Reni-Cel, an Investigational AsCas12a Gene-Edited Cell Medicine, Led to Successful Engraftment, Increased Hemoglobin, and Reduced Transfusion Dependence in Patients with Transfusion-Dependent Beta-Thalassemia Treated in the Edithal Trial

Introduction: Transfusion-dependent β-thalassemia (TDT) is a genetic blood disorder caused by reduced or absent production of β-globin, which results in profound morbidity and reduced lifespan. Clinical evidence has shown that increased fetal hemoglobin (HbF, α2γ2) can lead to transfusion-independence, reduced disease severity, and improved quality of life (QoL). Renizgamglogene autogedtemcel (reni-cel) is an investigational gene-edited autologous hematopoietic stem cell medicine comprised of CD34⁺ cells edited at the distal CCAAT box (-118 to -113) of the promoter regions of the γ-globin genes (HBG1 and HBG2) with a highly specific and efficient, proprietary gene-editing nuclease, AsCas12a. These edits mimic naturally occurring variants of hereditary persistence of HbF in the HBG1 and HBG2 promoters and reactivate γ-globin expression, resulting in sustained and clinically meaningful production of HbF. In preclinical studies, editing CD34⁺ cells from patients with TDT at this genomic region led to improved erythropoiesis in vitro and erythroid progeny with increased total hemoglobin (Hb) production. The ongoing EdiThal trial (NCT05444894) is a Phase I/II, multicenter, open-label, single-arm study evaluating safety, tolerability, and efficacy of reni-cel in patients with TDT. Interim clinical data are reported and updated data will be presented.

Methods: Eligible patients must be 18-35 years and have a diagnosis of TDT, defined as at least 100 mL/kg/year or 10 U/year of packed red blood cell (RBC) transfusions in the 2 years prior to informed consent. After plerixafor and filgrastim mobilization, autologous CD34⁺ hematopoietic stem and progenitor cells are collected by apheresis and edited at the HBG1 and HBG2 promoters. Patients then undergo myeloablative conditioning with pharmacokinetically adjusted busulfan and receive a single infusion of reni-cel (≥3 × 10⁶ CD34⁺ cells/kg). Patients are monitored for engraftment, allelic editing levels, total Hb, HbF production, percentage of F-cells, transfusion requirement, and adverse events (AEs) for 24 months.

Results: As of June 28, 2024, 7 patients with TDT had been dosed with reni-cel. The median (range) age of these patients was 19 (18-24) years, 57.1% were female, 42.9% had the β⁰/β⁰ or β⁰/β⁰-like genotype, and the majority (85.7%) were Asian. Patients were a median (range) of 10.5 (6.3-15.1) months post-reni-cel infusion, with 2 patients having >1 year follow-up. Neutrophil and platelet engraftment were achieved after a median (range) of 23.0 (16-30) and 38.0 (24-49) days (n=7), respectively. After reni-cel infusion, mean (standard deviation [SD]) total Hb levels remained above the transfusion-independence threshold of 9.0 g/dL, and increased to 12.5 (1.5) g/dL by Month 6 (n= 7). The mean (SD) HbF concentration increased early and was 11.3 (1.7) g/dL by Month 6 (n=7). The percentage of F-cells was 99.2% (0.8%) by Month 6 (n=5), indicating pancellular distribution of HbF. After receiving the last RBC transfusion at 0.7-2.2 months post-reni-cel infusion, all 7 patients have been transfusion independent for a range of 5.8-14.5 months. Patients showed sustained high levels of editing, with mean (SD) editing levels at Month 6 being 75.4% (5.3%) and 79.9% (9.1%) in peripheral blood nucleated cells (n=6) and bone marrow-derived CD34⁺ cells (n=4), respectively. The safety profile of reni-cel was consistent with myeloablative conditioning with busulfan. No serious AEs related to reni-cel were reported.

Conclusions: Reni-cel treatment showed promising results for gene editing of the HBG1 and HBG2 promoters, with a rapid and sustained increase in total Hb well above the transfusion threshold and an increase in HbF levels with pancellular distribution. The data also demonstrate sustained high levels of editing and a favorable safety profile with successful engraftment. Additionally, patients have been transfusion-independent for up to 14.5 months. These findings, which include additional outcomes, build on clinical evidence to support the continued investigation of reni-cel in the EdiThal clinical trial.

Frangoul:Rocket Pharma: Consultancy; Vertex Pharmaceuticals: Consultancy; Editas Medicine: Consultancy; Jazz Pahrmaceuticals: Speakers Bureau; BioLineRx: Consultancy. Hanna:AbbVie: Consultancy; Vertex: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; SOBI: Speakers Bureau; Sanofi: Consultancy. Walters:Ensoma: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee member; Sanofi: Consultancy. Chang:Editas Medicine INC: Current Employment. Jaskolka:Editas Medicine, Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:Editas Medicine: Current Employment. Mei:Editas Medicine: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Afonja:Editas Medicine: Current Employment. Thompson:Global Blood Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; CRISPR/Vertex: Consultancy, Research Funding; Novartis: Research Funding; Editas: Consultancy, Research Funding; Beam Therapeutics: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding.