Journal Publication

RAG-17 shows safety and SOD1 knockdown in first-in-human ALS trial

A six-patient Phase 1 study of the siRNA conjugate RAG-17 met its safety endpoint and cut CSF SOD1 protein by up to 69% in patients with SOD1-linked ALS.

A first-in-human Phase 1 trial of RAG-17, an siRNA conjugate targeting SOD1, reported that the therapy was safe and tolerable in six patients with SOD1-mutant ALS and reduced SOD1 protein and neurofilament light chain from baseline.

By AppliedXLJuly 15, 2026Trial NCT05903690

Executive Summary

A first-in-human trial dosed a small group of patients carrying SOD1 gene mutations with an siRNA conjugate designed to lower production of the mutant protein that drives their form of amyotrophic lateral sclerosis.
The therapy met its safety and tolerability endpoint, with only mild, resolving side effects and no serious adverse events, while cerebrospinal fluid levels of the target protein and a nerve-damage marker both fell substantially from baseline.
The trial was not designed and was not large enough to establish whether these biological changes translate into slower functional decline or longer survival for patients with this genetic form of ALS.
SOD1 mutations cause a rare but well-defined and fatal subset of ALS, and a therapy that directly lowers the mutant protein addresses a genetic driver of the disease rather than only its downstream symptoms.

The trial

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease, and mutations in the SOD1 gene that cause the protein to gain a toxic function drive one of its identifiable genetic subtypes. Researchers developed RAG-17, a small interfering RNA (siRNA, a molecule that silences a target gene) conjugated to a delivery platform intended to improve distribution in the central nervous system. Before testing it in patients, the sponsors showed in SOD1G93A rodents that RAG-17 slowed disease progression, preserved motor function and extended survival, and in cynomolgus monkeys that intrathecal dosing (delivered directly into the spinal fluid) produced dose-dependent, durable drops in SOD1 messenger RNA and protein. Oligonucleotide-siRNA

How it was done

The first-in-human study enrolled six adults with confirmed SOD1-mutant ALS in an open-label design (no control group), registered as NCT05903690 with a primary completion date of February 28, 2024. Three patients received an initial 60 mg dose across seven total administrations (cohort 1), and three received an initial 90 mg dose across six administrations (cohort 2), with doses escalated in 30 mg steps to maintenance levels of 150 mg in five patients and 180 mg in one. The trial's registered primary outcomes spanned safety measures, including adverse-event incidence, laboratory and vital-sign monitoring, ECG, and neurological examination, tracked through 180 days after treatment. Key secondary measures included cerebrospinal SOD1 protein, plasma neurofilament light chain, and the ALS Functional Rating Scale-Revised. NCT05903690+1

The result

The trial met its primary safety endpoint. Treatment-emergent adverse events occurred in two of six patients, all mild to moderate and resolved, including muscle tremor and an elevated liver enzyme, with no serious adverse events reported. No clinically meaningful changes appeared in laboratory parameters, vital signs, the ALS Functional Rating Scale-Revised score, or physical, neurological or ECG examinations. On the key secondary measures, cerebrospinal fluid SOD1 protein fell 69% from baseline by day 240 in cohort 1 and 56% by day 210 in cohort 2, while plasma neurofilament light chain, a marker of neuronal injury, fell 62% in cohort 1 and 52% in cohort 2. No patient required invasive mechanical ventilation or died during the study. Oligonucleotide-siRNA

What it changes

For a genetically defined, fatal subtype of ALS, the finding establishes that lowering mutant SOD1 protein through this delivery approach is achievable without serious safety signals in a small first-in-human cohort. Tofersen, an antisense oligonucleotide targeting the same SOD1 mRNA, is approved for SOD1-ALS and previously demonstrated CSF SOD1 and neurofilament light chain reductions in its own trials; the exclusion of patients previously treated with tofersen from this study means RAG-17 was tested independent of that prior therapy. The biomarker reductions reported here sit in a similar direction to what has been reported for approved SOD1-targeting therapy, though this trial's six-patient, uncontrolled design cannot establish whether the magnitude or durability of RAG-17's effect on protein knockdown corresponds to a comparable or different clinical trajectory. Oligonucleotide-siRNA

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