Final Analysis of the Phase 1/2 Trial of Valoctocogene Roxaparvovec for Severe Haemophilia A

Valoctocogene roxaparvovec is an adeno-associated virus vector serotype 5 (AAV5)-mediated gene therapy for severe haemophilia A (HA).

Report the final safety and efficacy results of the phase 1/2 trial of valoctocogene roxaparvovec.

An open-label phase 1/2 trial (NCT02576795) enrolled adult males with severe HA (factor VIII [FVIII] ≤1 IU/dL) without FVIII inhibitors, anti-AAV5 antibodies, or liver dysfunction to receive 6 × 10¹³ or 4 × 10¹³ vg/kg valoctocogene roxaparvovec. Efficacy endpoints included FVIII activity (chromogenic), annualized bleeding rate (ABR) of treated bleeds, annualized FVIII infusion rate, and quality of life. Safety was assessed by adverse events (AEs). Year seven 6 × 10¹³ vg/kg cohort results were reported previously.

Five of six 4 × 10¹³ vg/kg cohort participants completed the 7-year study. Mean FVIII activity peaked within year 1 for the 4 × 10¹³ cohort (week 52 FVIII, 21.1 IU/dL) and decreased to 4.2 IU/dL at the end of year 7. Across all follow-up, mean ABR declined 87% from baseline to 1.6 bleeds/year and mean annualized FVIII use declined 93% to 10.3 infusions/year. Overall, 3/5 of the 4 × 10¹³ participants remain off prophylaxis. Haemo-QOL-A Total Score was mostly stable from baseline. The last treatment-related AE (TRAE) of alanine aminotransferase elevation occurred in year 1. No serious TRAEs occurred after year 1. No participants had thromboembolic events or developed FVIII inhibitors.

Over 7 years, valoctocogene roxaparvovec increased FVIII activity from baseline and improved haemostasis compared with FVIII prophylaxis for most participants. The 6 × 10¹³ vg/kg dose was more efficacious than 4 × 10¹³ vg/kg. No concerning long-term safety signals were identified.