Exa-Cel in Children With Transfusion-Dependent Beta Thalassemia or Sickle Cell Disease

Key Takeaways

• All evaluable children in the beta thalassemia cohort became transfusion independent, and all evaluable children in the sickle cell disease cohort had no severe vaso-occlusive crises.
• The findings came from two ongoing phase 3, open-label, single-group studies in children 5 to 11 years old who received dose-adjusted busulfan conditioning before infusion.
• Grade 3 or 4 adverse events occurred in all treated children, and two children with beta thalassemia had severe busulfan-related veno-occlusive liver disease, including one death.

In two ongoing phase 3 pediatric cohorts, all 8 evaluable children with transfusion-dependent beta thalassemia and all 8 with sickle cell disease met cohort-specific endpoints after exagamglogene autotemcel treatment. Exagamglogene autotemcel, or exa-cel, is an autologous CD34+ hematopoietic cell therapy edited ex vivo with CRISPR-Cas9 at the erythroid-specific enhancer of BCL11A to raise fetal hemoglobin expression. The analysis included children who had reached a prespecified 16-month follow-up threshold. The children were 5 to 11 years old and had transfusion-dependent beta thalassemia or sickle cell disease. These early efficacy findings were accompanied by substantial adverse events during the reported follow-up period.

CLIMB THAL-141 and CLIMB SCD-151 are ongoing, open-label, single-group phase 3 studies in children 5 to 11 years old. Fifteen children with transfusion-dependent beta thalassemia and 11 with sickle cell disease received exa-cel treatment. Before infusion, all participants underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan as the preparative regimen. Primary endpoints were transfusion independence for at least 12 consecutive months in beta thalassemia and freedom from severe vaso-occlusive crises for 12 consecutive months in sickle cell disease. At this stage, efficacy analyses included only children who had reached at least 16 months of follow-up.

Median follow-up was 16.0 months, ranging from 2.2 to 32.1, in the transfusion-dependent beta thalassemia cohort and 16.9 months, ranging from 7.6 to 33.1, in the sickle cell disease cohort. Among the 8 children with transfusion-dependent beta thalassemia followed to at least 16 months, all 8 were transfusion independent, and the remaining 7 were not yet evaluable. Among the 8 children with sickle cell disease followed to at least 16 months, all 8 were free of severe vaso-occlusive crises, and the remaining 3 were not yet evaluable. All evaluable children therefore met the prespecified endpoint for their disease cohort. In participants observed for at least 16 months, exa-cel was associated with transfusion independence or freedom from severe vaso-occlusive crises.

All treated children had at least one grade 3 or 4 adverse event during the study period. Two children with transfusion-dependent beta thalassemia developed severe veno-occlusive liver disease that investigators assessed as related to busulfan conditioning, and one of those children died. Within the reported follow-up window, early cohort-specific efficacy was paired with substantial toxicity, including busulfan-conditioning-related veno-occlusive liver disease.