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

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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 &amp;gt; 1 to ≤24 months.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Patients categorized by age (cohort 1: ≥6 to ≤24 months; cohort 2: ≥3 to &amp;lt; 6 months; cohort 3: &amp;gt; 1 to &amp;lt; 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trials Registration</jats:title> <jats:p>NCT02593851.</jats:p> </jats:sec>

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion

“…In general, as observed in other reported inhibitors of RSV F protein, chains with four to five atoms were acceptable in terms of potency and, most interestingly, cyclic systems such as cyclohexanol ( 22 ) or pyran ( 23 ) were also potent in the RSV plaque and fusion assays (Table ). In the case of the pharmacokinetics of cyclohexanol 22 (Tables and ), low permeability and low clearance were observed in vitro ( P app MDCK-MDR1A2B/B2A; ER 0.13/2.8; 21 × 10 –6 cm s –1 , 0.13 mL/min/mg protein in rat microsomes), and high clearance and low bioavailability were observed in mice (82.7 mL/min/kg, F 4.4%).…”

Monitoring Severity of Respiratory Syncytial Virus (RSV) in Infants and Young Children Using the Pediatric RSV Electronic Severity and Outcome Rating System (PRESORS): Results of Initial Quantitative Validation

“…RSV1005 was a Phase Ib, randomized, partially double-blind, placebo-controlled trial in infants and young children hospitalized with RSV infection. Details of the study design, sample, and primary study results were published by Martinón-Torres et al 11 Infants and young children (later referred to as children) of 1 to 24 months of age were followed for 28 days including a 7-day treatment period and a 21-day follow-up period. Per protocol children could be discharged from the hospital as early as Day 3 of treatment if deemed appropriate by the investigator.…”

“…Once the initial ClinRO and ObsRO assessments were drafted, the reliability, validity, and ability to detect meaningful change in RSV severity with preliminary scores were tested using blinded data from a pediatric clinical trial of JNJ-53718678 (study 53718678RSV1005 - NCT02593851, later referred to as RSV1005). 11 This report describes the psychometric analyses of the ObsRO and ClinRO data in RSV1005.…”

¿Dónde se esconde el virus respiratorio sincitial?

“…También el desarrollo de las vacunas ha marcado un hito con la publicación de los datos del ensayo clínico fase 3 de una vacuna maternal frente al VRS basada en nanopartículas de la proteína F, que aunque no alcanzó por un margen muy limitado los objetivos primarios de eficacia planteados en el estudio, ha mostrado datos consistentes de seguridad, y además eficacia clínica en objetivos secundarios que justifican que se siga investigando con esta vacuna 6 . Hay diferentes antivirales específicos frente al VRS con resultados prometedores en fases iniciales, tanto inhalados 7 como orales 8 , si bien aún están lejos del mercado. Por todo ello, la única intervención posible sigue siendo la profilaxis con palivizumab, un anticuerpo monoclonal basado en la proteína F que se administra mensualmente durante la estación VRS en ciertos grupos de alto riesgo —fundamentalmente recién nacidos prematuros—, y que constituye el único fármaco actualmente aprobado e indicado para la prevención del VRS.…”