ARU-1801 Gene Therapy Safely Limiting VOCs in 5 Treated Patients
ARU-1801, Aruvant Sciences’ experimental gene therapy for sickle cell disease (SCD), led to the production of fetal hemoglobin in red blood cells and significantly lowered the number of vaso-occlusive crises (VOCs) in a group of five people with severe SCD, according to data from the ongoing Phase 1/2 MOMENTUM trial.
ARU-1801 also showed a promising safety profile, with no serious adverse events.
“The data demonstrate that the ARU-1801 gene therapy may not only be able to reduce severe vaso-occlusive events … but also reduce days in the hospital for SCD patients, which could provide a clinically meaningful benefit for patients and help reduce health care costs,” Punam Malik, MD, director of the Cincinnati Comprehensive Sickle Cell Center and program leader of the Cincinnati Children’s Hospital’s Hematology and Gene Therapy Program, said in a press release.
Malik presented the findings in the oral presentation “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,” (No. 50, p. 25) at the American Society of Gene and Cell Therapy (ASGCT) 25th annual meeting, running May 16–19 in Washington, D.C., and virtually.
SCD is characterized by the production of faulty hemoglobin, a red blood cell protein needed for oxygen transport. The faulty protein causes red blood cells to become misshapen, making it harder for them to pass through blood vessels. This results in slow or blocked blood flow, restricted oxygen supply, and consequent episodes of sudden and severe pain, or VOCs.
ARU-1801 is designed to deliver a healthy copy of the HBG gene, which encodes part of fetal hemoglobin, into patients’ own red blood cell-producing stem cells. Fetal hemoglobin is naturally present in the body at birth, but is not produced in adults. It is more efficient at transporting oxygen than the adult form of hemoglobin.
By delivering HBG, the treatment is designed to enable the body’s own stem cells to give rise to red blood cells able to produce fetal hemoglobin, which in turn is expected to restore their function and oxygen transport. Aruvant expects the therapy will ease SCD symptoms and lower the risk of VOCs.
MOMENTUM (NCT02186418) is evaluating ARU-1801’s safety and feasibility in 10 adults, ages 18–45, with severe SCD, partly defined by recurrent VOCs.
In steps, participants’ stem cells are collected, treated with ARU-1801, and then returned to patients via an into-the-vein infusion. Before this can be carried out, however, patients undergo a procedure called conditioning, which usually involves receiving chemotherapy and/or radiotherapy, to destroy their existing faulty blood cell precursors in order to make room for the soon-to-be-delivered, genetically corrected ones.
The ARU-1801 treatment protocol specifically uses a reduced intensity conditioning (RIC) regimen with a lower dose of chemotherapy — a single intravenous dose of melphalan (140 mg/m2) — that is associated with a lower risk of side effects and potentially shorter hospital stays.
“ARU-1801 is the only gene therapy in development that has been shown to achieve durable responses in patients with severe SCD using only reduced intensity conditioning — a key differentiator from other investigational gene therapy and gene editing regimens,” Malik said.
In a May 2021 trial update, the company reported that ARU-1801 was showing safety in three treated patients. The experimental therapy was also able to trigger the production of fetal hemoglobin in red blood cells and lower the number of VOCs.
Aruvant now presented data covering five patients treated with ARU-1801. According to the company, the treatment continued to be safe and effective in these five people, and led to long-term production of fetal hemoglobin.
Notably, it appears that ARU-1801’s carrier, called a lentivirus, may enable sufficient fetal hemoglobin levels to be reached with delivery of fewer carrier copies than those used in other gene therapies. This feature, coupled with lower intensity pre-treatment chemotherapy conditioning, “may increase the safety profile of ARU-1801 over other SCD gene therapies,” the research team wrote.
Treated patients had significant reductions in the number of severe VOCs, the company reported, with a complete resolution of these crises observed in four people either at two years post-treatment or their last follow-up exam.
Adverse events, reported in four patients as of January, were transient low levels of white blood cells (neutropenia) and platelets (thrombocytopenia), with “no other serious adverse events related to chemotherapy or ARU-1801 to date,” the scientists wrote.
These findings continue to support ARU-1801 as a potential treatment, the researchers concluded.
“ARU-1801 delivers a potent anti-sickling [fetal hemoglobin] with RIC, making it a promising gene therapy alternative to therapies that require myeloablative conditioning [high-dose chemotherapy] and offering amelioration of SCD symptoms without the toxicities and resources associated with full myeloablation,” they wrote.
MOMENTUM will follow participants for up to 15 years after the transplant to monitor the therapy’s safety and efficacy, and to determine if a single lifetime treatment is sufficient.