Hemophilia A is an inherited bleeding disorder resulting from a deficiency of the functional clotting protein factor VIII. Severe haemophilia A is defined as a factor VIII activity level of less than 1 IU per deciliter, and common complications include spontaneous bleeding and debilitating arthropathy. The current standard of care is prophylactic factor VIII treatment¹. However, even with this treatment regimen, many patients still experience spontaneous bleeding, highlighting the need for more effective treatments.
GENEr8-1
Valoctogenic roxaparvovec gene therapy involves the use of an adeno-associated virus vector to direct the production of exogenous factor VIII protein by administration of a B-domain deleted human factor VIII coding sequence. A recent open-label, single-arm, phase III study (GENEr8-1 study) published in NEJM investigated the change in the number of annual treated bleeds in 134 men with severe haemophilia A, who received factor VIII prophylaxis and also received a single infusion of valoctogene roxaparvovec². After a follow-up of 2 years, the balance was drawn up.
Findings
Data were available for a total of 132 patients at the two-year follow-up time point. It was found that the mean annual number of treated bleeds decreased by 84.5% from the baseline value in patients receiving the valoctogene roxaparvovec gene therapy treatment. In addition, annual factor VIII use was reduced by 98.2% from baseline to post-prophylaxis.
Factor VIII activity also increased from baseline by an average of 22 IU per deciliter as measured by a chromogenic assay in the modified intention-to-treat population. The risk of joint bleeding was estimated at 1 episode per year based on a transgene-derived factor VIII level of 5 IU per decilitre. Finally, no new side effects were identified, and no new serious treatment-related side effects occurred in the two years after treatment.
Conclusion
This study published by Mahlangu and colleagues supports the safety and efficacy of valoctogene roxaparvovec gene therapy for the treatment of hemophilia A.
References
1. Srivastava A, Santagostino E, Dougall A, et al; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Treatment of Haemophilia, 3rd Edition. Haemophilia. 2020 Aug;26 Suppl 6:1-158. doi: 10.1111/hae.14046. Epub 2020 Aug 3. Erratum in: Haemophilia. 2021 Jul;27(4):699. PMID: 32744769.
2. Mahlangu J, Kaczmarek R, von Drygalski A, et al; GENEr8-1 Trial Group. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. 2023 Feb 23;388(8):694-705. doi: 10.1056/NEJMoa2211075. PMID: 36812433.