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4955 Reni-Cel, an Investigational AsCas12a Gene-Edited Cell Medicine, Led to Sustained Hemoglobin Normalization and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease Treated in the RUBY Trial

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Genetic Disorders, Clinical Research, Hemoglobinopathies, Diseases
Monday, December 9, 2024, 6:00 PM-8:00 PM

Rabi Hanna, MD1, Haydar Frangoul, MD2, Christopher McKinney, MD3, Luis Pineiro, MD4*, Markus Mapara, MD, PhD5*, Jignesh Dalal, MD6*, Hemalatha Rangarajan, MD7, Harold Atkins, MD8*, Kai-Hsin Chang, PhD9, Baisong Mei, MD, PhD9*, Olubunmi Afonja, MD, MBA9* and Mark C. Walters, MD10*

1Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic, Cleveland, OH
2Sarah Cannon Center for Blood Cancer at the Children's Hospital at TriStar Centennial, Nashville, TN
3Children’s Hospital of Colorado, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
4Blood and Marrow Transplant Program and Marrow Processing Laboratory, Baylor University Medical Center, Dallas, TX
5Bone Marrow Transplantation and Cell Therapy Program, Columbia University Irving Medical Center, New York City, NY
6Rainbow Babies & Children’s Hospital, Cleveland, OH
7Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Nationwide Children's Hospital, Columbus, OH
8Transplant and Cell Therapy Program, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
9Editas Medicine, Inc., Cambridge, MA
10School of Medicine, University of California, San Francisco and Benioff Children’s Hospital, Oakland, CA

Introduction: Sickle cell disease (SCD) is a genetic blood disorder caused by a pathogenic variant in the β-globin gene. Sustained increases in fetal hemoglobin (HbF, α2γ2) can reduce or eliminate SCD symptoms, including vaso-occlusive events (VOEs). 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 (HBG1/2) with a highly specific and efficient, proprietary gene-editing nuclease, AsCas12a. These edits mimic naturally occurring variants of hereditary persistence of HbF in the HBG1/2 promoters and reactivate γ-globin expression, resulting in sustained and clinically meaningful production of HbF. In preclinical studies, editing this genomic region in CD34+ cells from patients with SCD led to ≥80% editing, robust HbF production, and significantly reduced sickling of erythroid progeny. The ongoing RUBY trial (NCT04853576) is a Phase I/II/III, multicenter, open-label, single-arm study evaluating safety, tolerability, and efficacy of reni-cel in patients with severe SCD. Interim clinical data are reported; updated data will be presented.

Methods: Eligible patients must be 12–50 years and have a diagnosis of severe SCD, defined as ≥2 severe VOEs per year in the 2 years prior to informed consent. After plerixafor mobilization, autologous CD34+ hematopoietic stem and progenitor cells are collected by apheresis and edited at the HBG1/2 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, VOEs, total hemoglobin (Hb), HbF production, percentage of F-cells, mean HbF concentration/F-cell (MCH-F/F-cell), markers of hemolysis, and adverse events (AEs) for 24 months and then followed in a long-term study for an additional 13 years.

Results: As of June 28, 2024, 21 patients with SCD had received reni-cel. Median (range) age was 28 (18–41) years, 52.4% were female, 95.2% had the βSS genotype, and the majority (95.2%) were Black or African American. Patients were a median (range) of 8.0 (0.6–24.1) months post-reni-cel infusion, with 7 patients having >1 year follow-up. Neutrophil and platelet engraftment were achieved after a median (range) of 23.0 (15–29) and 24.5 (18–51) days, respectively (n=20). After reni-cel infusion, patients achieved early correction of anemia, with durable normalization of total Hb; mean (standard deviation [SD]) total Hb was 14.2 (2.0) g/dL at Month 6 (n=10) and was maintained through last follow-up. Mean (SD) percentage of HbF was 48.2% (3.4%) by Month 6 (n=12) and was sustained at >40% through last follow-up. The percentage of F-cells and MCH-F/F-cell increased early, and MCH-F/F-cell was sustained above the anti-sickling threshold of 10 pg/F-cell through last follow-up. Markers of hemolysis, including absolute reticulocyte count, indirect bilirubin, lactate dehydrogenase, and haptoglobin, improved or normalized by Month 6 and were generally maintained over time. All patients were VOE-free post-reni-cel infusion as of the data cutoff date, compared with a mean (SD) of 4.9 (2.8) severe VOEs/year in the 2 years before enrollment (n=21). Patients showed sustained high levels of allelic editing in both peripheral blood nucleated cells and bone marrow–derived CD34+ cells, with mean (SD) editing levels of 80.9% (5.9% [n=4]) and 86.9% (4.1% [n=3]) at Month 12, 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 at the HBG1/2 promoters, with early Hb normalization and durable increases in HbF. The data also demonstrate an early increase in the percentage of F-cells, improvements in markers of hemolysis, sustained high levels of editing, resolution of VOEs, and a favorable safety profile, with successful engraftment in all patients. These findings, which are based on a larger cohort of patients and additional outcomes, build on clinical evidence that support the continued investigation of reni-cel in the RUBY trial.

Disclosures: Hanna: Sanofi: Consultancy; SOBI: Speakers Bureau; Vertex: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Consultancy. Frangoul: Vertex Pharmaceuticals: Consultancy; Jazz Pahrmaceuticals: Speakers Bureau; BioLineRx: Consultancy; Editas Medicine: Consultancy; Rocket Pharma: Consultancy. Mapara: Caelum: Current holder of stock options in a privately-held company; Incyte: Consultancy; CRISPR/Vertex: Consultancy; bluebird bio: Consultancy; Ossium: Consultancy. Rangarajan: Medexus (Treosulfan): Consultancy. Chang: Editas Medicine INC: 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. Walters: Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee member; Sanofi: Consultancy; Ensoma: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board.

*signifies non-member of ASH