Abstract Details

Title RAG-17, a Novel siRNA Therapy for SOD1-ALS: Safety and Preliminary Efficacy from a First-in-human Trial

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S5 - Updates on Amyotrophic Lateral Sclerosis (3:54 PM-4:06 PM)

Poster/Presentation
Number 003

Objective

To evaluate the safety, pharmacokinetics, and preliminary efficacy of RAG-17 in SOD1-ALS patients.

Background

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that typically results in survival of less than five years post-diagnosis. Superoxide Dismutase 1 (SOD1), the most frequently observed gene mutation in Asian ALS patients, has been targeted in past therapies with limited success. RAG-17 is a novel siRNA therapy targeting SOD1, conjugated to a smart chemistry aided delivery (SCAD) system for enhanced CNS delivery via intrathecal injection.

Design/Methods

This first-in-human, open-label, single-center, dose-escalation study (CREATION, NCT05903690) enrolled six SOD1-ALS patients to receive intrathecal injections of RAG-17 over a 240-day period.

Results Six participants received 6 to 7 doses, with dose escalations up to 150 mg, and one participant reaching 180 mg per dose. No dose-limiting toxicities (DLTs) or serious adverse events (SAEs) were reported. Adverse events were mild and included muscle tremors (2/6) and headaches (2/6). Plasma concentration of RAG-17 peaked at 6-12 hours post-administration and cleared within 48 hours. CSF SOD1 protein levels decreased by over 50% in five subjects. Plasma neurofilament light chain (NfL) levels also showed significant reductions. Notably, all subjects experienced an average decrease of 2.17 points in the ALS Functional Rating Scale-Revised (ALSFRS-R) score, equivalent to a 0.29-point decline per month. Forced vital capacity (FVC) remained stable in most patients, with two showing a significant increase from baseline.

Conclusions The CREATION study demonstrates that RAG-17 is safe and exhibits potential efficacy in treating ALS patients. The results from this study highlight the therapeutic promise of RAG-17, offering new avenues for the management of ALS.

Authors/Disclosures
weiqi chen, MD PRESENTER	Dr. chen has received research support from Ractigen Therapeutics, Suzhou,China. The institution of Dr. chen has received research support from Beijing Nova Program .
Jinyi Ye	The institution of Dr. ye has received research support from Ractigen Therapeutics, Suzhou, China.
Lingling Jiang, PhD	Dr. Jiang has nothing to disclose.
ling wang, MS	Miss wang has nothing to disclose.
Yuesong Pan, PhD	Dr. pan has nothing to disclose.
Xuan Wang, PhD	The institution of Dr. Wang has received research support from Ractigen Therapeutics, Suzhou,China.
Hui Qu, master of medicine	Mr. Qu has received research support from Ractigen Therapeutics, Suzhou,China.
xiaoling liao, MD	Dr. liao has received research support from Ractigen Therapeutics, Suzhou,China.
xuejiao zhou, Bachelor of Nursing	The institution of Miss zhou has received research support from Ractigen Therapeutics, Suzhou,China.
Shawn Zhang, MD	Ms. Zhang has nothing to disclose.
Moorim Kang, PhD	Dr. Kang has nothing to disclose.
Long-Cheng Li, MD	Dr. Li has stock in Ractigen Therapeutics. Dr. Li has received intellectual property interests from a discovery or technology relating to health care.
Yilong Wang, MD	Dr. Wang has nothing to disclose.

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