Diminished production of adult HbA is a common feature in transfusion-dependent β-thalassemia and sickle cell disease. Elevated production of foetal Hb is associated with improved outcomes in these diseases. Naturally occurring genetic polymorphisms in BCL11A are associated with reduced expression of BCL11A resulting in elevated production of foetal Hb and decreased severity of transfusion-dependent β-thalassemia and sickle cell disease1. Exa-cel, also known as CTX001, is a cell therapy designed to reactivate foetal Hb production by ex vivo CRISPR/Cas9 gene-editing of BCL11A in autologous CD34-positive haematopoietic stem and progenitor cells (HSPCs).
The open-label, single-arm CLIMB THAL-111 trial (NCT03655678) and CLIMB SCD-121 trial (NCT03745287) evaluate the efficacy and safety of exa-cel in patients with transfusion-dependent β-thalassemia and severe sickle cell disease, respectively. Prof. Franco Locatelli (University of Pavia, Italy) presented the results of these trials2.
In CLIMB THAL-111, 44 patients were infused with a single dose of exa-cel (median 7.5 x 106 cells/kg) and in CLIMB SCD-121, 31 patients were infused with a single dose of exa-cel (median 4.0 x 106 cells/kg). In the CLIMB THAL-111 trial, 42 of 44 patients became transfusion-independent after exa-cel therapy. Two patients had reductions (75% and 89%, respectively) in transfusion volume.
All patients in the CLIMB SCD-121 trial became free from vaso-occlusive crises after exa-cel therapy. In both trials, production of foetal Hb increased in time. In β-thalassemia patients, foetal Hb concentration was >9 g/dL by month 4 and thereafter further increased to 12 g/dL. In sickle cell disease patients, foetal Hb concentration was 5 g/dL by month 4 and thereafter further increased to 6 g/dL (total Hb 11 g/dL). Proportions of edited BCL11A alleles in bone marrow CD34-positive HSPCs and peripheral blood mononuclear cells were stable in patients with ≥1 year follow-up.
The exa-cell safety profile was consistent with that of busulfan myeloablation and autologous haematopoietic stem cell transplantation. Two patients with β-thalassemia had exa-cel-related serious adverse events.
“This data shows that a single dose of exa-cel in patients with transfusion-dependent β-thalassemia or sickle cell disease leads to an early increase in foetal Hb and total Hb that is durable up to 3 years,” concluded Dr Locatelli. “Therefore, exa-cel has the potential to be the first CRISPR/Cas9-based therapy to provide a functional cure for patients with transfusion-dependent β-thalassemia or severe sickle cell disease.”
1. Bauer DE, et al. Science 2013;342:253–257.
2. Locatelli F, et al. Efficacy and safety of a single dose of CTX001 for transfusion-dependent beta-thalassemia and severe sickle cell disease. Abstract LB2367. EHA2022 Hybrid Congress, 09–12 June.