Gene-edited stem cells show curative potential for beta-thalassemia, sickle cell disease
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The use of gene-edited stem cells has shown early positive results among patients with sickle cell disease and transfusion-dependent beta-thalassemia, according to data presented at the virtual ASH Annual Meeting and Exposition.
CTX001 (CRISPR Therapeutics, Vertex Pharmaceuticals), an investigational stem cell therapy, uses CRISPR-Cas9 gene-editing techniques to engineer a patient’s hematopoietic stem cells to produce high levels of fetal hemoglobin in red blood cells, with the goal of alleviating transfusion requirements for patients with beta-thalassemia and reducing vaso-occlusive crises among patients with sickle cell disease.
“Naturally occurring genetic polymorphisms in BCL11A are associated with elevated fetal hemoglobin and decreased severity of transfusion-dependent beta-thalassemia and sickle cell disease,” Haydar Frangoul, MD, medical director of pediatric hematology and oncology at Sarah Cannon Research Institute, said during a presentation. “CTX001 is produced using ex-vivo editing of the erythroid enhancer region of BCL11A in CD34-postive hematopoietic stem cells and reduces erythroid-specific expression of BCL11A.”
Frangoul and colleagues presented safety and efficacy data on 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 with CTX001.
The primary endpoint for the transfusion-dependent beta-thalassemia trial (CLIMB THAL-111) was the proportion of patients who achieved a 50% reduction in transfusions for at least 6 months after infusion with CTX001. The primary endpoint for the sickle cell disease trial was the proportion of patients who — 6 months after infusion with CTX001 — sustained a fetal hemoglobin level of at least 20% for at least 3 months.
Data were available for seven patients (median age, 23 years; range, 19-26; women, n = 5) with transfusion-dependent beta-thalassemia. Patients received a median dose of 11.6 × 106 cells/kg. Median neutrophil engraftment occurred on day 32 (range, 20-39), with median platelet engraftment on day 37 (range, 29-52).
Median follow-up was 8.9 months (range, 3.8-21.5).
Four patients experienced a serious adverse event, but only one of these was believed to be related to the study therapy. Two patients had a total of five serious adverse events that were attributed to the use of busulfan for myeloablative conditioning before CTX001 infusion.
Most adverse events occurred within 60 days of infusion with CTX001, according to Frangoul.
Clinically meaningful total and fetal hemoglobin levels were achieved early after infusion with CTX001, and increases have proved durable thus far, he added.
“The elevation of fetal hemoglobin translated into transfusion independence in all patients,” Frangoul said.
The first patient who received the gene-edited therapy has not required a transfusion for more than 20 months since infusion, he said.
Researchers also presented data on three patients (median age, 22 years; range, 22-33; women, n = 2) with sickle cell disease who received CTX001 at a median dose of 3.8 × 106 cells/kg. Median neutrophil engraftment occurred on day 22 (range, 17-30), with median platelet engraftment on day 30 (range, 30-33).
Median follow-up was 7.8 months (range, 3.8-16.6).
Two patients experienced severe adverse events after infusion with CTX001. However, none of these events were attributed to the study drug.
“There was clinically meaningful elevation in fetal and total hemoglobin that was also achieved early and maintained over time,” Frangoul said. The elevation in fetal hemoglobin translated into clinical benefit for all three patients with sickle cell disease, he added.
None of the patients experienced pain resulting from a vaso-occlusive episode after infusion with CTX001. The first patient who received CTX001 has not had a vaso-occlusive episode for more than 16 months.
CTX001 has been submitted to the FDA for the treatment of sickle cell disease and was granted fast track designation by the agency in January of last year.
“Clinical proof of concept for CTX001 has now been demonstrated for both transfusion-dependent beta-thalassemia and sickle cell disease,” Frangoul said, adding that the results indicate the therapy is “a potential functional cure” for both blood disorders.
Perspective
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Catherine Bollard, MD
The results of this study suggest that CRISPR-based gene editing shows early promise for sickle cell disease and transfusion-dependent thalassemia.
These results are remarkable. As a pediatric bone marrow transplant physician who has cured many patients with life-threatening blood diseases, the use of gene therapies like this one opens up a curative approach for many patients who would otherwise not be cured because they are ineligible for transplant or cannot find a suitable donor.
The George Washington University
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Frangoul H, et al. Abstract 4. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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