New Gene Therapy Product ARU-1801 Shows Durable, Safe Sickle Cell Effect

Michael Grimsley, MD (CCH)

A modified gene therapy, with reduced intensity conditioning (RIC), may provide durable and safe treatment of sickle cell disease.

New phase 1/2 data involving 3 patients with varying and severe forms of sickle cell disease, presented at the American Society of Hematology (ASH) 2020 Annual Meeting this week, support gene therapy ARU-1801 as a possible treatment.

ARU-1801 consists of autologous CD34+ hematopoietic stem cells and progenitors, transduced with a lentiviral vector encoding a modified γ-globinG16D gene.

The data, presented by investigators from Cincinnati Children’s Hospital Medical Center, complement earlier mice model findings that a highly potent anti-sickling globin would result in greater ARU-1801 efficacy with RIC. As investigators, led by Michael Grimley, MD, noted, g-globin^G16D LV produces up to twice as many more fetal hemoglobin (HbF)/vector copy number (VCN) than g-globin LV.

“We hypothesized a high potency anti-sickling globin would allow ARU-1801 to be effective with RIC,” they explained. “RIC would result in lower toxicities and resource utilization compared to myeloablative approaches, allowing access of gene therapy to a broader group of SCD patients.”

The new ASH 2020 data predates outcomes for 2 of the 3 patients observed in the ongoing assessment, who were treated with drug product from the initial ARU-1801 manufacturing process. These new findings are long-term for the first 2 patients, as well as early data with the third, with the new manufacturing process.

Eligible patients were adults with severe sickle cell disease, as per recurrent vaso-occlusive events (VOE) and acute chest syndrome. Prior to drug product infusion, all patients received single-dose intravenous melphalan 140 mg/m2, and were weaned off transfusions 3-6 months post-product infusion.

Safety, engraftment, VCN, anti-sickling Hb expression, and hematological and clinical manifestations of disease were assessed by investigators.

The findings, as of July 28 of this year, show 30-month follow-up among patients 1 and 2. To date, ARU-1801 has demonstrated a favorable safety profile and has not been associated with any treatment-related adverse events. Time to neutrophil engraftment was 9, 7, and 7 days, and time to platelet recovery was 12, 7, and 6 days post-transfusion among patients, respectively.

With the second process of ARU-1801, patient 3 demonstrated an engrafted VCN of 0.74.

“As P3 is being weaned off transfusions, HbF^G16D is progressively rising, showing the selective advantage to HbF^G16D-containing RBCs,” Investigators wrote. “(Patients 1 and 2) have maintained improvements in VOEs, no VOE in P3 so far (data will be presented).”

Investigators concluded that the presence of greater HbF^G16D may induce preventive sickling or ineffective erythropoiesis. The second process of ARU-1801 in patient 3 resulted in up to 4 times greater engraftment of transduced hematopoietic stem cells and progenitors at 6 months.

The findings are indicative of a possibly bettered gene therapy approach for sickle cell.

“Additional process enhancements are under development for future treated patients,” investigators wrote. “ARU-1801, administered with RIC, holds significant promise for achieving durable responses with a favorable safety profile in patients with severe SCD.”

The study, “Early Results from a Phase 1/2 Study of Aru-1801 Gene Therapy for Sickle Cell Disease (SCD): Manufacturing Process Enhancements Improve Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant,” was presented at ASH 2020.