VX-765

VX-765 (Belnacasan) is an orally absorbed prodrug of VRT-043198, which is a potent and selective inhibitor of interleukin-converting enzyme/caspase-1 with Ki of 0.8 nM; VRT-043198 exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9, VX-765 is converted rapidly to VRT-043198 under the action of plasma and liver esterases; inhibits LPS-induced IL-1β production, reduces disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation.Epilepsy Phase 2 Discontinued (In Vivo) :Belnacasan reduces inflammatory response in murine models of inflammatory disease.Belnacasan (50-200 mg/kg) significantly reduces serum IL-1β levels by as much as 60%. It is noteworthy that the effect of Belnacasan on the release of IL-1β induced by LPS reached a plateau at 100 mg/kg. Belnacasan (25-100 mg/kg x 2) significantly reduces ear edema. Belnacasan also dose-dependently reduces the concentrations of cytokines, chemokines, and inflammatory mediators in the ear biopsy samples.Belnacasan (25-200 mg/kg) significantly delays the time to seizure onset by 1.5- to twofold (p<0.01), reduces the number of seizures by 40% (p<0.01) and the total time spent in EEG seizure activity by 30 to 50% (p<0.01) .