RAG-17 Investigational Therapy: Clinical Progress in SOD1-ALS Treatment

Researchers are currently evaluating RAG-17, an investigational oligonucleotide therapy designed to target the SOD1 gene, in a clinical trial for patients with amyotrophic lateral sclerosis (ALS). The study, registered as NCT05903690, monitors the safety, tolerability, and pharmacokinetics of the drug as it moves through dose-escalation phases in patients with documented SOD1 mutations.

Clinical Trial Design and Patient Enrollment

The clinical trial, titled CREATION, is an open-label, single-center, dose-escalation study conducted at Beijing Tiantan Hospital. Between May 2023 and July 2024, six participants with SOD1-associated ALS were enrolled to receive RAG-17. The study protocols require participants to meet the revised El Escorial criteria for confirmed or probable familial or sporadic ALS and maintain a forced vital capacity (FVC) of at least 50% of the predicted value.

The treatment regimen involves intrathecal injections administered between the L2 and L5 lumbar vertebrae. During the initial dose-escalation phase, patients received injections every two weeks, with doses starting at 60 mg or 90 mg and increasing by 30 mg increments. Following this, participants moved into a maintenance phase, receiving fixed doses every two months over an eight-month cycle.

Safety and Primary Endpoints

The primary objective of the CREATION trial is to assess the safety and tolerability of RAG-17 over a 240-day period. Investigators are tracking the incidence of adverse events (AEs) and serious adverse events (SAEs) following the initial injection. Clinical assessments include regular monitoring of vital signs, neurological examinations, electrocardiograms (ECG), and laboratory evaluations of blood and cerebrospinal fluid (CSF) biochemistry. The study also utilizes the ALS Functional Rating Scale-Revised (ALSFRS-R) to track changes in bodily function, including bulbar, fine motor, gross motor, and breathing capabilities.

Biomarkers and Pharmacokinetics

To evaluate the biological activity of RAG-17, the study measures secondary endpoints, including changes in CSF SOD1 protein levels and plasma neurofilament light (NfL) levels. These biomarkers are critical for understanding how effectively the oligonucleotide reduces the production of the toxic SOD1 protein.

Preclinical Foundation

Before human testing, RAG-17 underwent evaluation in rodent and non-human primate (NHP) models to verify its mechanism of action and biodistribution. Studies in transgenic SOD1G93A mice and rats demonstrated the efficacy of the oligonucleotide in reducing SOD1 expression within the spinal cord and brain.

Toxicology studies, including those conducted in cynomolgus monkeys at WuXi AppTec, established the baseline safety profile for intrathecal administration. These preclinical results, combined with in silico off-target predictions and serum stability assays, supported the progression of RAG-17 into the clinical trial in China. The study continues to operate under the guidance of the Beijing Tiantan Hospital Ethics Committee and obtained record-filing approval from the Human Genetic Resources Administration of China.