General Updates | The safety and efficacy of currently approved gene therapies for hemophilia

Three gene therapies for hemophilia have been approved so far, one for hemophilia A and two for hemophilia B. These approvals came after three decades of experimentation with many fits and starts. And unfortunately, one of the hemophilia B gene therapies has been withdrawn from the market earlier this year. So in terms of access, we have currently two gene therapies for hemophilia, one for hemophilia A and one for hemophilia B. Both use adeno-associated viral vectors to deliver transgenes encoding coagulation factor VIII in hemophilia A and factor IX in hemophilia B. And all the three gene therapies show the ability to correct clotting factor deficiency in the long term and reduce bleeding rates with better efficacy than the standard protein replacement therapy. But there is a wide variability in factor levels achieved by individuals, so not all vector recipients have enjoyed the same protection from bleeding after the therapy and some needed to return to standard bleeding prophylaxis. And we can’t predict where individuals will land with their factor levels after vector dosing. 

Efficacy and safety outcomes have been more favorable for hemophilia B. One striking difference between hemophilia A and B gene therapies is the year-to-year factor VIII decline that we’ve seen and that we don’t really understand, and we’ve seen it in most individuals with hemophilia A. In people with hemophilia B, on the other hand, factor IX levels after gene therapy have been remarkably stable for as long as over a decade, so the therapeutic effect of hemophilia B gene therapy is remarkably durable. 

Also, markedly more vector recipients with hemophilia A have had liver enzyme elevations and have been put on immunosuppression with corticosteroids and other agents. Since in some individuals in early clinical trials, those elevations were associated with transgene expression loss and immune responses. Those elevations are mostly mild and transient, but we don’t really understand the mechanism underlying them, which has raised concerns over what they really mean for safety, because liver enzyme elevations may signify hepatocyte death. 

So the approved therapies are transformative, but there is room for improvement, and so the innovation in the field continues. There are alternative transgenes and alternative gene transfer systems in development. Some of them have already entered the clinic, and they are trying to solve the problems we’ve seen with the current gene therapies.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.