Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial.
Journal
Research and practice in thrombosis and haemostasis
Journal Volume
8
Journal Issue
8
ISSN
2475-0379
Date Issued
2024-11
Author(s)
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
Klamroth, Robert
Mason, Jane
Chambost, Hervé
Peyvandi, Flora
Majerus, Elaine
Pepperell, Dominic
Rivat, Christine
Yu, Hua
Robinson, Tara M
Ozelo, Margareth C
Abstract
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 × 10 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%; < .0001) and annualized FVIII infusion rate (-95.5%; < .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 ( < .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.
Subjects
adeno-associated virus
clinical trial
gene therapy
hemophilia A
quality of life
Type
journal article