Too early to tell on sickle cell 'cures'
New therapies for sickle cell disease create an opportunity for primary care physicians to ensure that their adult patients are regularly meeting with a specialist to review treatment options.
New gene therapies for sickle cell disease can notably reduce painful vaso-occlusive events in eligible patients, but access will initially be constrained by their daunting cost and treatment complexities, according to sickle cell specialists.
FDA officials approved two therapies in December 2023, describing them as milestone treatments for the inherited red blood cell disorder, which is characterized by abnormal hemoglobin, often typified by a crescent or "sickle" shape, and affects roughly 100,000 people in the U.S., most frequently Black adults and children.
One therapy, called lovotibeglogene autotemcel (Lyfgenia), or lovo-cel, uses a gene delivery vehicle, specifically a lentiviral vector. The therapy modifies a patient's blood stem cells to produce a new type of hemoglobin that functions similarly to normal hemoglobin A in adults. The other gene therapy, exagamglogene autotemcel (Casgevy), or exa-cel, relies upon CRISPR/Cas9 gene editing to modify the patient's stem cells to foster the production of fetal hemoglobin, which typically shuts down shortly after birth. The new fetal hemoglobin can help stop the sickling of red blood cells.
Both therapies hold tremendous promise to transform patients' lives, but don't call them curative, said Julie Kanter, MD, director of the adult sickle cell program at the University of Alabama at Birmingham (UAB), who was a site principal investigator for the two main studies that led to lovo-cel's approval.
"We want it to be; don't get me wrong," she said. "But to me, if you're going to call something curative, it really means we have to be able to say with assuredness that there's no potential complications from sickle cell disease any longer. And we don't know that. It's way too early."
One benefit of the buzz around the new therapies, said Dr. Kanter and other sickle cell specialists, is that it creates an opportunity for primary care physicians to ensure that their adult patients are regularly meeting with a sickle cell specialist to review treatment options, including the latest two. Research shows that patients too often fall out of subspecialty care, particularly once they reach adulthood. One analysis, which looked at three years of Medicaid data for adults with sickle cell disease living in California and Georgia, found that 56% of California patients and 34% of Georgia patients hadn't seen a hematologist even once during that time span, according to the findings, published Sept. 13, 2022, in Blood Advances.
Depending upon treatment and disease severity, adult patients might need to see a sickle cell specialist as often as every one to six months, even if that requires some telehealth visits for patients living in more remote locations, said ACP Member Francis Coyne, MD, an assistant professor of medicine and pediatrics and director of the Adult Sickle Cell Disease Program at the University of Rochester Medical Center in New York, who estimates that roughly one-third of his patients have the inherited blood disorder.
"Oftentimes people have horrid disease because they don't have access to quality disease maintenance," such as medications like hydroxyurea or chronic transfusion therapy, said Dr. Coyne. "People really need a chance for those to improve their lives" before moving on to more intensive treatments like a bone marrow transplant or gene therapy, he said.
Initial candidates
Both of the new therapies require a multistep process, including the collection of some of the patient's stem cells to be genetically modified. Shortly before those modified cells are delivered through a single infusion, the patient is given high-dose chemotherapy to clear cells from the bone marrow.
During the first six to 18 months after infusion, 90.9% of 33 patients who received the lovo-cell (Lyfgenia) therapy didn't experience any vaso-occlusive events, according to data presented in December 2023 at the American Society of Hematology's annual meeting. Other findings presented at the same meeting for exa-cel (Casgevy), looking at 20 patients, found that 95% had no vaso-occlusive events after at least 12 months.
Still, an allogeneic bone marrow transplant remains the only known potential cure, said Sophie Lanzkron, MD, MHS, who directs the Sickle Cell Center for Adults at Johns Hopkins School of Medicine in Baltimore. If the transplant is successful, "They don't have sickle cell disease anymore." Given that individuals with matched-sibling donors were excluded from the gene therapy studies, she said, a matched-sibling transplant is currently the preferred route for that population.
FDA officials approved the new gene therapies for use in adolescents and adults ages 12 years and older with a history of vaso-occlusive events. Though the FDA labels don't exclude their use in people who have had a stroke, there were too few stroke patients in the research studies to know how the therapies would impact that population, said John Strouse, MD, PhD, FACP, who directs the adult sickle cell program at Duke University in Durham, N.C. (Only the FDA prescribing label for lovo-cel notes the inclusion of patients with a history of stroke, with five enrolled.) "I would say it's a relatively small number to declare safety," Dr. Strouse said.
The FDA criteria also don't include an upper age limit for either gene therapy, Dr. Strouse said. But the optimal adult candidates initially will be those with limited organ damage who are resilient enough to withstand the high-dose chemotherapy, he said, such as someone who is 18 years old and has begun to develop very early renal dysfunction, which is progressive with sickle cell disease. "As people get older, they might have enough end-organ injury that they wouldn't meet inclusion criteria for the studies," said Dr. Strouse, who is also a coauthor of the American Society of Hematology's 2020 guidelines for management of acute and chronic pain in sickle cell disease.
FDA officials have required ongoing research follow-up for both new therapies. The lovo-cel therapy includes a black box warning that a type of hematologic malignancy has been diagnosed in patients. It's not clear whether the culprit is the gene therapy or the high-dose chemotherapy, with the latter suspected but not yet proven, said Charles S. Abrams, MD, the Francis C. Wood Professor of Medicine at the University of Pennsylvania School of Medicine in Philadelphia.
Meanwhile, the gene editing technique used with the exa-cel therapy involves some uncertainties, said Dr. Abrams, who also directs the Research Collaborative Sickle Cell Disease Clinical Trials Network for the American Society of Hematology. The technique that targets the mutation causing sickle cell disease could potentially lead to mutations in other genes, he said, adding, "but nothing has been shown to happen yet."
Moreover, the longer-term prognosis for these patients remains uncertain, Dr. Coyne said, noting that they will still carry any organ or joint damage that occurred prior to the gene therapy.
"But their blood is different now," he said. "We don't know in people who have gotten these treatments what changes. Will their kidney function worsen? What happens to their joints over time? How will the late effects of high-intensity chemotherapy impact patients?"
Initial cost and access
The price tag for both therapies runs in the millions, with lovo-cel manufacturer Bluebird Bio, Inc., setting the wholesale acquisition costs for U.S. patients at $3.1 million, according to a December 2023 press release. Vertex Pharmaceuticals, Inc., which manufactures exa-cel, the CRISPR/Cas9 gene-edited therapy, has reported a wholesale acquisition cost of $2.2 million.
Federal officials have announced a voluntary program, called the Cell and Gene Therapy Access Model, that's designed to provide a pathway for states to get access to gene therapies for Medicaid patients at a more affordable cost. The program's initial focus is sickle cell disease.
The federal model is a step in the right direction, said Dr. Lanzkron, who has served as a consultant for Bluebird Bio and who, like other sickle cell disease specialists interviewed, worries that the new therapies' price tags will exclude patients who could benefit. "Given the barriers that people with sickle cell disease have faced for such a long time because of the institutional structural racism, we cannot let this be the barrier," she said. "And I think people understand that."
But the costs aren't limited to the purchasing of the therapies, Dr. Strouse said. Patients will need to make multiple visits to the medical center where they will get the treatment and find temporary housing nearby while they go through the high-intensity chemotherapy and gene therapy infusion. "If your day-to-day is a struggle and you don't have much in the way of family support, this is going to be a really hard therapy to get," he said.
Given the lengthy process, Dr. Kanter estimated that fewer than 30 U.S. patients will receive one of the therapies in 2024. As of the end of February, there were nine certified treatment centers for the exa-cel therapy and 20 for lovo-cel in the United States, according to the manufacturers' websites. The University of Alabama at Birmingham is going through the certification process to become a treatment center for both therapies and, as of February, Dr. Kanter hoped that approval would happen by spring. Once UAB receives approval, clinicians can verify insurance coverage for optimal patient candidates and begin treatment, which typically includes at least three months of blood transfusions to improve the health of the patient's bone marrow prior to stem cell collection.
Modification of patients' stem cells will also be time-consuming, Dr. Kanter said. As of February, she had heard that the lovo-cel therapy would require eight to 12 weeks to manufacture for a particular patient and the CRISPR/Cas9 gene-editing therapy at least four months.
Managing follow-up
Although it's early, Dr. Strouse is already concerned that some patients might be unable to stick with the rigorous follow-up care that the new treatments require. Patients who feel better might return to work and thus earn too much to qualify for Medicaid coverage, he said. If patients become uninsured or have more limited employer-based coverage, they might be unable to afford the testing needed to monitor the heart, lungs, and other organs, as well as any long-term effects related to the high-dose chemotherapy, he said.
Primary care physicians also should be aware that patients might continue to live with pain, whether they undergo gene therapy or a bone marrow transplant, Dr. Coyne said. The pain might be due to preexisting joint damage or more chronic pain linked to years of living with the disease.
"Chronic pain, when it gets started, is sometimes very hard to treat and is often lifelong," Dr. Coyne said. "The body tends to feel pain everywhere and the experience of acute pain can be worse, which comes from years and years and years of pain and chronic tissue damage."
These innovative therapies represent only the leading edge of other sickle cell interventions in the research pipeline, according to physician specialists. As two examples of ongoing research, Dr. Kanter cited the RUBY study, which uses a gene editing approach to create healthy red cells with fetal hemoglobin, targeting a different area from the CRISPR/Cas9 approach, and the BEACON study (UAB is one of the sites), which is using another more precise editing approach to promote fetal hemoglobin's production.
For now, physicians need to be aware that the recently approved options require "a long process, even though it's a one-and-done treatment," Dr. Kanter stressed. Patients must be closely followed in the years to come, she said, "to continue treating what may be preexisting issues or to ensure that there aren't any new ones."
