The Food and Drug Administration’s approval Friday of two gene therapies for sickle cell disease opens up their use by as many as 20,000 people in the U.S.
But in their first year on the market, and maybe for a year or two after that, physicians expect the uptake of the powerful, but complex treatments to be gradual at best.
“I think it'll be a slow ramp up,” said Akshay Sharma, a pediatric hematologist at St. Jude Children’s Research Hospital who was an investigator in testing. “Most of us clinicians are taking a very cautious approach, because many of us are looking for long-term data before we start saying, ‘Hey, everybody should get it.’”
The reasons are many. Fewer than 100 people received the therapies in clinical testing, the earliest treated of whom have now been followed for four or five years. While the data show dramatic benefit — treatment eliminated the pain crises associated with sickle cell — there are still outstanding questions on safety and on their use in sicker individuals, such as those who have a history of stroke.
The personalized treatments are also cumbersome to manufacture and require “conditioning” chemotherapy beforehand that carries risks of its own, particularly infertility. They’ll be among the most expensive medicines sold, too, priced at $3.1 million for Bluebird Bio’s Lyfgenia and $2.2 million for Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy. Working out payment and getting insurers onboard may take time.
"I anticipate very few patients that first year for both products, maybe for the first couple of years,” said Alexis Leonard, also a pediatric hematologist at St. Jude’s.
Who should receive gene therapy?
While sickle cell is considered a rare disease, it still affects an estimated 100,000 people in the U.S., a figure President Joe Biden cited in a statement hailing Lyfgenia and Casgevy as “major breakthroughs.”
The indications approved by the FDA — 12 years or older with recurrent sickle cell crises — significantly shrink the number of people who could receive treatment. Vertex estimates about 16,000 people will be eligible, while Bluebird believes that number to be higher than 20,000.
Notably, the FDA did not restrict use of either Lyfgenia or Casgevy in people who have matched stem cell donors, the only other curative therapy for the blood disease. (Regulators in the U.K., where Casgevy was approved weeks prior, chose to exclude these individuals from the drug’s approved labeling.)
People with matched stem cell donors were not enrolled in testing of either treatment, so insurers might balk at paying for gene therapy in these individuals.
“I don't know if I would be as enthusiastic in recommending this over a matched sibling donor transplant,” said Sharma. “But the label clearly doesn't say that.”
Physicians also expressed uncertainty about treating sickle cell patients with a history of stroke with either therapy. Bluebird did enroll five such people in its trial before changing its study criteria, while Vertex excluded them.
“Stroke is a major indication for transplant so that should change,” said John Tisdale, a branch chief at the National Institutes of Health who specializes in sickle cell research, at a Monday session during the American Society of Hematology’s annual meeting. “The companies have been reluctant to accept the risk of [central nervous system] bleeding while trying to figure out if the approach works.”
Vertex’s study also capped the age of participants at 35, meaning physicians wanting to prescribe Casgevy won’t have data on its use in older individuals with sickle cell, who may have more organ damage as a result of their disease. They may also be unable to tolerate the chemotherapy conditioning.
How quickly can centers get up to speed?
Initially, only a handful of treatment centers around the country will offer Casgevy or Lyfgenia.
Vertex will make its drug available at nine sites across six states and Washington, D.C., while Bluebird said that 27 centers in 12 states are now ready to receive patient referrals. Both companies envision a broader network, but discussions at ASH made clear that the process for onboarding new hospitals will take time.
“We got approval [Friday], but that doesn't mean that all these centers are ready to provide the therapy,” said Leonard, of St. Jude’s, who presented at ASH Saturday on the topic. She noted a survey of 50 hospitals by the National Alliance of Sickle Cell Centers. Only 32 had participated in a gene therapy clinical trial, which Leonard described as an experience gap.
Prospective treating centers need comprehensive care teams that can include pain specialists, pulmonologists, infectious disease doctors and social workers. They also need access to a blood bank, space to draw and collect patient stem cells, cell processing facilities and fertility preservation services.
“The first step to getting these therapies is you have to be a qualified treatment center,” said Leonard. “We actually went to the Vertex and asked them, ‘What's your definition?’ And we got a very wishy-washy, no answer.”
In an email, a Vertex spokesperson said the company has been in “close dialogue” with all of its targeted authorized treatment centers. Many of these prefer to complete contracting discussions until after Casgevy’s approval, the spokesperson added.
Are there alternative treatments?
Matched bone marrow transplants can be a curative option for sickle cell. But only a small minority of patients, about 15% or so, have a donor who’s a suitable genetic match. Even then, the transplants still require patients to be healthy enough to undergo preconditioning with the toxic chemotherapy busulfan.
Research presented at ASH Monday suggested haploidentical, or half-match, transplants could be used in more patients, and with a gentler conditioning regimen. Haploidentical transplants use stem cells from family members such as parents, aunts, uncles or cousins, greatly broadening the pool of people who may be donors for a person with sickle cell.
The study, which was funded by the NIH, found that haploidentical transplants with a modified, less toxic regimen still led to good outcomes.
Adetola Kassim, director of Vanderbilt University's adult sickle cell disease program and an investigator, described how the studied procedure boosted hemoglobin levels as well as gene therapy. He noted, too, that transplants are about one-fifth the cost of the new therapies.
“The ideal curative therapy profile should offer protection from sickle cell related complications,” Kassim said during a Monday presentation at ASH. “[But] it also must be accessible and available to most patients.”
More broadly, researchers are looking at other ways to prepare patients for gene therapy, such as by using medicines known as antibody-drug conjugates for conditioning. Not only could these drugs be gentler on older people or those with organ damage, they could also preserve fertility. Further out, gene therapies involving an inside-the-body, or “in vivo” approach, could sidestep preconditioning altogether.
Ultimately, gene therapy offers new promise for treating sickle cell, said Tisdale. The NIH scientist included in his presentation a nod to Rodrick Murray, an early volunteer to receive sickle cell gene therapy in the U.S.
Murray was declared sickle cell-free two years after therapy, but died in 2020 from complications of leukemia he developed from preconditioning. The data recorded while tracking his treatment effects helped doctors adjust the treatment for later clinical trial participants.
“He told me he wanted to do this not for himself, but for other patients with sickle cell disease,” Tisdale said. “I was really happy to be in communication with his wife … on Friday to let her know he succeeded.”