Publication date: Mar 01, 2025

Severe acute respiratory syndrome caused by the coronavirus (SARS-CoV-2) in the COVID-19 pandemic has highlighted the need for effective treatments, as rapid viral mutations complicate therapeutic development. SNS812, a fully modified inhaled siRNA that targets the conserved RNA-dependent RNA polymerase (RdRP) gene of SARS-CoV-2, has been shown to possess its suppression ability against wide-spectrum SARS-COV-2 variants preclinically. To evaluate the safety and tolerability of inhaled SNS812 in healthy participants, a randomized, double-blind, placebo-controlled phase 1 trial was conducted. To justify the first-in-human inhalation study, this research was divided into two parts: single ascending doses (0. 3, 0. 6, and 1. 2 mg/kg) and multiple doses (0. 6 and 1. 2 mg/kg) of daily inhalation for seven consecutive days to assess the safety, tolerability, immunogenicity, and pharmacokinetics of SNS812. Of the 44 participants, 3 in the 0. 3 mg/kg single-dose group, 2 in the 1. 2 mg/kg multiple ascending doses group, and 1 in the placebo group reported treatment-emergent adverse events (TEAEs). No serious adverse events (SAEs), treatment-related adverse events (TRAEs), or TEAEs caused discontinuation or deaths were observed. PK showed rapid absorption of SNS812, with peak concentrations (median T) reached at 1. 5-2 h, and an elimination half-life (t ) between 4. 96 and 7. 08 h. No antidrug antibodies (ADAs) were detected in either group. The results demonstrated that the first-in-human, fully modified with wide-spectrum anti-SARS-COV2 siRNA by inhalation following a single dose and multiple doses was safe and well tolerated in healthy participants. Trial Registration: NCT05677893.

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