DURABLE CLINICAL BENEFITS in SEVERE SICKLE CELL DISEASE with EXAGAMGLOGENE AUTOTEMCEL

Abstract

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. Method(s): 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. Result(s): 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(s): 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.