Plain language summary of the GENEr8-1 clinical trial of valoctocogene roxaparvovec gene therapy for hemophilia A

What is this summary about? In healthy people, a protein called factor VIII (FVIII) helps blood to clot and prevents excessive bleeding. People with hemophilia A lack FVIII because a faulty F8 gene is giving the wrong instructions to the liver cells that make it. Valoctocogene roxaparvovec (ROCTAVIAN™) is a gene therapy designed to transfer working copies of the F8 gene into liver cells. This summary describes the GENEr8-1 study, which looked at how well valoctocogene roxaparvovec works for treating people with severe hemophilia A compared with their usual FVIII replacement therapy, and its safety. 134 men received valoctocogene roxaparvovec; results from the first 2 years are reported. What were the results? Valoctocogene roxaparvovec significantly improved bleed control in men with severe hemophilia A. A single infusion reduced average treated bleeding episodes per year from almost 5 while on FVIII prophylaxis to less than one after gene therapy. Eight out of every 10 participants had no bleeds needing treatment and 9 out of every 10 had no joint bleeds needing treatment; FVIII levels improved to normal or mild hemophilia ranges. All except 6 participants remained off regular FVIII prophylaxis for at least 2 years. All participants had at least one side effect and 22 (16%) reported serious adverse events. Nine out of every 10 participants (89%) showed increased blood levels of liver enzymes, indicating an expected immune response to the product's viral shell; this was manageable with steroids. Other common side effects included headache (41%), joint pain (40%), feeling sick (38%), and side effects to steroids (60%). What do the results mean? After a one-time dose of valoctocogene roxaparvovec, people with severe hemophilia A start producing their own FVIII and require fewer or no FVIII injections to protect them from bleeds. Results showing bleed control for at least 2 years have led to approvals of valoctocogene roxaparvovec in Europe and the USA for use in adults with severe hemophilia A who do not have antibodies against FVIII or AAV type 5. How well valoctocogene roxaparvovec works and the side effects over a longer period are still being studied. Clinical Trial Registration: NCT03370913 (GENEr8-1 study) ( ClinicalTrials.gov )