Safety and Antiviral Effects of Nebulized PC786 in a Respiratory Syncytial Virus Challenge Study

• Published in: The Journal of infectious diseases Vol. 225; no. 12; pp. 2087 - 2096
• Main Authors: DeVincenzo, John, Cass, Lindsey, Murray, Alison, Woodward, Kathy, Meals, Elizabeth, Coates, Matthew, Daly, Leah, Wheeler, Vicky, Mori, Julie, Brindley, Charlie, Davis, Amanda, McCurdy, Meabh, Ito, Kazuhiro, Murray, Bryan, Strong, Pete, Rapeport, Garth
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 15.06.2022
• Subjects: Antiviral drugs; Clinical trials; Epithelial cells; Infections; Inoculation; Major and Brief Reports; Pharmacokinetics; Placebos; Respiratory syncytial virus; Statistical analysis; Viruses; pharmacokinetics; challenge; nasal wash; respiratory syncytial virus; nonnucleoside polymerase inhibitor; healthy volunteers
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiaa716

Abstract Background PC786 is a nebulized nonnucleoside respiratory syncytial virus (RSV) polymerase inhibitor designed to treat RSV, which replicates in the superficial layer of epithelial cells lining the airways. Methods Fifty-six healthy volunteers inoculated with RSV-A (Memphis 37b) were randomly dosed with either nebulized PC786 (5 mg) 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 reverse-transcription quantitative polymerase chain reaction with any positive value (intention-to-treat infected [ITT-I] population) or RSV RNA ≥1 log10 plaque-forming unit equivalents (PFUe)/mL (specific intention-to-treat infection [ITT-IS] population) in nasal wash samples. Results In the ITT-I population, the mean VL area under the curve (AUC) was lower in the PC786 group than the placebo group (274.1 vs 406.6 log10 PFUe/mL × hour; P = .0359). PC786 showed a trend toward reduction of symptom score and mucous weight. In ITT-IS (post hoc analysis), the latter was statistically significant as well as VL AUC (P = .0126). PC786 showed an early time to maximum plasma concentration, limited systemic exposure, and 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 antiviral effect against RSV, warranting further clinical study. Clinical Trials Registration ClinicalTrials.gov: NCT03382431; EudraCT: 2017-002563-18. This manuscript reports the first human therapeutic proof of principle for a novel nonnucleoside respiratory syncytial virus (RSV) polymerase inhibitor, PC786. Nebulized PC786 exhibited significant antiviral effects and was well tolerated in healthy volunteers experimentally infected with RSV.