Efficacy and Safety of Fidanacogene Elaparvovec in Adults with Moderately Severe or Severe Hemophilia B: Results from the Phase 3 BENEGENE-2 Gene Therapy Trial

Introduction Fidanacogene elaparvovec (PF-06838435, formerly SPK-9001) is an adeno-associated virus-based gene therapy vector transferring the high-activity variant of human factor IX (FIX) FIX-R338L for the treatment of hemophilia B. The aim of this study was to evaluate the efficacy and safety of fidanacogene elaparvovec in participants with moderately severe or severe hemophilia B. Method BENEGENE-2 (NCT03861273) is a phase 3, open-label, single-arm trial that enrolled adult males with hemophilia B (FIX:C≤2 IU/dL) who had completed≥6 months of FIX prophylaxis prior to administration of 5e11 vg/kg fidanacogene elaparvovec. The primary endpoint was non-inferiority on annualized bleeding rate (ABR) for total (treated and untreated) bleeds from Week 12 to Month 15 post-infusion vs the pre-infusion prophylaxis period. Key secondary endpoints included FIX activity, ABR for treated bleeds, and annualized infusion rate. Other secondary endpoints included annualized FIX consumption, ABR of specific bleed types (eg, spontaneous), and frequency of target joint bleeds. Adverse events (AEs) were monitored. Participants provided written informed consent and the study was approved by the relevant regulatory/ethics committees. Results Forty-five participants (median [range] age, 29 [18, 62] years) were dosed with fidanacogene elaparvovec. Total ABR was reduced by 71% post-fidanacogene elaparvovec treatment vs prophylaxis (mean ABR, 1.3 vs 4.4; P <0.0001; [ Fig. 1 ]) and was stable over time (0.4 at Year 3; n=21). Mean FIX activity, measured by one-stage SynthASil, one-stage Actin-FSL, and chromogenic assays, is shown in [ Fig. 2 ]. FIX activity remained relatively stable at Month 24 ([ Fig. 2 ]). Data for other secondary efficacy endpoints are shown in [ Fig. 1 ]. Twenty-eight participants (62%) received corticosteroids for presumed immune response. No deaths, infusion-related serious AEs, thrombotic events, or FIX inhibitors were reported. Fig. 1 Total bleeds, treated bleeds, annualized infusion rate and resumption of prophylaxis in the pre-infusion prophylaxis and post-infusion periods Fig. 2 Mean FIX activity levels (%) by one-stage SynthASil, one-stage Actin-FSL and chromogenic assays Conclusion Fidanacogene elaparvovec yielded endogenous FIX expression in participants with moderately severe to severe hemophilia B, resulting in significant decreases in bleeding and was generally well tolerated. Funding statement This study was sponsored by Pfizer. Publication History Article published online: 26 February 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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