Exagamglogene Autotemcel for Severe Sickle Cell Disease
Authors: Frangoul Haydar , Locatelli Franco , Sharma Akshay , Bhatia Monica , Mapara Markus , Molinari Lyndsay , Wall Donna , Liem Robert I. , Telfer Paul , Shah Ami J. , Cavazzana Marina , Corbacioglu Selim , Rondelli Damiano , Meisel Roland , Dedeken Laurence , Lobitz Stephan , de Montalembert Mariane , Steinberg Martin H. , Walters Mark C. , Bower Laura , Imren Suzan , Simard Christopher , Xuan Fengjuan , Zhou Weiyu , Morrow Phuong Khanh , Hobbs William , Grupp Stephan 
Published: December 2023

Background: Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy designed to reactivate fetal hemoglobin via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of the BCL11A gene in patients (pts) with severe sickle cell disease (SCD). We report that in a pre-specified interim analysis, the pivotal CLIMB SCD-121 trial of exa-cel met primary and key secondary endpoints.

Methods: CLIMB SCD-121 is an ongoing, 24-mo, phase 3 trial of exa-cel in pts age 12-35y with SCD and a history of ≥2 VOCs/y in 2y prior to screening. Primary efficacy endpoint is proportion of pts free of severe VOCs for ≥12 consecutive months (mos) (VF12); key secondary efficacy endpoints are proportion of pts free from inpatient hospitalization for severe VOCs for ≥12 consecutive mos (HF12) and proportion of pts free from severe VOCs for ≥9 consecutive mos (VF9). Evaluable pts for VF12 and HF12 had ≥16 mos follow-up after exa-cel infusion; pts evaluable for VF9 had ≥12 mos follow-up after infusion. Evaluation of primary and key secondary endpoints began 60 days after last RBC transfusion for post-transplant support or SCD management. Pts completing trial enrolled in long-term follow-up Study 131. Mean (SD) are shown except where noted.

Results: As of 10 Feb 2023, 42 pts with SCD (age 21.2[range 12-34]y; 12[28.6%] age ≥12 to &lt;18y; 4.2 VOCs/y at baseline) received exa-cel. Following infusion, all pts engrafted neutrophils and platelets (median 27 and 34.5 days, respectively). 19/20 (95.0%) pts evaluable for primary endpoint were free of VOCs for ≥12 consecutive mos (VF12; 95% CI, 75.1% to 99.9%; P&lt;0.0001), 20/20 (100%) were free from hospitalizations for VOCs for ≥12 consecutive mos (HF12; 95% CI, 83.2 to 100.0; P&lt;0.0001), and 29/30 (96.7%) were free of VOCs for ≥9 consecutive mos (VF9; 95% CI, 82.8 to 99.9; P&lt;0.0001). In pts achieving VF12, VOC free duration was 21.8 (range 12.3-41.4) mos; 18 pts remained VOC free through follow-up and 1 pt had an adjudicated VOC in the setting of parvovirus infection ~22.8 mos after exa-cel; pt recovered fully and has since been VOC free (Fig). For all pts, total Hb was 12.1 g/dL at Month 3 and was maintained at ≥11.0 g/dL from Month 6 onward; HbF was 36.0% at Month 3 and was generally maintained at ≥ 40.0% from Month 6 onward with pancellular distribution (≥95% RBCs expressing HbF). Proportion of edited BCL11A alleles was stable over time in bone marrow CD34 + and peripheral blood nucleated cells. 36/39 pts with ≥60 days follow-up after last RBC transfusion (including those not yet evaluable) remained VOC free (up to 41.4 mos; Fig). Quality-of-life (QOL) measures showed clinically significant improvements from baseline.

All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 40 (95.2%) pts had AEs of Grade 3 or 4 severity. Most common AEs were nausea (66.7%), stomatitis (61.9%), febrile neutropenia (52.4%), headache (52.4%), and vomiting (52.4%). Most AEs and serious AEs (SAEs) occurred within first 6 mos after infusion. No pts had SAEs considered related to exa-cel. As previously reported, 1 pt died from respiratory failure due to COVID-19 unrelated to exa-cel. There were no study discontinuations or malignancies.

Conclusions: The CLIMB SCD-121 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to elimination of VOCs in 95% of pts, elimination of inpatient hospitalization for VOCs in 100% of pts and improved QOL. Safety profile of exa-cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel has the potential to deliver a one-time functional cure to pts with severe SCD.