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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

29 Jan 2020 → ongoing

Decision date (initial)

2024-04-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Pfizer Inc., 66 Hudson Boulevard East, New York, NY 10001, USA

External identifiers

EU CT number

2022-502844-11-00

EudraCT number

2018-003086-33

ClinicalTrials.gov

NCT03861273

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Efficacy, Therapy, Pharmacogenetic, Pharmacodynamic, Pharmacokinetic, Safety

To demonstrate the efficacy of a single infusion of PF-06838435 in male participants ≥18 years of age with moderately severe to severe hemophilia B (FIX:C ≤2%).

Secondary objectives 4

1. Key secondary objectives: To demonstrate the efficacy of PF-06838435 in terms of the use of exogenous FIX, the treated bleeds, and FIX:C.
2. To compare additional efficacy parameters post-PF-06838435 infusion to baseline in order to further characterize PF-06838435 treatment, including use of exogenous FIX, information on bleeding events, and patient reported outcomes addressing health related quality of life, activities of daily living and general health status
3. Safety and tolerability of PF-06838435, including immunogenicity, for the study duration of 6 years after PF-06838435 infusion
4. Assess durability of efficacy up to 6 years

Conditions and MedDRA coding

severe to moderately severe hemophilia B (FIX:C ≤ 2%)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Paul Ehrlich Institute

Plan to share 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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1 Participants must have completed at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy as per their usual care during the lead-in study (C0371004) prior to providing consent at the screening visit for this study.
2. 2 Participants who have documented moderately severe to severe hemophilia B, defined as FIX:C ≤2%.
3. 3 Participants who have previous experience with FIX therapy (≥50 documented exposure days to a FIX protein product such as recombinant, plasma-derived, or extended half-life FIX product).
4. 4 Participants must agree to suspend prophylaxis therapy for hemophilia B after administration of the IP. FIX replacement therapy is allowed as needed
5. 5 Acceptable screening laboratory values as follows: • Hemoglobin ≥11 g/dL; • Platelets ≥100,000 cells/µL; • Creatinine ≤2.0 mg/dL.
6. 6 Sex: Male. Participants are eligible to participate if they agree to the following requirements starting on Day 1/Visit 3 (IP infusion visit) and continue until at least 3 consecutive ejaculate samples test negative for vector shedding: • Refrain from donating sperm. PLUS either: • Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR •Must agree to use contraception/barrier as detailed below: •Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person
7. 7 Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol. • For German sites please refer to Germany Appendix
8. 8 Participants between the ages of 18 (or the minimum country specific age of consent if >18) and ≤65 years, inclusive, at Visit 1 (Screening Period).

Exclusion criteria 20

1. 1 Anti-AAVRh74var nAb titer above the established threshold (ie, positive for nAb), performed by a central laboratory during screening. nAb testing may be repeated, if necessary. In such cases, a new sample must be drawn for re-testing.
2. 19 Sensitivity to heparin or heparin induced thrombocytopenia.
3. 7 Alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) >2 × upper limit of normal (ULN), based on central laboratory results
4. 20 Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or the sponsor’s medical monitor, contraindicates participation in the study.
5. 2 Prior history of inhibitor to FIX or positive inhibitor testing as measured by the central laboratory ≥0.6 Bethesda Units (BU) during screening. Clinical signs or symptoms of decreased response to FIX.
6. 3 Known hypersensitivity to FIX replacement product or intravenous immunoglobulin administration
7. 4 History of chronic infection or other chronic disease that investigator deems as an unacceptable risk
8. 6 Any concurrent clinically significant major disease or condition that the investigator deems unsuitable for participation or other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior (including alcoholism) or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. In addition, any participant with a history of a neoplasm (including hepatic malignancy) that required treatment (eg, chemotherapy, radiotherapy, immunotherapy), is excluded, except for adequately treated basal or squamous cell carcinoma of the skin or a surgically removed benign neoplasm not requiring chemotherapy, radiotherapy, and/or immunotherapy. Any other neoplasm that has been cured by resection should be discussed between the investigator and sponsor.
9. 8 Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%), based on central laboratory results
10. 5 Any participant with conditions associated with increased thromboembolic risk, such as known inherited or acquired thrombophilia, or a history of thrombotic events including but not limited to: stroke, myocardial infarction, and/or venous thromboembolism.
11. 11 Any participant with a planned surgical procedure requiring FIX surgical prophylactic factor treatment in the next 15 months.
12. 10 Currently on antiviral therapy for hepatitis B or C
13. 12 Participants using therapies that are restricted
14. 13 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
15. 14 Active hepatitis B or C; HBsAg, HBVDNA positivity, or HCVRNA positivity.
16. 15 Significant liver disease, as defined by preexisting diagnosis of portal hypertension, splenomegaly, or hepatic encephalopathy. Additionally, during screening, a serum albumin level below normal limits and/or significant liver fibrosis by one of the following diagnostic modalities (please note only 1 test is needed for screening purposes): FibroScan median stiffness score >8 kPa units OR Fibro Test/FibroSURE >0.48*. A FibroScan is preferred if available. If there is concern regarding the FibroTest or the FibroScan results due to a confounding medical history (eg, proteinuria can impact FibroTest result), or in the event of conflicting results between the modalities, the investigator should contact the sponsor. *Please note: if a participant has a known history of Gilbert's syndrome, a FibroTest cannot be used for fibrosis testing. However, the participant could be tested using FibroScan.
17. 16 Serological evidence of HIV1 or HIV2 infection with either CD4+ cell count ≤200 mm3 and/or a viral load >20 copies/mL, and remain on highly active antiretroviral therapy (HAART) throughout the study.
18. 17 Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or participants who are Pfizer employees, including their family members, directly involved in the conduct of the study.
19. 18 Unable to comply with scheduled visits, treatment plan (participants must agree to suspend prophylaxis therapy for hemophilia B after administration of the study intervention), laboratory tests, and other study procedures for up to six years postinfusion of PF-06838435 in the investigator’s judgement.
20. 9 Current unstable liver or biliary disease per investigator assessment defined by the presence 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, is acceptable if the participant otherwise meets entry criteria).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Non-inferiority on annualized bleeding rate (ABR) for total bleeds (treated and untreated) from Week 12 to Month 15 versus usual care FIX prophylaxis replacement regimen, comparing pre- and post-IP infusion

Secondary endpoints 10

1. Non-inferiority on ABR for treated bleeds from Week 12 to Month 15 versus usual care FIX prophylaxis replacement regimen, comparing pre- and post-IP infusion
2. Annualized infusion rate (AIR) of exogenous FIX from Week 12 to Month 15 versus AIR of FIX with usual care FIX replacement regimen pre IP infusion
3. Vector derived FIX:C level at steady state (from Week 12 to 15 months) demonstrated to be greater than 5%. FIX:C will also be summarized descriptively by study visit
4. The following parameters will be compared with usual 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: spontaneous and traumatic, and untreated. •Frequency of target joint bleeds. •Percentage of the participants without bleeds.
5. The following parameters will be compared with usual care FIX replacement regimen, comparing pre- and post-IP infusion at 12 months: •Change in joint health as measured by the Hemophilia Joint Health Score (HJHS) instrument. •PRO instruments: •Haem A QoL Physical Health domain;•HAL Complex Lower Extremity Activities Component Score
6. Incidence and severity of adverse events collected during the study.
7. Adverse Events of special interest: •Hypersensitivity reactions; • Clinical thrombotic events; • FIX inhibitors, • Hepatic malignancies. • Drug related elevated hepatic transaminases that fail to improve or resolve • Malignancy assessed as having reasonable possibility of being related to study drug
8. Other immunogenicity-based laboratory data including: immune response (presumed T-cell activation) to AAV capsid protein and/or FIX transgene
9. The following parameters will be assessed throughout the 6-year study period according to the SoA. Summaries will be provided for the overall follow-up period, as well as by yearly intervals: •Annualized Bleeding Rate for total bleeds (treated and untreated). • ABR for treated bleeds. •AIR of exogenous FIX. • Vector-derived FIX:C level by study visit and the geometric mean at each yearly interval.
10. (continued from endpoint no. 9) • Annualized FIX consumption. • Annualized number of bleeding events of specific type: spontaneous and traumatic, and untreated. • HJHS total score. • Frequency of target joint bleeds. • PROs instruments. • Haem A QoL Physical Health domain. • HAL Complex Lower Extremity Activities Component Score.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

235 East 42nd Street

City

New York

Postcode

10017-5703

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Trials.gov Call Centre

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Trials.gov Call Centre

Third parties 19

Locations

7 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

17 submissions — initial application plus substantial / non-substantial modifications