FDA expands exagamglogene autotemcel to children ages 2 and older with SCD

The FDA has issued a supplemental approval for Casgevy (exagamglogene autotemcel; Vertex Pharmaceuticals), extending the CRISPR-based gene therapy's indication to patients aged 2 years and older with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) or transfusion-dependent β-thalassemia (TDT).^1.

The July 1, 2026 decision makes exagamglogene autotemcel the first gene therapy approved for SCD in children younger than 12 years and marks the lowest age threshold yet for a CRISPR-edited cell therapy approved in the United States, expanding access to a potentially disease-modifying one-time treatment during an early developmental window.

"These disorders carry a heavy burden for children and their families, affecting growth, development, and long-term health in profound ways," said Megha Kaushal, MD, MSc, acting deputy director of the Office of Therapeutic Products in the FDA's Center for Biologics Evaluation and Research and a pediatric hematologist in a news release from the FDA. "Grounded in the scientific evidence that earlier treatment reduces the risk of lasting end-organ damage, making this therapy available to younger patients opens a critical window for intervention and gives these children a meaningful chance at a healthier future."¹

Regulatory action and supporting clinical data

Exagamglogene autotemcel received its original FDA approval on December 8, 2023, for SCD with recurrent VOCs in patients aged 12 years and older, based on results from the phase 1/2/3 CLIMB-121 trial (NCT03745287) and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529).² Among 31 evaluable patients with SCD in those trials, 29 achieved the primary end point of freedom from severe VOCs for at least 12 consecutive months within the first 24 months after infusion. TDT approval followed in January 2024, based on the same clinical program.

The supplemental approval expanding the indication to patients aged 2 through 11 years was supported by data from a clinical trial of 11 patients with SCD aged 5 to less than 12 years and 15 patients with TDT in the same age range.¹ In the SCD cohort, all 8 patients evaluable for efficacy achieved VF12—defined as no protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after infusion. Among TDT patients, 8 of 9 efficacy-evaluable patients achieved transfusion independence for 12 or more consecutive months, with a median transfusion independence duration of 20.1 months. For children aged 2 to less than 5 years, the FDA granted indication expansion on the basis of extrapolation from product characteristics and the data from the 5-to-11-year age group, rather than direct clinical trial enrollment in that youngest cohort.

The approval was processed in 53 days after filing and was selected as the eighth approval under the Commissioner's National Priority Voucher pilot program—a new FDA initiative designed to accelerate review of therapies addressing critical unmet medical needs.¹ Exagamglogene autotemcel had previously received Orphan Drug, Regenerative Medicine Advanced Therapy, and Fast Track designations from the FDA.

Mechanism of action and treatment process

Exagamglogene autotemcel is an autologous cell therapy manufactured from the patient's own hematopoietic stem cells, which are collected, edited ex vivo using CRISPR/Cas9 technology, and reinfused as a one-time intravenous dose.^1,3 The CRISPR/Cas9 editing targets the BCL11A gene in erythroid progenitor cells, reducing expression of BCL11A—a transcriptional repressor of fetal hemoglobin (HbF)—thereby reactivating HbF production in red blood cells. In SCD, increased HbF reduces the intracellular concentration of sickle hemoglobin (HbS), preventing the polymerization that causes red blood cells to adopt the rigid sickle shape responsible for vascular occlusion, hemolysis, and downstream end-organ damage. In TDT, elevated HbF raises total functional hemoglobin levels, eliminating or reducing the need for chronic transfusions.

Before infusion, patients must undergo full myeloablative conditioning—a high-intensity chemotherapy regimen—to clear the bone marrow and allow engraftment of the edited cells.¹ This conditioning process carries risks independent of the gene therapy itself, including prolonged cytopenias, infection, and infertility risk, and requires specialized centers with expertise in stem cell transplantation. The treatment process from stem cell collection through infusion and recovery typically spans several months of intensive inpatient and outpatient management.

Disease burden and rationale for early intervention

SCD affects approximately 100,000 individuals in the United States, with the majority of diagnoses identified through mandatory newborn screening programs.⁴ The disease causes progressive end-organ damage beginning in early childhood: splenic sequestration, stroke, acute chest syndrome, and nephropathy are among the serious complications that can emerge in the first years of life. Repeated VOCs contribute to cumulative ischemic injury across multiple organ systems, and younger children with more documented complications at an earlier age have been shown to carry greater longitudinal morbidity.

Current management for most children relies on hydroxyurea, which increases HbF production and reduces VOC frequency, and on chronic transfusion programs for high-stroke-risk patients.⁴ Allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor offers a potential cure but is available to fewer than 20% of patients due to donor limitations. The CLIMB trial data, now extended to younger patients, position exagamglogene autotemcel as a curative-intent option for patients who lack a matched donor or who continue to have severe disease despite hydroxyurea, with the biological rationale that early intervention may reduce the cumulative end-organ injury that accrues with each VOC or transfusion cycle.

References

1. US Food and Drug Administration. FDA approves first gene therapy for young children with sickle cell disease. Press release. July 1, 2026. Accessed July 1, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-young-children-sickle-cell-disease

2. Frangoul H, Altshuler D, Cappellini MD, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662. doi:10.1056/NEJMoa2309676

3. Esrick EB, Bauer DE. Genetic therapies for sickle cell disease. Semin Hematol. 2018;55(2):76-86. doi:10.1053/j.seminhematol.2018.04.007

4. Brandow AM, DeBaun MR. Key components of pain management for children and adults with sickle cell disease. Hematol Oncol Clin North Am. 2018;32(3):535-550. doi:10.1016/j.hoc.2018.01.014