EHA 2022 | CLIMB THAL-111 and CLIMB SCD-121: exa-cel gene therapy in TDT and SCD

Transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD) are severe, inherited blood disorders caused by mutations in the hemoglobin β subunit gene. These diseases are associated with reduced levels of hemoglobin and ineffective erythropoiesis, but children with these diseases tend not to require blood transfusions or develop symptoms due to the residual synthesis of hemoglobin F (HbF), the predominant fetal hemoglobin. Nevertheless, BCL11a, a transcription factor encoded by a gene on chromosome 2, represses the expression of HbF-encoding genes. Hence, an innovative therapeutic approach under investigation is that of inactivating BCL11a production through CRISPR/Cas9 genome editing, which should lead to elevated levels of HbF and improvements in patient morbidity and mortality. Franco Locatelli, MD, PhD, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, presents the results of two trials, namely CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287), in which exagamglogene autotemcel (exa-cel; formerly known as CTX001), a novel cell therapy in which autologous hematopoietic stem and progenitor cells are genetically edited to reactivate the production of HbF, was administered to 44 patients with TDT and 31 patients affected by SCD, respectively. The primary endpoints of these trials were to determine the proportion of TDT patients that became transfusion independent as well as the proportion of SCD patients that stopped experiencing severe vaso-occlusive crises. Prof. Locatelli explains that the current data showed that 95% of TDT patients became transfusion independent, with the two remaining individuals seeing a reduction in transfusion volume. In the 31 SCD patients, all patients were free from vasoactive disease after exa-cel infusion. Further support for the effectiveness of exa-cel was observed upon patient follow-up, whereby the increased HbF and total hemoglobin levels were sustained over time. Lastly, the safety profile of exa-cel was deemed to be consistent with autologous transplants, as there were no deaths or occurrences of secondary malignancies. According to Prof. Locatelli, exa-cel has the potential to become the first CRISPR/Cas9 therapy to functionally cure TDT and SCD. This press briefing was recorded at the European Hematology Association (EHA) Congress 2022 held in Vienna, Austria.