Single-dosed exa-cel leads to early and durable increase of foetal haemoglobin

Exa-cel, an ex vivo CRISPR/Cas9 gene-editing therapy, is associated with an early, consistent, and durable increase in foetal haemoglobin (Hb) and total Hb in patients with transfusion-dependent β-thalassaemia or severe sickle cell disease, results from CLIMB THAL-111 and CLIMB SCD-121 showed.

Diminished production of adult Hb is a common feature in transfusion-dependent β-thalassaemia 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-thalassaemia and sickle cell disease [1]. 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-thalassaemia and severe sickle cell disease, respectively. Prof. Franco Locatelli (University of Pavia, Italy) presented the results of these trials [2].

In CLIMB THAL-111, 44 β-thalassaemia patients were infused with a single dose of exa-cel (median 7.5 x 10⁶ cells/kg) and in CLIMB SCD-121, 31 sickle cell disease 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, the production of foetal Hb increased with time. In β-thalassaemia 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 of follow-up.

The exa-cell safety profile was consistent with that of busulfan myeloablation and autologous haematopoietic stem cell transplantation. Two patients with β-thalassaemia had exa-cel-related serious adverse events.

“This data shows that a single dose of exa-cel in patients with transfusion-dependent β-thalassaemia 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-thalassaemia 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.

 

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Posted on 1 July 202217 May 2024