Safety and Antiviral Effects of Nebulized PC786 in a Respiratory Syncytial Virus Challenge Study. (20th November 2020)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of infectious diseases. Volume 225:Number 12(2022)
• Page Start: 2087
• Page End: 2096
• Publication Date: 2020-11-20
• Subjects: challenge -- respiratory syncytial virus -- nonnucleoside polymerase inhibitor -- nasal wash -- pharmacokinetics -- healthy volunteers; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiaa716
• Languages: English
• ISSNs: 0022-1899

Abstract

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. Abstract : 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.