Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial

• Published in: Research and practice in thrombosis and haemostasis Vol. 8; no. 8; p. 102615
• Main Authors: Leavitt, Andrew D., Mahlangu, Johnny, Raheja, Priyanka, Symington, Emily, Quon, Doris V., Giermasz, Adam, López Fernández, Maria Fernanda, Kenet, Gili, Lowe, Gillian, Key, Nigel S., Millar, Carolyn M., Pipe, Steven W., Madan, Bella, Chou, Sheng-Chieh, Klamroth, Robert, Mason, Jane, Chambost, Hervé, Peyvandi, Flora, Majerus, Elaine, Pepperell, Dominic, Rivat, Christine, Yu, Hua, Robinson, Tara M., Ozelo, Margareth C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Wiley; Elsevier
• Subjects: adeno-associated virus; clinical trial; gene therapy; hemophilia A; Life Sciences; Original; quality of life; clinical trial; hemophilia A; gene therapy; adeno-associated virus; quality of life
• ISSN: 2475-0379; 2475-0379
• DOI: 10.1016/j.rpth.2024.102615

Valoctocogene roxaparvovec, an adeno-associated virus-mediated gene therapy for severe hemophilia A, enables endogenous factor (F)VIII expression and provides bleed protection. Determine valoctocogene roxaparvovec durability, efficacy, and safety 4 years after treatment. In the phase 3 GENEr8-1 trial, 134 adult male persons with severe hemophilia A without inhibitors and previously using FVIII prophylaxis received a 6 × 1013 vg/kg infusion of valoctocogene roxaparvovec. Efficacy endpoints included annualized bleed rate, annualized FVIII infusion rate, FVIII activity, and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Adverse events and immunosuppressant use were assessed. Change from baseline was assessed after participants discontinued prophylaxis (scheduled for week 4). Median follow-up was 214.3 weeks; 2 participants discontinued since the previous data cutoff. Declines from baseline in mean treated annualized bleed rate (−82.6%; P < .0001) and annualized FVIII infusion rate (−95.5%; P < .0001) were maintained from previous years in the primary analysis population of 112 participants who enrolled from a noninterventional study. During year 4, 81 of 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 participants. Seven participants resumed prophylaxis since the previous data cutoff. Mean change from baseline to week 208 in Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score (P < .0001) remained clinically meaningful for modified intention-to-treat participants. Alanine aminotransferase elevation was the most common adverse event during year 4 (56/131 participants); none required immunosuppressants. Valoctocogene roxaparvovec provides persistent FVIII expression, hemostatic control, and health-related quality of life improvements with no new safety signals. •Valoctocogene roxaparvovec is an approved gene therapy for severe hemophilia A.•The phase 3 GENEr8-1 trial enrolled adult men with severe hemophilia A without factor VIII inhibitors.•Bleeds were reduced ≥4 years with acceptable safety; 24 of 134 participants resumed prophylaxis.•Self-reported health-related quality of life remains improved 4 years after treatment.