Exa-Cel Eliminates Transfusions in TD Thalassemia and VOCs in Sickle Cell Disease

Exagamglogene autotemcel (exa-cel; CTX001; CRISPR Therapeutics/Vertex Pharmaceuticals) eliminated the need for transfusion in treated patients with transfusion-dependent β-thalassemia (TDT) as well as vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD).

Results from the phase 2/3 CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) studies were presented in a late-breaker at the European Hematology Association (EHA) 2022 Congress, June 9-12, held both virtually and in Vienna, Austria, by Franco Locatelli, MD, PhD, professor of pediatrics, University of Pavia, and head, pediatric hematology and oncology, IRCCS Ospedale Bambino Gesù, Rome.

During his presentation, Locatelli explained that “patients with hereditary persistence of hemoglobin F (HbF), despite the fact that they inherit the sickle cell or beta thalassemia gene, do not develop the clinical signs of these conditions because of the increase of HbF... the line of reasoning [behind exa-cel] is that inactivating the BCL11A gene with the CRISPR/Cas9 genome editing approach would inactivate the production of BCL11A,” which deactivates HbF production.

Locatelli discussed results from the 75 patients that have received exa-cel treatment as of February 2022, 44 with TDT enrolled in the CLIMB THAL-111 trial and 31 with SCD enrolled in the CLIMB SCD-121 trial. Both trials are international multi-center, open-label, single-arm studies.

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CLIMB THAL-111's primary endpoint is proportion of patients maintaining a weighted average Hb of at least 9 grams per deciliter without red blood cell transfusion for at least 12 consecutive months after infusion. CLIMB SCD-121's primary endpoint is proportion of patients who have not experienced a severe VOC for at least 12 consecutive months after infusion. Both trials are assessing engraftment, total Hb, HbF, BCL11A edited alleles, transfusions, and adverse events (AEs).

Of patients with TDT, 42 (95%) reached transfusion independence (follow-up, 0.8-36.2 months), with the remaining 2 patients achieving a 75% and 89% reduction in transfusion volume. All patients (100%) with SCD became free of VOCs (follow-up, 2.0-32.3 months).

No participants in the CLIMB-SCD-121 study developed serious AEs related to exa-cel and safety profile was consistent with that of busulfan myeloablation conditioning and autologous hematopoietic stem cell transplantation. Two participants in the CLIMB-THAL-111 study did develop SAEs related to exa-cel, 1 participant developed idiopathic pneumonia syndrome, hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, and headache, while the other developed delayed neutrophil engraftment and thrombocytopenia. All SAEs have resolved.

“In conclusion the data from these 75 patients with either TDT or SCD show that a single dose of exa-cel leads to early increases in HbF total Hb that are sustained over time. Thus, we conclude that exa-cel has the potential to be the first CRISPR/Cas9 therapy to provide a functional cure for patients with thalassemia or SCD,” Locatelli concluded.

To read more coverage of EHA 2022, click here.

REFERENCE

Locatelli F, Frangoul H, Corbacioglu S, et al. Efficacy and safety of a single dose of CTX001 for transfusion-dependent βeta-thalassemia and severe sickle cell disease. Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Late-breaker 2367.