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Data from two pivotal trials suggest that a single infusion of the CRISPR-based gene therapy exagamglogene autotemcel (exa-cel) can provide a "functional cure" for patients with transfusion-dependent beta-thalassemia or severe sickle cell disease, a researcher reported.

In the thalassemia study, 89% (95% CI 70.8-97.6, P<0.0001) of evaluable patients achieved transfusion independence for at least 12 consecutive months following infusion with exa-cel while maintaining a weighted average hemoglobin of 9 g/dL or above, meeting the trial's primary endpoint, reported Franco Locatelli, MD, PhD, of the Catholic University of the Sacred Heart in Rome.

And 94% (95% CI 71.3-99.9, P=0.0001) of the evaluable sickle cell disease patients remained free of severe vaso-occlusive crises (VOCs) for at least 12 consecutive months after treatment, a group who had a history of at least two VOCs per year heading into the trial, according to findings presented at the annual congress in Frankfurt, Germany.

"These values are highly statistically significant as compared to the prespecified hypothesis of an efficacy of 50%," Locatelli said during a press briefing. "The data indicate that exa-cel can provide a one-time functional cure to patients with either thalassemia or sickle cell disease, and in this prespecified interim analysis, the results that we obtained are sustained over time."

Patients in the thalassemia trial remained transfusion independent for up to 40.7 months while the sickle cell disease group remained VOC-free and free of inpatient hospitalization for VOCs for up to 36.5 months, according to findings from the two single-arm phase III trials.

Exa-cel utilizes non-viral, ex vivo CRISPR/Cas9 gene-editing in autologous CD34+ hematopoietic stem and progenitor cells at the erythroid enhancer region of BCL11A to reactivate fetal hemoglobin in these patients.

Participants enrolled in the two trials had their own hematopoietic stem and progenitor cells collected from peripheral blood. The cells, after being edited using the CRISPR/Cas9 technology, were then infused back into the patient as part of an autologous hematopoietic stem cell transplant (HSCT) after the patient underwent busulfan myeloablative conditioning.

Vertex Pharmaceuticals, the developer of exa-cel, said an FDA decision on the product is expected by December 2023 for sickle cell disease and March 2024 for transfusion-dependent beta-thalassemia.

Trial Details, Safety

Data presented by Locatelli in beta-thalassemia came from 27 evaluable patients in the , of 48 dosed with exa-cel at data cutoff. The study enrolled individuals ages 12 to 35 years with transfusion-dependent thalassemia (including β0/β0 genotypes), defined as a history of at least 100 mL/kg/year or at least 10 units/year of packed red blood cell transfusions in the previous 2 years.

The sickle cell disease data included 17 evaluable patients from , which included 35 dosed patients in the same age range who had severe sickle cell disease and a history of at least two VOCs per year in the previous 2 years before screening. This study also met a key secondary endpoint, with 100% (95% 80.5-100.0, P<0.0001) of the evaluable patients remaining free from inpatient hospitalization for severe VOCs for at least 12 months.

Regarding safety, Locatelli observed that exa-cel's safety profile was consistent with busulfan myeloablative conditioning and autologous HSCT.

Serious adverse events related to exa-cel occurred in two patients (4.2%) in the thalassemia study and none in the sickle cell disease study. There was one sickle cell disease patient who died due to an adverse event (a COVID-19 infection followed by respiratory failure), which was determined to be unrelated to exa-cel.

Patients who complete these two trials are eligible to enroll in for 13 years of additional follow-up.

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