AsCas12a Gene Editing of HBG1/2 Promoters with Edit-301 Results in Early and Sustained Normalization of Hemoglobin and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

Rationale Complications of sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT), hereditary blood disorders caused by mutations in the β-globin gene, can be reduced by increased fetal hemoglobin (HbF).EDIT-301, an investigational gene-edited autologous hematopoietic stem cell medicine edited with the highly efficient, specific AsCas12a nuclease, has a unique genomic modification in the γ-globin gene (HBG1/2) promoters where naturally occurring HbF-inducing mutations occur. In preclinical studies, edited CD34+ cells from patients (pts) with SCD or TDT showed improved erythropoiesis and generated red blood cells (RBCs) with robust HbF production and reduced sickling.RUBY (NCT04853576) and EdiThal (NCT05444894) are Phase I/II, multicenter, open-label, single-arm studies evaluating the safety, efficacy and tolerability of EDIT-301 in pts with severe SCD and TDT, respectively. Preliminary clinical efficacy and safety data are reported. Methods Pts aged 18–50 years with severe SCD and pts aged 18–35 years with TDT were eligible to enroll. After pharmacokinetically adjusted myeloablative busulfan conditioning, pts received a single infusion of EDIT-301 (≥3 × 106 CD34+ cells/kg) and are monitored for 24 months (mos). Results As of June 28, 2023, SCD Pts 1–7 were 12-, 9-, 4-, 4-, <1-, <1-, <1-mos and TDT Pts 1–2 were 3- and <1-mos post-EDIT-301 infusion, respectively.Neutrophil and platelet engraftment were achieved after a mean of 25 and 27 days in SCD Pts 1–4 and on Day 23 and 26 in TDT Pt 1, respectively.There were no VOEs in SCD pts post-EDIT-301 infusion, compared with a mean (range) of 4.2 (3.0–5.5) VOEs/year in the 2 years pre-enrollment (n=6). After EDIT-301 infusion, Hb levels increased from 10.5 (8.5–11.9) g/dL at baseline (n=5) to 14.2 (12.4–15.7) g/dL by Mo 4 (n=4), reaching normal physiological range. By Mo 4, HbF concentration was 6.8 (5.7–7.6) g/dL and HbF was >40% (n=4; >50% in Pts 3–4). Mean HbF concentration/F-cell and % F-cells also increased. Key hemolysis markers improved or normalized in all SCD pts.TDT Pt 1 had 7.2 g/dL HbF by Mo 3, stopped receiving RBC transfusions 20 days post-EDIT-301 infusion, and remained transfusion free through the 3-mo period. TDT Pt 2 also showed early improvements.The safety profile of EDIT-301 in SCD and TDT was consistent with myeloablative conditioning with busulfan. No serious adverse events were reported after EDIT-301 infusion. Conclusion These data demonstrate successful engraftment, sustained normalization of Hb as early as Mo 4 after infusion, an increase in HbF and % F-cells, resolution of VOEs (SCD) and transfusion independence (TDT), improvements in key hemolysis markers (SCD) and a favorable safety profile. These promising results for the first clinical use of AsCas12a in SCD and TDT support further investigation of EDIT-301. Updated data with additional outcomes will be presented.