Durable Clinical Benefits with Exagamglogene Autotemcel for Severe Sickle Cell Disease

Background: Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy that reactivates fetal hemoglobin (HbF) 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 as a one-time treatment for patients aged ≥12 years with severe sickle cell disease (SCD). We report long-term efficacy and safety for participants with SCD in the ongoing phase 3 CLIMB SCD-121 and CLIMB-131 studies.

Methods: CLIMB SCD-121 is a 2-year, phase 3 study of a single-infusion of exa-cel in participants aged 12 through 35 years with SCD and a history of ≥2 vaso-occlusive crises (VOCs)/year for 2 years before screening. Enrollment and dosing are complete; the study is ongoing. The primary efficacy endpoint is the proportion of participants free of severe VOCs for ≥12 consecutive months (VF12); the key secondary efficacy endpoint is the proportion of participants free from inpatient hospitalization for severe VOCs for ≥12 consecutive months (HF12). Evaluation of VF12 and HF12 began 60 days after the last red blood cell (RBC) transfusion for post-transplant support or SCD management. Participants evaluable for the primary and key secondary endpoints had ≥16 months of follow-up after exa-cel infusion. Participants who complete CLIMB-121 may enroll in the 13-year long-term extension study, CLIMB-131, where they will be followed for a total of 15 years.

Results: As of May 2024, a total of 46 participants (mean age of all participants: 21.4 years, range: 12, 34; mean age of adolescents 12 through 18 years of age [N=12]: 14.5 years, range: 12, 17) with mean 4.2 VOCs/year at baseline received exa-cel after myeloablative busulfan conditioning and had a median follow-up of 29.9 months (range: 8.9, 58.9). Of these participants, 31 completed 2 years of follow-up in CLIMB SCD-121 and transitioned to CLIMB-131. After exa-cel infusion, all 46 participants engrafted neutrophils and platelets at a median of 27 days (range: 15, 40) and 34.5 days (range: 23, 126), respectively. Of the 46 participants, 40 were evaluable for the primary and key secondary endpoints of which 36 (90.0%) achieved VF12 (95% CI: 76.3%, 97.2%) and 38 (95.0%) achieved HF12 (95% CI: 83.1%, 99.4%). In participants achieving VF12, mean VOC-free duration was 29.3 months (range: 14.0, 56.3). All participants, including those who did not achieve VF12, maintained increased levels of hemoglobin (Hb) and HbF and stable allelic editing, supporting that the effects from exa-cel are durable over time in all patients. For all participants, mean total Hb was 11.9 g/dL from Month 3 and was maintained at normal or 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 (≥95% RBCs express HbF). Proportion of edited BCL11A alleles was stable in bone marrow CD34⁺ and peripheral blood nucleated cells. Clinically meaningful improvements in hemolysis markers (lactate dehydrogenase, haptoglobin, reticulocyte count, indirect bilirubin) were observed and maintained over time. Quality of life (QOL) measures showed clinically meaningful improvements compared to baseline. Most common adverse events (AEs) were nausea (69.6%), stomatitis (63%), vomiting (58.7%), febrile neutropenia (54.3%), headache (54.3%), abdominal pain (52.2%), and pruritis (50%). Most AEs and serious AEs (SAEs) occurred within first 6 months after exa-cel infusion. No participants had SAEs 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: Exa-cel demonstrated elimination of VOCs in 90% of participants that was maintained for up to 4.7 years. All participants had durable increases in Hb and HbF levels and stable allelic editing; clinically meaningful improvements were also seen in hemolysis markers and QOL measures. The safety profile of exa-cel remains consistent with myeloablative busulfan conditioning and autologous transplantation. These results confirm the potential for exa-cel to provide a one-time functional cure to patients with severe SCD.

Frangoul:Vertex Pharmaceuticals: Consultancy; Jazz Pahrmaceuticals: Speakers Bureau; Editas Medicine: Consultancy; BioLineRx: Consultancy; Rocket Pharma: Consultancy. Sharma:Novartis: Other: Clinical Trial site-PI; Beam Therapeutics: Other: Clinical Trial site-PI; Medexus Inc.: Consultancy; CRISPR Therapeutics: Other: Clinical Trial site-PI, Research Funding; Editas Medicine: Consultancy; Sangamo Therapeutics: Consultancy; Vertex Pharmaceuticals: Consultancy, Other: Clinical Trial site-PI. Mapara:CRISPR Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ossiumhealth: Consultancy; Bluebirdbio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wall:Editas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex Pharmaceuticals Incorporated: Membership on an entity's Board of Directors or advisory committees, Other: Steering committee. Molinari:Vertex Pharmaceuticals Incorporated: Other: funded this study. Kuo:Sangamo: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Consultancy, Honoraria; Forma Therapeutics: Consultancy; Agios Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex Pharmaceuticals: Consultancy, Honoraria; Biossil: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Novo Nordisk: Consultancy. Telfer:Celgene: Other: Clinical Trial Activity ; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees, Other: Investigator-led funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Activity, Data Monitoring Committee ; Apopharma: Honoraria, Other: Clinical Trial Activity; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Activity ; Napp Pharmaceuticals: Other: Clinical Trial Activity; Kyowa Kirin Limited: Other: Clinical Trial Activity; Terumo: Honoraria. Shah:Vertex Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana:Smart Immune: Consultancy, Current Employment, Current equity holder in private company. Corbacioglu:Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Eckrich:Vertex Pharmaceuticals: Consultancy. Rondelli:Vertex Pharmaceuticals: Honoraria. Meisel:Vertex: Consultancy. Lobitz:Vertex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Global Blood Therapeutics: Consultancy, Honoraria, Speakers Bureau. De Montalembert:vertex: Membership on an entity's Board of Directors or advisory committees; Theravia: Consultancy, Membership on an entity's Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Steinberg:Vertex Pharmaceuticals: Consultancy, Honoraria; Fulcrum Therapeuticc: Honoraria; Edital Medicine: Honoraria. Walters:Sanofi: Consultancy; Ensoma: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee member. Bower:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Imren:Vertex Pharmaceuticals: Ended employment in the past 24 months. Liu:Vertex Pharmaceuticals: Current Employment. Zhou:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Hobbs:Vertex Pharmaceuticals Incorporated: Current Employment. Grupp:Kite: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Research Funding; Adaptimmune: Consultancy; Cellectis: Research Funding; Vertex: Consultancy, Research Funding; Servier: Research Funding; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cabaletta: Consultancy.