Durable Clinical Benefits in Severe Sickle Cell Disease with Exagamglogene Autotemcel

BACKGROUND Exagamglogene autotemcel (exa-cel) is a cell therapy that reactivates HbF via non-viral, ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34 + hematopoietic stem and progenitor cells (HSPCs). Exa-cel is approved for patients aged ≥12 years with severe sickle cell disease (SCD). We report results from the ongoing Phase 3 CLIMB SCD-121 and CLIMB-131 trials. METHODS Participants (12-35 years) with severe SCD and history of ≥2 vaso-occlusive crises (VOCs)/year in 2 years before screening were eligible. Following pharmacokinetic-adjusted busulfan myeloablation and exa-cel infusion, pts are monitored for engraftment, Hb, HbF, BCL11A -edited alleles, VOCs, and adverse events (AEs). Primary endpoint is proportion of patients with at least 16 months of follow-up who have not experienced a severe VOC for at least 12 consecutive months after infusion, starting 60 days after last RBC transfusion (VF12). Data reported as mean (range) unless noted. RESULTS As of May 2024, 46 patients (21.4 [12-34] years), including 12 adolescents (14.5 [12-17] years), were infused with exa-cel following 2.4 (range 1.0-6.0) mobilization cycles and myeloablative busulfan conditioning, with a median follow-up of 29.9 months (8.9-58.9) and 4.2 VOCs/year at baseline. 31/46 patients completed 2 years of follow-up in CLIMB SCD-121 and transitioned to CLIMB-131. After exa-cel infusion, all patients engrafted neutrophils and platelets (median 27 [15-40] and 34.5 [23-126] days). Median duration of neutropenia was 17 [6-30] days and time to hospital discharge was 31.5 [21-54] days. Notably, 36/40 (90%) evaluable pts achieved VF12 in CLIMB SCD-121 with VOC-free duration of 29.3 months (14.0-56.3). All 46 patients maintained increased levels of Hb, HbF, and stable allelic editing. For all patients, mean total Hb was 11.9 g/dL from Month 3 and has remained at normal/near normal levels of ≥12 g/dL from Month 6 onward. Mean HbF was 37.4% at Month 3 and generally ≥40% from Month 6 onward with pancellular distribution. Proportion of edited BCL11A alleles were stable in bone marrow CD34 + and peripheral blood nucleated cells. Clinically meaningful improvements in hemolysis markers were observed and maintained over time. Most AEs occurred within the first 6 months. No patients had serious AEs considered related to exa-cel; there were no study discontinuations or malignancies. As previously reported, there was 1 death from respiratory failure due to COVID-19 infection unrelated to exa-cel. CONCLUSION Elimination of VOCs was achieved in 90% of pts receiving exa-cel, with clinically meaningful increases in HbF and total Hb that were maintained over time. Exa-cel's safety profile remains consistent with myeloablative busulfan conditioning and autologous transplantation. These findings confirm the potential of exa-cel as a one-time functional cure for patients with severe SCD.

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