Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia

Background: Elevated fetal hemoglobin (HbF) is associated with improved outcomes in patients with transfusion-dependent β-thalassemia (TDT). Exagamglogene autotemcel (exa-cel; formerly known as CTX001) is a cell therapy designed to reactivate 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). Recent data from the pivotal CLIMB THAL-111 (NCT03655678) trial showed that a single dose of exa-cel increased HbF and total hemoglobin (Hb) sufficiently to eliminate the need for red blood cell (RBC) transfusions in patients with TDT. Here, we report efficacy and safety data from the first 44 patients dosed with exa-cel in the ongoing CLIMB THAL-111 trial.

Methods: Patients aged 12 to 35 years with TDT receiving RBC transfusions of ≥100 mL/kg/year or ≥10 units/year in the previous 2 years were eligible. Following pharmacokinetic-adjusted busulfan myeloablation and infusion of exa-cel, patients are monitored for engraftment, total Hb, HbF, BCL11A-edited alleles, transfusions, and adverse events (AEs). The primary endpoint is the proportion of patients achieving a maintained weighted average Hb ≥9 g/dL without RBC transfusion for ≥12 months after exa-cel infusion, starting 60 days after their last RBC transfusion. Updated efficacy and safety results on all dosed patients will be included in the presentation. Data are reported as mean (min-max), unless noted.

Results: At the most recent data cut in February 2022, 44 patients with TDT (age 21.3 [12-35] years) had been infused with exa-cel (follow-up 12.3 [1.2-37.2] months), of whom 15 (34.1%) were between the ages of 12 and <18 years. Twenty-six patients (59.1%) had β⁰/β⁰ or a β⁰/β⁰-like genotype (β⁰/IVS-I-110, IVS-I-110/IVS-I-110). In the 2-year period before screening, patients received 36.0 (15.0-71.0) units of RBCs per year. After exa-cel infusion, all patients engrafted neutrophils and platelets with a median time of 29.0 and 43.5 days, respectively.

Overall, 42 of 44 patients with TDT stopped RBC transfusions. The median time since last transfusion was 9.0 (0.8-36.2) months, with 16 patients having at least 12 months since their last transfusion (Figure). Two patients had not yet stopped transfusions but had 75% and 89% reductions in transfusion volume. By Month 3, increases in HbF and mean total Hb levels (>9 g/dL) were achieved, with mean total Hb levels increasing to and maintained at >11 g/dL thereafter. At Month 6, the mean proportion of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells was 74.3% and 63.4%, respectively. These proportions remained stable in all patients with ≥1 year of follow-up (Figure).

Two patients had serious AEs (SAEs) considered related to exa-cel. One patient had concurrent events of headache, hemophagocytic lymphohistiocytosis, and acute respiratory distress syndrome considered related to exa-cel, as well as idiopathic pneumonia syndrome considered related to both exa-cel and busulfan. Another patient had delayed neutrophil engraftment and thrombocytopenia considered related to both exa-cel and busulfan. All SAEs resolved. There were no deaths, discontinuations, or malignancies.

Conclusions: Exa-cel infusion led to the elimination of transfusions in almost all patients with TDT across all genotypes, with associated clinically meaningful increases in HbF and total Hb that were maintained over time. Proportions of CRISPR/Cas9-edited BCL11A alleles have remained stable after ≥1 year, indicating that long-term HSCs were successfully edited. The safety profile was generally consistent with that of 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.

Figure. Clinical data for patients with TDT (N=44) infused with exa-cel. Time (months) of post-transplant RBC transfusion support is indicated by the light blue bar and time since last transfusion is indicated by the dark blue bar. Inset depicts the percentage of BCL11A-edited alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells of patients with TDT infused with exa-cel over time.

Locatelli:NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Membership on an entity's Board of Directors or advisory committees; MILTENYI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MEDAC: Speakers Bureau; GILEAD: Speakers Bureau; TAKEDA: Speakers Bureau; BLUEBIRD BIO: Speakers Bureau; NEOVII: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JAZZ PHARMACEUTICALS: Speakers Bureau; PFIZER: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Speakers Bureau. Li:Novartis Pharmaceuticals, Canada: Consultancy. de la Fuente:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Wall:CRISPR/Vertex: Other: Steering committee & Institutional PI; Novartis: Other: Steering Committee. Liem:BlueBird Bio: Research Funding; GBT: Research Funding; NHLBI: Research Funding; Editas: Research Funding. Meisel:Gilead/KITE: Research Funding; Neovii: Research Funding; Miltenyi Biotech: Research Funding; Jazz: Research Funding; CRISPR Therapeutics/Vertex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Bellicum: Membership on an entity's Board of Directors or advisory committees; Celgene BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEDAC: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mapara:Ossium: Consultancy. Shah:Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Cappellini:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Vertex: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Silence: Membership on an entity's Board of Directors or advisory committees. Kattamis:VERTEX: Consultancy, Honoraria; AGIOS Pharmaceuticals: Consultancy; IONIS: Consultancy; ViFOR: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; AMGEN: Consultancy. Sheth:Agios: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Fulcrum: Consultancy; CRISPR/Vertex: Other: Member of Clinical Trial Steering committee; Forma: Consultancy, Research Funding; Chiesi: Consultancy. Bobruff:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company; CRISPR Therapeutics, Inc: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Bower:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Zhang:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Sharma:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Song:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Hobbs:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Frangoul:Jazz Pharmaceuticals: Speakers Bureau; Rocket Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Editas Medicine: Consultancy; Vertex Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.