Abstract
INTRODUCTION: SRN001 is a small interfering RNA (siRNA) drug targeting amphiregulin. It was developed using a novel SAMiRNA(®) platform, in which the siRNAs are protected within a self-assembled micelle. This platform eliminates the need for additional excipients to reduce unintended immune reactions. Amphiregulin plays a critical role in tissue repair and immune modulation. By silencing it, SRN001 is expected to be a therapeutic option for various pathologically fibrotic and cancerous diseases. This study aimed to evaluate safety and pharmacokinetics (PK) of SRN001 in humans for the first time. METHODS: A randomized, double-blind, placebo-controlled, single ascending dose, Phase 1 trial was conducted (NCT05984992). Participants randomly received a single intravenous dose of SRN001 (15, 45, 135, or 210 mg) or placebo. Safety was assessed with vital signs, clinical laboratory tests, electrocardiograms, and inflammatory cytokine assays (IL-1β, IL-6, IFN-γ, and TNF-α). Serial blood samples were collected until 168 hours post-dose to quantify plasma antisense siRNA concentrations. Anti-drug antibodies (ADAs) were measured at pre-dose, 15 days, and 29 days post-dose. RESULTS: Among 25 participants, SRN001 was generally well tolerated. Unlike other approved siRNA drugs, no systemic symptoms or cytokine elevation suggestive of infusion-related reactions (IRRs) were observed in any subjects receiving SRN001, even without premedication. SRN001 exhibited dose-proportional exposure, with the average AUC(inf) of 1.35 ug·hour/mL in the 15 mg dose group, achieving the therapeutic exposure in preclinical studies. The average plasma half-life was 0.48 hours. No ADAs were detected. CONCLUSION: A single IV administration of SRN001 demonstrated a favorable safety profile and dose-proportional PK in this small first-in-human phase 1 clinical trial. By minimizing the need for excipients, the SAMiRNA platform is anticipated to facilitate the development of safer siRNA drugs in the future. Therapeutic potential of SRN001 will be explored in subsequent clinical trials.