Hemophilia A Gene Therapy Displays Superiority in Phase 3 AFFINE Trial

Andrew Leavitt, MD

Credit: UCSF Health

Topline data from the Phase 3 AFFINE study demonstrate the potential advantage of giroctocogene fitelparvovec, an investigational one-time gene therapy, for the treatment of adults with moderately severe to severe hemophilia A.¹

Announced by Pfizer on July 24, 2024, giroctocogene fitelparvovec met the primary non-inferiority and key superiority objectives of total annualized bleeding rate (ABR) in a 15-month follow-up period compared with standard-of-care Factor VIII (FVIII) replacement prophylaxis.

“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,” said Andrew Leavitt, MD, AFFINE lead investigator and director of the Adult Hemophilia Treatment Center, University of California, San Francisco.¹

Giroctocogene fitelparvovec is a novel gene therapy containing a bio-engineered AAV6 capsid and a modified B-domain deleted human coagulation FVIII gene. A single infusion of the investigational therapy could allow people living with hemophilia A to produce FVIII for an extended period, allowing for bleeding protection and a reduced burden of routine prophylaxis.

AFFINE is an open-label, multi-center, single-arm study designed to assess the efficacy and safety of a single infusion of giroctocogene fitelparvovec in adult male participants (n = 75) with moderately severe to severe hemophilia A. Eligible participants were enrolled in a lead-in study and continued into AFFINE where they received a single 3e13 vg/kg dose of giroctocogene fitelparvovec by intravenous infusion.

Participants were screened with a validated assay to identify those who tested negative for neutralizing antibodies to the gene therapy vector. All AFFINE participants will be evaluated over 5 years, for up to 15 years for long-term follow-up.

In AFFINE, giroctocogene fitelparvovec met the primary endpoint and achieved non-inferiority and superiority in total ABR from Week 12 across ≥15-months follow-up post-infusion versus routine prophylaxis. After a single 3e13 vg/kg dose, the investigational gene therapy showed a statistically significant reduction in mean total ABR, compared with the pre-infusion period (1.24 vs. 4.73; P = .0040).

The study also met key secondary endpoints with superiority over prophylaxis—84% of participants maintained FVIII activity >5% at 15 months post-infusion (P =.0086), with most achieving FVIII activity ≥15%.

Participant’s average treated ABR experienced a statistically significant 98.3% reduction, from 4.08 pre-infusion to 0.07 post-infusion, from Week 12 up to >15 months (P <.0001). Among all dosed patients in AFFINE, only a single participant returned to prophylaxis post-infusion.

Giroctocogene fitelparvovec remained generally well-tolerated in the safety report—15 patients (20%) reported serious adverse events, including 13 reported by 10 patients (13.3%) deemed related to treatment, which resolved after clinical management.

Approximately half (49.3%) of dosed participants experienced transient elevated FVIII levels ≥150%, but investigators determined no impact on the efficacy and safety results.

Full analyses of the Phase 3 data on giroctocogene fitelparvovec are ongoing and are expected at upcoming medical meetings. The hemophilia A gene therapy candidate has received Fast Track and Regenerative Medicine Advanced Therapy Designations from the US Food and Drug Administration (FDA), and Orphan Drug Designations in the US and European Union.

“We are very pleased with these positive results from the Phase 3 AFFINE study demonstrating the safety and efficacy of our one-time gene therapy candidate for people with hemophilia A,” said James Rusnak, MD, PhD, senior vice president, chief development officer, Internal Medicine and Infectious Diseases, Research and Development, Pfizer.¹

Pfizer previously received FDA approval in April for fidanocogene elaparvovec (BEQVEZ™), a one-time gene therapy for adults with moderate to severe hemophilia B who are currently on factor IX (FIX) prophylaxis therapy.²

“We look forward to advancing this latest innovation to help address the medical and treatment burden associated with frequent and time-consuming IV infusions or injections, building on Pfizer’s more than 40-year effort to advance hemophilia treatment,” Rusnak added.¹

References

1. _{Pfizer Announces Positive Topline Results From Phase 3 Study of Hemophilia A Gene Therapy Candidate. July 24, 2024. Accessed July 24, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-topline-results-phase-3-study}
2. _{U.S. FDA Approves Pfizer’s BEQVEZTM (fidanacogene elaparvovec-dzkt), a One-Time Gene Therapy for Adults with Hemophilia B. April 26, 2024. Accessed July 24, 2024. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-beqveztm-fidanacogene-elaparvovec.}