Gene therapy for haemophilia A with valoctogene roxaparvovec

March 2023 Clinical trials James Collins
Vein, artery, rupture cut blood hemorrhage, 3d rendering

Haemophilia A is an X-linked bleeding disorder that results from functional clotting protein factor VIII deficiency. Cases of severe haemophilia A are defined as having a factor VIII activity level of less than 1 IU per decilitre, and common complications include spontaneous bleeding and debilitating arthropathy, and the current standard of care is prophylactic treatment with factor VIII. 1 However, even with this treatment regimen, many patients still have spontaneous bleeding episodes, highlighting the need for more effective treatments.

Study design and methodology

Valoctogene roxaparvovec gene therapy involves the use of an adeno-associated virus vector to trigger exogenous factor VIII protein production via delivery of a B-domain-deleted human factor VIII coding sequence. A recent open-label, single group phase III trial (GENEr8-1 trial) recently published in NEJM investigated the change in annualised treated bleeding rate in 134 men with severe haemophilia A who were receiving factor VIII prophylaxis and also received a single infusion of valoctogene roxaparvovec. 2 Outcome measures were reported at 2-years post-treatment.


Data from a total of 132 patients was available at the 2-year follow up timepoint. Importantly, the mean annualised treated bleeding rate decreased by 84.5% from baseline in patients who received the gene therapy treatment with valoctogene roxaparvovec. Further, the annualised rate of factor VIII use was reduced by 98.2% from baseline to post-prophylaxis. Factor VIII activity also increased from baseline by a mean of 22 IU per decilitre as measured by chromogenic assay in the modified intention-to-treat population. 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 safety signals were identified, and no new serious treatment-related adverse events occurred at 2-years post-treatment.

Concluding remarks

This study published by Mahlangu and colleagues supports the safety and efficacy of gene therapy with valoctogene roxaparvovec for the treatment of haemophilia A.


  1. Srivastava A, Santagostino E, Dougall A, et al; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 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.