Gene therapy a potential ‘functional cure’ for sickle cell disease, beta thalassemia
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Key takeaways:
- Exe-cel conferred clinically meaningful increases in fetal hemoglobin and total hemoglobin levels.
- No treatment-related adverse events occurred among patients with sickle cell disease.
Treatment with exagamglogene autotemcel conferred clinically meaningful increases in fetal hemoglobin and total hemoglobin levels among patients with beta-thalassemia and sickle cell disease, results of two pivotal studies showed.
The latest follow-up data from the CLIMB THAL-111 and CLIMB-SCD-121 trials — presented at American Society for Gene & Cell Therapy Annual Meeting — revealed that 95% of patients with beta-thalassemia have not required a red blood cell transfusion after a single infusion of the investigational gene therapy.
Meanwhile, those with sickle cell disease treated in the study have not reported further severe vaso-occlusive events.
“Exa-cel 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,” Haydar Frangoul, MD, medical director of pediatric hematology/oncology for the Sarah Cannon Pediatric Transplant and Cellular Therapy Program at TriStar Centennial, said during a presentation.
Background
Exagamglogene autotemcel, or exa-cel (CRISPR Therapeutics, Vertex Pharmaceuticals) uses ex vivo CRISPR/Cas9-mediated editing of the BCL11A gene that reduces erythroid-specific expression of BCL11A to produce high levels of fetal hemoglobin in red blood cells, according to Frangoul.
“In [preclinical] models, editing of BCL11A reactivated gamma-globin expression and formation of fetal hemoglobin,” he said. “Infusion of exa-cel leads to an increase in fetal hemoglobin and erythroid cells in vivo.”
Methodology
Frangoul and colleagues reported results of two ongoing pivotal trials evaluating exa-cel.
The multicenter, open-label, single-arm phase 1/phase 2 studies assessed the safety and efficacy of exa-cel in patients aged 12 to 35 years with transfusion-dependent beta-thalassemia (CLIMB THAL-111) or severe sickle cell disease (CLIMB SCD-121).
Frangoul presented data on 44 patients (mean age, 21.3 years; range, 12-35ok; 52.3% women) treated in CLIMB SCD-121 and 31 patients (mean age, 22.5 years; range, 12-34; 51.6% men) infused as part of the CLIMB THAL-111 protocol as of February 2022.
Study participants underwent pharmacokinetic-adjusted busulfan myeloablation followed by a single infusion of exa-cel and subsequent monitoring for engraftment, total hemoglobin level, fetal hemoglobin level, BCL11A-edited alleles, transfusions, vaso-occlusive events and adverse events.
The proportion of patients who achieved and maintained a weighted average hemoglobin level greater than 9 g/dL without the need for a red blood cell transfusion in the 12 months since exa-cel transfusion served as the primary efficacy endpoint for the CLIMB THAL-111 trial. The proportion of patients who did not experience a severe vaso-occlusive event for at least 12 months after exa-cel infusion served as the primary endpoint for the CLIMB SCD-121 study.
Participants with transfusion-dependent beta-thalassemia had median follow-up of 11.9 months (range, 1.2-37.2), whereas those with sickle cell disease had median follow-up of 10.2 months (range, 2-32.3).
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.
Patients with transfusion-dependent beta-thalassemia required a mean 36 red blood cell transfusion units per year (range, 15-71) during the 2-year period before treatment. As of the data cutoff date, 42 of 44 participants with beta-thalassemia stopped receiving red blood cell transfusions (duration range, 0.8-36.2 months) after a single infusion of exa-cel.
The remaining two patients had not yet stopped receiving red blood cell transfusions but experienced 75% and 89% reductions in transfusion volume.
Participants with sickle cell disease experienced a mean of 3.9 severe vaso-occlusive events (range, 2-9.5) per year during the 2 years prior to study enrollment. After infusion with exa-cel, they reported no longer experiencing vaso-occlusive events as of the data cutoff date (duration range, 2-32.3 months).
Researchers also 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.
The investigators noted that the proportion of CRISPR/Cas9-edited BCL11A alleles remained stable for greater than 1 year after exa-cel infusion, which indicated long term successful editing of hematopoietic stem cells.
Two patients with transfusion-dependent beta-thalassemia experienced serious treatment-related adverse events, both of which resolved. No patient with sickle cell disease had a reported treatment-related serious adverse event.
Investigators reported no deaths, treatment discontinuation or subsequent malignancies during the study.
“The exa-cel safety profile is consistent with that which we have seen in the setting of busulfan myeloablation conditioning and autologous hematopoietic stem cell transplantation,” Frangoul said.
Clinical implications
The latest results of both studies showed exa-cel not only delivers effective clinical benefits for both patient groups, it does so with durability lasting up to at least 3 years from a single infusion, Frangoul said.
“Treatment with exa-cel is associated with early, consistent and durable increases in fetal hemoglobin levels, leading to elimination of transfusions in almost all patients with [beta-thalassemia] and elimination of vaso-occlusive events in all patients with sickle cell disease,” he added.
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Frangoul H, et al. Abstract 1. Presented at: American Society of Gene & Cell Therapy Annual Meeting; May 16-20, 2023; Los Angeles.
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