A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B (BENEGENE-2)

Phase 3, Open-label, Single-arm Study to Evaluate Efficacy and Safety of FIX Gene Transfer With PF-06838435 (rAAV-Spark100-hFIX-R338L) in Adult Male Participants With Moderately Severe to Severe Hemophilia B (FIX:C ≤2%) (BeneGene-2)

This study will evaluate the efficacy and safety of PF-06838435 (a gene therapy drug) in adult male participants with moderately severe to severe hemophilia B (participants that have a Factor IX circulating activity of 2% or less). The gene therapy is designed to introduce genetic material into cells to compensate for missing or non-functioning Factor IX. Eligible study participants will have completed a minimum 6 months of routine Factor IX prophylaxis therapy during the lead in study (C0371004). Participants will be dosed once (intravenously) and will be evaluated over the course of 6 years. The main objective of the study will evaluate the annualized bleeding rate [ABR] for participants treated with gene therapy versus standard of care (SOC) therapy (FIX prophylaxis replacement regimen).

Study Overview

• Status: Active, not recruiting
• Conditions: Hemophilia B
• Intervention / Treatment: Biological: PF-06838435/ fidanacogene elaparvovec

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pfizer CT.gov Call Center; Phone Number: 1-800-718-1021; Email: ClinicalTrials.gov_Inquiries@pfizer.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
• Brazil
  • Rio de Janeiro, Brazil, 20211-030
    • Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti - HEMORIO
  • Rio de Janeiro, Brazil, 20211-030
    • Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti- HEMORIO
  • Espirito Santo
    • Vitoria, Espirito Santo, Brazil, 29047-105
      • Centro Estadual de Hemoterapia e Hematologia Marcos Daniel Santos - Hemoes
  • SÃO Paulo
    • Campinas, SÃO Paulo, Brazil, 13083-878
      • Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Medical Centre - Hamilton Health Sciences
    • Hamilton, Ontario, Canada, L8V 1C3
      • Juravinski Hospital - Hamilton Health Sciences
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
• France
  • Bron, France, 69677
    • Hopital Cardiologique Louis Pradel - CRTH
  • Paris, France, 75015
    • Hopital Necker
• Germany
  • Berlin, Germany, 10249
    • Vivantes Klinikum im Friedrichshain
  • Berlin, Germany, 10249
    • Vivantes Klinikum Friedrichshain
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn, Anstalt des öffentlichen Rechts
  • Homburg/Saar, Germany, 66421
    • Universität und Universitätsklinikum des Saarlandes
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens "LAIKO", 2nd Regional Blood Transfusion Center
• Japan
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 004-0041
      • Sapporo Tokushukai Hospital
  • Nara
    • Kashihara, Nara, Japan, 634-8522
      • Nara Medical University Hospital
  • Saitama
    • Iruma-gun, Saitama, Japan, 350-0495
      • Saitama Medical University Hospital
  • Tokyo
    • Setagaya-ku, Tokyo, Japan, 157-8535
      • National Center For Child Health And Development
• Korea, Republic of
  • Seoul, Korea, Republic of, 05278
    • Kyung Hee University Hospital at Gangdong
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • King Faisal Specialist Hospital and Research Centre
• Sweden
  • Malmö, Sweden, 205 02
    • Skåne University Hospital, Department of Hematology, Oncology and Radiation Physics
  • Malmö, Sweden, 211 24
    • ApoEx AB
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Taichung City, Taiwan, 40201
    • Chung Shan Medical University Hospital
  • Taichung City, Taiwan, 40201
    • Chung Shan Medical University
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
• Turkey
  • Adana, Turkey, 01130
    • Acibadem Adana Hospital
  • Gaziantep, Turkey, 27310
    • Gaziantep University Sahinbey Training and Research Hospital
  • Istanbul, Turkey, 34093
    • Istanbul University Oncology Institute
  • Izmir, Turkey, 35040
    • Ege University Medical Faculty Hospital
• United Kingdom
  • Glasgow, United Kingdom, G4 0SF
    • Glasgow Royal Infirmary
  • Newcastle upon Tyne, United Kingdom, NE2 4HH
    • Newcastle Upon Tyne Hospitals NHS Foundation Trust
  • Tyne & Wear
    • Newcastle Upon Tyne, Tyne & Wear, United Kingdom, NE1 4LP
      • Newcastle upon Tyne Hospitals NHS FT
    • Newcastle upon Tyne, Tyne & Wear, United Kingdom, NE2 4HH
      • Newcastle upon Tyne Hospitals NHS FT
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco - Clinical Research Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco - Outpatient Hematology Clinic
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Hemophilia and Thrombosis Center at the University of Colorado Anschutz Medical Campus
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia and Thrombosis Center, Inc
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Hospital & Health Care Center, Inc.
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia & Thrombosis Center, Inc.
  • Mississippi
    • Madison, Mississippi, United States, 39110
      • Mississippi Center for Advanced Medicine
    • Madison, Mississippi, United States, 39110
      • Madison Radiological Group
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Center for Human Phenomic Science CHPS
    • Philadelphia, Pennsylvania, United States, 19104
      • Center for Human Phenomic Science
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Blood Disorder Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Investigational Drug Service

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Males who completed 6 months of Factor IX prophylaxis therapy during the lead-in study (C0371004) prior to providing consent at the screening visit for this study.
• Documented moderately severe to severe hemophilia B (Factor IX activity < =2%)
• Previous experience with FIX therapy (=>50 documented exposure days to a FIX protein product)
• Suspension of prophylaxis therapy for hemophilia B after administration of the study drug
• Laboratory values (hemoglobin, platelets and creatinine) within study specified limits
• Agree to contraception until components of the drug are eliminated from their body
• Capable of giving signed informed consent

Exclusion Criteria

• Anti-AAVRh74var neutralizing antibodies (nAb) titer above the established threshold (ie, positive for nAb).
• History of inhibitor to Factor IX or inhibitor detected during screening. Clinical signs or symptoms of decreased response to Factor IX
• Hypersensitivity to Factor IX replacement product or IV immunoglobulin administration
• History of chronic infection or other chronic disease
• Any conditions associated with increased thromboembolic risk
• Concurrent clinically significant major disease or condition unsuitable for participation and/or may interfere with the interpretation of study results
• Laboratory values at screening visit that are abnormal or outside acceptable study limits
• Current unstable liver or biliary disease
• Currently on antiviral therapy for hepatitis B or C
• Planned surgical procedure requiring Factor IX surgical prophylactic factor treatment 15 months from screening visit
• Use of restricted therapies (e.g., blood products, acetylsalicylic acid [aspirin] or ibuprofen, other investigational therapy, and by-passing agents)
• Previously dosed in a gene therapy research trial at any time or in an interventional clinical study within 12 weeks of screening visit
• Active hepatitis B or C; hepatitis B surface antigen, hepatitis B virus deoxyribonucleic acid positivity, or hepatitis C virus ribonucleic acid positivity
• Significant liver disease
• Serological evidence of HIV1 or HIV2 infection with either CD4+ cell count <=200 mm3 and/or a viral load >20 copies/mL
• Study and sponsor staff involved in the conduct of the study and their families
• Unable to comply with study procedures
• Sensitivity to heparin or heparin induced thrombocytopenia
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-06838435/ fidanacogene elaparvovec	Biological: PF-06838435/ fidanacogene elaparvovec; Gene Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Bleeding Rate (ABR) for Total Bleeds (Treated and Untreated) From Week 12 to Month 15	ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Treated Bleed: An event necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding (protocol definition, unless specifically referring to untreated bleed). Untreated Bleed: A bleeding event not necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ABR for Treated Bleeds From Week 12 to Month 15	ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Treated Bleed: An event necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding (protocol definition, unless specifically referring to untreated bleed). This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)
Annualized Infusion Rate (AIR) of Exogenous FIX From Week 12 to Month 15	AIR = number of exogenous infusions (for any reason) received during given time period *365.25/ (Date of last day - date of first day +1) in that time period. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)
Steady State Circulating Factor IX (FIX:C) From Week 12 to Month 15	The certified central clinical laboratory analyzed the sample by two one-stage assays and a chromogenic assay. The first one-stage assay was performed on BCSXP analyzer with Actin-FSL reagent. The second one-stage assay used the same analyzer but SynthAsil as reagent. Data reported in this Outcome Measure is the geometric mean of all assessments from week 12 to Month 15.	Week 12 to Month 15
Circulating Factor IX (FIX:C) at Week 12, Week 24, Week 65	The certified central clinical laboratory analyzed the sample by two one-stage assays and a chromogenic assay. The first one-stage assay was performed on BCSXP analyzer with Actin-FSL reagent. The second one-stage assay used the same analyzer but SynthAsil as reagent.	Week 12, Week 24, Week 65
Annualized Factor IX (FIX) Consumption From Week 12 to Month 15	Annualized FIX consumption was reported by International Units per kilogram (IU/kg). This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002. Data reported in this Outcome Measure is average of all assessments from Week 12 to Month 15.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)
ABR for Spontaneous Bleeds From Week 12 to Month 15	ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Surgical procedures were excluded from summary/analyses. Spontaneous Bleeds: Bleeding for no apparent/known reason particularly into the joints, muscles, and soft tissues. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)
ABR for Traumatic Bleeds From Week 12 to Month 15	ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Surgical procedures were excluded from summary/analyses. Traumatic Bleeds: Bleeding event occurring for an apparent/known reason. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)
ABR for Untreated Bleeds From Week 12 to Month 15	ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Surgical procedures were excluded from summary/analyses. Untreated Bleed: A bleeding event not necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)
Number of Target Joint Bleeds From Week 12 to Month 15	Target Joint: Defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and ankle) into which repeated bleeds occurred (three or more spontaneous bleeds into a single joint within a consecutive 6-month period). A target joint was considered resolved when there were =<2 bleeds into the joint within a 12-month period. Joint Bleed: A bleeding episode characterized by rapid loss of range of motion as compared with baseline that was associated with any combination of the following: pain or an unusual sensation in the joint, palpable swelling, and warmth of the skin over the joint. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.	Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm)
Percentage of the Participants Without Bleeds From Week 12 to Month 15	Percentage of participants without bleeds (total bleeds and treated bleeds) were summarized by type from Week 12 to Month 15.	Week 12 to Month 15
Change From Baseline in Joint Health as Measured by the Hemophilia Joint Health Score (HJHS) Instrument at Month 12	A qualified healthcare professional assessed six joints (left ankle, right ankle, left elbow, right elbow, left knee, right knee) scored from 0 to 20 based on: duration of swelling, muscle atrophy, crepitus, flexion loss, extension loss, instability, joint pain, and strength. Gait was scored (0 to 4) based on walking, stairs, running, hopping on one leg. Total score = sum of scores from all joints + gait score ranged from 0 to 124, with the higher the number equating to more severe joint damage.	Baseline, Month 12
Change From Baseline in Hemophilia Quality of Life (Haem A QoL) Physical Health Domain at Month 12	The Haem-A-QoL questionnaire contained 46 items with ten domains that assessed health in the following areas: Physical Health; Feelings; View of Self; Sports and Leisure; Work and School; Dealing with Haemophilia; Treatment; Future; Family Planning; and Partnership and Sexuality. The physical health domain was considered as the primary domain in this questionnaire, had a transformed score range from 0 to 100, with lower scores representing higher quality of life. In this Outcome Measure Physical Health domain scores of Haem A QoL are reported.	Baseline, Month 12
Change From Baseline in Hemophilia Activities List (HAL) Complex Lower Extremity Activities Component Score at Month 12	The HAL was a multiple domain measure of the impact of hemophilia on functional abilities in adults. The 7 domains of this instrument contained 42 items in total, as follows: lying/sitting/kneeling/standing; lower (leg) functioning; upper (arm) functioning; transportation; self-care; household tasks; and sports/leisure. Selected items from five of the domains were used to create three components: upper extremity; basic lower extremity; and complex lower extremity activities. The component score of "complex lower extremity activities" was the most important in this questionnaire, had a transformed score range from 0 to 100, higher values indicated less functional limitations in performing tasks.	Baseline, Month 12
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
Number of Participants With Adverse Events of Special Interest	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
Number of Participants With Positive Neutralizing Antibody (nAb) to Adeno-associated Virus Vector (AAV) and Anti-Drug Antibody (ADA)	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
ABR for Total Bleeds (Treated and Untreated) Through the Study	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
ABR for Treated Bleeds Through the Study	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
AIR of Exogenous Factor IX Through the Study	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
FIX: C Level Through the Study	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
Annualized Factor IX Consumption Through the Study	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
ABR for Spontaneous and Traumatic, and Untreated Bleeds Through the Study	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
Change From Baseline in Joint Health as Measured by the HJHS Instrument Through the Study	Results would be posted at secondary completion date.	Baseline, 6 years
Number of Target Joint Bleeds Through the Study	Results would be posted at secondary completion date.	Maximum up to 6 years (Week 312) after PF-06838435 infusion
Change From Baseline in Haem A QoL Physical Health Domain Through the Study	Results would be posted at secondary completion date.	Baseline, Maximum up to 6 years (Week 312) after PF-06838435 infusion
Change From Baseline in HAL Complex Lower Extremity Activities Component Score Through the Study	Results would be posted at secondary completion date.	Baseline, 6 years

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2019
• Primary Completion (Actual): November 16, 2022
• Study Completion (Estimated): July 4, 2030

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Gene Therapy; Hemophilia B; Infusion; Hemophilia; FIX; Factor IX; PF 06838435; rAAV Spark100 hFIX Padua; BeneGene 2; Hematological Diseases; Annualized bleeding rate (ABR); rAAV Spark100-hFIX-R338L; R338L
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: C0371002; 2018-003086-33 (EudraCT Number); 2022-502844-11-00 (Other Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes