Transfusion Independence after Exagamglogene Autotemcel in Patients with Transfusion-Dependent β-Thalassemia

Introduction and objectives Exagamglogene autotemcel (exa-cel) is a cell therapy designed to reactivate fetal hemoglobin (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). We report results from the first 44 patients (pts) dosed with exa-cel in the CLIMB THAL-111 trial. Methods Pts age 12-35y with TDT and history of ≥100 mL/kg/y or ≥10 units/y RBC transfusions in previous 2y were eligible. Primary endpoint is proportion of pts achieving a maintained weighted average Hb ≥9g/dL without RBC transfusion for ≥12 months (mo) after exa-cel infusion, starting 60d after last RBC transfusion. Data reported as mean (min–max) unless noted. Results At data cut (Feb 2022), 44 pts (age 21.3 [12-35] y) were infused with exa-cel (follow-up 12.3 [1.2-37.2] mo); 15 (34.1%) between age 12 and <18 y and 26 (59.1%) had β0/β0 or β0/β0-like genotype. Pts received 36.0 (15.0–71.0) units RBCs/y in 2-y prior to screening. After infusion, all pts engrafted neutrophils and platelets (median 29.0 and 43.5 d, respectively). 42 of 44 pts stopped RBC transfusions. Median time since last transfusion was 9.0 (0.8–36.2) mo; 16 pts had ≥12 mos since last transfusion. Two pts had not stopped transfusions but had 75% and 89% reductions in transfusion volume. Increases in HbF and Hb levels (>9g/dL) were achieved by Mo 3; mean total Hb increased to >11g/dL and was maintained thereafter. Proportion of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells (74.3% and 63.4% respectively at Mo 6) remained stable in pts with ≥1y of follow-up, indicating successful editing of long-term HSCs. Two pts had serious AEs considered related to exa-cel: one pt had SAEs of headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome (latter also considered related to busulfan) all in the context of HLH, and another pt had SAEs of delayed engraftment and thrombocytopenia (both also considered related to busulfan). All SAEs resolved. There were no discontinuations or malignancies. Conclusion Exa-cel infusion led to elimination of transfusions in almost all patients with TDT, with associated clinically meaningful increases in HbF and total Hb that were sustained. Safety profile was generally consistent with busulfan myeloablation and autologous transplant. Exa-cel has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for TDT.