May 5, 2022 – Pfizer/Sangamo have reported a severe adverse event (SAE) learning of a below-the-knee deep vein thrombosis (DVT) in one participant of its giroctocogene fitelparvovec clinical trial, who had elevated Factor VIII levels. A serious adverse event (SAE) is the term used to describe the occurrence of a serious health issue in a study, regardless of whether the treatment under investigation caused that health issue.

Giroctocogene fitelparvovec (SB-525 or PF-07055480) is a gene therapy trial for the treatment of haemophilia A in development by Pfizer/Sangamo Therapeutics. The Phase 3 AFFINE (NCT04370054) study is an open-label, multicentre, single-arm study to evaluate the efficacy and safety of a single infusion of giroctocogene fitelparvovec in more than 50 adult male participants (ages 18-64 years) with moderately severe to severe haemophilia A. This is an adeno-associated virus (AAV) delivering the B-domain deleted factor VIII gene.

Pfizer reported that the participant who developed a DVT had a history of thrombotic events prior to participation in the study, a known risk factor for subsequent events and an exclusion criterion for participation in AFFINE. The participant should not have been enrolled in the study, but occasionally these events can occur and are referred to as a “protocol deviation.” The case was assessed to understand all potential contributing factors, including missed doses of investigator-prescribed direct oral anti-coagulants. The patient is doing well. Pfizer shared this information with study investigators, health authorities and the independent external Data Monitoring Committee (DMC). Pfizer also responded to queries from health authorities. The World Federation of Hemophilia (WFH), EHC and National Hemophilia Foundation (NHF) is reporting this information which is available in the public domain. Further discussion may take place during the World Federation of Hemophilia (WFH) 2022 World Congress during the Coagulation Product Safety, Supply, and Access workshop: Current treatment landscape: Part 1 of 2: Safety and efficacy, to be held on Sunday, May 8th.

In November 2021, the US Food and Drug Administration (FDA) had placed AFFINE on clinical hold, following the company’s voluntary hold, to implement a protocol amendment following the observance of factor VIII levels much greater than 150% in some participants in the trial. The protocol amendment was intended to provide guidelines for clinical management of elevated factor VIII levels. Shortly after these events, in November 2021, the EHC, WFH and the NHF jointly reported on this hold.

In March 2022, the FDA lifted its above-mentioned clinical hold on the phase 3 AFFINE study. At the time, Pfizer reported that its voluntary pause would remain in place until all necessary conditions were met, including approval of updated study protocols by regulatory authorities.

Surveillance for safety issues for a new technology like gene therapy is critical for our community. Toward that end, the Gene Therapy Registry is being developed to capture most or all of the patients who are treated with gene therapy as these products are licensed.

The 3 organizations will continue to keep our patient community informed of further relevant developments.

We advise our members to contact their treating physicians and haemophilia treatment centre for any further questions.