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

BACKGROUND: This Phase 1b study evaluated the pharmacokinetics, safety and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ8678) in hospitalized RSVinfected patients (aged >1- /=6- /=3- 1-<3 months) were randomized to oral JNJ-8678 or placebo once-daily for 7 days. Dose increases followed Data Review Committee recommendations (doses respectively: 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 qRT-PCR. RESULTS: Patients received JNJ-8678 (n=37) or placebo (n=7). Pharmacokinetic parameters were similar at the highest doses for Cohorts 1-3 (AUC24h at Day 7; 35,840, 34,980 and 39,627 ng.hr/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. CONCLUSION: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed.