FDA Grants Orphan Drug Designation to RAG-21 for Treatment of ALS

The FDA granted an orphan drug designation to RAG-21 (Ractigen Therapeutics) for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical data showcases RAG-21’s potential to mitigate motor neuron degeneration and improve disease outcomes for patients.¹

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ALS is a neurodegenerative disease that significantly impairs a patient’s quality of life and currently does not have a cure. Most patients experience respiratory failure within 2 to 5 years of diagnosis. According to experts, mutations in the FUS gene are associated with an aggressive form of ALS, characterized by early onset and rapid progression. These mutations can lead to protein accumulation, mis-localization, and the formation of abnormal inclusions in neurons that ultimately lead to motor neuron degeneration.¹

RAG-21 is a small interfering RNA (siRNA) therapy specifically designed to target FUS-ALS, which is 1 of the most aggressive subtypes. It utilizes RNA interference to selectively reduce FUS mRNA transcripts, preventing the production of toxic FUS proteins and addresses the underlying pathology of FUS-ALS. RAG-21 can achieve targeted, efficient, and durable gene knockdown within the central nervous system.¹

"The FDA's orphan drug designation for RAG-21 underscores the critical need for innovative therapies targeting ALS, particularly for patients with FUS mutations," Long-Cheng Li, MD, founder and CEO of Ractigen Therapeutics, said in a news release. "FUS-ALS represents one of the most severe and rapidly progressing subtypes of ALS, with no curative treatments currently available. We are committed to developing innovative therapies like RAG-21 to provide meaningful treatment options for patients with ALS and other life-threatening rare diseases."¹

Additionally, RAG-21 is similar to RAG-17 (Ractigen Therapeutics), which is an agent that instead targets the expression SOD1 in patients with pathogenic mutations that are known to cause ALS.² It was granted an orphan drug designation by the FDA in March 2023.³ Both RAG-21 and RAG-17 are administered using the same method, and RAG-17 has demonstrated positive data in an open-label, single center, first-in-human dose escalation study (NCT05903690).^1,2

The goal was to evaluate the safety, tolerability, and pharmacokinetics of RAG-17 in patients with SOD1-mutated ALS. Patients received 60 mg of RAG-17 intrathecally and within 14 days following the first administration, patients were given a dose escalation every 30 mg or 14 days of the observation period if they did not experience any adverse events (AEs) or serious AEs. Three to 4 dose escalations were planned to reach the dose limiting toxicity, with optimal doses for continual 6-month treatment cycles. A total of 6 patients were enrolled in this study.^2,4

The results demonstrated that RAG-17 was well-tolerated across all dose levels, and any AEs that occurred were mild in severity. Additionally, the investigators noted that comprehensive safety evaluations—including laboratory assessments, electrocardiograms, and vital signs—had further supported the favorable safety profile.³

Further, early signs of clinical benefit were also present. There were notable changes in clinical outcomes as well as key biomarkers which indicate RAG-17’s efficacy in patients with SODI-mutated ALS. Additional data will be presented at the 2024 International Symposium on ALS/MND in Montreal, Canada, which will be held December 6 through 8. These findings align with preclinical data, showing significant therapeutic effects in SOD1-G93A ALS mouse and rat models, including delayed disease progression and improved survival.³

"These initial clinical results are truly encouraging and bring us one step closer to our goal of offering new hope to ALS patients," said Li in a news release. "The positive outcomes from this trial underscore the potential of RAG-17 as a disease-modifying therapy for ALS-SOD1."³

REFERENCES

1. Ractigen Therapeutics Announces FDA Orphan Drug Designation for RAG-21 for the Treatment of ALS. News release. PR Newswire. November 19, 2024. Accessed November 19, 2024. https://prnmedia.prnewswire.com/news-releases/ractigen-therapeutics-announces-fda-orphan-drug-designation-for-rag-21-for-the-treatment-of-als-302309985.html

2. ALS Therapy Development Institute. Safety and Tolerability of RAG-17 in the Treatment of Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation. Accessed November 19, 2024. https://www.als.net/als-trial-navigator/500087/

3. Ractigen Announces Positive Clinical Data for RAG-17 in ALS-SOD1 Treatment from Investigator-Initiated Trial. News release. PR Newswire. September 10, 2024. Accessed November 19, 2024. https://www.prnewswire.com/news-releases/ractigen-announces-positive-clinical-data-for-rag-17-in-als-sod1-treatment-from-investigator-initiated-trial-302243520.html

4. Safety and Tolerability of RAG-17 in the Treatment of Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation. ClinicalTrials.gov identifier: NCT05903690. Updated June 15, 2023. Accessed November 19, 2024. https://clinicaltrials.gov/study/NCT05903690