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

John DeVincenzo, Lindsey Cass, Alison Murray, Kathy Woodward, Elizabeth Meals, Matthew Coates, Leah Daly, Vicky Wheeler, Julie Mori, Charlie Brindley, Amanda Davis, Meabh McCurdy, Kazuhiro Ito, Bryan Murray, Pete Strong, Garth Rapeport, John DeVincenzo, Lindsey Cass, Alison Murray, Kathy Woodward, Elizabeth Meals, Matthew Coates, Leah Daly, Vicky Wheeler, Julie Mori, Charlie Brindley, Amanda Davis, Meabh McCurdy, Kazuhiro Ito, Bryan Murray, Pete Strong, Garth Rapeport

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.

Keywords: challenge; healthy volunteers; nasal wash; nonnucleoside polymerase inhibitor; pharmacokinetics; respiratory syncytial virus.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Study design and participant disposition. A, Schematic overview of the study. B, Subject disposition flowchart. Of the 56 participants (intention-to-treat [ITT] population), 41 (73%) met the criteria to be included in the ITT infected population (respiratory syncytial virus [RSV] RNA cutoff >0 log10 plaque-forming unit equivalents (PFUe)/mL, determined by a Simplexa reverse-transcription quantitative polymerase chain reaction assay), and 34 (61%) were included in the specific ITT infected population (RSV RNA cutoff ≥1 log10 PFUe/mL). *, Quantitative RSV RT-PCR assay was conducted in nasal wash samples. Abbreviations: BID, twice daily; ECG, electrocardiogram; F/U, follow-up; ITT, intention-to-treat; ITT-I, intention-to-treat infected; ITT-IS, specific intention-to-treat infected; PCR, polymerase chain reaction; RSV, respiratory syncytial virus; SSS, study-specific screening.
Figure 2.
Figure 2.
Viral load, total symptom score, and daily mucous weight over time in the intention-to-treat infected (ITT-I) population. Mean viral loads (A), total symptom scores (B), and daily mucous weights (C) in the ITT-I population are shown from the time immediately before administration of the first dose up to 10 days afterward. Although participants were inoculated with respiratory syncytial virus on the same day, they became infected on different days and consequently, began treatment at different timepoints. Viral loads were determined with the use of a reverse-transcription quantitative polymerase chain reaction assay of nasal-wash samples, which were collected twice daily (A). Participants recorded symptoms in diaries 3 times daily (B). Mucous weights were measured daily and plotted at the time corresponding to the midpoint of the mucous collection period each day (ie, weights plotted midway between the first and second days of treatment are from facial tissues collected between the morning of the first day of study treatment and the morning of the second day) (C). Mean + standard error (SE) for placebo and mean - SE for PC786 are shown. PFUe denotes plaque-forming unit equivalents.

References

    1. Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. Pediatr Infect Dis J 2002; 21:629–32.
    1. Jain S, Williams DJ, Arnold SR, et al. ; CDC EPIC Study Team . Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med 2015; 372:835–45.
    1. Nair H, Nokes DJ, Gessner BD, et al. . Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010; 375:1545–55.
    1. Walsh EE, Falsey AR. Respiratory syncytial virus infection in adult populations. Infect Disord Drug Targets 2012; 12:98–102.
    1. Mehta J, Walsh EE, Mahadevia PJ, Falsey AR. Risk factors for respiratory syncytial virus illness among patients with chronic obstructive pulmonary disease. COPD 2013; 10:293–9.
    1. Darveaux JI, Lemanske RF Jr. Infection-related asthma. J Allergy Clin Immunol Pract 2014; 2:658–63.
    1. Abman SH, Ogle JW, Butler-Simon N, Rumack CM, Accurso FJ. Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis. J Pediatr 1988; 113:826–30.
    1. Abdallah A, Rowland KE, Schepetiuk SK, To LB, Bardy P. An outbreak of respiratory syncytial virus infection in a bone marrow transplant unit: effect on engraftment and outcome of pneumonia without specific antiviral treatment. Bone Marrow Transplant 2003; 32:195–203.
    1. American Academy of Pediatrics Committee on Infectious Diseases, American Academy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134:415–20.
    1. DeVincenzo JP, Whitley RJ, Mackman RL, et al. . Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med 2014; 371:711–22.
    1. Blair W, Cox C. Current landscape of antiviral drug discovery. F1000Res 2016; 5:1000. doi:10.12688/f1000research.7665.1.
    1. . Safety, efficacy and pharmacokinetics of BTA-C585 in a RSV viral challenge study (NCT02718937). 2016. Available at: . Accessed 30 November 2020.
    1. Stevens M, Rusch S, DeVincenzo J, et al. . Antiviral activity of oral JNJ-53718678 in healthy adult volunteers challenged with respiratory syncytial virus: a placebo-controlled study. J Infect Dis 2018; 218:748–56.
    1. Detalle L, Stohr T, Palomo C, et al. . Generation and characterization of ALX-0171, a potent novel therapeutic nanobody for the treatment of respiratory syncytial virus infection. Antimicrob Agents Chemother 2016; 60:6–13.
    1. DeVincenzo JP, McClure MW, Symons JA, et al. . Activity of oral ALS-008176 in a respiratory syncytial virus challenge study. N Engl J Med 2015; 373:2048–58.
    1. DeVincenzo J, Tait D, Efthimiou J, et al. . A randomized, placebo-controlled, respiratory syncytial virus human challenge study of the antiviral efficacy, safety, and pharmacokinetics of RV521, an inhibitor of the RSV-F protein. Antimicrob Agents Chemother 2020; 64:e01884-19.
    1. Hall CB, Douglas RG Jr, Schnabel KC, Geiman JM. Infectivity of respiratory syncytial virus by various routes of inoculation. Infect Immun 1981; 33:779–83.
    1. Buckingham SC, Bush AJ, Devincenzo JP. Nasal quantity of respiratory syncytical virus correlates with disease severity in hospitalized infants. Pediatr Infect Dis J 2000; 19:113–7.
    1. DeVincenzo JP, El Saleeby CM, Bush AJ. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis 2005; 191:1861–8.
    1. El Saleeby CM, Bush AJ, Harrison LM, Aitken JA, Devincenzo JP. Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J Infect Dis 2011; 204:996–1002.
    1. DeVincenzo JP, Wilkinson T, Vaishnaw A, et al. . Viral load drives disease in humans experimentally infected with respiratory syncytial virus. Am J Respir Crit Care Med 2010; 182:1305–14.
    1. Uusitupa E, Waris M, Heikkinen T. Association of viral load with disease severity in outpatient children with respiratory syncytial virus infection. J Infect Dis 2020; 222:298–304.
    1. Thwaites RS, Coates M, Ito K, et al. . Reduced nasal viral load and IFN responses in infants with respiratory syncytial virus bronchiolitis and respiratory failure. Am J Respir Crit Care Med 2018; 198:1074–84.
    1. Welliver TP, Garofalo RP, Hosakote Y, et al. . Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J Infect Dis 2007; 195:1126–36.
    1. DeVincenzo JP. A new direction in understanding the pathogenesis of respiratory syncytial virus bronchiolitis: how real infants suffer. J Infect Dis 2007; 195:1084–6.
    1. Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS. The histopathology of fatal untreated human respiratory syncytial virus infection. Mod Pathol 2007; 20:108–19.
    1. Coates M, Brookes D, Kim YI, et al. . Preclinical characterization of the inhaled small molecule respiratory syncytial virus L-protein polymerase inhibitor, PC786. Antimicrob Agents Chemother 2017; 61:e00737-17.
    1. Brookes DW, Coates M, Allen H, et al. . Late therapeutic intervention with a respiratory syncytial virus L-protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium. Br J Pharmacol 2018; 175:2520–34.
    1. . A study to investigate the safety and tolerability of single and repeat doses of PC786 (NCT03236233). 2017. Available at: . Accessed 30 November 2020.
    1. Cass L, Davis A, Murray A, et al. . Safety and pharmacokinetic profile of PC786, a novel inhibitor of respiratory syncytial virus L-protein polymerase, in a single and multiple-ascending dose study in healthy volunteer and mild asthmatics. 2018; 5:S407–S8.
    1. Kim YI, DeVincenzo JP, Jones BG, et al. . Respiratory syncytial virus human experimental infection model: provenance, production, and sequence of low-passaged memphis-37 challenge virus. PLoS One 2014; 9:e113100.
    1. DeVincenzo J, Lambkin-Williams R, Wilkinson T, et al. . A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci U S A 2010; 107:8800–5.
    1. Perkins SM, Webb DL, Torrance SA, et al. . Comparison of a real-time reverse transcriptase PCR assay and a culture technique for quantitative assessment of viral load in children naturally infected with respiratory syncytial virus. J Clin Microbiol 2005; 43:2356–62.
    1. Strong P, Ito K, Murray J, Rapeport G. Current approaches to the discovery of novel inhaled medicines. Drug Discov Today 2018; 23:1705–17.
    1. Mirabelli C, Jaspers M, Boon M, et al. . Differential antiviral activities of respiratory syncytial virus (RSV) inhibitors in human airway epithelium. J Antimicrob Chemother 2018; 73:1823–9.
    1. Thompson TM, Roddam PL, Harrison LM, Aitken JA, DeVincenzo JP. Viral specific factors contribute to clinical respiratory syncytial virus disease severity differences in infants. Clin Microbiol 2015; 4:206.
    1. Stray K, Perron M, Porter DP, et al. . Drug resistance assessment following administration of respiratory syncytial virus (RSV) fusion inhibitor presatovir to participants experimentally infected with RSV. J Infect Dis 2020; 222:1468–77.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe