Gene Therapy ARU-1801 Showing Early Efficacy, Safety in Phase 1/2 Trial

ARU-1801, an experimental gene therapy for sickle cell disease (SCD), lowered the number of vaso-occlusive crises and led to  blood cells producing fetal hemoglobin in a first group of three treated patients, according to data from an ongoing Phase 1/2 trial.

Favorable safety is also being seen, with two of these patients two years post-treatment at the time of this analysis and the third up to 10 months out.

These findings from the MOMENTUM study (NCT02186418) were presented by Punam Malik, MD, director of the Cincinnati Comprehensive Sickle Cell Center and program leader of the Hematology and Gene Therapy Program at the Cincinnati Children’s Hospital Medical Center, at the 24th American Society of Gene and Cell Therapy (ASGCT) Annual Meeting, held online May 11–14.

“The oral presentation at ASGCT represents tremendous progress in our mission to find a cure for sickle cell disease patients,” Will Chou, MD, CEO of Aruvant Sciences, the therapy’s developer, said in a press release.

The presentation was titled, “Early Results from a Phase 1/2 Study of ARU-1801 Gene Therapy for Sickle Cell Disease (SCD): Safety and Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant” (presentation No. 78).

ARU-1801 is designed to insert a modified copy of the HBG gene directly into patients’ blood stem cells, in order to increase the production of fetal hemoglobin in red blood cells generated from their own genetically modified blood cell precursors. Fetal hemoglobin is a form of hemoglobin found in newborns that is more effective at transporting oxygen than its adult counterpart.

By increasing the production of fetal hemoglobin, ARU-1801 is expected to restore red blood cell function and improve oxygen transport. This would ease SCD symptoms and lower the risks of vaso-occlusive crises — pain crises that occur when sickled red blood cells block blood vessels, obstructing blood flow and oxygen supply to tissues.

MOMENTUM is evaluating the safety and efficacy of ARU-1801 in 10 adults, ages 18–45, with severe SCD. During the trial, participants’ blood stem cells are collected, genetically modified with ARU-1801, and then returned to patients through a single intravenous (IV) infusion.

Prior to this infusion, patients go through a reduced intensity chemotherapy (RIC) conditioning regimen — usually consisting of low-intensity chemotherapy and/or radiotherapy — to wipe out faulty blood cell precursors and so “make room” for the genetically modified precursor cells.

A newer manufacturing process, one meant to strengthen engraftment (transplant success) and the expression, or activity, of the modified HBG gene was used with the therapy given to the third patient.

Treated under the original manufacturing process, the first two patients achieved 20–22% of stable gene expression. Over their two years of follow-up, they showed 36–64% of red blood cells producing fetal hemoglobin (also known as F-cells), and 22–31% of total anti-sickling globin (including, naturally produced and artificially induced fetal hemoglobin and hemoglobin A2).

The third patient achieved 27% of stable gene expression at nine months post-treatment, and 41% of total anti-sickling globin at  10 months, with 92% of immature red blood cells producing fetal hemoglobin at six months out.

VOCs in the first two patients dropped in number by 85–93% over two years, and no pain crises over the 10 months following treatment were reported in the third, a reduction of 100%.

Correspondingly, the total number of days of VOC-related hospitalizations decreased by 93.8% — from a median of 15 days (range of 1 to 91 days) prior to treatment, to a median of 0 days (range, 0 to 17 days) after treatment.

No treatment-related adverse effects have been reported to date.

“These results are an encouraging sign of the therapeutic benefit of ARU-1801 with RIC [reduced intensity conditioning] for patients with SCD,” the scientists concluded.

Patients will be evaluated for up to 15 years after treatment in the MOMENTUM trial.

Aruvant announced a long-term manufacturing agreement with Lonza, a cell and gene therapy manufacturing group, this year to produce ARU-1801 under Good Manufacturing Practices — standards set to ensure batches of a medicine are produced with consistent high quality. 

ARU-1801 received rare pediatric disease and orphan drug designations from the U.S. Food and Drug Administration in 2020, both meant to support and speed its development.