Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A

Journal article

Background Valoctocogene roxaparvovec, an adeno-associated virus-mediated gene therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) expression and provides bleed protection. Objectives Determine valoctocogene roxaparvovec durability, efficacy, and safety 4 years post-treatment. Methods In the phase 3 GENEr8-1 trial, 134 adult males with severe hemophilia A without inhibitors and previously using FVIII prophylaxis received a 6x1013 vg/kg infusion of valoctocogene roxaparvovec. Efficacy endpoints included annualized bleed rate (ABR), annualized FVIII infusion rate, FVIII activity, and the Haemophilia-Specific Quality of Life Questionnaire for Adults (Haemo-QOL-A). Adverse events (AEs) and immunosuppressant use were assessed. Change from baseline was assessed after participants discontinued prophylaxis (scheduled for week 4). Results Median follow-up was 214.3 weeks; 2 participants discontinued since the previous data cutoff. Declines from baseline in mean treated ABR (−82.6%; P<0.0001) and annualized FVIII infusion rate (−95.5%; P<0.0001) were maintained from previous years in the primary analysis population of 112 participants who enrolled from a noninterventional study. During year 4, 81/110 rollover participants experienced 0 treated bleeds. Week 208 mean and median chromogenic FVIII activity were 16.1 IU/dL and 6.7 IU/dL, respectively, in 130 modified intention-to-treat (mITT) participants. Seven participants resumed prophylaxis since the previous data cutoff. Mean change from baseline to week 208 in Haemo-QOL-A Total Score (P<0.0001) remained clinically meaningful for mITT participants. Alanine aminotransferase elevation was the most common AE during year 4 (56/131 participants); none required immunosuppressants. Conclusions Valoctocogene roxaparvovec provides persistent FVIII expression, hemostatic control, and health-related quality of life improvements with no new safety signals

Authors: Madan, B; Ozelo, MC; Raheja, P; Symington, E; Quon, DV

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Journal of Thrombosis and Haemostasis
• Volume: 22
• Issue: 7
• Pages: 1880-1893
• Publication date: 2024-04-12
• DOI: 10.1016/j.jtha.2024.04.001
• EISSN: 1538-7836
• ISSN: 1538-7933
• Language: English
• Keywords: Genetics; Medicine; Gene; Genetic enhancement; Pediatrics; Internal medicine; Biology