Pharmacokinetics, Safety, and Antiviral Effects of Multiple Doses of the Respiratory Syncytial Virus (RSV) Fusion Protein Inhibitor, JNJ-53718678, in Infants Hospitalized With RSV Infection: A Randomized Phase 1b Study

Federico Martinón-Torres, Sarah Rusch, Dymphy Huntjens, Bart Remmerie, Johan Vingerhoets, Katie McFadyen, Fernando Ferrero, Eugenio Baraldi, Pablo Rojo, Cristina Epalza, Marita Stevens, Federico Martinón-Torres, Sarah Rusch, Dymphy Huntjens, Bart Remmerie, Johan Vingerhoets, Katie McFadyen, Fernando Ferrero, Eugenio Baraldi, Pablo Rojo, Cristina Epalza, Marita Stevens

Abstract

Background: This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to ≤24 months.

Methods: Patients categorized by age (cohort 1: ≥6 to ≤24 months; cohort 2: ≥3 to < 6 months; cohort 3: > 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction.

Results: Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng × hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL.

Conclusions: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed.

Clinical trials registration: NCT02593851.

Keywords: JNJ-53718678; JNJ-8678; fusion inhibitor; infants; 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. Patient disposition (parts 1 and 2) at time of the final analysis for each dose cohort. Within each age group (cohorts 1–3) and dose level (cohorts a–d, f), patients were randomized to JNJ-53718678 (JNJ-8678) or placebo (except for cohorts 1a, 2a, and 3a, who all received JNJ-8678). Data were categorized by dose level for analysis: low (cohorts 1a, 2a, and 3a), mid (cohorts 1b, 2b, and 3b), mid-high (cohort 1c), and high (cohorts 1d, 2c, and 3c). aStudy drug was administered for 7 days. bPlanned randomization active: placebo was 2:1. cPlanned randomization active: placebo was 4:1. dThe target dose regimen for part 2 of cohort f was not yet determined when the study was terminated. eThis age group had to include overall at least 5 patients > 1 month and ≤ 2 months of age over the first 3 cohorts combined, with a minimum of 1 patient > 1 month and ≤ 2 months of age in each of these cohorts. Abbreviations: DRC, data review committee, PK, pharmacokinetic; QD, once daily.
Figure 2.
Figure 2.
A, Median viral load over time to day 7 by treatment group and placebo. B, Median (and IQR) viral load changes from baseline over time by dose level and placebo. C, JNJ-53718678 (JNJ-8678) median viral load over time to day 7 viral load changes from baseline over time in all doses combined. D, JNJ-8678 median (and IQR) viral load over time to day 7 viral load changes from baseline over time in all doses combined. For respiratory syncytial virus (RSV) A, the limit of detection (LOD) was 2.75 log10 copies/mL and the lower limit of quantification (LLOQ) was 3.00 log10 copies/mL; for RSV-B, the LOD was 1.89 log10 copies/mL and the LLOQ was 2.40 log10 copies/mL. Abbreviation: IQR, interquartile range.
Figure 3.
Figure 3.
Kaplan-Meier graphs of length of hospital stay (A) and time to clinical stability (B), all JNJ-53718678 (JNJ-8678) doses combined vs all placebo doses. Clinical stability was defined as maximum of time to end supplemental oxygen, time to end of supplemental feeding, time to normalized heart rate, and time to normalized respiratory rate.

References

    1. Shi T, McAllister DA, O’Brien KL, et al. . Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017; 390:946–58.
    1. Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ 2008; 86:408–16.
    1. Feltes TF, Sondheimer HM. Palivizumab and the prevention of respiratory syncytial virus illness in pediatric patients with congenital heart disease. Expert Opin Biol Ther 2007; 7:1471–80.
    1. Hall CB, Weinberg GA, Blumkin AK, et al. . Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics 2013; 132:e341–8.
    1. Sommer C, Resch B, Simões EA. Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol J 2011; 5:144–54.
    1. Centers for Disease Control and Prevention. Respiratory syncytial virus (RSV) season, U.S., 2011–2012. Available at: . Accessed 02 April 2019.
    1. Simões EA, DeVincenzo JP, Boeckh M, et al. . Challenges and opportunities in developing respiratory syncytial virus therapeutics. J Infect Dis 2015; 211(Suppl 1):S1–20.
    1. European Medicines Agency. Palivizumab—summary of product characteristics. Available at: . Accessed 22 November 2019.
    1. US Food and Drug Administration. Palivizumab—product information. Available at: . Accessed 22 November 2019.
    1. Electronic Medicines Compendium. Ribavirin—summary of product characteristics. Available at: . Accessed 15 May 2019.
    1. US Food and Drug Administration. Ribavirin—product information. Available at: . Accessed 15 May 2019.
    1. Ralston SL, Lieberthal AS, Meissner HC, et al. . American Academy of Pediatrics Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics 2014; 134:e1474–502.
    1. Mazur NI, Martinón-Torres F, Baraldi E, et al. . Respiratory Syncytial Virus Network (ReSViNET) Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics. Lancet Respir Med 2015; 3:888–900.
    1. Wainwright C. Acute viral bronchiolitis in children—a very common condition with few therapeutic options. Paediatr Respir Rev 2010; 11:39–45; quiz 45.
    1. Ralston SL, Lieberthal AS, Meissner HC, et al. . American Academy of Pediatrics Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics 2014; 134:e1474–502.
    1. Roymans D, Alnajjar SS, Battles MB, et al. . Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor. Nat Commun 2017; 8:167.
    1. Huntjens DRH, Ouwerkerk-Mahadevan S, Brochot A, Rusch S, Stevens M, Verloes R. Population pharmacokinetic modeling of JNJ-53718678, a novel fusion inhibitor for the treatment of respiratory syncytial virus: results from a phase I, double-blind, randomized, placebo-controlled first-in-human study in healthy adult subjects. Clin Pharmacokinet 2017; 56:1331–42.
    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. National Institute of Allergy and Infectious Diseases. Available at: . Accessed 22 November 2019.
    1. Bracht M, Basevitz D, Cranis M, Paulley R. Impact of respiratory syncytial virus: the nurse’s perspective. Drugs R D 2011; 11:215–26.
    1. Brint ME, Hughes JM, Shah A, et al. . Prolonged viral replication and longitudinal viral dynamic differences among respiratory syncytial virus infected infants. Pediatr Res 2017; 82:872–80.
    1. Lau JW, Kim YI, Murphy R, et al. . Deep sequencing of RSV from an adult challenge study and from naturally infected infants reveals heterogeneous diversification dynamics. Virology 2017; 510:289–96.
    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. Geoghegan S, Erviti A, Caballero MT, et al. . Mortality due to respiratory syncytial virus. burden and risk factors. Am J Respir Crit Care Med 2017; 195:96–103.
    1. Pelaez A, Lyon GM, Force SD, et al. . Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection. J Heart Lung Transplant 2009; 28:67–71.
    1. Kim Y‐I, Pareek R, Murphy R, et al. . The antiviral effects of RSV fusion inhibitor, MDT‐637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin. Influenza Other Respir Viruses 2017; 11:525–30.
    1. DeVincenzo J, Tait D, Oluwayi O, et al. . Safety and efficacy of oral RV521 in a human respiratory syncytial virus (RSV) phase 2a challenge study. Am J Respir Crit Care Med 2018; 197:A7715.
    1. Toovey S, Wu J, Wang V, et al. . Safety and pharmacokinetics in healthy volunteers of the anti-RSV antiviral AK0529. First International Meeting on Respiratory Pathogens. Singapore: International Society for Influenza and other Respiratory Virus Diseases, 2015.
    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. Coakley E, Ahmad A, Larson K, et al. . LB04 EDP-938, a novel RSV N-inhibitor, administered once or twice daily was safe and demonstrated robust antiviral and clinical efficacy in a healthy volunteer challenge study. Open Forum Infect Dis 2019; 6(Suppl 2):S995.
    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. 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. Chemaly RF, Dadwal SS, Bergeron A, et al. . A phase 2, randomized, double-blind, placebo-controlled trial of presatovir for the treatment of respiratory syncytial virus upper respiratory tract infection in hematopoietic-cell transplant recipients [manuscript published online ahead of print 3 December 2019]. Clin Infect Dis 2019. doi:10.1093/cid/ciz1166.
    1. GlobeNewswire. Aviragen therapeutics announces top-line results from phase 2a RSV challenge study of BTA585. Aviragen press release. 2017. Available at: . Accessed 22 November 2019.
    1. . Study to evaluate safety and antiviral activity of doses of JNJ-53718678 in children (≥28 days to ≤3 years) with respiratory syncytial virus infection. NCT03656510. Available at: . Accessed 22 November 2019.

Source: PubMed

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