investigator.
x
PCR of vector DNA in blood, saliva, urine, semen, and stools (if required)
o
Sample testing during Years 2-5 is not required if at least 3 consecutive
samples are below the limit of detection during the Post-Infusion Follow-Up 
period in Weeks 1-52.
12.7
Early Termination Visit
The Early Termination visit will occur on the date the subject withdraws from the study, even 
if the date does not correspond to a protocol-specific visit.
If a subject leaves the study prior to the Week 260 visit, the subject will be asked to return to 
the study site and complete an Early Termination visit. At the Early Termination visit, as 
many of the following assessments as possible should be done:
x
Complete physical examination
x
Weight
x
Assessment of Adverse Events and Concomitant Medications
x
Documentation of bleeding episodes and FVIII usage (by either subject or clinical 
information)
x
Vital signs
x
Blood chemistry, hematology, and coagulation tests (refer to Table 9.7.6.2.1)
x
Urine Tests (refer to Table 9.7.6.2.1)
x
Liver Tests (refer to Table 9.7.6.4.1)
x
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
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o
hFVIII inhibitors (Bethesda assay with Nijmegen modification)
o
hFVIII antigen assay 
x
hFVIII total antibody assay
x
Exploratory biomarker assessments
x
Blood sample for AAV5 Total Antibody assay
o
Sample will be tested with a AAV5 TAb post-dose immunogenicity 
monitoring assay
x
Blood sample for AAV5 TI assay
x
Cytokine profiling
x
PBMC collection
x
VWF:Ag 
x
Liver ultrasound
x
Haemo-QoL-A assessment
x
EQ-5D-5L
x
Hemophilia Activities List (HAL)
x
Work Productivity and Activity Impairment plus Classroom Impairment Questions: 
Hemophilia Specific (WPAI+CIQ:HS) questionnaire
x
PCR of vector DNA in blood, saliva, urine, semen, and stool
o
Sample testing at the Early Termination Visit is not required if at least 
3 consecutive samples are clear during the period of the subject’s 
participation in the study.
12.8
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, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records. 
Sites will enter study data into eCRFs into the study EDC system.  Data Quality Control will 
be performed by BioMarin Clinical Data Management or designee through implementation 
of quality control checks specified in the study data management plan and edit check 
specifications. 
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. Unless otherwise stated, all analyses will be performed using SAS.
14.1.1 Interim Analyses
No interim analysis is planned.
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort should be made to ensure complete, accurate, and timely data collection 
and, therefore, avoid missing data.
Sensitivity analyses will be conducted to assess the impact of missing data on the primary 
efficacy endpoint analysis. Additional details regarding the handling of missing data will be 
provided in the SAP.
14.2
Efficacy Analysis
The subjects will be followed in a longitudinal manner, and all the relevant information will 
be collected. The analysis of the data will be descriptive in nature, but data collected in a 
longitudinal manner may be analyzed using longitudinal methods, such as mixed effect 
model, which take into account the correlation among the observations taken at various time
points within a subject. Efficacy is a secondary endpoint, defined as biologically active FVIII 
at ≥ 5 IU/dL at 26 weeks following study treatment. We can only assess the true steady state 
of FVIII produced from BMN 270 after a minimum of 72 hours (or 5x the known half-life of 
the FVIII replacement therapy administered) has elapsed since the last infusion of FVIII 
concentrates.
14.3
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. 
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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. 
Analysis of neutralizing antibody response and other immunological parameters as well as 
vector shedding will be primarily descriptive and involve both inter-subject and intra-subject 
comparisons across doses. 
Detailed statistical methods will be provided in the SAP.
14.4
Determination of Sample Size
The sample size is based upon clinical considerations and is sufficient to detect a strong 
clinical efficacy signal. Approximately 10 subjects may be dosed in the study.
14.5
Analysis Populations
The efficacy analysis set will be comprised of all subjects who have received the BMN 270
infusion.
The safety population will consist of all subjects who receive BMN 270 infusion during the 
study.
14.6
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/EC must be sought, and 
the Investigator should inform BioMarin and the full IRB/EC within 2 working days after the 
emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/EC 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/EC 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/EC, and 
all active subjects (or their legally authorized representative, if required) must again provide 
informed consent.
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DATA MONITORING COMMITTEE
The Data Monitoring Committee (DMC) will consist of experts in clinical trials, statistics, 
and hemophilia. The DMC will review available safety and efficacy data during the study on 
an ongoing basis to determine, based on emerging data and the benefit/risk profile, whether 
further enrollment should continue. 
Duties of the DMC include:
x
Conducting an ongoing review of individual subject safety and efficacy data during 
the study;
x
Recommending whether to proceed with enrollment of subjects at a different gating 
schedules based on emerging data from 270-203 and the overall risk/benefit analysis 
of BMN 270;
x
If applicable, considering whether to restrict dosing to subjects with anti-AAV5 titers 
below levels that appear to be causing clinically significant inhibition of transduction.
x
Making other recommendations on the conduct and reporting of the trial based on 
their evaluation of clinical data including institution of any pause or stopping stages.
Guidance on proceeding from Cohort 1 to Cohort 2 and completion of each cohort will be 
based on DMC determination of safety and efficacy in treated subjects with the following 
triggers for pausing further enrollment: 
x
any related SAE;
x
any related AE with a severity > Grade 3; or 
x
FVIII activity < 5% in at least 2/3 subjects after a minimum of 6 weeks 
post-BMN 270 infusion.
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COSTS, COMPENSATION, AND SUBJECT INJURY
BioMarin will pay the full costs of the study-related tests, procedures, and treatments set 
forth in the protocol. In addition, after IRB/EC approval, BioMarin may reimburse the 
reasonable cost of travel for study-related visits in accordance with BioMarin’s travel and 
reimbursement policy.
The Investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the study drug or by procedures performed as part of the study. Any 
subject who experiences a study-related injury should be instructed by the Investigator to 
seek immediate medical treatment at a pre-specified medical institution if possible, or at the 
closest medical treatment facility if necessary. The subject should be given the name of a 
person to contact to seek further information about, and assistance with, treatment for 
study-related injuries. BioMarin or the institution may pay for reasonable and necessary 
medical services to treat the injuries caused by the study drug or study procedures. In some 
jurisdictions, BioMarin is obligated by law to pay for study-related injuries. If this is the case, 
BioMarin will comply with the law. BioMarin will not pay for any hospitalizations, tests, or 
treatments for medical problems of any sort related solely to the study subject’s primary 
disease or any concurrent disease that are unrelated to this study.
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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 (or their legally authorized 
representative) must also allow access to their medical records, and subjects (or their legally 
authorized representative) 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. 
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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 
source data verified.  The Data Manager, or designee, will set the status of the forms, visits, 
and the entire casebook to Locked. The Investigator will then electronically sign the 
casebook, specifying that the information on the eCRFs is accurate and complete. Upon 
completion of the CSR, an electronic copy of each site’s casebooks will be copied to a 
compact disk (CD) and sent to each site for retention with other study documents.
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STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
Investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees. When in person site 
monitoring or source data verification cannot be conducted, remote site monitoring and/or 
source data verification will be conducted where allowed by country and local health 
authorities and ECs/IRBs.
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify BioMarin 
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files.
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RETENTION OF RECORDS
The Investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The Investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The Investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by a BioMarin agreement. BioMarin must be notified and will 
assist with retention should Investigator /institution be unable to continue maintenance of 
subject files for the full 15 years. It is the responsibility of BioMarin to inform the 
Investigator /institution as to when these documents no longer need to be retained.
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USE OF INFORMATION AND PUBLICATION
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable, peer-reviewed scientific journals and at 
seminars or conferences. The details of the processes of producing and reviewing reports, 
manuscripts, and presentations based on the data from this study will be described in the 
Clinical Trial Agreement between BioMarin and the Investigator/Institution. Consideration 
for authorship of all publications will be based on compliance with the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) 
of the International Committee of Medical Journal Editors (ICMJE) 
(http://www.icmje.org/ethical_1author.html) and good publication practices (GPP). 
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21
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, et. al. European retrospective study of real-life haemophilia 
treatment. Haemophilia. 2017 Jan;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.
Boutin S, Monteilhet V, Veron P et al. Prevalence of serum IgG and neutralizing factors 
against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: 
implications for gene therapy using AAV vectors. Hum Gen Ther. 2010;21:704-712.
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37:53-72.
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16:199-208.
George LA, Sullivan S, Teitel J, Cuker A et al. Preliminary results of a phase 1/2 trial of 
SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent 
factor IX activity levels at the lowest dose cohort. Haemophilia. 2016;22(Suppl.4):151-152.
Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: 
a randomized dose comparison. Blood 119[6], 1335-1344. 2012.
Hayes G, Andreeva T, Gregg K, Klamroth R et al. Global seroprevalence of pre-existing 
immunity against various AAV serotypes in the hemophilia A population. International 
Society on Thrombosis and Haemostasis (ISTH) 2019 XXVII Congress. Presentation.
Haemo-QoL Study Group.  Scoring Manual.  Available at: http://haemoqol.de/scoring/ 
manual. Last accessed 17 May 2021.
Kaufman, RJ, Powell, JS. Molecular approaches for improved clotting factors for 
hemophilia. Blood 122[22], 3568-3574. 2013.
Majowicz A, Lampen M, Petry H, Meyer C et al. Pre-existing Anti-AAV5 Neutralizing 
Antibodies Measured Using a Highly Sensitive Assay in Sera of Hemophilia B Patients in a 
Phase I/II Clinical Trial of AMT-060 Do Not Predict Efficacy of AAV5-mediated 
Liver-directed Gene Transfer. Res Pract Thromb Haemostasis. 2017;1(Suppl. 1):766.
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Manno CS, Pierce GF, Arruda VR, Glader B et. al. Successful transduction of liver in 
hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat 
Med. 2006;12(3):342-347.
Miesbach W, Tangelder M, Klamroth R, Schutgens R et al. Updated results from a dose 
escalating study in adult patients with haemophilia B with AMT-060 (AAV5-hFIX) gene 
therapy. Haemophilia. 2016;22(Suppl.4):151-152.
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 U, Tuddenham E, et al. Adeno-Associated Mediated Gene Transfer for 
Hemophilia B:8 Year Follow up and Impact of Removing "Empty Viral Particles" on Safety 
and Efficacy of Gene Transfer. Blood. 2018;132:491.
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. 2011;19(5):876-885.
Nathwani, AC, Tuddenham, EG. Epidemiology of coagulation disorders. Baillieres Clin 
Haematol 5[2], 383-439. 1992.
National Center for Biotechnology Information (NCBI). LiverTox: Clinical and Research 
Information on Drug-Induced Liver Injury. Available at: https://livertox.nih.gov (last 
accessed 17 May 2021).
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.
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.
Reilly, M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ 
WPAI_Scoring.html. Last accessed 17 May 2021.  
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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, Santagostino E, Dougall A, Kitchen S et. al. WFH guidelines for the 
management of hemophilia, 3rd edition. Haemophilia. 2020;26(Suppl 6):1-158.
Stonebraker, JS, Brooker, M, Amand, RE, Farrugia, A et. al. A study of reported factor VIII 
use around the world. Haemophilia 16[1], 33-46. 2010.
United States Department of Health and Human Services. Panel on Antiretroviral Guidelines 
for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and 
Adolescents with HIV. 2019. Available at: http://www.aidsinfo.nih.gov/ContentFiles/ 
AdultandAdolescentGL.pdf (last accessed 17 May 2021).
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.
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22
INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Subjects
In accordance with FDA Form 1572 and/or principles of ICH E6 GCP, the Investigator will 
ensure that:
x
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects.
x
He or she will personally conduct or supervise the study.
x
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/EC review and 
approval in 21 CFR Part 56 and/or ICH E6 Section 2.6 are met. 
x
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64 and/or ICH E6 Section 4.11.
x
He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug.
x
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments
x
Adequate and accurate records in accordance with 21 CFR 312.62 and/or ICH E6 
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.
x
The IRB/EC complies with the requirements of 21 CFR Part 56, ICH E6 Section 3.0, 
and other applicable regulations, and conducts initial and ongoing reviews and 
approvals of the study. He or she will also ensure that any change in research activity 
and all problems involving risks to human subjects or others are reported to the 
IRB/EC. Additionally, he or she will not make any changes in the research without 
IRB/EC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects.
x
He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312 and/or 
ICH E6.
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2 7 0- 2 0 3 A me n d me nt 4
Pa ge 1 2 8
Pr o prietar y a n d C o nfi de ntial
4 A u g ust 2 0 2 1
2 3 
SI G N A T U R E P A G E
Pr ot oc ol Title: A P has e 1/ 2 Safet y, T ol era bilit y, a n d Efficac y St u d y of B M N 2 7 0, a n 
A de n o- Ass oci ate d Vir us Vect or – Me di ate d Ge n e Tra nsfer of H u ma n Fact or VIII i n 
He m o p hilia A Patie nts wit h Resi d ual F VIII Le vels ≤ 1 I U/ d L a n d Pre- e xisti n g A nti b o dies 
A gai nst A A V 5
Pr ot oc ol N u m ber: 2 7 0- 2 0 3 A me n d me nt 4
I h a ve rea d t he f ore g oi n g pr ot oc ol a n d a gree t o c o n d uct t his st u d y as o utli ne d. I a gree t o 
c o n d uct t he st u d y i n c o m plia nce wit h all a p plica bl e re g ulati o ns a n d g ui deli nes, i ncl u di n g 
E 6 R 2 I C H, as stat e d i n t he pr ot oc ol, a n d ot her i nf or mati o n s u p plie d t o me.
I n v esti gat or Si g nat ure
Date
Pri nte d na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Acce pte d f or t he S p o ns or:
Me dical M o nit or Si g nat ure
Date
Pri nte d na me:
,  M D, 
, Cli nical Scie nces _ _ _ _ _ _ _ _ _
PI
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APPENDIX 1: SAMPSON’S ANAPHYLAXIS CRITERIA
According to the National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network (NIAID/FAAN) Second Symposium on the definition and 
management of anaphylaxis, anaphylaxis is highly likely when any one of the following 3 
criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula)
13. 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)
14. 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)
15. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a.
Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease is systolic BP
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline.
Source: Sampson 2006.
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PROTOCOL AMENDMENT TEXT REVISIONS
The following table summarizes the revisions made to Protocol Amendment 4 and relates the changes to the appropriate rationale (refer to 
pages 2-5). Added text is indicated by underlined font and deleted text is indicated by strikethrough font.
Section No./Title
Revision
Rationale
2/Synopsis (Study 
Sites)
Approximately  5-614 sites globally
12
2/Synopsis (Study 
Rationale)
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived or recombinant human FVIII 
protein (rhFVIII) concentrates, both as prophylaxis 2 -3 times per week or 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. 
While infusion of FVIII is a major advance in the treatment of HA, severe HA patients continue to have bleeding events on 
prophylactic therapy; median ABRs were 1-4 with prophylactic treatment in a recently published retrospective observational 
study and between 1-2 in 6 prospective FVIII interventional studies.  Median ABRs were 4.5-18 and between 20-60 with 
episodic (on -demand -only) therapy in the same studies, respectively. Continued repeated bleeding events compound 
debilitating multiple-joint arthropathies as well as the risk of catastrophic events such as intracranial hemorrhage and death.
…
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose escalation study in subjects 
with severe HA designed to assess the safety and efficacy of BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 
vg/kg, 6E13 vg/kg). Specifically, 270--201 explores the relationship of vector dose to the augmentation of residual FVIII 
activity and whether these levels are sufficient to alter the clinical phenotype. ThreeAn additional study has been undertaken at 
the 6E13 vg/kg dose (270-301 in subjects with severe HA), as well as a study in subjects receiving the 4E13 vg/kg dose 
(270-302).
Four-year results from 270 -201 and one-year results from 270-301 have demonstrated that following gene transfer, mean and 
median FVIII activity levels above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are achievable and 
sustained following a single infusion of 6E13 vg/kg of BMN 270, with administration of prophylactic corticosteroids and an 
acceptable safety profile (Pasi, 2019). In addition, an interim analysis of clinical study 270 301, an ongoing phase 3 study 
designed to assess the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg and administration of therapeutic corticosteroids 
(ie, in response to ALT elevations), demonstrated FVIII activity levels that were also well above 15%, albeit lower than what 
was observed for the 6E13 vg/kg cohort in 270 201 at 26 weeks (Pasi, 2019).. Preliminary results from optional liver biopsies 
(in subjects receiving lower doses of BMN 270 in 270-201) confirm dose-dependent pan-lobular and otherwise healthy liver 
transduction at 2.7-4.1 years.
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects in 270-301; in 270-201, 
subjects were scheduled to start corticosteroids by Week 3 (either before Week 3, in response to an alanine aminotransferase 
(ALT) elevation, or at Week 3 otherwise, per protocol), whereas in 270-301 subjects received corticosteroids only in response 
6, 12
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Section No./Title
Revision
Rationale
to an ALT elevation. Possibly as a result of this difference, subjects receiving 6E13 vg/kg in 270-201 started corticosteroids at 
an earlier date in reference to the date of BMN 270 infusion and showed later onset of first ALT elevations when compared 
with subjects in 270-301. Recently published data from 270-201 and recent analysis of 270-301 data suggest that corticosteroids 
may have assisted in rescue or protection of FVIII activity levels during elevations of ALT and in resolution of elevated ALT
levels in some subjects.
Subjects enrolled and infused in 270-201 screened negative for AAV5 antibodies, as the prevailing expectation has been that 
vector-specific antibodies could interfere with receptor binding and effectively neutralize efficient transduction of the target cell
population. As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted out of an abundance of 
caution. Subjects enrolled and infused in 270-301 also screened negative for AAV5 antibodies. These pre-existing 
vector-specific antibodies are thought to arise from previous exposure to AAV, with seroprevalence varying across human 
populations and across studies. AAV5 has consistently been shown to have the lowest seroprevalence among the common AAV 
serotypes. 
2/Synopsis (Study 
Design and Plan)
This is a Phase 1/2, single-arm, open-label study in severe HA patients (FVIII ≤1 IU/dL), with a history of at least 150 
exposure days to FVIII concentrates/cryoprecipitates, with pre-existing antibodies to the AAV5 vector capsid as measured by 
total antibody [TAb] assay. Approximately 10 subjects may be enrolled at 5-614 sites in 2 cohorts (5 subjects in each cohort) 
and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion.
…
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening AAV5 TAb titers. Subjects
in Cohort 2 can be dosed after a minimum of 3 and a maximum of 5 subjects have been dosed in Cohort 1 and had their safety 
and efficacy data (from a minimum of 1-6 weeks post-infusion) reviewed.  FVIII activity ≥ 5% after six weeks post-infusion is 
expected to be the earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who later achieved 
normal FVIII activity levels, compared with the one subject who had a slightly lower response, based on data from 270-201. Up 
toBetween 1 and 6 weeks post-infusion will provide an appropriate timeframe to evaluate the development of any potential 
delayed hypersensitivity reaction (eg, serum sickness).  
…
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 24 hours post-infusion for 
any immediate hypersensitivity or adverse drug reaction. In case of suspected hypersensitivity or adverse drug reaction, safety 
assessments, in addition to physical examination and vital signs, will be performed. Additional blood samples will be collected 
(tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine bead arrayprofiling, as well as possible additional exploratory testing) within 
1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead arrayprofiling (and possible additional exploratory 
testing) will be collected between 8 -24 hours after the reaction. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead arrayprofiling.
…
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Section No./Title
Revision
Rationale
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII activity 
≥ 5 IU/dL by Week 52 orand inability to maintain independence from prophylactic FVIII replacement therapy due to joint 
bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor or Sponsor-designated Data Monitor, follow an abbreviated visit schedule after Week 52 by attending only the 
Q12W and End of Year visits during Years 2-5.
2/Synopsis (Inclusion 
Criteria)
Individuals eligible to participate in this study must meet all of the following criteria:
5. 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. If the subject is unable to provide consent, a legally authorized representative may provide written 
informed consent.
11
2/Synopsis (Exclusion 
Criteria)
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
1. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, including HIV infection except 
for HIV infection. HIV-positive patients who meet all other eligibility criteria may be included if they have a CD4 count > 
200/mm3 and an undetectable viral load (unquantifiable viral load as defined as less than the limit of quantification by the 
testing laboratory’s assay is permitted) while receiving an antiretroviral therapy (ART) regimen that does not contain efavirenz 
or another potentially hepatotoxic ART.
7. Liver cirrhosis or other clinically significant liver disease of any etiology as assessed by liver ultrasound/FibroScan. 
4, 12
2/Synopsis (Statistical 
Methods)
Approximately 10 subjects may be dosed in the study. The subjects will be followed in a longitudinal manner, and all the 
relevant information will be collected. The analysis of the data will be descriptive in nature, but data collected in a longitudinal 
manner may be analyzed using longitudinal methods, such as a mixed effect model, which take into account the correlation 
among the observations taken at various time points within a subject. Efficacy is a secondary endpoint, defined as biologically 
active FVIII at ≥5 IU/dL at 26 weeks following study treatment. FVIII activity will be assessed weekly during the study period.
12
5.2/Ethical Conduct of 
Study
Specifically, this study is based on adequately performed laboratory and animal experimentation. The study will be conducted 
under a protocol reviewed and approved by an IRB/EC and will be conducted by scientifically and medically qualified persons. 
The benefits of the study are in proportion to the risks. The rights and welfare of the subjects will be respected and the 
investigators conducting the study do not find the hazards to outweigh the potential benefits. Each subject (or his legally 
authorized representative, if required) will provide written, informed consent before any study -related tests or evaluations are 
performed.
11
6/Investigators and 
Study Administrative 
Structure
During administration of informed consent, expectations regarding participation in the study should be made clear to subjects.
(and their legally authorized representatives, if required). Subjects who are not willing and/or are not able to comply with all 
aspects of the study should not be encouraged to participate.
11
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Section No./Title
Revision
Rationale
7/Introduction
Hemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males (Nathwani, 
1992Iorio 2019).
…
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 2020); thus, the therapeutic goal for 
gene therapy is a modest increase in hFVIII.
12
7.2/Ongoing Clinical 
Studies
Ongoing clinical studies for BMN 270 include:
x
270 203, a phase 1/2 study in patients with severe HA who have anti AAV5 antibody titers
x
270-205, a phase 1/2 study in patients with severe HA who have active or prior FVIII inhibitors
x
270-303, a phase 3 study in patients with severe HA who received BMN 270 at the 6E13 vg/kg dose level along with 
prophylactic corticosteroids
A comprehensive review of safety, efficacy, and immunogenicity results from 270 201 and 270 301 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.
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7.3/Study Rationale
Treatment of severe HA presently mainly consists of intravenous injection of plasma-derived or recombinant human FVIII 
protein (rhFVIII) concentrates, both as prophylaxis 2--3 times per week or 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. 
While infusion of FVIII is a major advance in the treatment of HA, severe HA patients continue to have bleeding events on 
prophylactic therapy; median ABRs were 1 -4 with prophylactic treatment in a recently published retrospective observational 
study (Berntorp, 2017) and between 1-2 in 6 prospective FVIII interventional studies.  Median ABRs were 4.5-18 and between 
20-60 with episodic (on-demand-only) therapy in the same studies, respectively. Continued repeated bleeding events compound 
debilitating multiple--joint arthropathies as well as the risk of catastrophic events such as intracranial hemorrhage and death.
…
BMN 270 is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose escalation study in subjects 
with severe HA designed to assess the safety and efficacy of BMN 270 at various dose levels (6E12 vg/kg, 2E13 vg/kg, 
4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual FVIII 
activity and whether these levels are sufficient to alter the clinical phenotype. ThreeAn additional study has been undertaken at 
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the 6E13 vg/kg dose (270-301 in subjects with severe HA), as well as a study in subjects receiving the 4E13 vg/kg dose 
(270-302).
Four-year results from 270 -201 and one-year results from 270-301 have demonstrated that following gene transfer, mean and 
median FVIII activity above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are achievable and sustained 
following a single infusion of 6E13 vg/kg of BMN 270, with administration of prophylactic corticosteroids and an acceptable 
safety profile (Pasi, 2019). In addition, an interim analysis of clinical study 270 301, an ongoing phase 3 study designed to 
assess the efficacy and safety of BMN 270 at a dose of 6E13 vg/kg and administration of on demand corticosteroids (ie, in 
response to ALT elevations), demonstrated FVIII activity levels that were also well above 15% at 26 weeks, albeit lower than 
what was observed for the 6E13 vg/kg cohort in 270 201 (Pasi, 2019). For additional information on preliminary data in 
270 201, refer to the current version of the Investigator’s Brochure.. Preliminary results from optional liver biopsies (in subjects 
receiving lower doses of BMN 270 in 270-201) confirm dose-dependent pan-lobular and otherwise healthy liver transduction at 
2.7-4.1 years.
Subjects receiving 6E13 vg/kg in 270-201 received a different corticosteroid regimen than subjects in 270-301; in 270-201, 
subjects were scheduled to start corticosteroids by Week 3 (either before Week 3, in response to an alanine aminotransferase 
(ALT) elevation, or at Week 3 otherwise, per protocol), whereas in 270-301 subjects received corticosteroids only in response 
to an ALT elevation. Possibly as a result of this difference, subjects receiving 6E13 vg/kg in 270-201 started corticosteroids at 
an earlier date in reference to the date of BMN 270 infusion and showed later onset of first ALT elevations when compared 
with subjects in 270-301. Recently published data from 270-201 and recent analysis of 270-301 data suggest that corticosteroids 
may have assisted in rescue or protection of FVIII activity levels during elevations of ALT and in resolution of elevated ALT
levels in some subjects.
Subjects enrolled and infused in 270-201 were screened and negative for AAV5 antibodies, as the prevailing expectation has 
been that vector-specific antibodies could interfere with receptor binding and effectively neutralize efficient transduction of the 
target cell population. As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted out of an 
abundance of caution. Subjects enrolled and infused in 270-301 also screened negative for AAV5 antibodies.
7.4/Summary of Risks 
and Benefits
Transient ALT elevation (Grade 1 to 3 in severity) has been observed in most subjects administered BMN 270 shortly after 
dosing, with no evidence for major impacts upon liver function; no events meeting the Hy’s Law criteria have been identified.
Liver function has remained stable over time. ALT elevations have been reported as events of interest in 13 subjects in 270 201, 
1 subject in 270 302, and 91 subjects in 270 301. Although the majority of events have been Grade 1 or Grade 2 in severity, 11 
subjects (1 in 270 302 and 10 in 270 301) had a reported Grade 3 ALT elevation. Only one serious event of ALT increased has 
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been reported by investigators (in addition to one event that BioMarin conservatively assessed as serious based on the details of 
the case).Across the 6E13 vg/kg cohort of 270-201 and 270-301, subjects enrolled in 270-201 developed ALT elevation about 
5.5 weeks later than subjects in 270-301, generally once the first course of corticosteroids was being tapered, and experienced 
lower peak elevations in ALT (75.7 U/L) than subjects in 270-301 (112.5 U/L). The difference in the ALT profile seen between 
the 6E13 vg/kg subjects in 270-201 and the subjects in 270-301 could be attributed to the difference in the protocol-specified 
corticosteroid regimens in place in those studies, including the early use of corticosteroids (ie, by Week 3 post-BMN 270 
infusion). While the majority of ALT elevations responded rapidly to corticosteroids, given current interest in the field of AAV 
gene therapy for the use of non-steroidal approaches to managing or preventing ALT elevations, alternate non-steroidal 
systemic immunosuppressive agents have also been used to manage hepatic reactions where corticosteroids have proven to be 
ineffective or where high doses/and or prolonged exposure to corticosteroids have led to unwanted side effects. Overall, the 
literature and clinical experience with BMN 270 suggests that transient elevations in liver enzymes are expected following 
AAV-based gene therapy for the treatment for hemophilia A or B without any long-term concerns of hepatic injury
(Manno, 2006; Nathwani, 2011; George, 2016; Miesbach, 2016; Pasi, 2017 2020). 
Short-lived infusion reactions associated with one-time BMN 270 administration have included symptoms such as nausea, 
maculopapular rash, urticaria, diarrhea, watery eyes, rigors, chills, myalgia, fever, tachycardia and hypotension emerging within 
24 hours of receiving BMN 270. Most infusion-related reactions were Grade 1 or Grade 2 in severity, and all events resolved, 
typically within 48 hours following medical management. Three of theseWhile some cases required temporary interruption of 
the infusion, followed by re-initiation at a slower rate., all subjects completed their infusions. The reactions with onset during or 
within approximately 5 hours after the end of infusion responded to treatment with systemic antihistamines and/or 
corticosteroids, where administered. Infusion-related reactions were effectively mitigated by managing infusion rate and 
medications. 
No subjects have experienced thromboembolic events or developed inhibitors to FVIII following BMN 270 infusion.
AtSubjects given the highest6E13 vg/kg dose tested in 270-201 (6E13 vg/kg), the majority of subjectsand 270-301 have
achieved mean FVIII levelsactivity above 5040 IU/dL at 49-52 weeks post-infusion.  Subjects in that cohort also reported 
markedly decreased bleeding compared with pre study rates and the ability to discontinue prophylactic FVIII infusions. 
Subjects at all dose levels continue to be followed. 
In 270 301, an interim analysis has shown increased FVIII activity in the majority of subjects to mild HA or normal levels at 26 
weeks post infusion, also, with markedly decreased bleeding compared with pre-study rates and the ability to discontinue 
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prophylactic FVIII infusions. All subjects who will be included in the final analysis have been dosed with 6E13 vg/kg 
andSubjects at all dose levels continue to be followed. 
9.1/Overall Study 
Design and Plan
This is a Phase 1/2, single-arm, open-label study in severe HA patients (FVIII ≤1 IU/dL), with a history of at least 150 
exposure days to FVIII concentrates/cryoprecipitates, with pre -existing antibodies to AAV5 vector capsid as measured by total 
antibody [TAb] assay. Approximately 10 subjects may be enrolled at 5-614 sites globally in 2 cohorts (5 subjects in each 
cohort) and will receive a single dose of 6E13 vg/kg BMN 270 as an IV infusion. Subjects in Cohort 1 will have a Screening 
AAV5 TAb ≤ 500, while subjects in Cohort 2 will have a Screening AAV5 TAb > 500. Choosing a titer cutoff of 500 reflects 
the observed distribution of existing titer data with the BioMarin titer assay seen to date.
…
Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening AAV5 TAb titers. Subjects 
in Cohort 2 can be dosed after a minimum of 3 and a maximum of 5 subjects have been dosed in Cohort 1 and had their safety 
and efficacy data (from a minimum of 1-6 weeks post-infusion) reviewed.  Based on data from 270 -201, FVIII activity ≥ 5% 
after six weeks post-infusion is expected to be the earliest differentiating time point for the majority of subjects dosed with 
6E13 vg/kg who later achieved normal FVIII activity levels, compared with the one subject who had a slightly lower response. 
Up toBetween 1 and 6 weeks post-infusion will provide an appropriate timeframe to evaluate the development of any potential 
delayed hypersensitivity reaction (eg, serum sickness).  
…
Dosing will be administered at a qualified infusion site, and subjects will be monitored for at least 24 hours post-infusion for 
any immediate hypersensitivity or adverse drug reaction. In case of suspected hypersensitivity or adverse drug reaction, safety 
assessments, in addition to physical examination and vital signs, will be performed. Additional blood samples will be collected 
(tryptase, C3, C3a, C4, Bb, sC5b-9, and cytokine bead arrayprofiling, as well as possible additional exploratory testing) within 
1 hour of hypersensitivity reaction, and samples for IgE and cytokine bead arrayprofiling (and possible additional exploratory 
testing) will be collected between 8 -24 hours after the reaction. In addition, a blood sample should be taken 1 week after the 
hypersensitivity reaction for assessment of the cytokine bead arrayprofiling. Exploratory biomarker samples at baseline and at 
post-infusion study visits may also be used to assess changes in these biomarkers to better elucidate the mechanisms of 
infusion -related hypersensitivity reactions.  Any safety signal may trigger a review of the data and possible additional 
immunogenicity studies or other diagnostics deemed necessary to assess cellular immune responses using collected peripheral 
blood mononuclear cells (PBMCs).  The duration of observation may be extended and additional blood samples collected at the 
discretion of the Investigator and Medical Monitor.
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…
In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume 
prior FVIII prophylaxis. Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure 
to achieve FVIII activity ≥ 5 IU/dL by Week 52 orand inability to maintain independence from prophylactic FVIII replacement 
therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after 
discussion with the Medical Monitor or Sponsor-designated Data Monitor, follow an abbreviated visit schedule after Week 52
by attending only the Q12W and End of Year visits during Years 2-5.
Figure 9.1.1/270-203
Dosing Schedule
Figure 9.1.1 has been updated consistent with changes made elsewhere in the protocol.
12
Table 9.1.1 through 
Table 9.1.5 –
Schedules of Activities
Tables 9.1.1 through 9.1.5 have been updated consistent with changes made elsewhere in the protocol and in the table footnotes
(detailed below).
1, 2, 5, 7, 
8, 9, 12
Table 9.1.1 – footnotes
ccAll patients must have a liver ultrasound performed during the Screening period to screen for significant liver disease and 
hepatocellular carcinoma. A FibroScan may also be performed at the discretion of the Investigator.
g COVID 19hSARS-CoV-2 RT-PCR testing is required during Screening, and all subjects must have at least one negative test result 
prior to dosing. If the test is performed locally an additional 2nd test is recommended, but negative results from the 2nd test 
must be received prior to dosing. A SARS-CoV-2 vaccine is recommended for subjects if indicated and if available. If a 
two-step SARS-CoV-2 vaccine is being used, sites should consider using the flexible re-screen option to allow subjects to 
receive both doses at least 14 days prior to treatment with BMN 270 (or at least 30 days prior to treatment with BMN 270 for 
any live-virus vaccines). It is preferable for SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. Investigators 
should use clinical judgment, taking into consideration local factors, individual risk factors, and benefit/risk related to timing 
of vaccine administration.
jk 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 those 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.
klComplement panel should include C3, C3a, C4, Bb, and sC5b-9 and should be collected within 2 hours post-infusion. While 
exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples will be 
performed only as deemed necessary by the Sponsor.
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m Smart rescreening should only be performed if a subject 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 (28 + 14 days). 
COVID 19SARS-CoV-2 RT-PCR testing is required as part of smart rescreening, and all subjects must have at least one 
negative test result prior to dosing. If the test is performed locally an additional 2nd test is recommended, but negative results 
from the 2nd test must be received prior to dosing. Subjects who undergo smart rescreening must complete the rescreening 
assessments and receive the infusion within 90 days of signing the original consent.  Subjects who do not complete dosing 
within 90 days will be required to re-consent and undergo all screening procedures.  Subjects may not undergo smart 
rescreening more than once.
mo With the exception of the collection of samples for PCR vector DNA analysis and the collection of the complement 
panel/exploratory cytokine profiling sample, assessments on the day of infusion must be performed prior to the infusion. 
Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. On the day of 
the BMN 270 Infusion, vital signs will be monitored prior to the infusion, during the infusion every 15 minutes (± 5 minutes), 
and following the infusion hourly (± 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Shedding samples 
for PCR of vector DNA analysis (blood, saliva, urine, semen, stool) should be collected between 2 and 24 hours after the 
infusion has been completed.
o Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and should be collected within 2 hours post-infusion.
pqIn case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination, vital signs will be 
done and additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, 
Bb, sC5b-9, and cytokine bead arrayprofiling, as well as possible additional exploratory testing) and samples for IgE and 
cytokine bead arrayprofiling (and possible additional exploratory testing) between 8-24 hours after the reaction, if possible. In 
addition, a blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead 
arrayprofiling. Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes 
in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. 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.
Table 9.1.2 – footnotes
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. Urine tests will be 
performed locally and centrally; all other laboratory assessments will be performed at the central laboratory. LTs assessment 
is weekly, but may be monitoredchecked more or less frequently (and in particular when ALT values are > ULN or ≥ 1.5x 
baseline value) or based onupon discussion between the Medical Monitor and the Investigator and review of subject data, but 
LTs will be monitored at least twice weekly during periods when a subject’s ALT is ≥ 3x ULN.. Subjects with ALT > ULN 
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or ≥ 1.5x baseline value during the study and either an alternative etiology considered or for further evaluation of the lab 
abnormality may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, 
and/or liver biopsy) at the discretion of the Investigator. Additional testing of FVIII and LTs during any study week may be 
performed if: (1) the ALT has increased to 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/orIf ALT values are stable over the course of several weeks, assessment of FVIII activity 
and ALT levels may be adjusted based on discussion between the Medical Monitor and the Investigator. In case of a safety 
concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to 
facilitate timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central 
laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample.
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with 
Nijmegen modification) for hFVIII inhibitor level, coagulation exploratory assay, and hFVIII antigen assay. Chromogenic 
Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. If a subject has used 
FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 
72 -hour interval without FVIII use is achieved; the 72 -hour wash-out period is only intended for subjects who have achieved 
FVIII ≥5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy.  If FVIII levels 
are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion 
between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity 
levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. 
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may choose 
to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to
be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for TGA assay and any other exploratory assessments) will be performed only as deemed 
necessary by the Sponsor.
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 [or his legally authorized representative, if 
required] 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, 
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and FVIII use. For MN visits, the service will collect this information. The physical examination and vital signs assessments
listed in the Schedule of Activities will not be performed at these MN or lab draw-only visits.
h Complement panel should include C3, C3a, C4, Bb, and sC5b-9. While exploratory samples for cytokine profiling will be 
collected at the time points indicated above, testing of these samples will be performed only as deemed necessary by the 
Sponsor.
Table 9.1.3 - footnotes
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. Urine tests will be 
performed locally and centrally; all other laboratory assessments will be performed at the central laboratory. LTs assessment 
may be monitoredchecked more or less frequently (and in particular when ALT values are > ULN or ≥ 1.5x baseline value) or
based onupon discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be 
monitored at least twice weekly during periods when a subject’s ALT is ≥3x ULN.  Subjects with ALT > ULN or ≥ 1.5x 
baseline value during the study and either an alternative etiology considered or for further evaluation of the lab abnormality 
may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, and/or liver 
biopsy) at the discretion of the Investigator.  Additional testing of FVIII and LTs during any study week may be performed if: 
(1) the ALT has increased to 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. In case of a safety concern, 
additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely 
and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should 
be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with 
Nijmegen modification) for hFVIII inhibitor level, coagulation exploratory assay, and hFVIII antigen assay. Chromogenic 
Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. If a subject has used 
FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 
72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved 
FVIII ≥5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy. If FVIII levels 
are elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion 
between the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity 
levels are above the normal physiological range and/or if there is a concern for a venous thromboembolism. 
6, 7, 11, 
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e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may choose 
to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to 
be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for TGA assay and any other exploratory assessments) will be performed only as deemed 
necessary by the Sponsor.
f The scheduled visits at Week 17, Week 19, Week 21, Week 23, Week 25, Week 27, Week 29, and Week 31 may be 
performed by a mobile nursing (MN) professional at the subject’s home or another suitable location (if the subject [or his 
legally authorized representative, if required] 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 Activities will not be performed at these MN or lab 
draw-only visits.
g While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples 
will be performed only as deemed necessary by the Sponsor.
Table 9.1.4 – footnotes
b Refer to Table 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. LTs assessment may 
be monitoredchecked more or less frequently (and in particular when ALT values are > ULN or ≥ 1.5x baseline value) or
based onupon discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be 
monitored at least twice weekly during periods when a subject’s ALT is ≥ 3x ULN.. Subjects with ALT > ULN or ≥ 1.5x 
baseline value during the study and either an alternative etiology considered or for further evaluation of the lab abnormality  
may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, and/or liver 
biopsy) at the discretion of the Investigator. Additional testing of FVIII and LTs during any study week may be performed if: 
(1) the ALT has increased to 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. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the 
Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where possible, a 
2, 6, 7, 11, 
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matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time 
as the local unscheduled sample.
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with
Nijmegen modification) for hFVIII inhibitor level, coagulation exploratory assay, and hFVIII protein assay.antigen assay. 
Chromogenic Nijmegen-Bethesda Assay for hFVIII inhibitor level will be tested as deemed necessary by the Sponsor. If a 
subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity 
measurements when a 72--hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for 
subjects who have achieved FVIII ≥5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed FVIII 
replacement therapy. If FVIII levels are elevated or stable over the course of several weeks, assessment of FVIII activity may 
be adjusted based on discussion between the Medical Monitor and the Investigator. A D-dimer may be considered under 
circumstances in which FVIII activity levels are above the normal physiological range and/or if there is a concern for a venous 
thromboembolism.
d Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may choose 
to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to 
be associated with hemophilia A. While exploratory samples will be collected at the time points indicated above, testing of 
these samples (including those for TGA assay and any other exploratory assessments) will be performed only as deemed 
necessary by the Sponsor.
e The scheduled visits at Week 33, 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 [or his legally authorized 
representative, if required] 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 Activities will not be performed at these MN or lab 
draw-only visits.
f While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples 
will be performed only as deemed necessary by the Sponsor.
g Additional liver ultrasounds may be performed prior to Week 52 at the discretion of the Investigator.
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Table 9.1.5 – footnotes
ETV: Early Termination Visit
a BriefComplete physical examination should be performed at allthe End of Year visits during Years 2 5(genitourinary 
examination may be deferred); brief physical examination may be performed at Q12W 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 9.7.6.2.1 for laboratory assessments to be included, and to Table 9.7.6.4.1 for liver tests. LTsLT assessment
may be monitoredchecked more or less frequently (and in particular when ALT values are > ULN or ≥ 1.5x baseline value) or
based onupon discussion between the Medical Monitor and the Investigator and review of subject data, but LTs will be 
monitored at least twice weekly during periods when a subject’s ALT is ≥ 3x ULN. Subjects with ALT > ULN or ≥ 1.5x 
baseline value during the study and either an alternative etiology considered or for further evaluation of the lab abnormality  
may undergo additional evaluations (eg, imaging studies including MRI or ultrasound, additional blood tests, and/or liver 
biopsy) at the discretion of the Investigator. Additional testing of FVIII and LTs during any study week may be performed if:
(1) the ALT has increased to 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; oror (2) after a discussion between the Medical Monitor 
and the Investigator based on a review of subject data. If FVIII levels and/orIf ALT values are stable over the course of 
several weeks, assessment of FVIII activity and ALT levels may be adjusted based on discussion between the Medical 
Monitor and the Investigator. During Years 2-5 of the Post-Infusion Follow-Up period, urine tests and blood, chemistry, and 
coagulation tests should be performed at the second Q12W visit each year and at every End of Year visit.
c Includes FVIII activity level (chromogenic substrate FVIII assay and one-stage clotting FVIII assay), Bethesda assay (with 
Nijmegen modification) for hFVIII inhibitor level, and coagulation exploratory assay, and . Chromogenic Nijmegen-Bethesda 
Assay for hFVIII protein assay.inhibitor level will be tested as deemed necessary by the Sponsor. If a subject has used FVIII 
within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72 -hour 
interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII ≥ 
5 IU/dL at 16 weeks after BMN 270 infusion and who have not resumed FVIII replacement therapy. If FVIII levels are 
elevated or stable over the course of several weeks, assessment of FVIII activity may be adjusted based on discussion between 
the Medical Monitor and the Investigator. A D-dimer may be considered under circumstances in which FVIII activity levels 
are above the normal physiological range and/or if there is a concern for a venous thromboembolism. If a subject tests positive 
in the Bethesda assay (with Nijmegen modification) during Years 2-5, a fresh sample should be collected within 4 weeks of 
the initial visit that had a positive result.
e Blood samples will be collected to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to 
hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may choose 
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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.
ehThe scheduled Q6W visits during Years 2-5 may be performed by a mobile nursing (MN) professional at the subject’s home 
or another suitable location (if the subject [or his legally authorized representative, if required] 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 
Activities will not be performed at these MN or lab draw-only visits.
i While exploratory samples for cytokine profiling will be collected at the time points indicated above, testing of these samples
will be performed only as deemed necessary by the Sponsor.
j Additional liver ultrasounds may be performed at interim timepoints (ie, between the End of Year visits) at the discretion of
the Investigator.
k PBMC collection should occur at each Q12W visit during Year 2, then at every other Q12W visit during Years 3-5, as well as 
at all End of Year Visits for Years 2-5.
Table 9.1.6 – footnotes
b Following initiation or completion of corticosteroid regimen, if a recurrence of ALT values ≥ ULN or ≥ 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 timing of ALT elevation (prior to or after Week 52), as 
well as possible confounders for the ALT elevation, relationship between increases in ALT and FVIII activity, ALT/FVIII 
levels post-corticosteroid initiation, and adverse events related to corticosteroid dosing. Guidance for tapering oral 
corticosteroid dosing can be found in Section 9.4.8.2, although a discussion between the PI and Medical Monitor should take 
place prior to tapering the corticosteroid dose.
6, 12
9.2/Discussion of 
Study Design
Study 270-203 is designed to be a Phase 1/2, single-arm, open-label study in hemophilia A patients with residual FVIII levels ≤ 
1 IU/dL and pre-existing antibodies to the AAV5 vector capsid. Hemophilia A patients who provide written informed consent
(or who have a legally authorized representative provide consent, if required) and meet the entry criteria will be eligible to 
enroll in the study.
11
9.3.1/Inclusion Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
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5. 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. If the subject is unable to provide consent, a legally authorized representative may provide written 
informed consent.
9.3.2/Exclusion 
Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
1. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, including HIV infection except 
for HIV infection. HIV-positive patients who meet all other eligibility criteria may be included if they have a CD4 count > 
200/mm3 and an undetectable viral load (unquantifiable viral load as defined as less than the limit of quantification by the 
testing laboratory’s assay is permitted) while receiving an antiretroviral therapy (ART) regimen that does not contain efavirenz 
or another potentially hepatotoxic ART.
7. Liver cirrhosis or other clinically significant liver disease of any etiology as assessed by liver ultrasound/FibroScan. 
4, 12
9.4.4/Directions for 
Administration
In case of hypersensitivity reactions, safety assessment, including physical examination and vital signs, will be done and 
additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, Bb, sC5b-9,
and cytokine bead arrayprofiling, as well as possible additional exploratory testing) and samples for IgE and cytokine bead 
arrayprofiling (and possible additional exploratory testing) between 8 -24 hours after the reaction, if possible. In addition, a 
blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead arrayprofiling.
12
9.4.8/Prior and 
Concomitant 
Medications
All prescription and over-the-counter medications (including dietary and herbal supplements) taken by a subject for 30 days 
before Screening will be recorded on the designated eCRF. For HIV-positive patients, prior to enrollment, the Medical Monitor 
will review the patient’s ART regimen to assess that it does not contain efavirenz or another potentially hepatotoxic ART. 
The 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:
x
Any investigational therapy other than BMN 270
…
It is preferable for SARS-CoV-2 vaccination to occur prior to BMN 270 infusion. If a two-step SARS-CoV-2 vaccine is being 
used, sites should consider using the flexible re-screen option to allow subjects to receive both doses at least 14 days prior to 
treatment with BMN 270. If a live-virus SARS-CoV-2 vaccine is being used, subjects should wait at least 30 days after 
vaccination to receive a BMN 270 infusion. Investigators should use clinical judgment, taking into consideration local factors, 
individual risk factors, and the benefit/risk related to timing of vaccine administration. Administration of SARS-CoV-2 vaccine 
after BMN 270 infusion may occur after consultation between Investigator and Medical Monitor. 
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9.4.8.2.1/Prophylactic 
Corticosteroids
All subjects will be started on prophylactic corticosteroids starting on the day of infusion (Day 1). Table 9.1.6 provides an 
example of a possible the recommended prophylactic corticosteroid course, including taper and post-corticosteroid additional 
monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical judgment, weightingweighing the potential 
risks and benefits of corticosteroid treatment, should always be exercised when considering adjustment of corticosteroid doses. 
Discussions between the Investigator and Medical Monitor are advised for any questions or concerns.
12
9.4.8.2.2/Reactive 
Corticosteroids
Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased (eg, > ULN or ≥
1.5x baseline value) and alternative etiologies have been ruled out, prompt institution of therapeutic or on demandnewly 
administrated or an increased dose of reactive (ie, started in response to an ALT elevation) oral corticosteroids (prednisone or 
converted equivalent) should be considered after consultation with the Medical Monitor (refer to Table 9.7.6.34.8.2.2.1).
x
Whenever possible, a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, 
prior to initiating reactive oral corticosteroids.
x
Corticosteroids may be delayedNewly administered corticosteroids or dose increases are not indicated if elevations in 
ALT are clearly not related to BMN 270 (eg, elevated in ALT with concurrent increase in CPK due to intensive 
exercise) although this should be discussed with the Medical Monitor (in particular, for elevations occurring at least 52 
weeks after the BMN 270 infusion).
x
Alternative immunosuppressive agents may also be considered for use on a case-by-case basis and following 
consultation with the Medical Monitor (eg, if prolonged corticosteroid use is contraindicated).
TherapeuticUnless otherwise indicated, reactive corticosteroid treatment should be initiated at a dose of 60 mg/day. At 
minimum,If the recommended duration ALT level remains stable or declines after 2 weeks, consider gradual taper of 
therapeutic corticosteroids is 60 mg/day for 3 weeks, : 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a 
gradual taper thereafter.1 week, 20 mg/day for 1 week, and 10 mg/day for 1 week. Should a scenario arise in which a deviation 
from the minimum recommended dose and/or duration of therapeuticreactive corticosteroids may be clinically indicated, a 
discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments. 
TaperingManagement of corticosteroid dosagesALT elevations with reactive corticosteroids, including tapering of doses and 
managing worsening and/or recurrent ALT elevations, should be guided by the following (Table 9.4.8.2.2.1):
…
When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT workup, the following tests should be 
performed (Table 9.4.8.2.2.2):
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…
After discontinuation of reactive oral corticosteroids, labs for ALT and FVIII levels will be measured once a week for 4 weeks 
to ensure stability in values.
Following initiation or completion of therapeutic oral corticosteroids, if increased ALT levels (eg, > ULN or ≥1.5x baseline 
value) are reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical 
Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation 
and impact on FVIII expression.  
Table 9.4.8.2.2.1/ 
Management of ALT 
Elevations with 
Corticosteroids
Table 9.4.8.2.2.1 has been relocated from Section 9.7.6.3, and updated consistent with changes made elsewhere in the protocol.
6, 12
Table 9.4.8.2.2.2/ 
Viral and Autoimmune 
Hepatitis Testing
Table 9.4.8.2.2.2 has been relocated from Section 9.7.6.3.
6
9.4.8.3/Monitoring of 
HIV-Positive Subjects
HIV-positive subjects may be enrolled in 270-203 if the subject is well controlled on an ART regimen that does not contain 
efavirenz or another potentially hepatotoxic ART, has a CD4 count > 200/mm3, and has an undetectable viral load 
(unquantifiable viral load as defined as less than the limit of quantification by the testing laboratory’s assay is permitted).
HIV-positive subjects were initially included in prior BMN 270 studies. However, after an HIV-positive subject in 270-302
developed markedly elevated liver enzyme levels after receiving 4E13 vg/kg of BMN 270, out of an abundance of caution for 
the long-term liver health of HIV-positive patients, further enrollment of HIV-positive subjects was suspended in 270-301
(Protocol Amendment 3) and 270-302 (Protocol Amendment 3). The subject in 270-302 referenced above was receiving 
efavirenz and lamivudine as part of his ART regimen. Following discussion with a liver advisory board and review of the 
accumulated 270-301 data, efavirenz and not lamivudine has been implicated as the most likely medication that interacted with 
BMN 270 and contributed to the 270-302 subject's elevated liver enzyme levels. Due to its hepatotoxicity, efavirenz is a 
prohibited medication in all BMN 270 studies.
The two HIV-positive subjects on stable, non-efavirenz-containing ART regimens who were enrolled in and dosed in 270-301
study prior to Amendment 3 have been monitored closely. Following BMN 270 infusion, these subjects continued their ART as 
prescribed and followed routine monitoring of CD4 count and viral load. Results from 270-301 show similar safety results for 
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the two HIV-positive subjects compared to those who are HIV-negative. The Sponsor believes that HIV infection, in and of 
itself, is not a contraindication to receive BMN 270 and has therefore removed the exclusion of HIV-positive subjects.
Subjects should continue ART as prescribed and follow routine monitoring of CD4 count and viral load (US Dept Health 
Human Services 2019). Investigators will continue to monitor HIV-positive subjects per routine standard of care.
9.7.2.1/FVIII Activity
In the event of an FVIII activity level decline during the study:
x
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
x
If FVIII activity has declined >35% from the peak and has declined for at least 2 consecutive assessments, FVIII 
activity and LTs should be repeated every 72 hours until FVIII activity is stable or increasing.
Note that fluctuations in FVIII activity after gene therapy are common, and if no clear trend indicating a decline in more 
frequent monitoring of FVIII activity levels is observed, then this additional testing may be deferred (not needed in the absence 
of a concurrent or recent ALT elevation or upon consultation between the Investigator and the Medical Monitor) until either a 
more clear trend of decline has been demonstrated or until the FVIII activity levels stabilize or increase..
Subjects who do not respond to BMN 270 treatment (ie, treatment failure, manifesting as either failure to achieve FVIII activity 
≥ 5 IU/dL by either Week 26 or Week 52 orand inability to maintain independence from prophylactic FVIII replacement 
therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after 
discussion with the Medical Monitor, follow an abbreviated visit schedule after Week 52, as applicable and at the discretion of 
the Investigator.
8, 12
9.7.2.2/FVIII 
Replacement Therapy/ 
Bleeding Episodes
During the study, subjects will be asked at each study visit to report the use of factor replacement therapy and the number of
bleeding episodes since the previous visit. This information will be captured on the subject’s diary or other subject records. 
Subjects will be encouraged to discuss any bleeding episodes with the Investigator and attempt to objectively assess any 
reported bleeds through use of ultrasound or non-invasive imaging.
12
9.7.5/Exploratory 
Assessments
A cytokine bead array assayprofiling assessment will be performed at Baseline and then at the timepoints listed in the Schedule 
of Activities.
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9.7.6.2/Clinical 
Laboratory 
Assessments
In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel (including triglycerides, total cholesterol, 
HDL cholesterol, and LDL cholesterol) and fasting FibroTest will be assessed at the BMN 270 infusion visit. Subjects will fast 
for at least 8 hours prior to pre -infusion laboratory sampling on the day of the infusion visit.
In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination and vital signs, will be 
done and additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, 
Bb, sC5b-9, and cytokine bead arrayprofiling, as well as possible additional exploratory testing) and samples for IgE and 
cytokine bead arrayprofiling (and possible additional exploratory testing) between 8 -24 hours after the reaction. In addition, a 
blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead arrayprofiling.
Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these 
biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" as described in the rationale of 
changes.
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 (or his legally authorized 
representative, if required) gives written informed consent to participate in MN visits, the MN network will communicate with 
the patient and the patient’s site. Potential MN visits are designated in the Schedules of Events.
1, 11, 12
9.7.6.3/Malignancies
A liver ultrasound (and FibroScan, at the discretion of the Investigator) will be performed at Screening to screen for HCC. 
Thereafter, liver ultrasounds will be performed annually at each End of Year visit starting at Year 1 (Week 52) through the end 
of the study to screen for HCC. Additional liver ultrasounds may be performed prior to Week 52 and/or between the End of 
Year visits at the discretion of the Investigator.
Any development of a malignancy (except non-melanoma skin cancers) during the course of the study will be considered an
EOSI (refer to Section 10.2.1) and is subject to expedited reporting. In addition, it is recommended that genomic analyses be 
performed on any malignancy (except non-melanoma skin cancers) diagnosed during the course of the study. The study site will 
coordinate sending samples from the malignancy for genomic analyses, if available.
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9.7.6.4/Liver and 
Hepatitis Testing
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.
A liver ultrasound/FibroScan , fasting FibroTest, and liver tests (LTs) during Screening will identify anybe performed to assess 
for clinically significant hepatic dysfunctionliver disease and HCC. A FibroScan may also be performed during Screening at the 
discretion of the Investigator. Fasting FibroTest results must be available prior to BMN 270 infusion.
…
Elevated ALT levels should be evaluated according to the following plan outlined in Table 9.4.8.2.2.1 (note that these 
evaluations may indicate additional testing of LTs and FVIII levels at unscheduled visits; these unscheduled laboratory tests 
may be completed by a mobile nursing professional at sites where the use of MN services has been approved).
1, 6, 12
9.7.6.5/HIV Testing
HIV testing will be performed at Screening. Subjects with documented negative results within the last 30 days prior to 
screening do not need to be retested. Refer to Section 9.4.8.3 for guidance on monitoring of HIV-positive subjects.
4
9.7.6.6/Vital Signs, 
Physical Exams, and 
Other Safety
A complete physical examination should be performed at Screening, Week 26, Week 52, and at the End of Year visits. A
complete physical examination will include general appearance (head, eyes, ears, nose, and throat), cardiovascular, 
dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. The 
genitourinary examination may be deferred for visits after Year 1 unless the subject has genitourinary-related complaints.
12
10.2.1/EOSI
The following EOSI need to be reported to the Sponsor within 24 hours of site awareness, irrespective of seriousness, severity 
or causality: 
x
Any new diagnosis of malignancy (except non-melanoma skin cancer)
3
10.8/Urgent Safety 
Measures
The reporting period for these events which may require the implementation of urgent safety measures is the period from the 
time of signing of the ICF through the completion of the last study visit or at the Early Termination Visit (ETV). Investigators 
are required to report any events which may require the implementation of urgent safety measures to BioMarin within 24 hours
of becoming aware of the event.
12
10.9/Contact 
Information
Contact information for the medical monitor is as follows:
Nina Mitchell, MA MB BChir MScThomas Machnig, MD
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+44 (0) 207 420 34143405 (office)
+4449 (0) 7761 659 5351522/1825323 (mobile)
nina.mitchellthomas.machnig@bmrn.com
12.1/Prestudy
An ICF must be signed and dated by the subject, (or the subject’s legally authorized representative), the Investigator or designee 
and witness (if required) before any study-related procedures are performed.
11
12.2/Screening
During the first part of the Screening Period (Day -42 to Day -29), testing for AAV5 TAb titers using the ARUP screening 
assay may be performed, so that subjects can verify their AAV5 TAb status. Subjects who agree to participate in this activity
(or their legally authorized representative) will be asked to sign a separate ICF documenting this decision. Subjects who do not 
agree will have the ARUP AAV5 TAb screening assay performed along with other assessments during the regular Screening 
period.
The following procedures will be performed during the Screening Period (Day -28 to Day -1):
x
Full medical history, including hemophilia A history, Hepatitis B, Hepatitis C, and HIV. Subjects with a history of 
hepatitis B or, hepatitis C, or HIV will be asked for information about the treatments received. Any prior 
pharmacokinetics information obtained while the subject was receiving prophylactic or on-demandepisodic FVIII 
therapy prior to the study should also be collected.
x
Liver Ultrasound/FibroScan
x
Liver ultrasound to screen for hepatocellular carcinoma and clinically significant liver disease (FibroScan can be 
performed additionally at the discretion of the Investigator)
x
Screen for COVID 19SARS-CoV-2 screening (local or central testing)
o
COVID 19SARS-CoV-2 RT-PCR testing is required during Screening, and all subjects must have at 
least one negative test result prior to dosing. If the test is performed locally an additional 2nd test is 
recommended, but negative results from the 2nd test must be received prior to dosing. A SARS-CoV-2
vaccine is recommended for subjects if indicated and if available (refer to Section 9.4.8 for vaccine 
guidance).
x
Fasting FibroTest
o
Subjects will fast for at least 8 hours prior to sampling on the day of the FibroTest Screening visit. 
Fasting FibroTest results must be available prior to BMN 270 infusion.
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12.2.1/Smart 
Rescreening
If a patient has to be screened again because the original assessments have fallen out of the 28 + 14 day period allowed for 
Screening (refer to Section 12.2), then only the following assessments need to be performed (rather than the full list indicated in 
Section 12.2) for the patient to be successfully re-screened for the study:
x
Screen for COVID 19SARS-CoV-2 screening (local or central testing)
o
COVID-19SARS-CoV-2 RT-PCR testing is required during smart rescreening, and all subjects must 
have at least one negative test result prior to dosing. If the test is performed locally an additional 2nd test 
is recommended, but negative results from the 2nd test must be received prior to dosing. A SARS-CoV-2
vaccine is recommended for subjects if indicated and if available (refer to Section 9.4.8 for vaccine 
guidance)
5
12.3/Baseline
The following procedures will be performed during the Baseline Period:
x
Thrombin Generation Assay
x
Cytokine bead array assayprofiling
7, 12
12.4/Infusion Visit
The following procedures will be performed during the BMN 270 Infusion Visit:
x
Brief physical examination (pre-infusion)
x
Assessment of Adverse Events and Concomitant Medications (pre-infusion)
x
Fasting FibroTest
x
Complement panel and exploratory cytokine profiling
o
Complement panel should include C3, C3a, C4, Bb, and sC5b-9 and should be collected within 2 hours 
post-BMN 270 infusion.
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 within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4,
Bb, sC5b-9, and cytokine bead arrayprofiling, as well as possible additional exploratory testing) and samples for IgE and 
cytokine bead arrayprofiling (and possible additional exploratory testing) between 8 -24 hours after the reaction, if possible. In 
addition, a blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead 
arrayprofiling . 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. Exploratory biomarker samples at baseline and at post-infusion study visits 
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may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity 
reactions" as described in the rationale of changes.
12.5/Infusion 
Follow-Up Visits
If the investigator at a participating site determines that MN services are appropriate for a patient and the patient (or his legally 
authorized representative, if required) gives written informed consent to participate in MN visits, the MN network will 
communicate with the patient and the patient’s site.
11
12.5.1.1/Day 2
On Study Day 2, the following assessments will be performed:
x
Cytokine bead array assayprofiling
12
12.5.1.3/Day 8
On Study Day 8, the following assessments will be performed:
x
Cytokine bead array assayprofiling
12
12.5.2.1/Once per 
Week, Weeks 2-26
The following procedures will be performed once per week from Weeks 1 through 26:
x
Liver Tests (refer to Table 9.7.6.34.1)
o
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT 
values are > ULN or ≥ 1.5x baseline value) or based onupon discussion between the Medical Monitor 
and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during 
periods when a subject’s ALT is ≥3x ULN.
6
12.5.2.8/Weeks 2, 6, 
10, 14, 20, 24, 26
The following procedure will be performed at Weeks 2, 6, 10, 14, 20, 24, and 26:
x
Cytokine bead array assayprofiling
12
12.5.2.11/Week 16
The following procedure will be performed at Week 16:
x
Testing for reactivation of hepatitis B and hepatitis C (only in subjects with evidence of prior exposure to hepatitis B 
and/or hepatitis C)
o
Subjects who receive therapeuticreactive 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.
6
12.5.2.12/Weeks 20, 
24, 26
The following procedure will be performed at Weeks 20, 24, and 26:
x
Thrombin Generation Assay
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12.5.3.1/Every Visit 
Weeks 27-52
At every visit (Weeks 27-36, 38, 40, 42, 44, 46, 48, 50, and 52), the following procedures will be performed:
x
Liver Tests (refer to Table 9.7.6.34.1)
o
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT 
values are > ULN or ≥ 1.5x baseline value) or based onupon discussion between the Medical Monitor 
and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during 
periods when a subject’s ALT is ≥ 3x ULN.
6
12.5.3.4/Weeks 32, 36, 
44, 52
At Weeks 32, 36, 44, and 52, the following procedures will be performed:
x
Cytokine bead array assayprofiling
12
12.5.3.5/Weeks 32, 36, 
40, 44, 48, 52
At Weeks 32, 36, 40, 44, 48, and 52, the following procedures will be performed:
x
TGA Assay
7
12.5.3.7/Week 52
At Week 52, the following procedures will be performed:
x
Liver ultrasound
o
Additional liver ultrasounds may be performed prior to Week 52 at the discretion of the Investigator.
2
12.6/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 orand inability to maintain independence from prophylactic FVIII replacement therapy due to joint 
bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the 
Medical Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of Year 
visits during Years 2-5.
8
12.6.1/Years 2-5, 
Every 6 Weeks
During Years 2-5, every 6 weeks (± 2 weeks), the following procedures will be performed:
x
Liver Tests (refer to Table 9.7.6.34.1)
o
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT 
values are > ULN or ≥ 1.5x baseline value) or based onupon discussion between the Medical Monitor 
and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during 
periods when a subject’s ALT is ≥ 3x ULN.
x
FVIII Assays
o
FVIII protein assay 
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12.6.2/Years 2-5, 
Every 12 Weeks and 
End of Year Visits
At the every 12 week and End of Year visits, the following procedures will be performed:
x
Brief physical examination (at every 12 week visits) or complete physical examination (at End of Year visits;
genitourinary examination may be deferred)
x
Liver Tests (refer to Table 9.7.6.34.1)
o
LTsLT assessment may be monitoredchecked more or less frequently (and in particular when ALT 
values are > ULN or ≥ 1.5x baseline value) or based onupon discussion between the Medical Monitor 
and the Investigator and review of subject data, but LTs will be monitored at least twice weekly during 
periods when a subject’s ALT is ≥3x ULN.
x
AAV5 TAb Assay (at Week 64, Week 76, Week 88, Week 104, then at End of Year visit for Years 3-5)
x
AAV5 TI Assay (at End of Year visit for Years 2-5 only)
x
FVIII antibody titer (at Week 64, Week 76, Week 88, Week 104, then at End of Year visit for Years 3-5)
x
PBMC collection
x
Cytokine profiling
x
PBMC collection (at Week 64, Week 76, Week 88, Week 104, Week 128, Week 156, Week 180, Week 208, Week 
232, and Week 260)
x
TGA Assay
x
Liver ultrasound (at End of Year visits only)
o
Additional liver ultrasounds may be performed at interim time points (ie, between the End of Year visits) 
at the discretion of the Investigator.
2, 6, 7, 9, 
12
12.7/ETV
At the Early Termination visit, as many of the following assessments as possible should be done:
x
Cytokine bead array assayprofiling
x
PBMC collection for CTL baseline
x
Thrombin Generation Assay
x
Liver ultrasound
2, 7, 12
14.2/Efficacy Analysis
The subjects will be followed in a longitudinal manner, and all the relevant information will be collected. The analysis of the 
data will be descriptive in nature, but data collected in a longitudinal manner may be analyzed using longitudinal methods, such 
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as mixed effect model, which take into account the correlation among the observations taken at various time points within a 
subject. Efficacy is a secondary endpoint, defined as biologically active FVIII at ≥ 5 IU/dL at 26 weeks following study 
treatment. FVIII activity will be assessed weekly during the study period.
14.6/Changes in Study 
Conduct
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/EC, and all active subjects (or their legally authorized representative, if 
required) must again provide informed consent.
11
17/CRFs and Source 
Documents
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 (or their legally authorized representative) 
must also allow access to their medical records, and subjects (or their legally authorized representative) will be informed of this 
and will confirm their agreement when giving informed consent.
11
18/Study Monitoring
Qualified individuals designated by BioMarin will monitor all aspects of the study according to GCP and standard operating 
procedures for compliance with applicable government regulations. The Investigator agrees to allow these monitors direct 
access to the clinical supplies, dispensing, and storage areas and to the clinical files, including original medical records, of the 
study subjects, and, if requested, agrees to assist the monitors. The Investigator and staff are responsible for being present or 
available for consultation during routinely scheduled site visits conducted by BioMarin or its designees. When in person site 
monitoring or source data verification cannot be conducted, remote site monitoring and/or source data verification will be 
conducted where allowed by country and local health authorities and ECs/IRBs.
12
21/References
Haemo-QoL Study Group.  Scoring Manual.  Available at: http://haemoqol.de/scoring/ manual. Last accessed 28 July 201717
May 2021.
National Center for Biotechnology Information (NCBI). LiverTox: Clinical and Research Information on Drug-Induced Liver 
Injury. Available at: https://livertox.nih.gov (last accessed 20 August 202017 May 2021).
Pasi KJ, Rangarajan S, Mitchell N, Lester W et al. First in human Evidence of Durable Therapeutic Efficacy and Safety of 
Durable Therapy Over Three years with Valoctocogene Roxaparvovec for Severe Haemophilia A (BMN 270 201 Study). Res 
Pract Thromb Haemost. 2019;3(S2):2.
Reilly, M. WPAI Scoring. 2002. Available at: http://www.reillyassociates.net/ WPAI_Scoring.html. Last accessed 28 July 
201717 May 2021.
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Srivastava, A, Brewer, AK, Mauser Bunschoten, EP, Key, NSSantagostino E, Dougall A, Kitchen S et. al. WFH guidelines for 
the management of hemophilia 128., 3rd edition. Haemophilia 19[. 2020;26(Suppl 6):1], e1 47. 2013-158.
United States Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. 
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. 2019. Available at: 
http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf (last accessed 17 May 2021).
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