RAG-17 safe, shows early signs of efficacy as SOD1-ALS treatment
Trial results 'truly encouraging' in patients with SOD1 gene mutations
RAG-17, an investigational therapy from Ractigen Therapeutics, was safe and well tolerated across all tested doses in people with amyotrophic lateral sclerosis (ALS) carrying mutations in the SOD1 gene — cases in which the disease is known as SOD1-ALS.
Those are the findings of an investigator-initiated trial (NCT05903690) conducted at a single center in China, in which the candidate therapy also led to meaningful changes in clinical outcomes and disease biomarkers, which researchers noted as early signs of efficacy.
“These initial clinical results are truly encouraging and bring us one step closer to our goal of offering new hope to ALS patients,” Long-Cheng Li, MD, founder and CEO of Ractigen, said in a company press release.
“The positive outcomes from this trial underscore the potential of RAG-17 as a disease-modifying therapy for ALS-SOD1. We are fully committed to advancing its clinical development and ultimately delivering this much-needed treatment to patients,” Li added.
The new data will be presented at upcoming international conferences, including the 35th International Symposium on ALS/MND, which will take place Dec. 6-8 in Canada, the company said.
Treatment for SOD1-ALS tested in 6 adults in Chinese trial
Up to 20% of cases of familial ALS — when more than one person in the same biological family is affected by the disease — and as many as 2% of sporadic cases, or those that occur spontaneously, are associated with SOD1 gene mutations. This gene contains the instructions for the enzyme SOD1, an antioxidant enzyme that helps to prevent damage caused by free radicals produced as part of the cell’s normal metabolism.
When the gene is mutated, however, cells produce an abnormal SOD1 protein that cannot exert its function properly, causing the buildup of free radicals that damage cells. The protein also is prone to form toxic clumps, or aggregates, which further contribute to cell damage and death.
RAG-17 is a small interference RNA (siRNA) molecule designed to reduce the levels of the abnormal SOD1 protein. It works by binding to SOD1‘s messenger RNA — an intermediate molecule generated from DNA that serves as a template for protein production — and targeting it for destruction, ultimately preventing the production of SOD1.
Designed with the company’s proprietary delivery platform Smart Chemistry-Aided Delivery, RAG-17’s siRNA molecule is linked to a second molecule called an accessory oligonucleotide, which boosts its delivery into the brain and spinal cord.
The open-label study, led by Yilong Wang, MD, PhD, at the Beijing Tiantan Hospital, enrolled six adults with SOD1-ALS. All received RAG-17 via injections into the spinal canal, known as intrathecal administration.
The starting, minimum dose was 60 mg for each participant. It could be increased every two weeks by up to 30 mg until the maximum-tolerated dose — the highest dose that can be given without unacceptable safety risks — was reached. Once the maximum-tolerated dose was determined for each patient, an optimal dose between the safe dose and the maximum tolerated dose was selected and given once every two months, for up to a total of eight months.
The trial’s main goals were to determine the treatment’s safety and tolerability, as well as changes in disease progression, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures include changes in SOD1 levels, as well as alterations in the nerve cell death biomarker neurofilament light chain, the pharmacological properties of RAG-17, and the time it took patients to require invasive ventilatory support, or their death.
While the exact benefits observed with RAG-17 were not disclosed in the press release, the company said the early clinical findings are in agreement with preclinical data in mouse and rat models of SOD1-ALS. In these models, RAG-17 led to significant therapeutic effects, including slower disease progression and better survival.
RAG-17 was designated an orphan drug by the U.S. Food and Drug Administration in 2023. That status aims to encourage the development of therapies for rare and serious diseases through benefits such as seven years of market exclusivity if approved and exemption from certain fees.
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