Durable Clinical Benefits with Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia

Background: Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy that reactivates fetal hemoglobin (HbF) via ex vivo CRISPR-Cas9 gene-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 (yrs) with transfusion-dependent β-thalassemia (TDT). We report long-term efficacy and safety for participants with TDT in the phase 3 CLIMB THAL-111 and CLIMB-131 studies.

Methods: CLIMB THAL-111 is a 2-yr, phase 3 study of a single-infusion of exa-cel in participants (12-35 yrs) with TDT and a history of ≥100mL/kg/yr or ≥10U/yr of packed RBC transfusions for 2 yrs before screening. Enrollment and dosing are complete; the study is ongoing. The primary efficacy endpoint is transfusion independence defined as proportion of participants maintaining a weighted average Hb ≥9g/dL without RBC transfusion for ≥12 consecutive months (TI12). Evaluation of TI12 started 60 days after the last RBC transfusion for post-transplant support or TDT management. Participants evaluable for the primary endpoint had ≥16 months of follow-up after exa-cel infusion. Participants who complete CLIMB-111 were offered enrollment in a 13-yr long term study, CLIMB-131; total follow-up in these 2 studies will be up to 15 yrs after exa-cel infusion.

Results: As of May 2024, 56 participants (mean age of all participants: 21.2 yrs, range: 12, 35; mean age of adolescents [N=20]: 14.8 yrs, range: 12, 17), including 35 (62.5%) with severe genotypes (β0/β0, β0/β0-like), with a median annualized transfusion volume of 206.7mL/kg received exa-cel after myeloablative busulfan conditioning and had a median follow-up of 34.7 months (range: 4.5, 63.8). Of these participants, 44 completed 2 yrs of follow-up in CLIMB-111 and transitioned to CLIMB-131. After exa-cel infusion, all 56 participants engrafted neutrophils and platelets: median of 29.0 days (range: 12, 56) and 43.5 days (range: 20, 200), respectively. Of the 52 participants evaluable for the primary endpoint in CLIMB-111, 49 (94.2%) achieved TI12 (95% CI: 84.1%, 98.8%); the proportion achieving TI12 was the same for adults and adolescents (94.1%; 95% CI: 80.3, 99.3 and 94.4%; 95% CI: 72.7, 99.9). Participants achieving TI12 stopped transfusions at a mean of 1.1 months (SD, 0.6) after exa-cel infusion and remained transfusion independent for up to 5 yrs (mean 32.4 months, range: 14.3, 60.8). Of the 3 participants who did not achieve TI12 in CLIMB THAL-111, 2 achieved TI12 in CLIMB-131 (stopped transfusions after 14.5 and 12.2 months) and have been transfusion independent for 23.0 and 15.7 months, respectively. One participant first stopped transfusions after 21.6 months but had transient gastroenteritis leading to anemia that required a transfusion at 32.2 months; this participant has since been transfusion free for 4.8 months. The mean total Hb was maintained at normal or near normal levels of ≥12g/dL from Month 5 onward and the mean HbF was ≥11g/dL from Month 5 onward with pancellular distribution (≥95% RBCs expressing HbF). The proportion of edited BCL11A alleles was stable after infusion in bone marrow CD34⁺ cells and stable from Month 2 onward in peripheral blood nucleated cells. Mean serum ferritin decreased to below baseline by Month 12, with 26/56 (46.4%) of participants stopping iron removal therapy. Quality of life (QOL) measures showed clinically meaningful improvements compared to baseline. Most common adverse events (AEs) were febrile neutropenia (60.7%), headache (55.4%), and stomatitis (53.6%). Most AEs and serious AEs (SAEs) occurred within the first 6 months after exa-cel infusion. As previously reported, 2 participants (3.6%) had SAEs related to exa-cel that resolved. There were no deaths, discontinuations due to AEs, or malignancies.

Conclusion: Exa-cel demonstrated durable transfusion independence in >94% of participants that was maintained for up to 5 yrs. Durable increases in Hb and HbF levels and stable allelic editing were observed. Additional efficacy was seen with improvement in iron overload and ability to stop iron removal therapy, as well as clinically meaningful improvements in QOL. 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 TDT.

Meisel:Vertex: Consultancy. 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. Corbacioglu:Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Li:Novartis Pharmaceuticals Canada: Membership on an entity's Board of Directors or advisory committees. de la Fuente:MAAT Pharma: Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sangamo: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Shah:Vertex Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Carpenter:Bluebird Biotech: Honoraria; Vertex Pharmaceuticals Incorporated: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kwiatkowski:Imara: Consultancy, Research Funding; Silence Therapeutics: Consultancy; Apopharma: Research Funding; Novo-Nordisk: Consultancy; BioMarin: Consultancy; Bristol Myers Squibb: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Vertex Pharmaceuticals: Consultancy; Pfizer: Research Funding; CRISPR/Vertex: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Research Funding; Chiesi: Consultancy; Editas Medicine: Research Funding. Mapara:Bluebirdbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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. Cappellini:Vifor: Membership on an entity's Board of Directors or advisory committees; Silence: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Algeri:Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee Membership. Kattamis:Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novo Nordisk: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Vifor: Consultancy; Vertex Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee Membership. Sheth:Fulcrum: Consultancy; CCO: Honoraria; CRISPR Therapeutics: Other: participation on a data safety monitoring board/steering committee; PER: Honoraria; Plexus: Honoraria; Chiesi: Consultancy; bluebird bio: Consultancy; Vertex Pharmaceuticals: Consultancy, Other: participation on a data safety monitoring board/steering committee; Forma (now Novo Nordisk): Consultancy, Research Funding; Bristol Myers Squibb (Celgene): Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding. Grupp:Novartis: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Kite: Research Funding; Vertex: Consultancy, Research Funding; Cellectis: Research Funding; Adaptimmune: Consultancy; Jazz: Consultancy, Research Funding; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cabaletta: Consultancy. Merkeley:Novartis: Other: Educational Grants, Clinical Trials; Vertex Pharmaceuticals: Other: Clinical Trials; Novo-Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trials, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medison: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kuo:Alexion Pharmaceuticals: Consultancy, Honoraria; Forma Therapeutics: Consultancy; Biossil: Consultancy; Sangamo: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria; Novo Nordisk: Consultancy; Vertex Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kohli:Vertex Pharmaceuticals Incorporated: Current Employment. Xu:Vertex Pharmaceuticals Incorporated: Current Employment. Ross:Vertex Pharmaceuticals Incorporated: Current Employment. Bobruff:Vertex Pharmaceuticals Incorporated: Current Employment. Tong:Vertex Pharmaceuticals Incorporated: Current Employment. Hobbs:Vertex Pharmaceuticals Incorporated: Current Employment. Frangoul:Rocket Pharma: Consultancy; BioLineRx: Consultancy; Jazz Pahrmaceuticals: Speakers Bureau; Editas Medicine: Consultancy; Vertex Pharmaceuticals: Consultancy.