Without functioning clotting factors, blood will flow freely by an injury site rather than forming a clot — leading to excessive bleeding and bruising. That’s the case for people with genetic mutations that cause the blood clotting disease hemophilia. The F8 gene that encodes clotting factor VIII causes hemophilia A, while the F9 gene that makes clotting factor IX causes hemophilia B.
In 2022, the FDA approved Hemgenix from CSL Behring as the first gene therapy to treat hemophilia B by delivering a healthy copy of the F9 gene. Soon after, in 2023, the FDA approved Roctavian from BioMarin Pharmaceutical to treat hemophilia A with a working copy of the F8 gene. With one-and-done gene therapies available, it seemed like many people with hemophilia might welcome the chance to say goodbye to weekly infusions of factor concentrates, lab-produced factor drugs, or, for hemophilia A, bispecific antibodies that mimic the activity of factor VIII by binding to two proteins.
Instead, uptake of both Hemgenix and Roctavian has remained low. As a consequence, in December 2024, Pfizer decided to terminate its partnership with Sangamo Therapeutics, which focused on a gene therapy for hemophilia A. Then in February 2025, Pfizer also announced that it would no longer commercialize the company’s gene therapy for hemophilia B, Beqvez, which the FDA had approved in 2024.
Comparing gene therapy for hemophilia A and B
There are a multitude of reasons behind the low sales of these gene therapies, experts said. These include differences in the therapies’ effectiveness, required lifestyle changes, and patient hesitancy based on historical harms from past hemophilia treatments.
Michael Recht is working to set up a gene therapy program for patients with hemophilia at Yale School of Medicine.
Credit: Zach Dobson Photography
To understand this lack of uptake, it’s important to examine the gene therapies for hemophilia A and hemophilia B separately. For people with hemophilia B taking Hemgenix, “the people who responded just aren't bleeding, and there are very few, if any, of the people who have responded, who are back on [their prior treatments] … Hemgenix is a game changer drug,” said Michael Recht, the Chief Medical and Scientific Officer of the National Bleeding Disorders Foundation and a pediatric hematologist at the Yale School of Medicine.
But, said Leonard Valentino, a hematology researcher at Rush University Medical Center and President of the World Federation of Hemophilia USA, “For hemophilia A, it's a different story.” He explained that the goal of factor replacement therapy, according to the World Federation of Hemophilia guidelines, is to achieve factor levels of three to five percent in the blood (where 100 percent is used as the benchmark for a normal level). This level prevents most spontaneous bleeding, but surgery or trauma would require levels of 20 to 30 percent or higher. At levels of 50 percent or greater, Valentino said people no longer have to think about their disease at all — achieving a “hemophilia-free mind.”
For hemophilia B, Hemgenix allowed patients to reach a stable level as high as 50 to 75 percent. In contrast, Roctavian treatment for hemophilia A initially led to similarly high levels, but “then they had this progressive fall off over time, and over six years and now seven years, most of those people are somewhere between about five to 10 percent,” said Valentino. That substantial decline in efficacy has made gene therapy a less favorable option for people with hemophilia A, especially since the 2017 FDA approval of Genentech’s bispecific antibody, Hemlibra. This new bispecific antibody has allowed people with hemophilia A to reach the equivalent of a 10 to 20 percent factor level.
Compared to what they can now achieve with Hemlibra, the drop off that patients with hemophilia A may experience with Roctavian is not appealing. “Patients in general are reluctant to take on a new therapy or a new treatment where the long-term value is uncertain,” said Valentino.
Currently, the best hypothesis for why gene therapy has been less effective in hemophilia A is due to where the genes are delivered, Valentino said. Both Hemgenix and Roctavian deliver the functional gene into hepatocytes in the liver, which works great for hemophilia B because those are the cells that normally make factor IX. But for hemophilia A, different liver cells — the sinusoidal endothelial cells — produce factor VIII. By delivering the gene therapy to hepatocytes, “you're asking a cell to do something it is not normally designed to do,” said Valentino.
Yet, research into how to make gene therapy work better for hemophilia A isn’t stopping, said Recht. “There are nonviral vectors that are looking at getting both factor VIII and factor IX into people. There are lipid nanoparticles that are being looked at. There is CRISPR technology that is being looked at, and then there are more innovative technologies, such as B cell medicines,” he said.
Leonard Valentino believes that most of the slow uptake of hemophilia gene therapies can be traced to institutional issues that get in the way of offering the therapies.
Credit: Leonard Valentino
Overcoming hurdles to gene therapy adoption for hemophilia
Even with Hemgenix’s success in hemophilia B, Valentino said that some patients are still hesitant to receive the gene therapy because it requires lifestyle modifications, including the use of contraception for one year, abstaining from alcohol to protect the liver, and intensive monitoring at least initially. It’s also not a complete cure. Valentino explained that the majority of patients already have damage to their joints and often have arthritis due to past bleeds, so the gene therapy can only stop their propensity to bleed in the future. Plus, he said that the currently approved gene therapies deliver a healthy gene to the liver cells but do not integrate into the genome, so they are unlikely to remain effective over the long term. As an example of a gene therapy that might change that, he pointed to a clinical trial currently ongoing from Regeneron Pharmaceuticals that seeks to insert the F9 gene into the liver cell genome in people with hemophilia B. In the future, clinicians could give such a gene therapy to young children before they’ve experienced severe bleeding episodes that lead to damage.
For patients with hemophilia B who do want the gene therapy, though, Valentino said there are also aspects making it difficult for them to get it. “I think the majority of the slow uptake has been a lot of institutional complexities,” he said. Valentino and Recht both emphasized that administering the gene therapy requires a pharmacy to handle a drug that costs several million dollars and prepare it for injection, and the institution must create new policies and procedures for safe administration that have not been in place before. The institution must also educate its providers about the intricacies of the different vectors and how to deliver them, and that institution must have the capacity to follow up with patients after they receive the therapy for up to 15 years.
“All of that takes time, and it takes effort, and you need a champion to move the institution [forward],” said Valentino.
Recht has been trying to act as that champion to set up a commercial gene therapy program at Yale School of Medicine, but so far, he has found it slow and challenging. “Our institutions are 100 percent behind what's best for the patient, but we also have to figure out how a three and a half million unbudgeted drug fits into the budget of the organization,” he said, referring to the fact that the institution must first purchase the drug and take on the risk that the insurance company will reimburse them later — all while knowing that insurance companies sometimes delay or deny payments.
A historical perspective: Patient caution with hemophilia treatments
On top of these difficulties, there’s some concern about unknown side effects that could happen down the line, since the clinical trials haven’t yet followed patients for decades. “Could these vectors be integrating into the host cells and then creating a cancer in the future?” asked Valentino. He added that so far, the data don’t show this to be the case, but “it’s still a concern that this will happen.”
The hemophilia community has been, I would say, very cautious of innovation because of that history.
– Leonard Valentino, President of the World Federation of Hemophilia USA
That unknown aspect of gene therapy could also be critically important in the hemophilia community, Valentino said, because it could remind patients about a prior hemophilia treatment that turned out to be unknowingly harmful at the time. In the 1970s and ‘80s, people with hemophilia received infusions of factor VIII or IX concentrates that could prevent bleeding episodes. Yet, the concentrates were made from pooled plasma that could include up to 60,000 donors. If a single donor was infected with a bloodborne pathogen, then patients with hemophilia could become infected too. “Upwards of 80 to 90 percent of the people with severe hemophilia A and B were infected with HIV, and most were also infected with hepatitis C,” said Valentino. As a result, what was hailed as a treatment that could be life-changing cost many patients their lives. “The hemophilia community has been, I would say, very cautious of innovation because of that history,” said Valentino.
From their point of view today, both Valentino and Recht emphasized that the Hemgenix gene therapy for hemophilia B is currently an excellent option and that patients should engage in shared decision making with their medical provider. “I think this will become one of the mainstays of therapy for people living with hemophilia B,” said Valentino. For hemophilia A, the durability and predictability issues must be solved, they said.
Moving forward, gene therapies for both hemophilia A and B will have to compete with other types of drugs too. On March 28th, the FDA approved Qfitlia, the first RNA silencing drug from Sanofi to treat hemophilia A and B. Qfitlia does not work by providing patients with factor VIII or IX, instead “it decreases the production of one of the key anticoagulants. … Now you're balanced, and you don't bleed anymore,” said Valentino.
For now, Recht said that he thinks many providers and hemophilia patients are also taking a wait-and-see approach to the gene therapies. “The majority of people are like, let me let this mature a little bit and see what it actually looks like,” he said.
Frequently asked questions about hemophilia and gene therapy
What is gene therapy for hemophilia?
Gene therapy for hemophilia is a one-time treatment that delivers a healthy copy of the gene responsible for producing a crucial clotting factor to a person's liver cells. This allows the body to produce its own factor, reducing or eliminating the need for regular infusions.
Why have gene therapies for hemophilia had low adoption rates?
The low adoption of gene therapies for hemophilia is due to several factors. For hemophilia A, the durability of the treatment has been a concern, with clotting factor levels decreasing over time. Patients also face institutional hurdles, such as the high cost of the drug and the need for new administrative procedures, in addition to personal factors like required lifestyle changes and a historical mistrust of new treatments due to past harms.
How effective is gene therapy for hemophilia A versus hemophilia B?
The article explains that gene therapy for hemophilia B has been highly effective, with patients maintaining stable, high levels of clotting factor IX. However, for hemophilia A, the effectiveness of the current therapy has been shown to decline over several years, making it a less appealing option compared to other available treatments.
Why is there patient hesitancy toward this new gene therapy?
Patient hesitancy stems in part from the history of hemophilia treatment. In the 1970s and '80s, many people with hemophilia were infected with HIV and hepatitis C from contaminated clotting factor concentrates, leading to profound caution toward new and unproven innovations.
