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.

Methods 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.

Results 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.

Conclusions 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.