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4996 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-ThalassemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Monday, December 11, 2023, 6:00 PM-8:00 PM

Rabi Hanna, MD1, Haydar Frangoul, MD2, Christopher McKinney, MD3*, Luis Pineiro, MD4*, Markus Mapara, MD5, Jignesh Dalal, MD6*, Kai-Hsin Chang, PhD7, Michael Jaskolka, PhD7*, Keunpyo Kim, PhD7*, Daphne L. Farrington, MS7*, Maha Wally, BS, MB7*, Baisong Mei, MD, PhD7, Adebayo Lawal, MD, MSc, MBA7, Olubunmi O. Afonja, MD, MBA7 and Mark C. Walters, MD8

1Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic, Cleveland, OH
2Sarah Cannon Research Institute at the Children's Hospital, Tristar Children's Hospital, Nashville, TN
3Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO
4Blood and Marrow Transplant Program and Marrow Processing Laboratory, Baylor University Medical Center, Dallas, TX
5Blood and Marrow Stem Cell Transplantation Program, Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, NY
6Division of Hematology and Bone Marrow Transplant, Rainbow Babies & Children’s Hospital, Cleveland, OH
7Editas Medicine, Inc., Cambridge, MA
8University of California, San Francisco Benioff Children’s Hospital, Oakland, CA

Background: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (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.

EDIT-301, an investigational gene-edited autologous hematopoietic stem cell medicine, has a unique genomic modification that mimics naturally occurring mutations of hereditary persistence of fetal hemoglobin in the γ-globin gene (HBG1/2) promoters. These mutations reactivate γ-globin expression and increase HbF production. EDIT-301 is manufactured with a highly efficient and specific, proprietary gene editing nuclease, AsCas12a. In preclinical studies, edited CD34+ cells from patients with SCD or TDT increased HbF production in red blood cells (RBCs) sufficient for a therapeutic effect, including reduced sickling (SCD) and improved erythropoiesis (TDT).

Aim: 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 patients with severe SCD and TDT, respectively. As of June 28, 2023, 7 SCD patients and 2 TDT patients have received EDIT-301 treatment. Preliminary clinical efficacy and safety data are reported.

Methods: Patients aged 18–50 years with severe SCD (defined as ≥2 severe vaso-occlusive events [VOEs] per year in the 2 years prior to informed consent [IC]) and patients aged 18–35 years with TDT (defined as at least 100 mL/kg/year or 10 U/year of packed RBC transfusions in the 2 years prior to IC) were eligible to enroll in RUBY and EdiThal, respectively. Autologous CD34+ hematopoietic stem and progenitor cells collected by apheresis after plerixafor (RUBY) or plerixafor + filgrastim (EdiThal) mobilization were edited at the HBG1/2 promoters with AsCas12a. After myeloablative conditioning with busulfan, patients received a single infusion of EDIT-301 (a minimum of 3 × 106 CD34+ cells/kg), and were monitored for engraftment, total hemoglobin (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.

Results: Based on a data cut of June 28, 2023, Patients 1–4 with SCD were 12-, 9-, 4-, and 4-months post-EDIT-301 infusion, respectively. Patients 5–7 with SCD were <1-month post-EDIT-301 infusion. Patients 1–2 with TDT were 3- and <1-months post-EDIT-301 infusion, respectively.

Neutrophil and platelet engraftment were achieved after a mean (range) of 25 (23–29) and 27 (19–37) days in Patients 1–4 with SCD and on Day 23 and 26 in Patient 1 with TDT, respectively.

There were no VOEs in SCD patients post-EDIT-301 infusion, compared with a mean (range) of 4.2 (3.0–5.5) VOEs/year in the 2 years before enrollment (n=6). Following EDIT-301 infusion, Hb levels rapidly increased to 14.2 (12.4–15.7) g/dL by Month 4 (n=4), reaching the normal physiological range, from a mean (range) of 10.5 (8.5–11.9) g/dL at baseline (n=5). By Month 4, the mean (range) HbF concentration was 6.8 (5.7–7.6) g/dL and HbF was >40% (n=4); Patients 3 and 4 had >50% HbF. Percentage of F-cells and MCH-F/F-cell also increased. Key markers of hemolysis improved or normalized in all patients with SCD.

Patient 1 with TDT had a HbF concentration of 7.2 g/dL by Month 3, stopped receiving RBC transfusions 20 days after EDIT-301 infusion, and remained transfusion free through the 3-month period. Patient 2 with TDT also showed early improvements.

The safety profile of EDIT-301 in both SCD and TDT was consistent with myeloablative conditioning with busulfan. No serious AEs were reported after EDIT-301 infusion.

Conclusion: 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. 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. Updated data with additional outcomes will be presented.

Disclosures: Hanna: SOBI: Speakers Bureau; Sanofi: Speakers Bureau; Vertex: Honoraria; EDITAS: Research Funding. Frangoul: Jazz Pharmaceuticals: Speakers Bureau; Editas Medicine: Consultancy; Vertex Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Other: Member of DSMB for a study. McKinney: Horizon Therapeutics: Other: Advisory Board; Bluebird Bio: Other: Advisory Board. Pineiro: Editas Medicine: Research Funding; Alexion Pharmaceuticals: Speakers Bureau. Mapara: Crispr/vertex: Consultancy; Incyte: Consultancy; Bluebird bio: Consultancy. Chang: Editas Medicine: Current Employment, Current equity holder in private company. Jaskolka: Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Kim: Editas Medicine: Current Employment. Farrington: Editas Medicine: Current Employment, Current equity holder in publicly-traded company; Eli Lilly and Company: Current equity holder in publicly-traded company. Wally: Editas Medicine: Current Employment. Mei: Editas Medicine: Current Employment. Lawal: Editas Medicine: Current Employment; Generation Bio Pharmaceuticals: Other: Previous Employer 2021-2022. Afonja: Editas Medicine: Current Employment. Walters: Ensoma, Inc: Consultancy; Vertex Pharmaceuticals: Consultancy; BioChip Labs: Consultancy, Other: Medical Director; AllCells, Inc: Consultancy, Other: Medical Director.

*signifies non-member of ASH