FDA clears first gene-edited cell therapy for severe sickle cell disease, paving way for wider use of CRISPR-based treatments in US hospitals
The U.S. Food and Drug Administration on December 8, 2023, approved CASGEVY™ (exagamglogene autotemcel), the first CRISPR/Cas9 gene-edited cell therapy, for patients 12 and older with severe sickle cell disease experiencing recurrent vaso-occlusive crises. According to FDA officials, the approval marks a major advance as the first CRISPR-based treatment authorized for clinical use in U.S. hospitals.
CASGEVY™ (exagamglogene autotemcel) is approved for patients 12 years and older with severe sickle cell disease (SCD) who experience recurrent vaso-occlusive crises (VOCs), the FDA said in its December 8 announcement. The therapy is the first to use CRISPR/Cas9 genome editing to treat any human disease in the United States, marking a regulatory milestone, officials said. On the same day, the FDA also authorized Lyfgenia™ (lovotibeglogene autotemcel), a lentiviral vector gene-addition therapy for patients 12 and older with SCD and a history of vaso-occlusive events (VOEs). Together, these are the first cell-based gene therapies approved for sickle cell disease in the U.S., according to the agency.
Clinical trial data submitted to the FDA showed promising results. Yale Medicine summarized findings that 28 of 32 patients (88%) treated with CASGEVY experienced no painful vaso-occlusive episodes for six to 18 months following infusion.
CASGEVY is an autologous ex vivo gene-edited cell therapy, meaning patients’ own hematopoietic stem and progenitor cells are collected, edited in the laboratory to disrupt the erythroid-specific enhancer of the BCL11A gene, and then reinfused after myeloablative conditioning chemotherapy, the FDA explained. This editing reactivates fetal hemoglobin (HbF) production, which compensates for defective adult sickle hemoglobin (HbS), reducing red blood cell sickling and hemolysis that cause painful vaso-occlusive episodes. Unlike Lyfgenia, which adds a modified β-globin gene via a lentiviral vector, CASGEVY’s approach involves precise gene editing of regulatory DNA, officials noted.
Peer-reviewed analyses reported durable induction of fetal hemoglobin and marked reductions or elimination of VOCs in the majority of participants. FDA reviewers determined that the benefit-risk profile is favorable for eligible patients given the high morbidity and mortality associated with severe SCD and the observed clinical improvements.
The FDA’s approval did not list any formal contraindications for CASGEVY. Common adverse effects related to the treatment process, including the conditioning regimen, include mouth sores, nausea, musculoskeletal and abdominal pain, vomiting, headache, pruritus, febrile neutropenia, and decreased appetite, according to clinical trial safety data. The therapies require administration at specialized centers with expertise in hematopoietic cell transplantation, reflecting the complexity and intensity of the treatment protocols, the FDA and industry sources said.
The Sickle Cell Disease Association of America (SCDAA) welcomed the approvals, calling them the first treatments of their kind for individuals with SCD in the United States. The association reported that gene therapy availability was expected to begin in early 2024. Vertex Pharmaceuticals and CRISPR Therapeutics, developers of CASGEVY, announced plans to establish a network of authorized U.S. treatment centers, initially including nine locations, to deliver the therapy under controlled conditions. Bluebird bio, maker of Lyfgenia, is pursuing similar implementation strategies.
Cost considerations remain significant. SCDAA cited estimated list prices of approximately $2.2 million for CASGEVY and $3.1 million for Lyfgenia, highlighting challenges related to reimbursement and access. Analysts have noted that despite the high upfront costs, these one-time therapies may offer long-term savings by reducing hospitalizations and chronic care needs associated with severe sickle cell disease.
The National Heart, Lung, and Blood Institute (NHLBI) described the FDA’s decision as opening a “new frontier” in SCD treatment by approving two gene therapies—one using gene editing and the other gene addition. Scientific reviews characterize the dual approvals as a “dual breakthrough” that expands curative-intent options beyond existing disease-modifying treatments such as hydroxyurea, L-glutamine, voxelotor, and crizanlizumab, none of which fully prevent progression to chronic organ damage.
Experts emphasize that CASGEVY’s approval establishes a regulatory precedent for future CRISPR-based medicines targeting other diseases, transitioning genome editing from experimental trials into routine clinical care in U.S. hospitals. However, advocacy groups and researchers also underscore the need for equitable access, long-term safety monitoring, and infrastructure development to ensure that people with sickle cell disease—who are disproportionately from historically marginalized communities—can benefit from these advances.
