Gene Therapy for Severe Hemophilia A Receives FDA Approval

The Food and Drug Administration last week approved valoctocogene roxaparvovec (Roctavian, BioMarin), the first gene therapy for adults with severe hemophilia A without pre-existing antibodies to adeno-associated virus (AAV) serotype 5. The agency also approved a companion diagnostic test (AAV5 DetectCDx, ARUP Laboratories) to help identify patients who may benefit from this therapy.

Hemophilia A is an inherited bleeding disorder that occurs due to a mutation on the gene that produces factor VIII, a protein that enables blood to clot. Patients with severe hemophilia A have especially low levels of factor VIII (less than 1% in the blood), which can increase the risk of life-threatening bleeding into vital body organs if left untreated.

Valoctocogene roxaparvovec is a one-time gene therapy that uses an AAV vector to transfer a DNA coding sequence for B-domain–deleted human factor VIII to patients with hemophilia A, resulting in endogenous factor VIII protein production in hepatocytes.

FDA based its approval on findings from a phase 3 trial of adult men with severe hemophilia A who were previously treated with factor VIII replacement therapy (the GENEr8-1 study). In the trial, the mean annualized bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year following treatment. The majority of patients received corticosteroids to suppress the immune system for the gene therapy to be effective and safe. FDA noted that the treatment response may decrease over time.

The most common adverse reactions associated with valoctocogene roxaparvovec included mild changes in liver function, headache, nausea, vomiting, fatigue, abdominal pain and infusion-related reactions. This therapy may also increase factor VIII activity levels above the normal limits and may carry the theoretical risk of developing hepatocellular carcinoma or other cancers. In clinical studies, investigators did not observe instances of thromboembolic events or cancers associated with the treatment.

FDA’s action follows that of the European Medicines Agency, which approved valoctocogene roxaparvovec in August 2022. While valoctocogene roxaparvovec is the first FDA-approved gene therapy for hemophilia A, FDA and the EMA previously approved a gene therapy for hemophilia B (Etranacogene dezaparvovec, Hemgenix, CSL Behring) in November 2022 and February 2023, respectively.