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50: High Anti-Sickling Potency of a Gamma Globin in the Phase 1/2 MOMENTUM Study of ARU-1801 Gene Therapy and Reduced Intensity Conditioning for Sickle Cell Disease

Type: Oral Abstract Session

Presentation Details
Session Title: Gene and Cell Therapy Trials in Progress
Location: Room 201
Start Time: 5/16/2022 13:30
End Time: 5/16/2022 13:45

Introduction: Sickle cell disease (SCD) is a genetic red blood cell (RBC) disorder that causes hemolytic anemia, painful vaso-occlusive crises, and life-threatening complications. Myeloablative allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only curative therapy for SCD, but has several limitations, including lack of donors, conditioning-related toxicities, and risk of graft-versus-host disease (GVHD). ARU-1801 is an autologous lentiviral gene therapy that utilizes reduced-intensity conditioning (RIC), designed to address these limitations and widen access for SCD patients. Updated data on an ongoing Phase 1/2 study (NCT02186418) are presented here.
Methods: Adults (18-45 years old) with severe SCD (as defined by recurrent vaso-occlusive events [VOE] and acute chest syndrome) were screened for eligibility. Prior to infusion of ARU-1801, all patients received a single intravenous dose of RIC melphalan (140 mg/m2). Endpoints included measures of safety, engraftment, vector copy number (VCN), hemoglobin, and frequency of VOEs. Patients were weaned off transfusions 3-6 months after drug product (DP) infusion. Outcomes are reported at 24 months or latest follow-up for each patient.
Results: As of 1 Jan 2022, four patients (mean age [range], 26 [19-34] years old) have been treated and followed for ≥12 months post-transplant. Transient neutropenia and thrombocytopenia lasted a median of 7 days. There have been no other serious adverse events related to chemotherapy or ARU-1801 to date. Marked improvements in SCD manifestations include 80-93% reduction in annualized VOEs in the first two patients and complete absence of VOEs (100% reduction) in the next two patients to date. Preclinical studies suggest HbFG16D may have superior anti-sickling potency compared to wild-type HbF. Clinically, patients in this study expressed a mean 42% HbFG16D per DP VCN, which appears more efficient at expressing anti-sickling globin (ASG) than other lentiviral vectors used for gene therapy, suggesting ARU-1801 may reach effective levels of HbF at relatively lower VCN. Combined, efficacy at low VCN and RIC may increase the safety profile of ARU-1801 over other SCD gene therapies. Furthermore, ARU-1801 appears to be a more potent ASG. At screening, Patient 4 had recurrent VOEs despite 16% HbF and 20% F cells; but, at 12 months following ARU-1801 gene therapy, had complete absence of VOEs with 18% HbF (15% HbFG16D) and 68% F-cells. Furthermore, Patient 4 showed a similar level of remarkable improvement in RBC sickling kinetics by oxygen gradient ektacytometry (Lorrca®) as seen in Patient 3 with 38% HbF.
Conclusion: ARU-1801 delivers a potent anti-sickling HbFG16D with RIC, making it a promising gene therapy alternative to therapies that require myeloablative conditioning and offering amelioration of SCD symptoms without the toxicities and resources associated with full myeloablation.

Michael Grimley1, Monika Asnani2, Michael Kent3, Archana Shrestha4, Sydney Felker1, Carolyn Lutzko1, Paritha Arumugam1, Scott Witting1, Jennifer Knight-Madden2, Omar Niss1, Charles Quinn1, Christopher Lo4, Courtney Little4, Alisa Dong4, Punam Malik1

1Cincinnati Children's Hospital Medical Center, Cincinnati, OH,2Caribbean Institute for Health Research, Kingston, Jamaica,3Atrium Health Levine Children's Hospital, Charlotte, NC,4Aruvant Sciences, New York, NY
  P. Malik: 1; Commercial Interest i.e. Company X; Aruvant Sciences. 1; What was received? i.e. Honorarium; Consulting Fees. 1; For what role? i.e. Speaker; Consultant. 2; Commercial Interest i.e. Company X; Forma Therapeutics. 2; What was received? i.e. Honorarium; Consulting Fees. 2; For what role? i.e. Speaker; Consultant. 3; Commercial Interest i.e. Company X; Aruvant Sciences. 3; What was received? i.e. Honorarium; Patents and Royalties. 3; For what role? i.e. Speaker; Inventor. 4; Commercial Interest i.e. Company X; CSL Behring. 4; What was received? i.e. Honorarium; Patents and Royalties. 4; For what role? i.e. Speaker; Inventor.

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