Pfizer and Sangamo voluntarily paused the trial after participants experienced FVIII activity levels of over 150%.
The FDA has placed Pfizer and Sangamo Therapeutics’ phase 3 AFFINE study (NCT04370054) of giroctocogene fitelparvovec (SB-525; PF-07055480) for the potential treatment of hemophilia A on clinical hold.1,2
The hold follows the companies’ voluntary pause of screening and dosing in the trial after some treated participants experienced Factor VIII (FVIII) activity greater than 150%. No patients have experienced thrombotic events and some have been treated with anticoagulants to reduce this risk. The trial will be paused until protocols are amended.
“Ensuring the safety of study participants is our first priority. All participants in the Phase 3 study are under close observation and are being carefully monitored for thrombotic events and FVIII activity levels, as per study protocol. Those participants with FVIII activity greater than 150% are being closely monitored and managed by the study investigators," Pfizer wrote in a study update.1
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 to 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.
“We are committed to resuming patient dosing in this phase 3 program and believe this gene therapy, if approved, could represent an important treatment option for patients with hemophilia A. We will submit the protocol amendment and associated documents to Health Authorities in the countries where the trial is being conducted and respond to the FDA clinical hold to obtain agreements to proceed. In addition, Ethics Review Boards approvals for the clinical management guidelines and other proposed changes will be obtained before the amendment will be implemented. We expect dosing will resume once these are completed. This will happen at different times for each site depending on local review timelines,” Pfizer wrote.1
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.