Pfizer and Sangamo Announce Updated Phase 1/2 Results Demonstrating Sustained Factor VIII Activity Levels Through One Year Following Giroctocogene Fitelparvovec Gene Therapy in Severe Hemophilia A

Compiled by Keke

On December 7, Pfizer and gene therapy company Sangamo Therapeutics jointly announced the latest follow-up data from the Phase 1/2 clinical study Alta of their investigational gene therapy giroctocogene fitelparvovec (also known as SB-525 or PF-07055480) for patients with severe hemophilia A at the 62nd Annual Meeting of the American Society of Hematology (ASH). The data included patients with up to 85 weeks of treatment. Results showed that all five patients in the high-dose cohort (3×10¹³ vg/kg) had been followed for at least one year, and all maintained sustained levels of human coagulation factor VIII (FVIII) activity. Chromogenic assay results indicated that from Week 9 to Week 52, the median FVIII activity level in the treatment group was 56.9%, and the geometric mean FVIII activity was 70.4%.

Furthermore, all patients in the 3×10¹³ vg/kg dose cohort achieved stable FVIII activity within 9 weeks post-treatment, with no bleeding events or need for FVIII infusions during the first year. As of August 31, 2020, one patient experienced a target joint bleed requiring FVIII treatment; however, this case occurred after Week 52 of treatment.

The Alta study is an open-label, dose-ranging, multicenter Phase 1/2 clinical trial designed to evaluate the safety and tolerability of giroocotogene fitelparvovec in patients with severe hemophilia A. Eleven male patients, with a mean age of 30 years (range: 18–47 years), were assigned to four dose cohorts (9 × 10¹¹ vg/kg, n=2; 2 × 10¹² vg/kg, n=2; 1 × 10¹³ vg/kg, n=2; and 3 × 10¹³ vg/kg, n=5). Following one year of follow-up for all patients in the study, participants were assessed every six months until they entered the long-term follow-up study.

The study also demonstrated that giroocotogene fitelparvovec was generally well tolerated. As previously mentioned, only one patient in the 3 x 10^13 vg/kg dose cohort experienced treatment-related serious adverse events, including hypotension (Grade 3) and fever (Grade 2), accompanied by headache and tachycardia. These symptoms occurred within 6 hours after drug administration and completely resolved within 24 hours. As of August 31, no other treatment-related serious adverse events were reported.

However, Pfizer also noted that among the 5 patients in the 3 x 10^13 vg/kg dose cohort, 4 received corticosteroid treatment to address elevated liver enzyme (alanine transaminase, ALT) levels. Three of these patients subsequently experienced ALT elevations that responded to corticosteroids. All episodes of alanine aminotransferase elevation were fully resolved with oral corticosteroids. As of August 31, no trial participants were using corticosteroids, nor had any initiated corticosteroid use after 52 weeks.

Pfizer and Sangamo Therapeutics plan to provide further follow-up data from the Alta study after all five patients in the 3 x 10^13 vg/kg dose cohort have been followed for at least two years. Patients with hemophilia A lack the protein required for normal factor VIII (FVIII) activity, leading to an increased risk of spontaneous bleeding and bleeding following injury or surgery. It is a lifelong condition requiring continuous monitoring and treatment. The two pharmaceutical companies believe that this investigational gene therapy has the potential to replace the current burdensome standard of care for patients with hemophilia A.

Pfizer and Sangamo also presented the Phase 3 AFFINE study (NCT04370054), an open-label, multicenter, single-arm study designed to evaluate the efficacy and safety of a single infusion of giroocotogene fitelparvovec in more than 60 adult male participants with moderate-to-severe or severe hemophilia A. Eligible participants will have completed at least six months of routine factor VIII (FVIII) prophylactic therapy in a Phase 3 study (NCT03587116) to collect pre-treatment data on efficacy and selected safety parameters. The primary endpoint is the effect of giroocotogene fitelparvovec treatment on the annualized bleeding rate (ABR) at 12 months post-treatment, compared with the ABR during prior FVIII prophylactic replacement therapy. Secondary endpoints include FVIII activity levels at steady state at study entry and at 12 months after infusion of giroocotogene fitelparvovec.

The investigational gene therapy giroocotogene fitelparvovec comprises a recombinant adeno-associated virus serotype 6 (AAV6) vector encoding complementary DNA for B-domain–deleted human factor VIII (FVIII). The expression cassette of this therapy is designed to optimize liver-specific expression of the FVIII protein and supports high-yield vector production; its transcription cassette incorporates multifactorial modifications, including a liver-specific promoter module, the FVIII transgene, a synthetic polyadenylation signal, and vector backbone sequences. Currently, the U.S. Food and Drug Administration (FDA) has granted this therapy orphan drug, fast track, and Regenerative Medicine Advanced Therapy (RMAT) designations, while the European Medicines Agency (EMA) has also awarded it orphan drug designation. Giroocotogene fitelparvovec is part of a global development and commercialization collaboration agreement between Sangamo Therapeutics and Pfizer for hemophilia A gene therapy. In late 2019, Sangamo Therapeutics transferred the manufacturing technology and the Investigational New Drug (IND) application for this therapy to Pfizer.

Reference Source:

1.Pfizer and Sangamo Announce Updated Phase 1/2 Results Showing Sustained Factor VIII Activity Levels in 3x1013 VG/KG Cohort Through One Year Following Hemophilia A Gene Therapy

2.PFIZER AND SANGAMO ANNOUNCE UPDATED PHASE 1/2 RESULTS SHOWING SUSTAINED FACTOR VIII ACTIVITY LEVELS AND NO BLEEDING EVENTS OR FACTOR USAGE IN 3E13 VG/KG COHORT FOLLOWING GIROCTOCOGENE FITELPARVOVEC (SB-525) GENE THERAPY

3.Update for the Alta Study, a Phase 1/2 Gene Therapy Trial of Giroctocogene Fitelparvovec (SB-525) in Adults With Severe Hemophilia A