Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia Α

Introduction: Hemophilia A, a sex-linked (F8 gene) disorder of hemostasis, results in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)–mediated gene transfer enables the delivery of a modified functional F8 coding sequence to hepatocytes. This subsequently synthesizes FVIII at levels preventing unprovoked bleeding events in the absence of exogenous FVIII. We present updated results with nearly 3-year follow-up on all participants from Alta, an ongoing gene therapy study in patients with severe hemophilia A (FVIII activity <1%).

Methods: The phase 1/2 Alta study (NCT03061201) is a dose-ranging study of giroctocogene fitelparvovec (PF-07055480, previously called SB-525), which is a recombinant AAV serotype 6 vector encoding a modified B-domain–deleted F8 coding sequence. Giroctocogene fitelparvovec was infused into adults aged ≥18 years with severe hemophilia A in 4 cohorts (n=2 each) across 4 ascending doses: 9e11, 2e12, 1e13, and 3e13 vg/kg. The 3e13-vg/kg dose cohort was expanded with 3 additional participants. Key endpoints included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. We present data with nearly 3 years of follow-up (data cutoff date: May 20, 2022).

Results: Eleven male patients participated in the study (mean [SD] age, 30.3 [7.8] years; White, 81.8%). As of the cutoff date, participants had been followed for 147 to 247 weeks and 2 had not completed 3 years (156 weeks) . The most common treatment-related adverse events (AEs) reported in the highest dose cohort (3e13-vg/kg) included elevated liver enzymes and infusion-related reactions (n/N [%]): increased alanine aminotransferase (ALT; 3/5 [60.0%]), increased aspartate aminotransferase (AST; 2/5 [40.0%]), pyrexia (3/5 [60.0%]), and tachycardia (2/5 [40.0%]). Treatment-related serious AEs were reported in 1 participant (in the 3e13-vg/kg cohort) who experienced hypotension and fever with onset ≈6 h after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge the next day. AEs (all causality) of ALT increases requiring ≥7 days of corticosteroids were observed in 4 of the 5 participants in the 3e13-vg/kg cohort: elevations in ALT were managed with a tapering course of corticosteroids (median duration: 56 days; range: 7–135 days), with maintenance of efficacious levels of FVIII activity, as evidenced by a lack of bleeding events around the time of corticosteroid treatment and minimal bleeding events afterwards. No participant in the 3e13-vg/kg cohort developed a confirmed inhibitor to FVIII, and there have been no thrombotic events or hepatoma detected. The three of the 5 participants in the 3e13-vg/kg cohort with available data through Week 156 had mean FVIII activity maintained in the mild to normal range (Table). Of the data available for the remaining 2 participants, 1 maintained FVIII activity levels in the mild range through Week 130 and 1 participant had FVIII activity levels below lower level of quantification (<3%) as measured with a chromogenic assay and 5.4% measured with a 1-stage assay at Week 130. In this cohort, the mean annualized total bleeding rate [(number of all bleeding episodes starting 3 weeks after study drug infusion) / (observation period in years)] was 0 for the first year postinfusion and 0.9 throughout the total duration of follow-up. In the 3e13-vg/kg cohort, 2 participants experienced an overall total of 12 bleeding events necessitating treatment with exogenous FVIII (participant 1 (n=1 event): circumstances of bleed unknown, event occurred in a target joint; participant 2 (n=11): 6 traumatic; 4 spontaneous; 1 unknown, no events occurred in a target joint). No participants in the 3e13-vg/kg cohort have resumed prophylaxis.

Conclusions: A single infusion of giroctocogene fitelparvovec gene therapy in participants with severe hemophilia A remains generally well tolerated over a period of nearly 3 years postinfusion, with associated increases in FVIII levels in the moderate to normal range, without sustained AEs and with minimal overall bleeding in the highest-dose cohort (3e13 vg/kg). The ongoing phase 3 study (NCT04370054) in a larger cohort will provide more long-term data to further characterize the safety and durability of giroctocogene fitelparvovec in patients with moderately severe to severe hemophilia A.