Gene Therapy for Hemophilia A: What You Need to Know

Gene Therapy for Hemophilia A: What You Need to Know

A hematologist answers some commonly asked questions about this potentially game-changing treatment.
Author: Donna Behen

In the summer of 2023, the U.S. Food and Drug Administration (FDA) approved ROCTAVIAN (valoctocogene roxaparvovec-rvox), a gene therapy for the treatment of adults with severe hemophilia A

The treatment, which is given as a one-time intravenous infusion, consists of a viral vector that carries a gene for factor VIII. The gene is expressed in the liver to increase blood levels of factor VIII and reduce the risk of uncontrolled bleeding. 

This long-awaited therapy could potentially increase a person’s factor levels to normal or close to normal and keep them from needing factor infusions for a long period of time. However, there’s no guarantee that it will work, and it isn’t clear how long the effects of the gene therapy may last. 

Below, Nigel Key, M.D., director of the UNC School of Medicine’s Hemophilia and Thrombosis Center in Chapel Hill, North Carolina, answers some commonly asked questions about gene therapy for hemophilia A.

Who do you think is an ideal candidate for this therapy?

That’s a hard question to answer because it’s a very personalized decision. There are some upfront exclusions, and one of these is the presence of antibodies to the viral vector that carries the working copy of the gene for factor VIII to the liver. The FDA approved ROCTAVIAN for patients with severe hemophilia A without pre-existing antibodies to the viral vector detected by an FDA-approved test. If someone has antibodies to the viral vector, the gene therapy may be less effective or ineffective. The other upfront exclusion is the presence of an inhibitor. People who either had an active inhibitor or a history of inhibitors were excluded from the clinical trials for this gene therapy. But if the inhibitor has been eradicated, the FDA-approved ‘package insert’ chose not to exclude these subjects (and I would agree). So, as you can appreciate, this really has to be a person-by-person decision.

What should people take into consideration when thinking about undergoing gene therapy?

One of the biggest differences between gene therapy and other previous treatments for hemophilia is that it’s a one-way door. You go through it and you can’t go back. If it doesn’t work the first time, you won’t get another chance using the same or similar vector. With other therapies, if it doesn’t work or there are short-term adverse events, it can be discontinued and you can move on to a different therapy. 

I also think that both patients and their doctors need to consider what patients hope to achieve by undergoing gene therapy. If someone is doing extremely well on their current therapy — for example their compliance is high and they’re not having any bleeds — then they need to think about what is the bar that they’re trying to reach by undergoing gene therapy?

What are the possible side effects of this therapy?

One of the short-term side effects is that the liver can get “stirred up” by the body’s immune reaction to the vector and so some people may need to take steroids to suppress this reaction for a period of time, but rarely is this a serious complication.

What’s more concerning is that this liver damage is sometimes associated with a loss of the expression of the gene that has been transferred to the liver. This can eradicate or at least curtail what could have been a better response. We know from the clinical trial data that patients can have quite widely variable levels of factor VIII with or without signs of this temporary liver injury. Some people can have a long-term level of 70% to 80% of factor VIII, while others may have levels in the 10% range, which is still a good result. But a potential concern is that there will be a decline in factor VIII levels over time (years). If you start out at 80%, then you can afford to lose some, but if you’re only at 10%, then you can’t. We don’t have a good understanding for why there’s such variability from person to person, and we probably won’t know the full story until some more ongoing studies are completed. 

Is there anything else people should keep in mind?

The main thing is to be informed. Educate yourself about hemophilia and what your treatment options are. Don’t be afraid to ask questions if you don't understand something, because this is a complicated issue and these are not easy decisions to make.