EDP-938, a novel nucleoprotein inhibitor of respiratory syncytial virus, demonstrates potent antiviral activities in vitro and in a non-human primate model

Author summary Respiratory syncytial virus (RSV) is a ubiquitous viral pathogen which inflicts a significant healthcare burden and is responsible for thousands of deaths annually. Currently no vaccine or targeted therapeutic exists. This work characterizes a newly discovered small molecule inhibitor of the virus, EDP-938, whose activity is mediated through the viral nucleoprotein. EDP-938 has potent in vitro activities against laboratory strains and clinical isolates of the virus, presents a high-barrier to resistance, can work synergistically with other known fusion or L protein inhibitors, and displays strong in vivo efficacy in a non-human primate model for RSV infection. EDP-938 is currently under evaluation in Phase 2 clinical studies. EDP-938 is a novel non-fusion replication inhibitor of respiratory syncytial virus (RSV). It is highly active against all RSV-A and B laboratory strains and clinical isolates tested in vitro in various cell lines and assays, with half-maximal effective concentrations (EC(50)s) of 21, 23 and 64 nM against Long (A), M37 (A) and VR-955 (B) strains, respectively, in the primary human bronchial epithelial cells (HBECs). EDP-938 inhibits RSV at a post-entry replication step of the viral life cycle as confirmed by time-of-addition study, and the activity appears to be mediated by viral nucleoprotein (N). In vitro resistance studies suggest that EDP-938 presents a higher barrier to resistance compared to viral fusion or non-nucleoside L polymerase inhibitors with no cross-resistance observed. Combinations of EDP-938 with other classes of RSV inhibitors lead to synergistic antiviral activity in vitro. Finally, EDP-938 has also been shown to be efficacious in vivo in a non-human primate model of RSV infection.

Automated summary

EDP-938 is a novel non-fusion replication inhibitor of respiratory syncytial virus (RSV) with potent in vitro activities and high barrier to resistance. It has been shown to synergistically work with other RSV inhibitors and demonstrate strong in vivo efficacy in a non-human primate model. EDP-938 is currently under evaluation in Phase 2 clinical studies.