The FDA has granted Orphan Drug Designation to Ractigen Therapeutics' RAG-21, a small interfering RNA (siRNA) therapy, for the treatment of amyotrophic lateral sclerosis (ALS), with a specific focus on the FUS subtype. This designation highlights the urgent need for innovative treatments for ALS, particularly for patients with FUS mutations, which often leads to early onset and rapid disease progression.
Addressing FUS-ALS with RAG-21
ALS is a devastating neurodegenerative disease affecting motor neurons, leading to muscle weakness, paralysis, and eventually respiratory failure, typically within 2 to 5 years of diagnosis. Mutations in the FUS gene are associated with an aggressive form of ALS, characterized by early onset and rapid progression. These mutations result in protein accumulation, mis-localization, and the formation of abnormal inclusions in neurons, ultimately leading to motor neuron degeneration.
RAG-21 is designed to combat FUS-ALS by using RNA interference to selectively reduce FUS mRNA transcripts. This prevents the production of toxic FUS proteins, addressing the underlying pathology of this aggressive ALS subtype. The therapy is engineered to achieve targeted, efficient, and durable gene knockdown within the central nervous system.
Ractigen's Commitment to ALS Therapies
"The FDA's orphan drug designation for RAG-21 underscores the critical need for innovative therapies targeting ALS, particularly for patients with FUS mutations," said Long-Cheng Li, MD, founder and CEO of Ractigen Therapeutics. "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."
RAG-21 shares similarities with Ractigen's RAG-17, another siRNA therapy targeting ALS, but designed to address SOD1 mutations. RAG-17 received orphan drug designation in March 2023 and is administered via the same method as RAG-21.
Promising Data from RAG-17 Clinical Trial
RAG-17 has demonstrated positive data in an open-label, single-center, first-in-human dose escalation study (NCT05903690). The study aimed to evaluate the safety, tolerability, and pharmacokinetics of RAG-17 in patients with SOD1-mutated ALS. Six patients were enrolled and received intrathecal administrations of RAG-17, with dose escalations occurring every 14 days, contingent on the absence of adverse events (AEs) or serious AEs. The trial aimed for three to four dose escalations to reach the dose-limiting toxicity and determine optimal doses for continuous 6-month treatment cycles.
Results from the RAG-17 trial indicated that the therapy was well-tolerated across all dose levels, with any observed AEs being mild in severity. Comprehensive safety evaluations, including laboratory assessments, electrocardiograms, and vital signs, further supported the favorable safety profile. Early signs of clinical benefit were also observed, with notable changes in clinical outcomes and key biomarkers suggesting RAG-17's efficacy in patients with SOD1-mutated ALS. Further data will be presented at the 2024 International Symposium on ALS/MND in Montreal, Canada, from December 6-8. These findings align with preclinical data demonstrating significant therapeutic effects in SOD1-G93A ALS mouse and rat models, including delayed disease progression and improved survival.
"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. "The positive outcomes from this trial underscore the potential of RAG-17 as a disease-modifying therapy for ALS-SOD1."
