The first gene therapy for hemophilia was approved by the Food and Drug Administration (FDA) in November 2022, and since that time, adoption has been far slower than originally hoped. Two gene therapy products have been withdrawn from the market and the one remaining option, for hemophilia B, encountered manufacturing supply problems in 2026.
To find out more about the state of gene therapy for hemophilia going into 2027 and what the future might hold for this potentially life-changing treatment, HemAware reached out to four experts in the bleeding disorders community:
- Nathan Connell, M.D., MPH, an associate director of the Boston Bleeding Disorders Center at Brigham and Women’s Hospital, and associate professor of medicine at Harvard Medical School
- Peter Kouides, M.D., medical and research director at the Mary M. Gooley Hemophilia Center in Rochester, New York, and a former member of the National Bleeding Disorders Foundation’s (NBDF) Medical and Scientific Advisory Council (MASAC)
- Glenn Pierce, M.D., Ph.D., a former president and board member of NBDF and most recently vice president, medical, of the World Federation of Hemophilia (WFH), who spent much of his career working in biotech at, among others, Amgen, Bayer HealthCare and Biogen
- Steven Pipe, M.D., a professor of pediatrics and pathology at the University of Michigan in Ann Arbor and former chair of MASAC who has been a principal investigator on hemophilia A and B gene therapy clinical trials
From your perspective, what have the last few years really looked like for gene therapy in hemophilia?
Steven Pipe, M.D.: It was an incredible milestone to have come from over 30 years of investigation in gene therapy for hemophilia, all the way through key pivotal trials and then approved products for both hemophilia A and B.
The approved therapies had demonstrated the ability to reach therapeutic levels of factor expression sufficient that the majority of recipients could remain off prophylaxis with marked reductions in bleeding. Following these initial approvals there were multiple programs that promised to further enrich the clinical options for patients. However, challenges and limitations that had been recognized from the clinical trial programs curtailed the availability of these therapies globally.
These included limitations in eligibility, safety concerns related to liver toxicity, unknown long-term risks, and most recently the development of inhibitors to some bioengineered transgenes. Durability and predictability of clinical outcomes limited the adoption of the approved therapies by both clinicians, patients, and national health systems.
There were continued concerns about the inability to re-dose patients — thus having to wrestle with the idea of a “once-in-a-lifetime” therapy choice. Real-world application was very limited due to these concerns as well as challenges with reimbursement, clinical resources, and institutional barriers and continued advances in other therapeutics giving patients very good options.
Ultimately, the approved hemophilia A gene therapy was withdrawn from the market and another hemophilia B gene therapy was approved but never marketed. Most other AAV [adeno-associated virus, a non-disease-causing virus that carries the working gene into liver cells] gene therapy programs were shuttered. This has been a major disappointment for all stakeholders given the buildup to this era.
Why have there been so many issues with gene therapy for hemophilia A?
Peter Kouides, M.D.: Gene therapy for hemophilia A has been challenging because factor VIII is difficult to deliver and produce reliably and its efficacy can decline over time. Most clinical experience involves AAV vectors. The main problems are the following:
- The gene is large. This makes delivery more difficult than for factor IX in hemophilia B.
- Factor VIII is difficult for cells to manufacture.
- Liver inflammation is common. Following treatment, liver enzymes can rise, requiring corticosteroids — sometimes for prolonged periods — as well as close monitoring.
- The response is variable and may wane. Some patients achieve substantial factor VIII levels; others respond less well, and levels often decline over subsequent years. The mechanism remains incompletely understood, making the duration of benefit difficult to predict.
Repeating treatment is difficult. Pre-existing antibodies to AAV can prevent eligibility, and treatment itself induces antibodies that make another dose with the same vector problematic.
Where do things stand now for gene therapy in hemophilia B?
Nathan Connell, M.D., MPH: The situation in hemophilia B is meaningfully different than it is for hemophilia A. The clinical results have generally shown higher and more sustained factor IX activity, with increasingly mature long-term follow-up.
For an appropriate patient, gene therapy can potentially eliminate routine factor IX prophylaxis for a prolonged period. That creates a clearer value proposition than we have sometimes seen in hemophilia A. Many people with hemophilia B have traditionally relied on intravenous factor prophylaxis. Although extended half-life factor products and newer rebalancing therapies provide excellent additional options, gene therapy offers something qualitatively different — the possibility of producing one’s own factor IX and discontinuing scheduled prophylactic treatment altogether.
There have certainly been commercial setbacks in hemophilia B as well, including the discontinuation of one approved product. But clinically, the experience with hemophilia B has reinforced that durable endogenous factor production is achievable. For carefully selected and fully informed patients, I think gene therapy remains an important option. The key is shared decision-making rather than assuming that there is one best treatment for everyone.
With so much happening, how should patients and families think about gene therapy versus other available treatments?
Glenn Pierce, M.D., Ph.D.: The good news is that people have more choices than ever before, especially in high-income countries. The flip side is that it makes decision-making more complicated.
For hemophilia A, we now have rebalancing agents, factor VIII mimetics, extended and ultra-extended half-life factors, and subcutaneous options. Patients can think about what matters most to them: Do I want something that’s not intravenous but is given subcutaneously? How often am I willing to dose — once a week, once a month, once every two months? How much protection do I need for my lifestyle — do I have a very physical job, do I want to climb mountains, am I older and just tired of dealing with hemophilia?
For both hemophilia A and B, one of the rebalancing agents is given once every two months. That’s six injections a year. Some people will say, “I can deal with that.” Others may prefer an intravenous factor that gives them near-normal levels for more than half the week. All of these options go into the decision-making equation.
All of these newer treatments also change how people think about gene therapy. Years ago, when our other treatments were much more burdensome, gene therapy looked like a big leap forward. Now, with very good non-gene therapies, it’s understandable that many people — especially younger adults — are interested but may decide to wait and see what the next generation of gene therapies look like.
What happens when a patient undergoes gene therapy and then the product is taken off the market? Are they still followed/surveilled?
Steven Pipe, M.D.: Our responsibilities as principal investigators working with the sponsors/manufacturers is to fulfill our obligations to the trial participants and to the community to report out the long-term efficacy and safety outcomes.
When programs are shuttered or approved products are no longer marketed, that does not change the obligation, but it does shift the responsibility. Now clinicians at the hemophilia treatment centers bear the load of reporting this data. National databases have been set up to do this and the World Federation of Hemophilia has a gene therapy registry that can be used.
With estimates of more than 500 individuals worldwide having received gene therapy within clinical trials or commercially, this is a large dataset that needs to be collated. All stakeholders need to work together to ensure that this gets done.
Have there been concerns in the bleeding community about transparency from manufacturers around gene therapy?
Glenn Pierce, M.D., Ph.D.: Yes, and a recent example is CSL’s shortage of Hemgenix. In March 2026, the company announced a shortage and said it was due to the “complexity of manufacturing gene therapies,” and then by May 2026 they said they were back to normal production levels. AAV is a difficult product to manufacture, but that hasn’t stopped other companies from treating large numbers of patients with other AAV products. It’s obvious the company had lot failures, but they haven’t talked about what actually happened.
That’s concerning when you think back 20 or 30 years. After the HIV/AIDS tragedies, recombinant clotting factors were not so easy to make either. Companies worked with the National Hemophilia Foundation [now the National Bleeding Disorders Foundation] and health care providers to be very transparent about problems. We developed a patient notification system so that whenever a lot was recalled or there was a manufacturing issue — such as fungal contamination, glass particles, or plant shutdowns — a notice went out to the entire community explaining exactly what the problem was. It was all transparent, and people accepted it and appreciated being told.
That’s not what’s happening today. Gene therapy technology is much more complex, but the transparency is less. I think patients have a right to know when there are manufacturing issues and what those issues are.