A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis

Abstract

PI3 Kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). Omipalisib was dosed, at 0.25 mg, 1 mg and 2 mg twice per day (BID) for approximately eight days in 4 cohorts of 4 subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg BID).Seventeen subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose related increases in insulin and glucose were observed. PK analysis demonstrated that exposure in the blood predicts lung exposure. Exposure dependent inhibition of PIP3 and pAKT confirmed target engagement in blood and lungs. [18F]-FDG-PET/CT scans revealed an exposure dependent reduction in [18F]-FDG uptake in fibrotic areas of the lung, as measured by target to background ratio (TBR) thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.