Exa-cel may offer functional cure for beta-thalassemia, sickle cell disease, new data show
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An investigational CRISPR/Cas9 gene-edited cell therapy demonstrated significant, durable efficacy among patients with transfusion-dependent beta-thalassemia and sickle cell disease, according to study results.
The new data, presented during European Hematology Association Hybrid 2022 Congress, showed increases in fetal hemoglobin levels after a single dose of exagamglogene autotemcel, or exa-cel (CRISPR Therapeutics, Vertex Pharmaceuticals) — formerly known as CTX001 — resulted in elimination of transfusions for nearly all 44 patients with beta-thalassemia and elimination of vaso-occlusive crises among all 31 patients with sickle cell disease.
Exa-cel also had a safety profile consistent with that of busulfan myeloablative conditioning and autologous hematopoietic stem cell transplantation.
Rationale and methods
Exa-cel uses ex vivo CRISPR-Cas9-mediated editing of BCL11A to produce high levels of fetal hemoglobin in red blood cells, Franco Locatelli, MD, PhD, head of the department of pediatric hematology and oncology at IRCCS Bambino Gesù Children’s Hospital in Rome, and professor of pediatrics at the Sapienza University of Rome, said during a presentation.
“Naturally occurring genetic changes in BCL11A are associated with elevated fetal hemoglobulin and decreased severity of transfusion-dependent beta-thalassemia and sickle cell disease,” Locatelli said. “Editing of BCL11A reactivates formation of fetal hemoglobulin, and exa-cel is produced using nonviral, ex vivo CRISPR-based editing at the erythroid enhancer region of BCL11A.”
During ASH Annual Meeting and Exposition in 2020, researchers reported safety and efficacy of exa-cel among the first 10 patients in the ongoing, phase 1/phase 2, multicenter CLIMB THAL-111 and CLIMB-SCD-121 trials who had at least 3 months of follow-up after infusion.
For the current analysis, Locatelli and colleagues reported data from the first 75 patients who received treatment with the agent.
At the time of data cutoff, 44 patients (median age, 21.3 years) with transfusion-dependent beta-thalassemia received exa-cel with 12.3-months follow-up and 31 patients (median age, 22.5 years) with sickle cell disease received the agent with 9.6-months follow-up.
Key findings
Result showed all patients experienced neutrophil and platelet engraftment, with median time of 29 days to neutrophil and 43 days to platelet engraftment among those with transfusion-dependent beta-thalassemia, and 27 days and 32 days among patients with sickle cell disease.
The majority (95%) of patients with transfusion-dependent beta-thalassemia ceased red blood cell transfusions, and the two patients who continued to require transfusions experienced reductions in transfusion volume by 75% and 89%.
Moreover, all 31 patients with sickle cell disease no longer experienced severe vaso-occlusive crises after exa-cel infusion.
Researchers additionally observed clinically meaningful increases in fetal hemoglobin and hemoglobin levels in both patient groups, with a mean proportion of fetal hemoglobin of more than 20% by month 3, rising to approximately 40% at month 4 and leveling off thereafter. Mean total hemoglobin levels exceeded 11 g/dL after month 3.
In addition, researchers observed stable proportions of edited BCL11A alleles in bone marrow autologous hematopoietic stem and progenitor cells and peripheral blood mononuclear cells.
Two patients with transfusion-dependent beta-thalassemia experienced serious adverse events that appeared associated with exa-cel and later resolved. No patients with sickle cell disease experienced treatment-related serious adverse events, and researchers observed no treatment-related deaths, discontinuations or malignancies.
Implications
“CTX001 has the potential to be the first CRISPR/Cas9-based therapy to provide a functional cure for patients with transfusion-dependent beta-thalassemia and severe sickle cell disease,” Locatelli said.
For more information:
Franco Locatelli, MD, PhD, can be reached at franco.locatelli@opbg.net.
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Locatelli F, et al. Abstract LB2367. Presented at: European Hematology Association Hybrid 2022 Congress; June 9-12, 2022; Vienna.
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