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

Abstract

BackgroundRespiratory syncytial virus (RSV) viral load and disease severity associate, and the timing of viral load and disease run in parallel. An antiviral must be broadly effective against the natural spectrum of RSV genotypes and must attain concentrations capable of inhibiting viral replication within the human respiratory tract.ObjectivesWe evaluated a novel RSV fusion inhibitor, MDT‐637, and compared it with ribavirin for therapeutic effect in vitro to identify relative therapeutic doses achievable in humans.Method MDT‐637 and ribavirin were co‐incubated with RSV in HEp‐2 cells. Quantitative PCR assessed viral concentrations; 50% inhibitory concentrations (IC 50) were compared to achievable human MDT‐637 and ribavirin peak and trough concentrations.Results and conclusionsThe IC 50 for MDT‐637 and ribavirin (against RSV‐A Long) was 1.42 and 16 973 ng/mL, respectively. The ratio of achievable peak respiratory secretion concentration to IC 50 was 6041‐fold for MDT‐637 and 25‐fold for aerosolized ribavirin. The ratio of trough concentration to IC 50 was 1481‐fold for MDT‐637 and 3.29‐fold for aerosolized ribavirin. Maximal peak and trough levels of oral or intravenous ribavirin were significantly lower than their IC 50s. We also measured MDT‐637 IC 50s in 3 lab strains and 4 clinical strains. The IC 50s ranged from 0.36 to 3.4 ng/mL. Achievable human MDT‐637 concentrations in respiratory secretions exceed the IC 50s by factors from hundreds to thousands of times greater than does ribavirin. Furthermore, MDT‐637 has broad in vitro antiviral activity on clinical strains of different RSV genotypes and clades. Together, these data imply that MDT‐637 may produce a superior clinical effect compared to ribavirin on natural RSV infections.

Respiratory syncytial virus infection in adults

“…MDT-637 is a fusion inhibitor that can be delivered as a dry inhaled powder. Preclinical data show that it can be delivered into the upper and lower airways, and achievable human concentrations in respiratory secretions were hundreds to thousands of times greater than those of ribavirin 152. Future studies are planned 153…”

Respiratory Viral Infections in Patients With Cancer or Undergoing Hematopoietic Cell Transplant

“…* inhibit RSV fusion through a similar mechanism, and RSV variants exhibiting drug resistance have displayed cross-resistance to these inhibitors. Adapted from (Douglas et al (2005); Triana-Baltzer et al (2009b); Boeckh and Englund (2010); Kiso et al (2010); Sleeman et al (2010); Watanabe et al (2010); Guzmán-Suarez et al (2012); Moss et al (2012); Adedeji et al (2013); Matz (2013); Clark et al (2014); DeVincenzo et al (2014, 2015); Rossignol (2014); Byrn et al (2015); Battles et al (2016); Waghmare et al (2016); Coates et al (2017); Heylen et al (2017); Jorquera and Tripp (2017); Kim et al (2017); Koszalka et al (2017); Mejias et al (2017); Roymans et al (2017); Shahani et al (2017); Heo (2018); Omoto et al (2018); Rossey et al (2018), and Stevens et al (2018) .…”

Viral Sepsis in Children

“…A randomized, controlled trial performed in adult patients with RSV infection compared the RSV entry inhibitor GS-5806 to placebo and demonstrated a decrease in both viral load and the clinical severity of infection in patients treated with GS-5806 ( 136 ). Similar fusion inhibitors such as ALX-0171 ( 137 ), JNJ-2408068 ( 138 ), MDT-637 ( 139 ), and VP14637 ( 138 ) demonstrate efficacy in vitro , and ALX-0171 is undergoing a phase II clinical trial in infants hospitalized for RSV (clinicaltrials.gov registration no. NCT02979431).…”