Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease

Background: Elevated fetal hemoglobin (HbF) is associated with improved outcomes in patients with sickle cell disease (SCD). 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 SCD-121 (NCT03745287) trial showed that a single dose of exa-cel increased HbF and total hemoglobin (Hb) sufficiently to eliminate vaso-occlusive crises (VOCs) in patients with severe SCD. Here, we report efficacy and safety data from the first 31 patients dosed with exa-cel in the ongoing CLIMB SCD-121 trial.

Methods: Patients aged 12 to 35 years with severe SCD and a history of ≥2 VOCs per year in the previous 2 years before screening were eligible. Following pharmacokinetic-adjusted, busulfan myeloablation and infusion of exa-cel, patients are monitored for engraftment, total Hb, HbF, BCL11A-edited alleles, transfusions, VOCs, and adverse events (AEs). The primary endpoint is the proportion of patients who have not experienced a severe VOC for at least 12 months after the infusion of exa-cel, 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, 31 patients with SCD (age 22.5 [12-34] years) had been infused with exa-cel (follow-up 9.6 [2.0-32.3] months), of whom 6 (19.4%) were between the ages of 12 and <18 years and 29 (93.5%) had the β^s/β^s genotype. In the 2-year period before screening, patients experienced 3.9 (2.0-9.5) severe VOCs per year. After exa-cel infusion, all patients engrafted neutrophils and platelets with a median time of 27 and 32 days, respectively.

All patients were VOC-free at the time of the data cut (duration of follow-up 2.0-32.3 months after exa-cel infusion; Figure). Median time from exa-cel infusion to last RBC transfusion was 19 (11-52) days. The mean proportion of HbF was >20% by Month 3, with mean total Hb levels >11 g/dL on and after Month 3. All 11 patients who have at least 12 months of follow-up after exa-cel infusion have maintained HbF levels >20% while experiencing no VOCs. At Month 6, the mean proportion of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells was 86.6% and 76.0%, respectively. These proportions remained stable in all patients who had ≥1 year of follow-up (Figure).

There were no patients who had serious AEs considered related to exa-cel. There were no deaths, discontinuations, or malignancies.

Conclusions: Exa-cel infusion led to the elimination of VOCs in all patients with SCD, 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 SCD.

Figure. Clinical data for patients with SCD (N=31) infused with exa-cel. Patients were VOC-free after exa-cel infusion. Time (months) since exa-cel infusion 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 SCD infused with exa-cel over time.

Frangoul:Editas Medicine: Consultancy; Rocket Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Vertex Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Locatelli:SOBI: Speakers Bureau; Neovii: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Speakers Bureau; Miltenyi: Speakers Bureau; BlueBird bio: Speakers Bureau; Amgen: Speakers Bureau. Bhatia:Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Columbia University Irving Medical Center: Membership on an entity's Board of Directors or advisory committees. Mapara:Ossium: Consultancy. Sharma:Spotlight Therapeutics: Consultancy; CRISPR Therapeutics: Research Funding; Vertex Pharmaceuticals/CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Other; Novartis: Other: Other; Medexus Inc: Consultancy; Magenta Therapeutics: Other: Research collaboration; Vindico Medical Education: Honoraria. Lobitz:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Patient booklet and educational papers; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AddMedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; German National Disease Management Program: Other: Spokesperson for children and adolescents with sickle cell disease; German National Treatment Guideline: Other: Corresponding author of the treatment guideline for children and adolescents with sickle cell disease. de Montalembert:Novartis: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees. Steinberg:Vertex/CRISPR: Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Membership on an entity's Board of Directors or advisory committees; MItobridge: Membership on an entity's Board of Directors or advisory committees. Walters:Ensoma, Inc.: Consultancy, Current holder of stock options in a privately-held company; BioLabs, Inc.: Consultancy; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AllCells, Inc.: Consultancy. Imren: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. Simard: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. Grupp:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex/CRISPR: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Janssen/JnJ: Consultancy; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; TCR2: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen: Consultancy; Cabaletta: Other: Membership on an entity's DSMB; Eureka: Consultancy.