Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study

Abstract

Patients with hemophilia A require exogenous factor VIII (FVIII) or nonfactor hemostatic agents to prevent spontaneous bleeding events. Adeno-associated virus (AAV) vector-based gene therapy is under clinical investigation to enable endogenous FVIII production. Giroctocogene fitelparvovec is a recombinant AAV serotype 6 vector containing the coding sequence for the B-domain-deleted human F8 gene. In the ongoing phase 1/2, dose-ranging Alta study, 4 sequential cohorts of male participants with severe hemophilia A received a single IV dose of giroctocogene fitelparvovec. The primary end points are safety and changes in circulating FVIII activity. Interim results up to 214 weeks after treatment for all participants are presented. Eleven participants were dosed. Increases in alanine and aspartate aminotransferases were the most common treatment-related adverse events (AEs), which resolved with corticosteroid administration. Two treatment-related serious AEs (hypotension and pyrexia) were reported in 1 participant within 6 hours of infusion and resolved within 24 hours after infusion. At the highest dose level (3 × 1013 vg/kg; n = 5), the mean circulating FVIII activity level at week 52 was 42.6% (range, 7.8%-122.3%), and at week 104 it was 25.4% (range, 0.9%-71.6%) based on a chromogenic assay. No liver masses, thrombotic events, or confirmed inhibitors were detected in any participant. These interim 104-week data suggest that giroctocogene fitelparvovec is generally well tolerated with appropriate clinical management and has the potential to provide clinically meaningful FVIII activity levels, as indicated by the low rate of bleeding events in the highest dose cohort. This trial was registered at www.clinicaltrials.gov as #NCT03061201.

Graphical abstract

Figure 1.

Summary of FVIII activity, ALT, AST, and corticosteroid dosing for individual participants in cohort 4 (giroctocogene fitelparvovec dose: 3 × 10¹³ vg/kg). Administration of corticosteroids (start and end) is shown for participants 7 (A), 8 (B), 9 (C), 10 (D), and 11 (E); participant 9 did not use glucocorticoids. Elevations in liver enzymes were managed with corticosteroids, with stabilization of transaminase levels and FVIII activity observed over time.

Figure 2.

Changes in circulating FVIII activity. (A-B) Individual plots showing FVIII activity for individual participants in all cohorts over time based on the chromogenic (A) and 1-stage (B) assays. (C-D) Box and whisker plots showing the group mean (diamond) and median (horizontal line) with quartiles (blue boxes) and minimum to maximum (whiskers) of FVIII activity in cohort 4 at each assessment using the chromogenic (C) and 1-stage (D) assays. (A-D) For results reported as below the limit of quantitation, a value of 0.009 IU/mL (0.9%) was used for analysis and plotting.