Phase I Study of RAG-17, an siRNA Therapy Targeting SOD1, in Patients with SOD1-ALS: Preliminary Safety, Biomarker and Efficacy Data
Zhi-Ying Wu1, Hong-Fu Li1, Wei-Qi Chen2, Hui-Fang Shang3, Qian-Qian Wei3, Xiaoxue Zhang4, Qiwen Chen4, Caiqin Zhang4, Moorim Kang4, Long-Cheng Li4, Yi-Long Wang2
1Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, 2Beijing Tiantan Hospital, Capital Medical University, 3West China Hospital of Sichuan University, 4Ractigen Therapeutics
Objective:

To evaluate the safety, tolerability, pharmacodynamics (PD), and preliminary efficacy of RAG-17, an intrathecal siRNA targeting SOD1, in patients with SOD1-associated amyotrophic lateral sclerosis (SOD1-ALS).

Background:

Mutations in the SOD1 gene cause a toxic gain-of-function and are a known cause of familial ALS. Reducing the production of the toxic mutant SOD1 protein may slow or halt disease progression. RAG-17 is designed to silence SOD1 mRNA using proprietary Smart Chemistry-Aided Delivery (SCAD™) technology.

Design/Methods:

This Phase I Single Ascending Dose (SAD) study enrolled 20 participants across five dose cohorts. Patients were randomized 3:1 (RAG-17:placebo) to receive a single intrathecal administration. Primary endpoints included safety, tolerability, and dose-limiting toxicities (DLTs). PD endpoints included cerebrospinal fluid (CSF) SOD1 protein levels and plasma neurofilament light chain (NfL). Clinical efficacy (ALSFRS-R) was assessed exploratory  in the highest dose cohort.

Results:

As of November 19, 2025, safety data is favorable across all cohorts. All adverse events were CTCAE Grade ≤2, with no SAEs or DLTs reported. Pharmacodynamic engagement was robust: a single dose of RAG-17 elicited rapid, sustained reductions in CSF SOD1 (max reduction: 58%) and plasma NfL (max reduction: 75%) observed from Day 29 through Day 90. Additionally, in the highest dose cohort, ALSFRS-R scores remained generally stable across the available blinded dataset over the 3-month observation period, aligning with the positive biomarker signals.

Conclusions:

RAG-17 demonstrates a favorable safety profile and compelling pharmacodynamic activity. The profound reduction in CSF SOD1 and plasma NfL following a single dose, combined with encouraging trends in clinical stability, highlights the efficiency of the SCAD™ delivery platform and supports RAG-17 as a promising therapeutic candidate for SOD1-ALS.

10.1212/WNL.0000000000217908
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