Background: Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo CRISPR/Cas9 gene-edited, autologous cell therapy approved for patients ≥12 years old with severe sickle cell disease (SCD). We report results for durable, long-term efficacy and safety for the completed phase 3 CLIMB SCD-121 and ongoing CLIMB-131 trials.

Methods: CLIMB SCD-121 is a 2-year, phase 3 trial of a single-infusion of exa-cel in participants (pts) aged 12-35 years with SCD and a history of ≥2 vaso-occlusive crises (VOCs)/year in the 2 years before screening. The primary efficacy endpoint is the proportion of pts free of severe VOCs for ≥12 consecutive months (VF12); the key secondary efficacy endpoint is the proportion of pts free from inpatient hospitalization for severe VOCs for ≥12 consecutive months (HF12). Secondary endpoints include VOC-free duration, total hemoglobin (Hb), hemoglobin F (HbF), allelic editing, hemolysis measures, and patient-reported outcomes (PROs). Following completion of CLIMB SCD-121, pts enroll in the long-term follow-up trial CLIMB-131 for up to 15 years after exa-cel. Data are from April 10, 2025; data will be updated to reflect the final analysis of the completed CLIMB SCD-121 trial.

Results:46 pts (12 adolescents, 34 adults [≥18 years]; mean age: 21.4 years, range: 12, 34) with mean 4.2 VOCs/year at baseline received exa-cel. The median number of mobilization/apheresis cycles was 2 (range: 1, 6); 92% of adolescents underwent 1-2 cycles. 42 pts completed 2 years of follow-up in CLIMB SCD-121 and enrolled in the ongoing CLIMB-131 trial. The median follow-up was 41.3 months (range: 8.9, 70.3). After exa-cel infusion, all pts engrafted neutrophils and platelets at a median of 27 days (range: 15, 40) and 35 days (range: 23, 126), respectively.

45 pts were evaluable for the primary and key secondary endpoints in CLIMB SCD-121; 41/45 (91.1%) achieved VF12 (95% CI: 78.8%, 97.5%) and 44/45 (97.8%) achieved HF12 (95% CI: 88.2%, 99.9%). In CLIMB SCD-121 and CLIMB-131 combined, 45/45 (100%) of pts achieved VF12 and HF12 with a mean VOC-free duration of 35.3 months ​(range: 12.9, 67.7). All evaluable pts had durable increases in mean HbF of ≥40% from Month 6 onward with pancellular distribution (~95% RBCs expressing HbF) resulting in normal or near normal total Hb levels. Allelic editing was stable over time in both bone marrow and peripheral blood cells. Clinically meaningful improvements in hemolysis markers (lactate dehydrogenase, haptoglobin, reticulocyte count, indirect bilirubin) and quality of life (QOL) measures were observed compared to baseline and were maintained over time. Exa-cel safety profile was consistent with myeloablative conditioning and autologous hematopoietic stem cell transplant. Efficacy and safety were consistent in adults and adolescents and across genotypes​. There was one death which occurred 8.9 months after exa-cel infusion, which was previously reported, from respiratory failure due to COVID-19 infection not related to exa-cel; no malignancies occurred.Conclusion: The completedCLIMB SCD-121 trial demonstrates elimination of VOCs after exa-cel in 91.1% of evaluable pts. 100% of pts achieved VOC free in CLIMB SCD-121 and CLIMB-131 combined, which was maintained long-term for up to 5.6 years. All pts had durable increases in Hb and HbF levels and stable allelic editing; clinically meaningful improvements were also seen in hemolysis markers and QOL measures. These results confirm the potential for exa-cel to provide a one-time functional cure for severe SCD.

This content is only available as a PDF.
2025
Sign in via your Institution