Safety and antiviral activity of inhaled siRNA SNS812 for treatment of mild-to-moderate COVID-19: a phase 2 randomized trial

BACKGROUND: SARS-CoV-2 remains a global health threat because ongoing viral evolution and immune evasion reduce the effectiveness of existing therapies. SNS812 is an inhaled small interfering RNA targeting a highly conserved region of the viral RNA-dependent RNA polymerase gene, representing a strategy that may enable broader antiviral activity against emerging variants. METHODS: In this phase 2, double-blind, randomised, placebo-controlled trial, adults with mild-to-moderate COVID-19 within 3 days of symptom onset were randomly assigned (1:1:1) to receive placebo or inhaled SNS812 (100 mg or 200 mg) once daily for 7 days (ClinicalTrials.gov identifier: NCT05941793). Safety was the primary endpoint. Secondary endpoints included the time to sustained alleviation (TTSA) and resolution (TTSR) for prespecified composite target symptoms and individual symptoms. Virological outcomes were exploratory. RESULTS: A total of 135 participants were enrolled, with more than 90% infected with immune-evasive SARS-CoV-2 variants. No treatment-related adverse events or serious adverse events were reported. In exploratory analyses, the 200 mg SNS812 group showed a shorter median time to SARS-CoV-2 antigen negativity (2.9 vs 3.6 days; p = 0.007) and a faster viral load reduction rate (- 0.755 vs - 0.652; p = 0.040), demonstrating dose-dependent virological effects. In the modified intention-to-treat population, exploratory symptom analyses showed shorter TTSA and TTSR for prespecified target symptoms with SNS812 200 mg compared with placebo (median TTSR 6.1 vs 8.1 days; adjusted hazard ratio 2.07, 95% CI 1.30-3.29; median TTSA 3.6 vs 6.5 days; adjusted hazard ratio 1.81, 95% CI 1.14-2.88). CONCLUSION: Inhaled SNS812 was safe and well tolerated and showed dose-dependent antiviral activity, with exploratory signals of symptomatic improvement in adults with mild-to-moderate COVID-19 infected with immune-evasive variants. These findings support further evaluation in larger, adequately powered trials, including older and higher-risk populations.