Positive topline results from phase III study of giroctocogene fitelparvovec a hemophilia A gene therapy candidate

The AFFINE study achieved its primary objective of non-inferiority, as well as superiority, of total annualized bleeding rate (ABR) from Week 12 through at least 15 months of follow up post-infusion compared with routine Factor VIII (FVIII) replacement prophylaxis treatment. Following a single 3e13 vg/kg dose, giroctocogene fitelparvovec demonstrated a statistically significant reduction in mean total ABR compared to the pre-infusion period (1.24 vs 4.73; one-sided p-value=0.0040).

Key secondary endpoints as defined by the trial protocol were met and also demonstrated superiority compared to prophylaxis. 84% of participants maintained FVIII activity greater than 5% at 15 months post-infusion (one-sided p-value = 0.0086) with the majority of participants having FVIII activity greater than 15%, and the mean treated ABR showed a statistically significant 98.3% reduction from 4.08 in the pre-infusion period to 0.07 post-infusion (from Week 12 up to at least 15 months [15-44 months]; one-sided p-value < 0.0001). Throughout the study, among all dosed participants, one participant (1.3%) returned to prophylaxis post-infusion.

In the AFFINE study, giroctocogene fitelparvovec was generally well tolerated. Transient elevated FVIII levels greater than 150% were observed in 49.3% of dosed participants, as measured via chromogenic assay, with no impact on efficacy and safety results. Serious adverse events were reported in 15 patients (20%), including 13 events reported by 10 patients (13.3%) assessed as related to treatment. Treatment-related adverse events generally resolved in response to clinical management.

“For people living with hemophilia A, the physical and emotional impact of needing to prevent and treat bleeding episodes through frequent IV infusions or injections cannot be underestimated,” said Professor Andrew Leavitt M.D., AFFINE lead investigator, Departments of Laboratory Medicine and Medicine Division of Hematology/Oncology Director, Adult Hemophilia Treatment Center, University of California, San Francisco, CA. “I’m excited by the strength of these positive results from the AFFINE trial that show giroctocogene fitelparvovec was generally well tolerated, and demonstrate the transformative potential of this gene therapy candidate to provide superior bleed protection compared with routine FVIII prophylaxis, while helping relieve the treatment burden for people living with hemophilia A.”

Giroctocogene fitelparvovec is a novel, investigational gene therapy that contains a bio-engineered AAV6 capsid and a modified B-domain deleted human coagulation FVIII gene. The goal of this investigational treatment for people living with hemophilia A is that a single infusion of giroctocogene fitelparvovec may allow them to produce FVIII themselves for an extended period of time, providing bleed protection and reducing the need for routine prophylaxis with intravenous (IV) infusions or injections.

In this Phase III study, eligible study participants were initially enrolled in a lead-in study (NCT03587116) and upon successful completion, were enrolled into the AFFINE study where they received a one-time 3e13 vg/kg dose of giroctocogene fitelparvovec by IV infusion. Participants in the AFFINE study were screened with a validated assay designed to identify individuals who test negative for neutralizing antibodies to the gene therapy vector. Clinical study participants will be evaluated in AFFINE over the course of five years, and up to a total of 15 years as part of a long-term follow-up study.

Analyses of the full Phase III dataset from the AFFINE study are ongoing and additional data will be presented at upcoming medical meetings. Giroctocogene fitelparvovec has been granted Fast Track and Regenerative Medicine Advanced Therapy designations from the FDA, as well as Orphan Drug designations in the U.S. and the European Union. Pfizer will discuss these data with regulatory authorities in the coming months.

Pfizer recently received FDA approval for Beqvez (fidanocogene elaparvovec), its hemophilia B gene therapy. Beqvez is also approved in Canada and is awaiting a decision from the European Commission following a positive opinion from the EMA’s Committee for Medicinal Products for Human Use in May 2024. Additionally, regulatory submissions for marstacimab are currently under review by the FDA and the EMA. Marstacimab is a potential novel subcutaneous therapy being studied for the treatment of people with hemophilia A and B with and without inhibitors. Pfizer announced the acceptance of the regulatory filings for the without inhibitors cohort in December 2023.

Giroctocogene fitelparvovec is being developed as part of a collaboration agreement for the global development and commercialization of gene therapies for hemophilia A between Sangamo Therapeutics and Pfizer. In late 2019, Sangamo transferred the manufacturing technology and the Investigational New Drug application to Pfizer. Under the agreement, Pfizer assumed responsibility for pivotal studies, any regulatory activities, and potential global commercialization of giroctocogene fitelparvovec.