Gene-Edited Cell Therapy Improves Sickle Cell, Transfusion-Dependent Thalassemia Phenotypes


Rabi Hanna, MD, presented updated data from the RUBY and EdiThal trials at ASH 2023.

EDIT-301 (Editas Medicine) gene-edited cell therapy improved manifestations of sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) in patients treated in the phase 1/2 RUBY (NCT04853576) and EdiThal (NCT05444894) trials.

New data from the trials were presented at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California, by Rabi Hanna, MD, Associate Professor, Department of Pediatrics, School of Medicine, and Member, Developmental Therapeutics Program, Case Comprehensive Cancer Center.

“SCD and TDT are hereditary blood disorders caused by mutations in the β-globin gene. Clinical evidence has demonstrated that increased fetal hemoglobin (HbF, α2γ2) can reduce or eliminate SCD and TDT complications,” Hanna and coauthors wrote in their abstract.

Hanna and colleagues reported preliminary clinical efficacy and safety data from 7 patients with SCD and 2 with TDT that have received EDIT-301 as of June 28, 2023. RUBY and EdiThal re multicenter, single-arm, open-label studies. EDIT-301 is an investigational gene-edited autologous hematopoietic stem cell product to mimic naturally occurring mutations of hereditary persistence of HbF in the γ-globin gene (HBG1/2) promoters to reactivate γ-globin expression and increase HbF production. EDIT-301 is manufactured with Editas’ proprietary gene editing nuclease, AsCas12a, designed to be highly efficient and specific. The therapy increased HbF production in red blood cells to a sufficient therapeutic level, yielding reduced sickling in SCD cells and improved erythropoiesis in TDT cells in preclinical studies.

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RUBY enrolled patients aged between 18 and 50 years with severe SCD and EdiThal enrolled patients aged between 18 and 35 years with TDT. Investigators collected autologous CD34+ hematopoietic stem and progenitor cells by apheresis after plerixafor (RUBY) or plerixafor + filgrastim (EdiThal) mobilization; these were then edited at the HBG1/2 promoters with AsCas12a. Participants received a single infusion of EDIT-301 (a minimum of 3 × 106 CD34+ cells/kg after myeloablative conditioning with busulfan. They were monitored for engraftment, total Hb, HbF, mean HbF concentration/F-cell (MCH-F/F-cell), percentage of F-cells, markers of hemolysis, transfusion requirement, VOEs (SCD only), and adverse events (AEs) for 24 months.

The first 4 patients in RUBY had 12, 9, 4, and 4 months of follow-up, and the 5th through 7th had less than 1 month of follow-up. The first 2 patients in EdiThal had 3 and less than 1 month of follow-up, respectively. In RUBY’s first 4 patients, neutrophil and platelet engraftment were achieved after a mean of 25 days (range, 23–29) and 27 days (range, 19–37), respectively. The first patient in EdiThal achieved these milestones at day 23 and 26.

The patients with SCD had no VOEs after infusion compared to a mean of 4.2 (range, 3.0-5.5) per year in the 2 years before enrollment (n = 6). Patients’ Hb levels rapidly increased to 14.2 g/dL (12.4–15.7) by Month 4 (n=4), reaching the normal physiological range, from a mean of 10.5 g/dL (range, 8.5–11.9) at baseline (n=5). By Month 4, the mean HbF concentration was 6.8 g/dL (range, 5.7–7.6) and HbF was over 40% (n=4). Patients 3 and 4 had over 50% HbF, and all patients had increased percentage of F-cells and MCH-F/F-cells and improved or normalized key markers of hemolysis.

The patient with TDT had a HbF concentration of 7.2 g/dL by Month 3, stopped receiving RBC transfusions 20 days after infusion, and remained transfusion free through the 3-month period. So far, the second patient 2 has shown early improvements. The safety profile of EDIT-301was consistent with myeloablative conditioning with busulfan in both clinical trials and no serious AEs were reported.

"These data demonstrated successful engraftment, a rapid and sustained normalization of Hb as early as 4 months after infusion, an increase in HbF and percentage of F-cells, resolution of VOEs (SCD) and transfusion independence (TDT). In addition, there were improvements in key markers of hemolysis (SCD) and a favorable safety profile in EDIT-301-treated patients,” Hanna and coauthors wrote.“EDIT-301 treatment showed promising results for the first clinical use of AsCas12a in both SCD and TDT patients after gene editing of the γ-globin gene (HBG1/2) promoters. These findings support further investigation of EDIT-301 in the RUBY and EdiThal trials."

Click here to read more coverage of the ASH 2023 meeting.

Hanna R, Frangoul H, McKinney C, et al. AsCas12a Gene editing of HBG1/2 promoters with EDIT-301 results in rapid and sustained normalization of hemoglobin and increased fetal hemoglobin in patients with severe sickle cell disease and transfusion-dependent beta-thalassemia. Presented at: 2023 ASH Annual Meeting & Exposition, December 9-12; San Diego, California. Abstract 4996
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