Phase 2a Randomized Placebo-Controlled Human Challenge Trial of the Respiratory Syncytial Virus L-Protein Inhibitor S-337395 for Respiratory Syncytial Virus Infection.

BACKGROUND

S-337395 is a novel inhibitor of the respiratory syncytial virus (RSV) L-protein, and a potential oral antiviral against RSV. This phase 2a, randomized, double-blind, placebo-controlled, single-center, proof-of-concept trial conducted in the United Kingdom (April-October 2024) evaluated the efficacy, safety, and dose-response relationship of S-337395 against RSV infection in a human challenge model.

METHODS

Healthy adults aged 18-55 years meeting predefined eligibility criteria were inoculated with RSV-A Memphis 37b on Day 0. Nasal washes were collected for quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) assessment twice daily on Days 2-12 and once on Day 13. Participants were randomized 5:13:13:13:13 to receive S-337395 (1, 10, 30, or 300 mg) or placebo, once daily for 5 days upon evidence of infection. Efficacy analyses were conducted in participants with confirmed RSV infection in intent-to-treat infected (ITT-I) set. Safety was assessed in all randomized participants. Dose-response was evaluated across a wide dose range (1-300 mg).

RESULTS

Of 114 randomized participants, 60 comprised the ITT-I set. Covariate-adjusted mean viral load area under the curve (VL-AUC) was significantly lower in the 30- and 300-mg groups by qRT-PCR (64.87% and 88.94% reductions, respectively, both P < .05) and by viral culture assay (72.32% and 86.17% reductions, respectively, both P < .05). Total symptom score AUC was 78.15% lower in the 300-mg group (P < .05). S-337395 was well-tolerated without any safety concerns.

CONCLUSIONS

S-337395 significantly reduced viral load, viral titer, and symptoms, and was well-tolerated in this human challenge study. Clinical Trial Registration: ISRCTN24865912.