CLIMB-111 and CLIMB-121 phase III trials of Exa-Cel meet their primary endpoint in beta thalassemia or severe sickle cell disease.- Vertex Pharma

Vertex Pharmaceuticals and CRISPR Therapeutics announced that both pivotal trials for Exa-Cel (exagamglogene autotemcel) in patients with transfusion-dependent beta thalassemia (TDT) or severe sickle cell disease (SCD) met primary and key secondary endpoints at pre-specified interim analyses.

Both CLIMB-111 and CLIMB-121 met their primary endpoint and key secondary endpoint at the pre-specified interim analysis for each trial. These analyses evaluated the efficacy and safety of exa-cel in patients with TDT or SCD in the ongoing Phase III trials as well as in the long-term follow up trial CLIMB-131. The data shared are from 83 patients (48 with TDT and 35 with SCD) dosed with exa-cel with follow-up up to 43.7 months. All patients treated with exa-cel demonstrated clinical benefit, and these data continue to demonstrate the potentially transformative profile of exa-cel.

In 24/27 (88.9%) of patients achieved the primary endpoint of transfusion-independence for at least 12 consecutive months (TI12) and the secondary endpoint of transfusion-independence for at least 6 consecutive months (TI6) with a mean weighted hemoglobin of at least 9 g/dL (95% CI: 70.8%, 97.6%; P<0.0001). mean duration of transfusion-independence was 20.5 months with a maximum of 40.7 months. of the 3 patients who did not achieve ti12, one patient has since stopped transfusions and has been transfusion-free for 2.9 months; the remaining 2 patients have had substantial reductions (80% and 96%) in transfusion volume from baseline. increases in total hemoglobin occurred early within the first few months and were maintained over time. in the analysis of all patients who received exa-cel, mean total hemoglobin was at least 11g dl at month 3 and at least 12g dl from month 6 onward with pancellular distribution of fetal hemoglobin. mean proportion of edited bcl11a alleles was stable over time in bone marrow and peripheral blood indicating successful permanent editing in the long-term hematopoietic stem cells. patients also had clinically significant improvements in patient-reported outcomes.>

In 16/17 (94.1%) of patients they achieved the primary endpoint of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12) (95% CI: 71.3%, 99.9%; P=0.0001). Mean duration of VOC-free was 18.7 months, with a maximum of 36.5 months. 17/17 (100%) achieved the key secondary endpoint of being free from hospitalizations related to VOCs for at least 12 consecutive months (HF12) (95% CI: 80.5%, 100.0%; P<0.0001). the one patient who did not achieve vf12 did achieve hf12 and has a complex set of comorbidities, including a history of chronic pain. one patient who achieved vf12 had a voc 22.8 months following exa-cel infusion in the setting of a parvovirus infection. this patient has since fully recovered from the infection and been voc-free. increases in fetal hemoglobin and total hemoglobin occurred early, within the first few months, and were maintained over time. in the analysis of all patients who received exa-cel, mean fetal hemoglobin was more than 30% of total hemoglobin by month 3 and was then maintained at approximately 40.0% through follow-up, with pancellular distribution. mean proportion of edited bcl11a alleles was stable over time in bone marrow and peripheral blood, indicating successful permanent editing in the long-term hematopoietic stem cells. patients also had clinically significant improvements in patient-reported outcomes.>

The safety profile of exa-cel was generally consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. All patients engrafted neutrophils and platelets after exa-cel infusion. The results are being presented at the Annual European Hematology Association (EHA) Congress.