Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial
Author(s)
Type
Journal Article
Abstract
Background
Valoctocogene roxaparvovec, an adeno-associated virus-mediated gene therapy for severe hemophilia A, enables endogenous factor (F)VIII expression and provides bleed protection.
Objectives
Determine valoctocogene roxaparvovec durability, efficacy, and safety 4 years after treatment.
Methods
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).
Results
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.
Conclusion
Valoctocogene roxaparvovec provides persistent FVIII expression, hemostatic control, and health-related quality of life improvements with no new safety signals.
Valoctocogene roxaparvovec, an adeno-associated virus-mediated gene therapy for severe hemophilia A, enables endogenous factor (F)VIII expression and provides bleed protection.
Objectives
Determine valoctocogene roxaparvovec durability, efficacy, and safety 4 years after treatment.
Methods
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).
Results
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.
Conclusion
Valoctocogene roxaparvovec provides persistent FVIII expression, hemostatic control, and health-related quality of life improvements with no new safety signals.
Date Issued
2024-11-01
Date Acceptance
2024-10-21
Citation
Research and Practice in Thrombosis and Haemostasis, 2024, 8 (8)
ISSN
2475-0379
Publisher
Wiley
Journal / Book Title
Research and Practice in Thrombosis and Haemostasis
Volume
8
Issue
8
Copyright Statement
© 2024 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39687929
PII: S2475-0379(24)00310-8
Subjects
adeno-associated virus
Cardiovascular System & Cardiology
CAREGIVERS
clinical trial
EMICIZUMAB PROPHYLAXIS
FVIII
gene therapy
Hematology
hemophilia A
IMPACT
INHIBITORS
Life Sciences & Biomedicine
OUTCOMES
PATIENT
Peripheral Vascular Disease
quality of life
Science & Technology
THERAPY
VALIDATION
Publication Status
Published
Coverage Spatial
United States
Article Number
e102615
Date Publish Online
2024-10-30