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FDA Signs Off on Restart of Pfizer’s Hemophilia Gene Therapy Trial

Although the agency has cleared the trial to restart, Pfizer will extend the voluntary hold on dosing new patients while the company talks through conditions of the restart.

After lifting the clinical hold on Pfizer’s phase 3 AFFINE trial (NCT04370054) of giroctocogene fitelparvovec (SB-525; PF-07055480) for the potential treatment of hemophilia A in March 2022, the US Food and Drug Administration (FDA) has now cleared the trial to restart, the company announced in its first-quarter earnings call.1

However, Pfizer claims it will continue to hold off on dosing new patients while working through “updated study protocols” with the regulatory agency.

The hemophilia A gene therapy program, in development by Pfizer and Sangamo Therapeutics, was halted in November 2021 after some participants who received the therapy experienced Factor VIII (FVIII) activity greater than 150%.2

“Pfizer was recently made aware of an event of below-the-knee deep vein thrombosis in 1 trial participant with elevated Factor VIII levels. This patient had a history of thrombotic events prior to participation in the study, which is a known risk factor for subsequent events and an exclusion criterion for participation in AFFINE,” Pfizer reported in the earnings statement. “The case was assessed to understand all potential contributing factors, including missed doses of investigator-prescribed direct oral anti-coagulants. The patient is reported to be doing well.”

The company expects to resume dosing in the AFFINE trial in the third quarter of 2022.

Overall, the study expects to enroll 63 participants with hemophilia A who have been followed on routine prophylaxis with FVIII products in the lead-in study (NCT03587116). The study is primarily assessing efficacy via annualized bleeding rate (ABR) over 12 months compared with ABR on FVIII replacement therapy as seen in the lead-in study period. Secondary outcome measures include FVIII activity levels, annualized infusion rate of exogenous FVIII activity, annualized FVIII consumption, joint health, patient-reported outcomes, quality-of-life measures, and adverse events (AEs) for up to 5 years after treatment.

The phase 1/2 Alta study (NCT03061201) previously demonstrated that giroctocogene fitelparvovec was generally well tolerated.3 The 5 patients in the high-dose cohort sustained FVIII activity levels without bleeds or the need for prophylactic factor through up to 85 weeks. FVIII activity levels were clinically meaningful, with a geometric mean of around 71% between weeks 9 and 52. Pfizer and Sangamo dosed the first participant in the AFFINE study in October 2020.

Giroctocogene fitelparvovec encodes complementary deoxyribonucleic acid for B domain deleted human FVIII, which is delivered via the AAV6 vector. The therapy is optimized for liver-specific expression by incorporating multi-factorial modifications to the liver-specific promoter module, FVIII transgene, synthetic polyadenylation signal, and vector backbone sequence. The FDA previously granted orphan drug, fast track, and regenerative medicine advanced therapy designations to the gene therapy. The EMA has also granted it orphan medicinal product designation.

The FDA also recently approved the restart of Pfizer’s phase 3 CIFFREO study (NCT04281485), which is evaluating its experimental mini-dystrophin gene therapy fordadistrogene movaparvovec, formerly known as PF-06939926, for the treatment of Duchenne muscular dystrophy in ambulatory patients.4

  1. Pfizer reports first-quarter 2022 results. Earnings release. Pfizer. May 3, 2022. https://s28.q4cdn.com/781576035/files/doc_financials/2022/q1/Q1-2022-PFE-Earnings-Release.pdf
  2. Johnson, V. Hemophilia A gene therapy placed on clinical hold. CGTLive. Published November 24, 2021. Accessed May 4, 2022. https://www.cgtlive.com/view/hemophilia-a-gene-therapy-clinical-hold
  3. Pfizer and Sangamo dose first participant in phase 3 study evaluating hemophilia A gene therapy treatment. News release. Pfizer. October 7, 2020. Accessed November 23, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-sangamo-dose-first-participant-phase-3-study
  4. Ward, A. FDA clears Pfizer to resume phase 3 gene therapy trial for duchenne muscular dystrophy. CGTLive. Published April 28, 2021. Accessed May 4, 2022. https://www.cgtlive.com/view/fda-clears-pfizer-to-resume-phase-3-gene-therapy-trial-for-duchenne-muscular-dystrophy