Gene Therapy Candidates Face ‘Once in a Lifetime’ Choice

People with hemophilia considering gene therapy are wrestling with concerns including the cost of treatment and variations in results.

You only get one chance.

Cutting-edge gene therapies that show the most promise for a permanent solution to hemophilia rely, for now, on a viral delivery system that people can attempt just once, and the results can vary widely.

Some recipients begin producing enough clotting factor afterward that the treatment feels like a cure. Others fall short of that, though the improvement is often still significant.

There’s no way to predict the outcome beforehand, which leaves some gene therapy candidates uncertain about whether to act now or wait and hope for developments that might improve their odds of getting optimal results.

“When I’m talking with patients, I have to tell them, ‘You probably can’t get this therapy again, but that doesn’t preclude other options in the future,’” says Steven Pipe, M.D., medical director of the Pediatric Hemophilia and Coagulation Disorders Program at the University of Michigan in Ann Arbor.

Pipe, who has been actively involved in clinical trials of gene therapy for hemophilia, says that new delivery systems may eventually allow additional doses. However, he cautions that gene therapies themselves are developed very slowly.

“If patients are thinking that they can wait like they do for an iPhone and that next year there’s going to be an even better therapy, I tell them that’s not what the landscape looks like,” he says. “The best therapies have already gone through a very extensive clinical trial program, they’ve been reviewed by the regulators, and there aren’t many options in the pipeline that have clearly differentiating characteristics to suggest that they’ll be better.”

The ABCs of Gene Therapy of Hemophilia

Hemophilia A and B are caused by mutations in a single gene: the one for clotting factor VIII production in hemophilia A and the one for clotting factor IX production in hemophilia B. Gene therapies place healthy copies of those genes inside a vector, or carrier, that delivers them to a person’s liver, the organ that produces clotting factor.

The goal is for enough working copies of the gene to reach the liver that a recipient no longer needs to rely on injections of clotting factor therapy to prevent and treat bleeds.

The most recent therapy to pass the U.S. Food and Drug Administration’s scrutiny is Beqvez (fidanacogene elaparvovec-dzkt), a treatment for hemophilia B that was approved on April 26. Hemgenix (etranacogene dezaparvovec-drlb), another treatment for hemophilia B, was approved in November 2022, and Roctavian (valoctocogene roxaparvovec-rvox), a treatment for hemophilia A, was approved in the summer of 2023.

All three are given as one-time IV infusions, with healthy copies of the genes for factor VIII or IX packed into an adeno-associated virus vector. While the virus does not cause disease, it triggers an immune response that would render a second dose ineffective.

Scientists are examining nonviral delivery systems that doctors hope may provide the option of additional doses if needed. Still, Pipe says, “until we move to a nonviral platform or a different strategy for gene therapy, this is, in a sense, a once-in-a-lifetime decision.”

For people with hemophilia who aren’t ready to make that decision and those who didn’t achieve the results they wanted, other new and promising treatments are available, Pipe notes.

Hemlibra (emicizumab), first approved by the FDA in 2017, and Altuviiio, approved in early 2023, either mimic or replace clotting factor VIII function and are administered much less frequently than prior factor-replacement therapies, e.g., only once a week. While Hemlibra is injected under the skin, Altuviiio requires intravenous infusion.

Additional prophylactic therapies are in development.

Such options “have given some patients reason to say, ‘Gene therapy will still be there for me at some point, but maybe I want to see how my life looks on some of these other novel therapies first,’” Pipe explains.

Paying for Gene Therapy

The cost of gene therapy — roughly $3 million — has also contributed to the slow interest in getting these advanced treatments, says Nigel Key, M.D., director of the Hemophilia and Thrombosis Center at the University of North Carolina School of Medicine in Chapel Hill.

“It’s a formidable cost up front, which, however it’s calculated, doesn’t make it easier to get approved,” he says. “There are levels of approval that have to occur, both at the third-party payer level and at the medical center, which has to be comfortable taking it on through the pharmacy because there’s an outlay of dollars that they have to be absolutely sure will be reimbursed.”

Additionally, as the UNC center evaluates the readiness of its patients for gene therapy, staff have found that some people want to learn more about it before proceeding and others are already satisfied with their current therapies.

“We’re trying to understand which are the patients who really want it and why, and do they have realistic expectations that are more nuanced than the idea that ‘I’m going to go and get cured of hemophilia,’ which may not happen,” Key says. “We make an effort to introduce it to all our patients in the clinics and try to assess their knowledge, attitudes, beliefs, and wishes on what they want to do with it.”

Source: National Bleeding Disorders Foundation, HemAware, June 2024

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