Final Full Clinical Study Report
Protocol C0371002

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: Phase 3, Open Label, Single Arm Study to Evaluate Efficacy and Safety of FIX
Gene Transfer With PF-06838435 (rAAV-Spark100-hFIX-Padua) in Adult Male ParticipantsWith Moderately Severe to Severe Hemophilia B (FIX:C≤2%) (BeneGene-2)
Study Number: C0371002
Regulatory Agency or Public Disclosure Identifier Number: 2018-003086-33,
NCT03861273
Study Phase: 3
Name of Study Intervention:
PF-06838435 /fidanacogene elaparvovec
Trade Name : PF-06838435 (trade name not yet assigned)
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date:

Document
VersionFinal CSR
(primary
completiondate) Version
1.0

ReportDate
22
February
2023

Number of Study Center(s) and Investigator(s):A list of study centers and investigators involved in this study is provided inAppendix 16.1.4.1.
Publications:
Not Applicable
Study Period:
Study Initiation Date: FSFV 29 July 2019
Primary Completion Date: 16 November 2022
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Final Full Clinical Study Report
Protocol C0371002

CLINICAL STUDY REPORT SYNOPSIS

List of Abbreviations
Abbreviation
AAV

Definition
adeno-associated virus vector

ABR

annualized bleeding rate

ADA

antidrug antibody

AESI

adverse events of special interestAIRannualized (FIX) infusion rate

ALP

alkaline phosphatase

ALT

alanine transaminase

aPTT

activated partial thromboplastin time

AST

aspartate aminotransferase

BMI

body mass index

BU

Bethesda Unit

CD4

cluster of differentiation 4

CSR

clinical study reportdL

deciliterDNA

deoxyribonucleic acidEQ-5D-5L

EuroQol, 5 dimensions, 5 levels

FIX

Factor IX

FIX:C

Factor IX circulating

FSFV

first subject first visit

Haem-A-QoL

Haemophilia Quality of Life Questionnaire for Adults

HAL

Haemophilia Activities List
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CLINICAL STUDY REPORT SYNOPSIS

Abbreviation
HBsAg

Definition
Hepatitis B surface antigen

HBV

hepatitis B virus

HCV

hepatitis C virus

hFIX-Padua

Padua mutation (R338L) of the human factor IX geneHIVhuman immunodeficiency virus

HJHS

Hemophilia Joint Health Score

HLIQ

Hemophilia Life Impacts Questionnaire

INR

international normalized ratio

IV

intravenous

MRI

magnetic resonance imaging

nAb

neutralizing antibody

PBMC

peripheral blood mononuclear cellPROpatient reported outcome

qPCR

quantitative polymerase chain reaction

RNAribonucleic acid

SAE

serious adverse event

SAP

statistical analysis planSDstandard deviation

SEstandard error

SMQStandardized MedDRA Queries

TAT

thrombin antithrombin level

TEAE

treatment-emergent adverse event
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CLINICAL STUDY REPORT SYNOPSIS

Abbreviation
TGA

Definition
thrombin generation assay

ULN

upper limit of normal

vg/kg

vector genomes per kilogram

Rationale:
The published data from the Phase 1/2a study for fidanacogene elaparvovec (SPK-9001-101)
indicate that treatment of hemophilia B with fidanacogene elaparvovec offers considerable
clinical advantage over routine prophylactic treatment with FIX product. A single infusion offidanacogene elaparvovec results in sustained FIX activity levels in the mild to normal range
with associated low bleeding rates and a marked reduction in the number of infusions of FIX
product. This Phase 3 confirmatory study will compare the efficacy of fidanacogene
elaparvovec treatment with routine prophylaxis administered as a part of usual care with theobjective to establish non inferiority and possibly superiority.

Objectives, Endpoints, and Statistical Methods:
The objectives and endpoints are provided in Table 1.
Table 1.
Type
Primary
Efficacy

Study Objectives and Endpoints

Objective

Endpoint

To demonstrate the efficacy of asingle infusion of fidanacogene
elaparvovec in male participants≥18 years of age with moderately
severe to severe hemophilia B(FIX:C ≤2%).

Primary endpoint: Non-inferiority on ABR for total
bleeds (treated and untreated) from
Week 12 to Month 15 versus
standard of care FIX prophylaxis
replacement regimen, comparing preand post-IP infusion.

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CLINICAL STUDY REPORT SYNOPSIS

Table 1.
Type
Secondary
Efficacy

Efficacy

Study Objectives and Endpoints
ObjectiveKey secondary objectives: To
demonstrate the efficacy offidanacogene elaparvovec in terms of
the use of exogenous FIX, the treatedbleeds, and FIX:C.

To compare additional efficacy
parameters post- fidanacogene
elaparvovec infusion to baseline inorder to further characterizefidanacogene elaparvovec treatment,
including use of exogenous FIX,
information on bleeding events, andpatient reported outcomes addressing
health related quality of life,
activities of daily living and general
health status.

EndpointKey secondary endpoints:


Non-inferiority on ABR fortreated bleeds from Week 12 toMonth 15 versus standard of care
FIX prophylaxis replacement
regimen, comparing pre- andpost-IP infusion.

AIR of exogenous FIX from
Week 12 to Month 15 versus
AIR of FIX with standard of care
FIX replacement regimen pre-IP
infusion.



Vector-derived FIX:C level atsteady state (from Week 12 to
15 months) demonstrated to begreater than 5%. FIX:C will also
be summarized descriptively bystudy visit.

The following parameters were comparedwith standard of care FIX replacement
regimen, comparing pre- and post-IP
infusion from Week 12 to Month 15:Annualized FIX consumption.

Annualized number of bleeding
events of specific type: spontaneousand traumatic, and untreated.

Frequency of target joint bleeds.

Percentage of the participants without
bleeds.
The following parameters were comparedwith standard of care FIX replacement
regimen, comparing pre- and post-IP
infusion at 12 months:
Change in joint health as measured
by the HJHS instrument.



PRO instruments:

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Haem-A-QoL Physical Healthdomain.



HAL Complex Lower Extremity
Activities Component Score.

Final Full Clinical Study Report
Protocol C0371002

CLINICAL STUDY REPORT SYNOPSIS

Table 1.

Study Objectives and Endpoints

Type
Safety

Objective
Safety and tolerability offidanacogene elaparvovec, including
immunogenicity, for the study
duration of 6 years after
fidanacogene elaparvovec infusion

Endpoint
Incidence and severity of adverse
events collected during the study.

Adverse Events of special interest:

EfficacyAssess durability of efficacy up to
6 years.

Hypersensitivity reactions;

Clinical thrombotic events;



FIX inhibitors,



Hepatic malignancies.



Drug related elevated hepatictransaminases that fail to
improve or resolve

Malignancy assessed as having
reasonable possibility of being
related to study drug

Other immunogenicity-basedlaboratory data including: nAb to
AAV capsid, immune response(presumed T-cell activation) to AAV
capsid protein and/or FIX transgene.

The following parameters were assessed
throughout the 6-year study period.
Summaries were provided for the overall
follow-up period, as well as by yearlyintervals:

ABR for total bleeds (treated anduntreated).



ABR for treated bleeds.

AIR of exogenous FIX.



Vector-derived FIX:C level by study
visit and the geometric mean at eachyearly interval.



Annualized FIX consumption.

Annualized number of bleeding
events of specific type: spontaneousand traumatic, and untreated.



HJHS total score.

Frequency of target joint bleeds.

PROs instruments:

Haem-A-QoL Physical Healthdomain.



HAL Complex Lower Extremity
Activities Component Score.

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CLINICAL STUDY REPORT SYNOPSIS

Table 1.

Study Objectives and Endpoints

Type
Tertiary/Exploratory
Pharmacodynamics 

Efficacy

EfficacyObjective
Pharmacodynamics of fidanacogene
elaparvovec.

To compare joint health postfidanacogene elaparvovec infusion tobaseline.

Impact on coagulation.

Endpoint

Vector shedding of fidanacogene
elaparvovec as measured by qPCR in
plasma, saliva, PBMC, urine, andsemen until 3 consecutive specimens
test negative for the given specimen
type.



FIX antigen levels.



Number of target joints.



Joint status as assessed by X-ray insome participants who consent toparticipate in an optional sub-study.



Joint status as assessed by MRI in
some participants who consent toparticipate in an optional sub-study.



Efficacy

To compare additional efficacy
parameters post-fidanacogene
elaparvovec infusion in order tofurther characterize fidanacogene
elaparvovec treatment in terms ofpatient-reported outcomes assessing
hemophilia life impacts and global
health status.

PRO instruments: Haem-A-QoL(domains not previously specified),
HAL (scores not previously
specified), HLIQ, and EQ-5D-5L, inthe first 12 months and annually inthe follow-up period, years 2-6.

The planned analyses, analysis populations, statistical tests, and determination of sample size
are described in the final version of the SAP and in the protocol. Any major modifications of
the primary endpoint definition and/or its analysis subsequent to the protocol finalization
were reflected in a protocol amendment.

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Protocol C0371002

CLINICAL STUDY REPORT SYNOPSIS

Methodology:
This Phase 3, open-label, single arm, multi-site study compared the efficacy of a single IV
infusion of fidanacogene elaparvovec with routine FIX prophylaxis in adult male participantsfrom the lead-in study (C0371004) with moderately severe to severe hemophilia B (FIX:C≤2%). Study C0371004 prospectively collected efficacy data and selected safety data on
participants for at least 6 months and these data are utilized as the FIX prophylaxis control
for comparison with data post-fidanacogene elaparvovec infusion in Study C0371002.
Eligible study participants completed a minimum 6 months of routine FIX prophylaxis
therapy during the lead in study (C0371004). The planned study duration for each participant
in this study was 312 weeks.

Number of Participants (planned and analyzed):
This study was conducted at 28 sites. A total of 45 participants were randomized in 27
centers in 13 countries.
A total of 51 participants who completed the lead-in study (C0371004) were screened in thisstudy and 45 participants received a single dose of fidanacogene elaparvovec. Since no morethan a single dose of study treatment on Day 1 was administered during the study, there wereno treatment discontinuations.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Key inclusion criteria were as follows:Participants completed at least 6 months of routine FIX prophylaxis therapy during thelead-in study (C0371004) prior to providing consent at the screening visit for this study.

Participants had documented moderately severe to severe hemophilia B, defined as FIX:C≤2%.

Participants agreed to suspend prophylaxis therapy for hemophilia B after administrationof the study intervention. FIX replacement therapy was allowed as needed.



Acceptable screening laboratory values as follows:

Hemoglobin ≥11 g/dL;

Platelets ≥100,000 cells/µL;

Creatinine ≤2.0 mg/dL.

Male.
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Protocol C0371002

CLINICAL STUDY REPORT SYNOPSISContraceptive use by men should be consistent with local regulations regarding themethods of contraception for those participating in clinical studies.



Male participants are eligible to participate if they agree to the following for at least
time required for 3 consecutive ejaculate samples to test negative for vector shedding:o Refrain from donating sperm.
PLUS either:Be abstinent from heterosexual or homosexual intercourse as their preferredand usual lifestyle (abstinent on a long term and persistent basis) and agree toremain abstinent.
ORMust agree to use contraception/barrier as detailed below:

Agree to use male condom when engaging in any activity that allows for passageof ejaculate to another person

Key exclusion criteria were as follows:Anti-AAVRh74var nAb titer ≥1:1 (ie, positive for nAb), performed by a central
laboratory during screening.



Prior history of inhibitor to FIX or positive inhibitor testing as measured by the central
laboratory ≥0.6 BU during screening. Clinical signs or symptoms of decreased response
to FIX.



Known hypersensitivity to FIX replacement product or IV immunoglobulin
administration.



History of chronic infection or other chronic disease that investigator deems as anunacceptable risk.



Any concurrent clinically significant major disease or condition that the investigatordeems unsuitable for participation or other acute or chronic medical or psychiatriccondition including recent (within the past year) or active suicidal ideation or behavior(including alcoholism) or laboratory abnormality that may increase the risk associatedwith study participation or may interfere with the interpretation of study results and, inthe judgment of the investigator, would make the participant inappropriate for entry into
this study.
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CLINICAL STUDY REPORT SYNOPSIS

ALT, AST, ALP >2×ULN, based on central laboratory results.

Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN was acceptable if bilirubin was
fractionated and direct bilirubin <35%), based on central laboratory results.

Current unstable liver or biliary disease per investigator assessment defined by thepresence of ascites, hepatic encephalopathy, coagulopathy, hypoalbuminemia, esophageal
or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease(including Gilbert’s syndrome, asymptomatic gallstones) was acceptable if the participant
otherwise met entry criteria.

Previously dosed in a gene therapy research trial at any time or in an interventional
clinical study within the last 12 weeks, excluding participation in study C0371004.

Significant liver disease, as defined by pre-existing diagnosis of portal hypertension,
splenomegaly, or hepatic encephalopathy.

Active hepatitis B or C; HBsAg, HBV-DNA positivity, or HCV-RNA positivity.



Serological evidence of HIV-1 or HIV-2 infection with either CD4+ cell count ≤200 mm3
or viral load >20 copies/mL.

Sensitivity to heparin or heparin induced thrombocytopenia.

Study Interventions, Dose, Mode of Administration, and Batch Number(s):Table 2.

Study Intervention(s) Administered

Investigational
Product Description

Vendor Lot
No.

Pfizer Lot
No.

PF-06838435 (SPK-9001)
Solution for Infusion, 1
mL/vial265-18001

18-003889

vg/ml

SOLUTION

PF-06838435 Solution for
Infusion, 1 mL/vial

H000018074CF0718

19-003791

vg/mL

SOLUTION

PF-06838435 Solution for
Infusion, 1 mL/vial

H000018074AH6804

19-002008

vg/mL

SOLUTIONPFIZER CONFIDENTIAL
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Strength/
Potency

Dosage Form

Final Full Clinical Study Report
Protocol C0371002

CLINICAL STUDY REPORT SYNOPSIS

Table 2.

Study Intervention(s) Administered

Investigational
Product Description

Vendor Lot
No.

Pfizer Lot
No.

PF-06838435 Solution for
Infusion, 1 mL/vial

H000018074CF0718;19003791

PA2035938

Strength/
Potency
vg/mL

Dosage Form
SOLUTION

Duration of Study Intervention:
The study intervention, a single infusion of fidanacogene elaparvovec, a gene transfer agent,
was administered on Day 1 at a dose of 5×1011 vg/kg of body weight (based on actual lot
concentration). For a participant with BMI >30 kg/m2, dose was calculated based on an
adjusted body weight determination that assumes a maximum permissible BMI of 30 kg/m2.
The manufacturing lot numbers for the study intervention dispensed in this study areprovided in Table 2.
Summary of Results:
Demographic and Other Baseline Characteristics:
All participants were male and the majority of the study participants were <35 years of age.
The median age was 29.00 years (min, max 18.0, 62.0 years), White (33 [73.3%])
participants, and not Hispanic or Latino or Spanish origin (35 [77.8%] participants). All (45[100.0%]) participants had a factor mutation. Target joints at baseline were identified in 13(28.9%) participants.
Exposure:
The actual dose was adjusted from the planned dose when a participant’s BMI was>30kg/m2.
Efficacy Results:With a one-time infusion, fidanacogene elaparvovec at a dose of 5×1011 vg/kg
resulted in statistically significant reduction in ABRtotal and ABRtreat compared toroutine FIX prophylaxisA statistically significant reduction in annualized infusion rate (AIR) represents asignificant improvement over FIX prophylaxis regimen
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Final Full Clinical Study Report
Protocol C0371002

CLINICAL STUDY REPORT SYNOPSISAt Month 15, the mean and median FIX:C was in the mild range across the 3 assays.
Mean steady state (geometric mean of measurements from Week 12 to Month 15)
FIX:C using One-stage assay with Actin-FSL and SynthASil reagent, andchromogenic assay was significantly higher than the pre-specified fixed threshold of5%.

ABRtotal, ABRtreat and AIR are similar during Year 2 and Year 3.

In parallel with reduced AIR, participants treated with fidanacogene elaparvovec hada significant reduction in mean FIX consumption from Week 12 to Month 15
compared to FIX prophylaxis.

Mean ABRtotal of specific types (spontaneous, joint, soft tissue/muscle/other andtarget joint) from Week 12 to Month 15 post-infusion were significantly reduced
comparing to mean ABRtotal collected in the run-in period up to vector infusion

Hemophilia Joint Health Score (HJHS) improved during the course of the first
12 months post-infusion with fidanacogene elaparvovec.



Post infusion with fidanacogene elaparvovec, statistically significant improvementfrom baseline was observed in patient-reported outcomes at Week 52 in Physical
Health Domain score of the Haem-A-QoL and in the Complex Lower Extremity
Activities component score of the Hemophilia Activities List (HAL), with the samemeasures assessed annually from baseline throughout the study.

Safety Results:
Over the total follow-up period, the TEAEs reported were generally mild or moderate.
A total of 205 TEAEs were reported in 38 (84.4%) participants during the entire study. SAEs
were reported in 7 (15.6%) participants. TEAEs for the first year, regardless of causality
were consistent with those reported during the overall follow-up.
Safety Conclusions


Fidanacogene elaparvovec was well tolerated in adult hemophilia B participants withlong-term follow-up of up to 3 years, based on current data.

Overall liver health was stable in the setting of elevation in transaminases in nearly
half of the population evaluated (46.7% had ALT elevation and 44.4% had AST
elevation) and corticosteroid use in ~60% for presumed cellular immune response.

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CLINICAL STUDY REPORT SYNOPSIS

There were no discontinuations from the study due to the occurrence of adverse
events.



Two treatment-related SAEs (duodenal ulcer hemorrhage and associated anemia)
occurred in one subject in the setting of corticosteroid use with no concomitant use ofgastric acid secretion inhibitor.



No AESIs of thrombotic events, development of FIX inhibitors, hepatic malignancies,
or malignancies related to study drug were observed with fidanacogene elaparvovec.
No serious AESIs were observed for hypersensitivity reactions (based on
hypersensitivity SMQ) and hepatic transaminases (most elevations in hepatictransaminases were mild to moderate and all events resolved with corticosteroid
treatment).

Pharmacokinetic Results:
In 17 participants in the Vector Shedding Substudy Analysis Set,
time to peak concentrations (mean[±SD]) were:

Plasma:Time to peak concentration (mean [±SD]) was 1.2 (0.39) days

PBMC:





Time to peak concentration (mean [±SD]) was 7.4 (22.22) days

Semen:
Time to peak concentration (mean [±SD]) was 3.8 (3.65) days

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Final Full Clinical Study Report
Protocol C0371002

CLINICAL STUDY REPORT SYNOPSISTime to peak concentration (mean [±SD]) was 1.2 (0.44) days

Urine:


Time to peak concentration (mean [±SD]) was 1.6 (0.50) days

Similar results for peak vector DNA concentrations and time to peak concentrations in the
Dosed Analysis Set were observed.
After reaching the peak within a matrix, vector DNA concentration declined steadily until
vector DNA concentration was undetectable (below limit of quantification).
In general, PBMCs were the slowest to clear with a mean (±SD) and median (min, max) timeto last undetectable vector of 163.3 (109.44) days and 130.0 (39, 513) days in the 45
participants included in the Dosed Analysis Set:


Plasma was 98.6 (54.69) days and 93.0 (30, 317) daysSemen was 41.1 (20.09) days and 35.0 (15, 104) days

Saliva was 42.4 (17.23) days and 37.0 (29, 105) daysUrine was 20.4 (13.26) days and 21.0 (4, 87) days

Note: This summary is based on central laboratory data without DNase treatment.

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CLINICAL STUDY REPORT SYNOPSIS

Immunogenicity ConclusionsAll participants developed nAb against AAVRh74var capsid following fidanacogene
elaparvovec infusion that persisted through the 1-year post-treatment periodThe development of ADA against AAVRh74var in majority of the participants(95.1%) post fidanacogene elaparvovec infusion did not appear to prevent
transduction in the 1-year post-treatment period.

Conclusions:Fidanacogene elaparvovec has demonstrated a favorable benefit risk assessment in the 45
participants that have been treated as part of this study. It demonstrated hemostatic efficacy
as demonstrated by a low ABR, FIX activity in the mild range in over 80% of participants
and low rate of infusions along with significant improvements in quality-of-life assessments.
It was generally well tolerated including overall liver health in the setting of corticosteroid
use in over 60% of participants.

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