Efficacy and Safety of Giroctocogene Fitelparvovec in Adults with Moderately Severe to Severe Hemophilia Α: Primary Analysis Results from the Phase 3 ΑFFINE Gene Therapy Trial
Authors: Leavitt Andrew D. , Kavakli Kaan , Frenzel Laurent , Antmen Ali Bülent , Ozelo Margareth , Matino Davide , Alzahrani Hazza , Konkle Barbara A. , Pipe Steven W. , Teitel Jerome M. , Tseng Li-Jung , Fang Annie F. , Ganne Florence , Dirusso Gregory , Rupon Jeremy , Klaus Pascal , Healy Jasmine , Agathon Delphine , Biondo Francesca , Plonski Frank 
Published: December 2024

Background
Giroctocogene fitelparvovec (PF-07055480), a hepatocyte-directed recombinant AAV serotype 6 vector encoding a B-domain-deleted variant of human factor VIII (FVIII), is a single-dose gene therapy aimed at enabling sustained endogenous FVIII expression in individuals with hemophilia A (HA). We present results from the primary analysis of an ongoing pivotal phase 3 study to evaluate the efficacy and safety of giroctocogene fitelparvovec in participants with moderately severe to severe HA.
Methods
AFFINE (NCT04370054) is a phase 3, open-label, single-arm trial that enrolled adult men with HA (FVIII:C ≤1%) who completed a lead-in study while on exogenous FVIII prophylaxis therapy prior to administration of a single infusion of 3e13 vg/kg giroctocogene fitelparvovec. Primary and secondary endpoints were assessed in the efficacy population corresponding to participants with ≥15 months follow-up post infusion and ≥6 months follow-up in the lead-in study (n=50). The primary endpoint was annualized bleeding rate (ABR) for total (treated and untreated) bleeds from Week 12 (estimated onset of clinically meaningful transgene-derived FVIII levels) through ≥15 months (up to data cutoff) post infusion compared with the pre-infusion prophylaxis period. Key secondary endpoints were the percentage of participants with FVIII activity &gt;5% (chromogenic assay) at 15 months and ABR for treated bleeds. Annualized infusion rate (AIR) of exogenous FVIII replacement from Week 12 to ≥15 months post infusion was a secondary endpoint. Additional secondary endpoints, including the incidence and severity of adverse events (AEs), were assessed for all dosed participants (n=75).
Results
As of June 2024, 75 participants (median age, 30 years [range 19-59]) were dosed with giroctocogene fitelparvovec (median duration of follow-up, 16.8 months [range 7.8-44.4]). Of those, 50 were included in the efficacy population (median duration of follow-up, 33.6 months [range 14.5-44.4]). Within this population, the study met its primary endpoint with a statistically significant decrease (non-inferiority and superiority; 1-sided P=0.004) in total ABR from Week 12 through ≥15 months post infusion vs pre-infusion prophylaxis (mean total ABR, 1.24 vs 4.73; treatment difference, −3.49 [95% CI: −6.06, −0.91]). At Month 15, 84% of participants had FVIII activity &gt;5% (95% CI: 70.9, 92.8; 1-sided P=0.0086 vs null hypothesis of ≤68%). Most participants continued to maintain FVIII activity &gt;5% at later timepoints (82.8% at Year 2 [n=29]). Treated ABR during Week 12 through ≥15 months post infusion was significantly reduced vs prophylaxis (mean treated ABR, 0.07 vs 4.08; treatment difference, −4.01 [95% CI: −5.57, −2.45]; 1-sided P&lt;0.0001), also demonstrating superiority. During the same period, 64% of participants had no bleeds and 88% of participants had no treated bleeds. AIR post infusion was reduced by 99.8% vs the pre-infusion period (mean AIR, 0.2 vs 124.4). At data cutoff, 1 (1.3%) dosed participant had resumed prophylaxis (at 16.1 months post infusion). A total of 624 AEs, mostly mild or moderate, were reported in 74 (98.7%) participants. There were 26 serious AEs (SAEs) in 15 (20%) participants, with pyrexia the most common (n=5 [6.7%]). The most common treatment-related AEs were pyrexia (in 54.7%), alanine aminotransferase (ALT) increased (in 46.7%), and headache (in 38.7%). There have been no study discontinuations. Post infusion, 62.7% of participants received ≥1 dose of corticosteroids due to ALT elevations or decreases in FVIII activity (median time to initiation, 84 days [range 7-193] and mean total time on corticosteroids, 114.6 days [range 11-296]). AEs related to corticosteroids were reported in 19 (25.3%) participants. Transient FVIII activity &gt;150% (defined as ≥1 central chromogenic assay measurement &gt;150%) was reached in 37 (49.3%) participants; based on protocol recommendations and upon investigator's decision, 23 (30.7%) were treated with prophylactic direct oral anticoagulants, which was well tolerated.
Conclusions
Giroctocogene fitelparvovec yielded endogenous FVIII expression in the mild to normal range in most participants, and resulted in superior bleed protection vs routine FVIII prophylaxis and significant reductions in bleeding. A single infusion was well tolerated and demonstrated durable efficacy on all primary and key secondary endpoints.