Beam to seek OK of gene-edited cell therapy risto-cel for sickle cell disease
The BEACON clinical trial showed therapy's lasting benefits in 31 patients
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Beam Therapeutics plans to ask the U.S. Food and Drug Administration (FDA) to approve ristoglogene autogetemcel, or risto-cel, its single-dose, gene-edited cell therapy candidate for people with sickle cell disease (SCD), as early as year’s end.
The application is expected to be supported by now-published interim data from the ongoing Phase 1/2 BEACON clinical trial (NCT05456880), which demonstrated the therapy’s lasting benefits in 31 severe SCD patients, with milder symptoms and no severe vaso-occlusive crises (VOCs) reported so far.
“We are focused on advancing risto-cel toward a planned [application] submission as early as year end 2026 and bringing this therapy to patients as quickly as possible,” Amy Simon, MD, chief medical officer of Beam, said in a company press release. “Risto-cel reflects our vision for how base editing can enable a new class of precision genetic medicines designed to deliver robust and durable benefits for patients.”
Base editing is a precise gene-editing technology that can create a change in the DNA’s sequence without cutting through both side rails of the DNA’s twisted ladder, a characteristic structure known as its double helix. Such cuts can damage DNA and create unwanted genetic abnormalities.
Interim trial data is described in the study “Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease,” which was published in The New England Journal of Medicine.
“The publication of these interim data … underscores the potential of risto-cel to make a transformational difference in the lives of patients living with SCD by reducing severe pain crises and the progressive complications that impact quality of life and lifespan,” said Matthew M. Heeney, MD, the study’s senior author and associate chief of hematology at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “Risto-cel has the potential to meaningfully alter the [underlying cause] of the disease and improve outcomes for patients with SCD.”
How does risto-cel work?
SCD is caused by mutations that result in a faulty form of adult hemoglobin, the protein that normally carries oxygen in red blood cells. This distorts red blood cells into a rigid, sickle shape, causing them to break down prematurely, and leading to anemia and blocked blood vessels, which drive painful VOCs.
Formerly BEAM-101, risto-cel is designed to reactivate the production of fetal hemoglobin (HbF), a form of the protein naturally present before birth, but that’s gradually replaced by adult hemoglobin in the first months of life. Because HbF doesn’t cause sickling, increasing its levels can counteract the damaging effects of faulty adult hemoglobin.
The therapy begins with harvesting a patient’s own hematopoietic stem cells, which give rise to all blood cell types, and then genetically modifying them to boost HbF production.
Before the re-infusion, the patient undergoes a conditioning regimen with the chemotherapy drug busulfan to eliminate existing stem cells. The modified cells are then re-infused, where they should generate HbF-producing red blood cells.
Therapeutic benefits of risto-cel
The FDA granted risto-cel both orphan drug and regenerative medicine advanced therapy designations, which come with incentives and support mechanisms to speed clinical development and regulatory review.
The multicenter, U.S.-based BEACON trial, which recruited its first participant in 2022, is evaluating risto-cel in 31 adults, ages 18 to 35, with severe SCD and a minimum of four VOCs in the two years before enrollment.
Similar to trial data reported last year, published details that cover a follow-up period of less than a month to nearly two years showed sustained therapeutic benefits with risto-cel. Gene-editing efficiency increased over time, with 72.8% of circulating red blood cells at one year producing HbF. In bone marrow samples taken at one year, 76.8% of targeted genes showed successful edits.
Total hemoglobin levels rose from a mean of 9.2 g/dL before treatment to 15.5 g/dL after six months, and remained at those levels during follow-up. Four patients recorded hemoglobin levels above the upper limit of normal after the sixth month, though no related symptoms or medical interventions were reported.
Also by the sixth month, nearly all red blood cells (mean, 99.3%) were HbF-producing cells, with HbF levels per cell well above the threshold considered protective against sickling. Blood levels of erythropoietin, a hormone that signals anemia or compensation for low oxygen, dropped dramatically after a year.
Markers of red blood cell breakdown also normalized or decreased with treatment, and the rate of red blood cell sickling fell to levels comparable to those seen in sickle cell trait carriers, that is, people who have a faulty copy of the gene that causes SCD, but don’t have overt disease symptoms.
None of the 13 participants with at least six months of follow-up had a severe VOC. All had at least one adverse event, with most occurring within the first three months, primarily consistent with expected outcomes of busulfan conditioning and stem cell transplants. No serious adverse events were deemed related to risto-cel.
The process of collecting and preparing risto-cel was consistent across multiple treatment centers, with patients needing a median of just one stem cell collection cycle and receiving their infusion after a median of 4.5 months.
“It is encouraging to see the often arduous and challenging operational aspects of the cell collection, manufacturing, and transplant process trending favorably and having consistency across multiple centers,” said Ashish Gupta, MD, the study’s first author and an associate professor at the University of Minnesota.
