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3970 Safety and Efficacy of Aru-1801 in Patients with Sickle Cell Disease: Early Results from the Phase 1/2 Momentum Study of a Modified Gamma Globin Gene Therapy and Reduced Intensity ConditioningClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Sickle Cell Disease, Biological, Clinical Research, Genetic Disorders, Clinically Relevant, Hemoglobinopathies, Diseases, Gene Therapy, Therapies, Transplantation
Monday, December 13, 2021, 6:00 PM-8:00 PM

Michael Grimley, MD1,2, Monika Asnani, MBBS, MSc, DM, PhD3*, Archana Shrestha, PhD4*, Sydney Felker, PhD5,6*, Carolyn Lutzko, PhD5,6*, Paritha I. Arumugam, PhD5,6*, Scott Witting, PhD5,6*, Jennifer Knight-Madden, MBBS, PhD3*, Omar Niss, MD6,7, Charles T. Quinn, MD, MS6,7, Chris Lo8*, Courtney R. Little, BSN9*, Alisa Dong, PhD8* and Punam Malik, MD6,10

1Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
2University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati, OH
3Caribbean Institute for Health Research, Sickle Cell Unit, The University of the West Indies, Kingston, Jamaica
4Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH
5Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
7Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
8Aruvant Sciences, New York, NY
9Aruvant Sciences, Felicity, OH
10Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hosp., Cincinnati, OH

Introduction: Sickle cell disease (SCD) is a genetic red blood cell (RBC) disorder that causes chronic hemolytic anemia, progressive organ damage, and life-threatening acute complications such as painful vaso-occlusive crises. Allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning remains the only curative therapy for SCD but has several limitations including low donor availability and conditioning-related toxicity. Genetic modification of autologous hematopoietic system cells (HSCs) with reduced-intensity conditioning (RIC) using a high-potency drug product may address these limitations.

ARU-1801 is a gene therapy that uses a modified γ-globin lentiviral vector to produce HbFG16D within autologous CD34+ HSCs. Preclinical studies in SCD mice have shown the G16D mutation enables γ-globinG16D to bind α-globin with higher affinity; lentiviral transfer of γ-globinG16D resulted in 1.5-2x more HbF per vector copy number (VCN) compared to analogous wild-type γ-globin vector. Early studies also suggested HbFG16D may be more potent for anti-sickling than HbF, lowering reticulocyte counts in SCD mice to a greater extent at similar protein levels. We hypothesize ARU-1801 with RIC could lessen toxicities and resource utilization relative to myeloablative approaches, allowing expanded access to gene therapy for a broader group of SCD patients. Updated data from patients in the ongoing Phase 1/2 study (NCT02186418) including laboratory and clinical markers of efficacy are presented here.

Methods: Adults (18-45 years old) with severe SCD (defined by recurrent vaso-occlusive events [VOE] and acute chest syndrome) were screened for eligibility. Prior to ARU-1801 drug product (DP) infusion, all patients received a single IV dose of RIC melphalan (140 mg/m2). Endpoints included measures of safety, engraftment, VCN, hemoglobin sub-fractions, and SCD-related outcomes. Patients were weaned off transfusions 3-6 months after DP infusion. Levels of anti-sickling globins (including HbFG16D) are presented as proportions of non-transfused total hemoglobin.

Results: As of 28 July 2021, four patients (mean, 26 [19-35] years old) have been treated with ARU-1801 gene therapy for SCD with three patients followed for ≥12 months post-transplant. Transient neutropenia and thrombocytopenia were the predominant adverse events, lasting a median seven days each. There have been no other serious adverse events related to chemotherapy or ARU-1801 to date.

At 36 months post-transplant, Patient 1 has shown stable HbF expression (27%) and 64% F-cells. Patient 2 has maintained 14% HbF and 37% F-cells at 36 months despite lower engraftment of ARU-1801 due to renal hyperfiltration (eGFR = 200 mL/min/1.73 m2) at time of conditioning, which resulted in lower melphalan exposure. Both patients saw marked improvements in SCD manifestations, including 93% and 85% fewer annualized VOEs, respectively, in the two years after receiving ARU-1801 gene therapy compared to two years prior.

Patient 3 received ARU-1801 manufactured with several process modifications (including improvements of HSC collection timing and lentiviral production) and has maintained 36% HbF at month 15 with pancellular distribution (96% F-cells). To date, Patient 3 has had no VOEs since ARU-1801 administration, representing 100% reduction from baseline.

Conclusion: Amelioration of SCD phenotype and engraftment of ARU-1801 gene-modified HSCs is possible with a single RIC dose of melphalan, as demonstrated in three patients. The first patient shows 27% HbF expression at three years, and 93% reduction in VOEs. The second patient had lower HSC engraftment due to below-target melphalan exposure (likely caused by renal hyperfiltration), with 14% HbF and 5% HbA2 at three years. Nonetheless, an 85% reduction in VOEs in Patient 2 demonstrates significant clinical benefit. Dose-adjusted melphalan has the potential to improve engraftment in SCD patients with renal hyperfiltration. Following manufacturing process improvements, the third patient has shown the highest HbF (36%) at one year, the highest F-cells (96%), and no VOEs since receiving ARU-1801. ARU-1801, with RIC melphalan conditioning, is a promising alternative to myeloablative transplants for achieving durable responses with a favorable safety profile in patients with severe SCD. Longer follow-up and additional patients will be presented.

Disclosures: Asnani: Avicanna Ltd.: Research Funding; Aruvant Sciences: Research Funding. Lutzko: Aruvant Sciences: Patents & Royalties: preclinical vector development. Quinn: Forma Therapeutics: Consultancy; Emmaus Medical: Research Funding; Novo Nordisk: Consultancy; Aruvant: Research Funding. Lo: Aruvant Sciences: Current Employment. Little: Aruvant Sciences: Current Employment. Dong: Aruvant Sciences: Current Employment. Malik: Forma Therapeutics: Consultancy; Aruvant Sciences: Consultancy; Aruvant Sciences: Patents & Royalties; CSL Behring: Patents & Royalties.

OffLabel Disclosure: Plerixafor was used for stem cell mobilization. Melphalan was used as chemotherapy conditioning prior to autologous transplant with ARU-1801

*signifies non-member of ASH