Phase 2a signal searching study with zelasudil in idiopathic pulmonary fibrosis (IPF)

Zelasudil, a highly potent, selective ROCK2 inhibitor, was designed to achieve antifibrotic effects whilst avoiding unwanted effects from systemic pan-ROCK inhibition (hypotension). This Phase 2a study assessed safety, tolerability, pharmacokinetics and initial efficacy of zelasudil treatment, in patients (pts) with IPF. <bold>Methods</bold> Pts were randomised 3:1, double blind, to zelasudil (20 and 50mg BID) or placebo for 12 weeks with the option to enter a 12-week open label extension (OLE at 20 or 50mg BID). The primary objective was to assess safety and tolerability of zelasudil alone/in combination with nintedanib/pirfenidone. Secondary objectives were to assess PK and potential for efficacy. <bold>Results</bold> From 83 screened pts, 48 were randomised and dosed, with 35 entering the OLE. Zelasudil was well tolerated with no treatment-related serious adverse events and >95% of treatment-emergent AEs being mild or moderate. 9 pts discontinued, 6 before Week 12 and 3 during OLE. Of these, 6/9 were considered treatment-related (ALT/AST increases with no changes in bilirubin and resolution following dose interruption). Systemic exposure of zelasudil was as predicted at both doses, with no significant impact on exposure of nintedanib/pirfenidone. Mean improvements in decline in absolute FVC and percent predicted FVC were observed for both doses over placebo at Week 12, supported by a numerical reduction in circulating biomarkers, including PRO-C3 post treatment. <bold>Conclusions</bold> Zelasudil, a best-in-class ROCK 2 inhibitor, is well tolerated both with and without background antifibrotic therapy. Antifibrotic activity has been demonstrated and warrants further exploration.