Pharmacokinetics and Safety Profile of SNS812, a First in Human Fully Modified siRNA Targeting Wide‐Spectrum SARS‐CoV‐2, in Healthy Subjects

• Published in: Clinical and translational science Vol. 18; no. 3; pp. e70202 - n/a
• Main Authors: Chang, Yi‐Chung, Chen, Yi‐Fen, Yang, Chi‐Fan, Ho, Hui‐Ju, Yang, Jen Fu, Chou, Yuan‐Lin, Lin, Ching‐Wen, Yang, Pan‐Chyr
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2025; Wiley
• Subjects: Administration, Inhalation; Adult; Adverse events; Aerosols; Antibodies; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Chronic illnesses; Coronaviruses; COVID-19; COVID-19 - virology; COVID-19 Drug Treatment; COVID-19 vaccines; Disease; DNA-directed RNA polymerase; Double-Blind Method; Drug dosages; Enzymes; Female; Health aspects; Healthy Volunteers; Humans; Immunogenicity; Inhalation; Male; Middle Aged; nasal spray; Pandemics; Pharmacokinetics; Placebos; RNA; RNA polymerase; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - adverse effects; RNA, Small Interfering - pharmacokinetics; SARS-CoV-2 - drug effects; SARS-CoV-2 - genetics; SARS‐COV2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Sinusitis; siRNA; siRNAs; Viral antibodies; Viruses; Young Adult; nasal spray; SARS‐COV2; siRNAs
• ISSN: 1752-8054; 1752-8062; 1752-8062
• DOI: 10.1111/cts.70202

ABSTRACT 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 Tmax) reached at 1.5–2 h, and an elimination half‐life (t 1/2) 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