First results of exagamglogene autotemcel in pediatric patients aged 5-11 years with transfusion-dependent β-thalassemia or sickle cell disease with recurrent severe vaso-occlusive crises

Abstract Background: Exagamglogene autotemcel (exa-cel) is a one-time, autologous cell therapy that reactivates fetal hemoglobin (HbF) synthesis via ex vivo CRISPR/Cas9 editing of autologous CD34+ hematopoietic stem and progenitor cells at the erythroid-specific enhancer region of BCL11A. Exa-cel is approved for individuals ≥12 years (y) old with transfusion-dependent β-thalassemia (TDT) or sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). Based on exa-cel's mechanism of action, efficacy is expected to be similar across all ages. We report safety and efficacy data from the pediatric trials CLIMB THAL-141 and CLIMB SCD-151. Methods: CLIMB THAL-141 (TDT) and CLIMB SCD-151 (SCD) are ongoing 2-y, Phase 3 trials of exa-cel in participants (pts) aged 2-11 y with history of ≥100 mL/kg/y or ≥10 U/y of packed red blood cell (RBC) transfusions for 2 y before screening (TDT) or a history of ≥2 severe VOCs per y for 2 y before screening (SCD). Data for pts aged 5-11 y are reported. In CLIMB THAL-141 and CLIMB SCD-151, exa-cel was infused following PK-adjusted busulfan myeloablation. Pts are monitored for engraftment, total hemoglobin (Hb), HbF, allelic editing, transfusions, VOCs (SCD only), and adverse events (AEs). In CLIMB THAL-141, the primary endpoint is transfusion independence: proportion of pts maintaining a weighted average Hb ≥9 g/dL without RBC transfusion for ≥12 consecutive months (mo; TI12). In CLIMB SCD-151, the primary endpoint is proportion of pts free of severe VOCs for ≥12 consecutive mo (VF12); key secondary endpoint is proportion of pts free from inpatient treatment of severe VOCs for ≥12 consecutive mo (HF12). Upon completion of CLIMB THAL-141 or SCD-151, pts enroll in long-term trial CLIMB-131 for up to 15 y follow-up after exa-cel. Results: As of April 10, 2025, 13 TDT children <12 y (mean age 7.4 [range 5, 11] y; 61.5% male) and 10 SCD children <12 y (mean age 8.2 [range 5, 11] y; 50.0% male) received exa-cel. 5/13 (38.5%) TDT pts had β0/β0 or β0/β0-like genotypes and 12/13 had an intact spleen; all SCD pts had βS/βS genotype. All 13 TDT pts required ≤2 mobilization cycles (median 1.0 [range 1, 2]). 80% of SCD pts (8/10) required ≤2 mobilization cycles (median 2.0 [range 1, 3]). In CLIMB THAL-141, median follow-up after exa-cel was 12.6 (range 2.2, 22.7) mo. Pts achieved neutrophil (13/13) and platelet engraftment (11/13) at a median of 30 (range 19, 38) and 52 (range 22, 82) days, respectively. As of the datacut, 9/13 pts were transfusion-free and 5/5 pts evaluable for the primary efficacy endpoint achieved TI12, with the longest transfusion-free duration of 19.1 mo. Increases in total Hb and HbF were similar to that of adults and adolescents. Mean total Hb increased to ≥11.8 g/dL by Mo 6, which exceeds the age adjusted LLN, and was stable thereafter. Mean HbF increased to ≥11.0 g/dL by Mo 6 and was stable thereafter. In CLIMB SCD-151, median follow-up after exa-cel was 8.3 (range 3.9, 23.7) mo. All pts achieved neutrophil and platelet engraftment at a median of 28.5 (range 20, 37) and 45.5 (range 24, 67) days, respectively. No pts had VOCs after exa-cel infusion, with longest duration VOC-free of 20.7 mo. 2/2 evaluable pts achieved VF12 and HF12. Increases in HbF were similar to adults and adolescents. Mean HbF% >40% was achieved by Mo 6 and was durable with a pancellular distribution and normal total Hb. Pts with TDT and SCD had stable allelic editing in bone marrow and blood. The overall safety profile of exa-cel was consistent with myeloablative conditioning and autologous transplant in both TDT and SCD, as established in clinical trials of exa-cel for adolescents and adults. One pt in CLIMB THAL-141 developed severe veno-occlusive disease (VOD; related to busulfan, not related to exa-cel) with multi-organ failure that was fatal. VOD, including fatal VOD, is a known risk of busulfan therapy and is known to occur at higher frequency in children compared to adults. Conclusion: Efficacy and safety data for pts aged 5-11 y from CLIMB THAL-141 and CLIMB SCD-151 are consistent with data from exa-cel trials in pts aged ≥12 y. Exa-cel demonstrated clinical benefit in pediatric pts, with a safety profile consistent with busulfan myeloablative conditioning and autologous transplant. These data support exa-cel as a potential one-time functional cure for children aged 5-11 y with TDT and SCD, with potential additional benefit of treating early, prior to development of chronic disease complications.