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).

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.

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.

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.

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.