RAG-17 Reduced SOD1 by 69% in Phase 1 Amyotrophic Lateral Sclerosis Trial

Ractigen Therapeutics has reported peer-reviewed data in Nature Medicine demonstrating the successful translation of its investigational RNA interference therapy, RAG-17, from preclinical studies to first-in-human clinical testing for amyotrophic lateral sclerosis (ALS) caused by mutations in the superoxide dismutase 1 (SOD1) gene.

The publication combines preclinical pharmacology, non-human primate findings, and Phase 1 clinical results, highlighting the performance of the company’s proprietary Smart Chemistry-Aided Delivery (SCAD™) platform. Following intrathecal administration, RAG-17 achieved broad central nervous system distribution and durable suppression of SOD1 expression.

The findings support ongoing Phase 2 development of RAG-17 as a potential disease-modifying therapy for patients with SOD1-associated ALS.

SCAD Platform Enables Durable CNS Delivery of siRNA

RAG-17 is an investigational small interfering RNA (siRNA) therapy that targets SOD1 messenger RNA, reducing production of the toxic mutant SOD1 protein implicated in familial ALS.

The therapy uses the SCAD™ delivery platform, which links the siRNA duplex to an accessory oligonucleotide to improve distribution throughout the central nervous system after intrathecal injection. Durable target suppression may allow longer dosing intervals than currently available intrathecal RNA therapies.

SOD1 mutations account for a proportion of inherited ALS cases and produce misfolded proteins that contribute to progressive motor neuron degeneration. Although disease-modifying therapies have emerged, sustained target suppression with less frequent dosing remains an important unmet need.

Phase 1 Trial Demonstrated Favorable Safety and Biomarker Reductions

The open-label, dose-escalation investigator-initiated Phase 1 trial (NCT05903690) evaluated multiple intrathecal doses of RAG-17 in six patients with SOD1-ALS. Primary objectives included safety, tolerability, pharmacokinetics, and pharmacodynamic activity.

The study met its primary safety endpoint. Investigators reported no serious adverse events, no requirement for invasive mechanical ventilation through the data cutoff, and only mild to moderate, transient treatment-emergent adverse events.

The therapy also produced robust biomarker responses. In the first treatment cohort:

• Cerebrospinal fluid SOD1 protein declined by a mean of 69% at Day 240.
• Plasma neurofilament light chain (NfL), a biomarker of neuroaxonal injury, fell by a mean of 62%, with some patients achieving reductions of up to 85% below baseline.

Exploratory clinical assessments also suggested disease stabilization or slower functional decline in selected participants. Some patients maintained or improved their predicted forced vital capacity (FVC), indicating preservation of respiratory function during follow-up.

Preclinical Studies Showed Durable Target Suppression and Survival Benefit

Preclinical studies across multiple animal models demonstrated consistent biological activity.

In aggressively progressing SOD1^G93A mouse models, treatment initiated well after symptom onset extended survival by up to 75.8% (128.5 days) compared with untreated controls while improving motor performance and preserving body weight. Rat studies similarly delayed disease onset and protected spinal motor neurons.

In cynomolgus monkeys, a single intrathecal dose reduced lumbar spinal cord SOD1 mRNA by up to 91%, with target suppression maintained for up to 72 days, supporting the possibility of extended dosing intervals in clinical practice.

Investigators Highlight Clinical Translation

Corresponding author Dr. Yilong Wang of Beijing Tiantan Hospital said the combination of favorable safety, strong biomarker reductions, and substantial survival benefits observed in advanced preclinical models supports the potential of RAG-17 as a disease-modifying therapy for SOD1-ALS.

Ractigen founder and CEO Dr. Long-Cheng Li said publication in Nature Medicine validates the SCAD platform’s ability to deliver siRNA efficiently throughout the central nervous system while producing durable gene silencing that translated from animal models into human clinical findings.

Regulatory Path Forward

RAG-17 has advanced into Phase 2 clinical development for SOD1-related ALS. The published findings provide clinical proof of concept for the SCAD delivery platform and support further evaluation of its potential to deliver durable RNA interference therapies for neurological diseases while reducing the frequency of intrathecal administration.

Reference

Ractigen Therapeutics Announces Landmark Publication in Nature Medicine Highlighting Unprecedented Preclinical Efficacy and Positive First-in-Human Clinical Data for RAG-17 in SOD1-ALS – Ractigen Therapeutics