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Safety and Anti-viral Effects of Nebulized PC786 in a Respiratory Syncytial Virus Challenge Study. BACKGROUND: PC786 is a nebulized non-nucleoside RSV polymerase inhibitor designed to treat RSV which replicates in the superficial layer of epithelial cells lining the airways. METHODS: 56 healthy volunteers inoculated with RSV-A (Memphis 37b) were randomly dosed with either nebulized PC786 (5mg) or placebo, twice daily for 5 days, from either 12 hours after confirmation of RSV infection or 6 days after virus inoculation. Viral load (VL), disease severity, pharmacokinetics and safety were assessed until discharge. RSV infection was confirmed by RT-qPCR with any positive value (ITT-I population) or RSV RNA ≥1 log10PFUe/mL (ITT-IS population) in nasal wash samples. RESULTS: In the ITT-I population, the mean VL-AUC was lower in the PC786 group than the placebo group (274.1 vs. 406.6 log10PFUe/mL*h, p=0.0359). PC786 showed a trend towards reduction of symptom score and mucous weight. In ITT-IS (post-hoc analysis), the latter was statistically significant as well as VL-AUC (p=0.0126). PC786 showed an early Tmax, limited systemic exposure, long half-life and consequently a 2-fold accumulation over the 5-day dosing period. PC786 was well tolerated. CONCLUSIONS: Nebulized PC786 demonstrated a significant anti-viral effect against RSV, warranting further clinical study. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03382431; EudraCT number: 2017-002563-18.