Elevated foetal haemoglobin (HbF) is associated with improved outcomes in patients with transfusion-dependent β-thalassemia and sickle cell disease. The results of the CLIMB THAL-111 and CLIMB SCD-121 trials show that exagamglogene autotemcel (exa-cel) increases the HbF and total Hb levels in these patients. After a single infusion, 95% of patients with β-thalassemia did not require a red blood cell transfusion, and participants with sickle cell disease experienced a notable reduction in the incidence of severe vaso-occlusive events. These results indicate exa-cel has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for these patients.
Elevated foetal haemoglobin (HbF) is associated with improved outcomes in patients with transfusion-dependent β-thalassemia and sickle cell disease. Exagamglogene autotemcel (exa-cel) 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. In (preclinical) models, infusion of exa-cel led to an increase in HbF and erythroid cells in vivo. This presentation at the American Society of Gene & Cell Therapy Annual Meeting 2023 reported efficacy and safety data from the first 75 patients receiving exa-cel in the ongoing CLIMB THAL-111 and CLIMB SCD-121 pivotal trials.
The multicentre, open-label, single-arm phase 1/phase 2 studies assessed the safety and efficacy of exa-cel in patients aged 12 to 35 years with transfusion-dependent β-thalassemia (CLIMB THAL-111; n=31) or severe sickle cell disease (CLIMB SCD-121; n=44). The participants underwent pharmacokinetic-adjusted busulfan myeloablation followed by a single infusion of exa-cel and subsequent monitoring for engraftment, total Hb level, HbF level, BCL11A-edited alleles, transfusions, vaso-occlusive events and adverse events. The primary endpoint of the CLIMB THAL-111 trial was the proportion of patients who achieved and maintained a weighted average Hb level greater than 9 g/dL without the need for a red blood cell (RBC) transfusion in the 12 months since exa-cel transfusion. The primary endpoint of the CLIMB SCD-121 study was the proportion of patients who did not experience a severe vaso-occlusive event for at least 12 months after exa-cel infusion.
Participants with transfusion-dependent β-thalassemia had a median follow-up of 11.9 months, whereas those with sickle cell disease had median follow-up of 10.2 months. All patients experienced neutrophil and platelet engraftment, with a median time of 29 days to neutrophil and 43 days to platelet engraftment among those with transfusion-dependent β-thalassemia, and 27 days and 32 days among patients with sickle cell disease, respectively. Patients with transfusion-dependent β-thalassemia required a mean 36 RBC transfusion units per year during the 2-year period before treatment. As of the data cutoff date, 95% of patients (42 of 44 patients) with β-thalassemia have not required an RBC transfusion after a single infusion of exa-cel. Participants with sickle cell disease experienced a mean of 3.9 severe vaso-occlusive events per year during the 2 years prior to study enrolment. After infusion with exa-cel, they reported no longer experiencing vaso-occlusive events as of the data cutoff date. Meaningful increases in HbF and Hb levels were also observed in both patient groups, with a mean proportion of HbF of more than 20% by month 3, rising to approximately 40% at month 4 and levelling off thereafter. Mean total Hb levels exceeded 11 g/dL after month 3. In addition, the proportion of CRISPR/Cas9-edited BCL11A alleles remained stable for greater than 1 year after exa-cel infusion, which indicated long-term successful editing of hematopoietic stem cells. Safety profile was generally consistent with busulfan myeloablation and autologous transplant. No deaths, treatment discontinuation or subsequent malignancies were reported during the study.
In summary, treatment with exa-cel conferred a clinically meaningful increase in HbF and total Hb levels among patients with β-thalassemia and sickle cell disease. Most patients with β-thalassemia required no transfusion after a single exa-cel infusion, while those with sickle cell disease treated in the study have not reported further severe vaso-occlusive events. These results indicate exa-cel has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for transfusion-dependent β-thalassemia and severe sickle cell disease.
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