High Hopes and Costs, Low Uptake

Gene therapy has been available since 2022 for hemophilia B and since 2023 for hemophilia A, yet some major medical institutions have barely treated any patients so far. What’s the holdup? 

Hematologists said that a range of factors could explain the slow uptake of a potentially life-transforming treatment. It’s tremendously expensive, for one thing, although insurers may save a bundle on prophylactic infusions. And clinics need to devote time, resources, and money to preparation.

Perhaps most importantly, patients may feel reluctant to take on a new treatment whose long-term value is uncertain. Yes, patients may be able to free themselves from weekly infusions of factor, a protein that helps blood clots to form.

But “as it is currently formulated, you can only get gene therapy once,” said Adam Cuker, MD, MS, section chief for Hematology and clinical director of Penn Blood Disorders Center and Penn Comprehensive Hemophilia Program, Philadelphia, in an interview.

Better and more reliable gene-therapy treatments could be just around the corner — or maybe not. For now, there’s plenty of uncertainty, and interested patients are making decisions that could have consequences for a lifetime.

Here are some questions and answers about gene therapy in hemophilia:

How does gene therapy compare to existing treatments?

As many as 33,000 men in the United States are estimated to have hemophilia. In recent years, they’ve benefited from newer medications that are more powerful and convenient than the traditional infusions of blood factor, the proteins that help blood clots form. The subcutaneous injection drug emicizumab (Hemlibra), for instance, greatly reduces bleeding in hemophilia A, the most common form of this bleeding disorder.

“It’s a great medication, but it has limitations,” said pediatric hematologist Ben Samelson-Jones, MD, PhD, of the Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia, Philadelphia, in an interview.

On one hand, Hemlibra “really provides excellent prophylaxis. After a few years, about 80% of people don’t have bleeds,” Samelson-Jones said. “But you have not normalized the hemostasis. There’s still a mild deficit, and you still have to think about what your activities are.” (Hemophilia can cause excessive bleeding when patients are injured.)

If you engage in high-intensity activities, he said, “your Hemlibra prophylaxis won’t support you.” In comparison, gene therapy “gives you at least the potential for a normalized hemostasis.” 

And “gene therapies are all made to be a one-and-done one-time therapy” compared with Hemlibra, which is given subcutaneously one to four times a month, he said. Factor therapy is an even bigger burden, requiring once- or twice-weekly infusions.

How does gene therapy work?

The currently licensed gene therapies for hemophilia A and B deliver genes via adeno-associated viruses.

“You’re basically programming the body to make the missing factor by giving it the missing gene,” Samelson-Jones said. “The gene you need — for factor VIII or factor IX — is surrounded by the viral capsid. The viral vector product is administered to the recipient via peripheral IV over 1-2 hours.” 

Infusion reactions can occur in roughly 10% of cases, or “maybe a little bit higher,” he said. “There can be some viremia-like symptoms such as chills, fever, and muscle aches. But in general, it’s very well-tolerated.”

Once the gene gets to the liver, the body begins to produce factor, he said. “There’s a lot of variability. Patients can get the same vector, and one patient can have factor IX at 80% and another patient is at 5%. Right now, we don’t understand before you get it where you’re going to be.”

Still, “at 1 year, the average in levels both hemophilia A and B, are going to be slightly more than 30%,” he said. “We would call that the low-to-mild range. By definition, there are people that are higher and lower.”

Who’s eligible for treatment?

Patients must have serious disease, Samelson-Jones said. “Generally, it’s patients that are

And while trials are in the works in adolescents, only adult men can get the therapies. “There are females who do have hemophilia, but we don’t have any clinical trial data on safety, at least in women of childbearing years,” said pediatric hematologist Steven Pipe, MD, of C.S. Mott Children’s Hospital, University of Michigan Health, Ann Arbor, Michigan, in an interview. “So, the recommendation is that this only be for men.”

Patients must have healthy livers, he added, which can be an obstacle for older patients who developed hepatitis C due to blood contamination decades ago.

Another important limitation is that some patients are ineligible because they’re immune to the viral vectors, Pipe said. “Anywhere from 25%-40%, or even 50%, of the hemophilia population have antibodies which preclude being able to receive this therapy. It’s a big deal. We don’t have a way around that right now.”

And patients, of course, must want to undergo the therapy. “Some people just want to see some additional data.”

Considering all the limitations, “most clinicians would tell you that probably about 10%, maybe 20%, of our patient population would meet all of those benchmarks to be able to receive this therapy,” Pipe said.

How many gene therapies are available?

In the United States, eligible patients may choose among the three:

• Roctavian for hemophilia A, approved in June 2023.

• Hemgenix, approved for hemophilia B in November 2022.

• Beqvez, approved in April 2024 for hemophilia B.

Other gene therapies are in development.

Are patients cured? 

“I don’t like to use the term ‘cured’ for a couple reasons,” Samelson-Jones said. “One is: Any type of joint disease that you’ve already accrued because of breakthrough bleeds, it doesn’t go away. People still have to live with that. And it obviously doesn’t prevent you from passing on hemophilia or the hemophilia-causing gene to your children.” 

Secondly, “we don’t know the long-term outcomes. In the best-case scenario, it will provide factor levels in the normal range and essentially normal hemostasis without having to give yourself medication for many years.”

He added that “in patients with hemophilia B in some of the earliest gene therapy trials now have pretty stable levels 10-12 years out. But this is one of the places where hemophilia A and B seem different. In hemophilia A, it’s much more variable.”

Why has gene therapy been slow to catch on?

For one thing, “there’s just a lot of logistics to getting an institution ready to provide this type of therapy. It’s not the kind of thing where someone wants it, and then the next week you’re giving it to them,” Samelson-Jones said. “There’s many months of labor just to be able to make it available to the patients.”

Cuker agreed, saying that “an enormous amount of work is required to build protocols and establish contracts before being able to offer gene therapy.” In late 2024, his institution, Penn Medicine, treated its first patient outside of a clinical trial.

Plenty of patient education is required. “We have a long discussion, usually 60-90 minutes, where we discuss effectiveness, safety and side effects, eligibility, cost/insurance, monitoring requirements and activity restrictions following gene therapy, and treatment alternatives,” Cuker said.

It’s crucial to discuss that patients can only get gene therapy once, at least as the treatment is currently formulated, he said. Essentially, he said, there’s “one shot on goal.”

Why can’t patients get gene therapy more than once?

Because patients can develop immunity to the viral vector used to deliver the therapy. “That’s a real limitation of the entire approach,” Samelson-Jones said. “There’s a lot of work being done trying to see how much you can mitigate that.” But nothing has worked so far.

“When I talk to potential patients,” he said, “I really emphasize that we don’t have a way to give you another gene therapy, at least for the foreseeable future.”

What about cost and insurance coverage?

“I tell patients that the products cost about $3.5 million,” Cuker said. “Although this is an enormous sum, it will pay for itself after a few years if it allows the patient to get off prophylaxis, which itself typically costs between $500,000 and $1 million per year.”

As for insurance coverage, “we have a special team dedicated to obtaining insurance authorization. So far, we have not met resistance.”

Samelson-Jones said he too hasn’t encountered unusual hassles on the insurance front.

The process “wasn’t trivial, but it wasn’t much different than getting other types of infusion approval,” he said. “Even though the drug is priced at several millions of dollars, current hemophilia therapy is already expensive — often hundreds of thousands of dollars per year. If you have an expectation that this drug will provide protection from bleeds for 10-20 years, the math is not that hard.”

What else should clinicians know?

“Gene therapy is not for everyone,” Cuker said. “There is an ever-expanding list of highly effective medications to treat hemophilia. With this embarrassment of riches, it is critically important for patients to discuss treatment options with a hemophilia expert so that they can make informed decisions about their treatment that best align with their values and goals.”

What’s on the horizon?

In December 2024, researchers reported on a small phase 3 study of an experimental gene therapy called giroctocogene fitelparvovec. In 50 patients, the AFFINE trial reported that mean annualized bleeding rates fell from 4.73 pre-infusion to 1.24 post-infusion (week 12 to 15 or more months, −3.49, −6.06 to −0.91; P = .004).

Meanwhile, Pipe said, researchers are exploring nonviral strategies to deliver genes. He expects to see “lots of really intriguing research over the coming years. Hopefully, it will take us to better outcomes for patients down the road.”

Cuker disclosed ties with MingSight, Pfizer, Sanofi, and Synergy. Piper reported relationships with Siemens, YawSavin, Apcintex, ASC, Bayer, BioMarin, CSL Behring, HEMA, Freeline, LFB, Metagenomi, Novo Nordisk, Pfizer, Poseida, Precision, Regeneron, Roche/Genentech/Chugai, Sanofi, Takeda, Spark, UniQure, GeneVentiv, and Equilibra. Samelson-Jones disclosed ties with Genentech, GeneVentiv, Amarna, Biomarin, Pfizer, Frontera, and Cabaletta.

Randy Dotinga is an independent writer and board member of the Association of Health Care Journalists.