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RAG-17 Shows Promising Results in Early-Stage Study of SOD1 ALS
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The phase 1 study of RAG-17 in patients SOD1-ALS revealed safety, tolerability, and early clinical benefits across all dose levels.
Long-Cheng Li
Recently announced results from a small-scale, investigator-initiated phase 1 study (NCT05903690) showed that treatment with investigational RAG-17 (Ractigen Therapeutics) was safe and well-tolerated across all dose levels, with early signs of clinical benefit in patients with SOD1-mutated amyotrophic lateral sclerosis (SOD1-ALS). RAG-17, which has received orphan drug designation by the FDA, is a siRNA therapeutic designed to target and knockdown the expression of SOD1 in patients with pathogenic mutations known to cause ALS.1
In the study, 6 patients with SOD1-ALS received escalating doses of RAG-17 ranging from a minimum of 60 mg to the maximum tolerated dose tolerated. After reaching the tolerated dose, a fixed dose of the drug was given once every 2 months for continuous treatment, with a total treatment cycle that lasted 2 years. The study comprised of individuals with confirmed SOD1 gene mutations who had not previously or are currently receiving tofersen (Qalsody; Biogen) treatment, the only FDA-approved medication for SOD1-ALS.
Conducted at Beijing Tiantan Hospital, results from the study revealed that RAG-17, administered intrathecally, was well-tolerated across all dose levels. Overall, the age was considered safe, with adverse events that were mild in nature. While Ractigen did not provide specifics on the data, it did note that there were notable changes in clinical outcomes and key biomarkers among RAG-17-treated patients, further supporting the drug’s development.
"These initial clinical results are truly encouraging and bring us one step closer to our goal of offering new hope to patients with ALS," Long-Cheng Li, founder and chief executive officer at Ractigen, said in a statement.1 "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."
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In addition to primarily focusing on safety, the study included several other outcomes including change in Revised ALS Functional Rating Scale, SOD1 protein levels, plasma neurofilament light levels, and pharmacokinetic changes. In addition, investigators also looked at lung function, severity of fatigue, muscle strength, electromyography measures, and other quality of life assessments. Participants also undergo neurological examinations, heart circulatory system examinations, respiratory system examinations, and abdominal examinations, among other assessments.
The newly announced positive findings align with previously published preclinical data, which demonstrated significant therapeutic effects of RAG-17 in SOD1-G93A ALS mouse and rat models. Published in 2023, in vivo studies demonstrated extensive central nervous system biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation with RAG-17. Furthermore, the therapy significantly reduced CSF SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys.2
The preclinical studies also displayed RAG-17’s effectiveness in late-stage treatment settings. In SOD1G93A ALS mice, administering RD-12500 after symptom onset significantly slowed disease progression, enhanced motor function, and extended survival. This represented a major improvement over other treatments, which are typically administered pre-symptomatically in the same model. Overall, these results indicated that RD-12500 may offer therapeutic benefits for both pre-symptomatic and post-symptomatic, late-stage patients with SOD1-ALS.
Earlier this year, Ractigen received approval for its investigational new drug application (IND) to initiate phase 1 trials in China testing RAG-17 in patients with SOD1 ALS. The IND-opening study is a phase 1, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of RAG-17 in the aforementioned patient population.
