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

Eur Respir J. 2019 Mar 18;53(3):1801992. doi: 10.1183/13993003.01992-2018. Print 2019 Mar.


Phosphatidylinositol 3-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 and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 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. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aged
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Idiopathic Pulmonary Fibrosis / diagnostic imaging
  • Idiopathic Pulmonary Fibrosis / drug therapy*
  • Lung / diagnostic imaging
  • Lung / pathology
  • Male
  • Middle Aged
  • Phosphatidylinositol 3-Kinases / metabolism
  • Positron Emission Tomography Computed Tomography
  • Pyridazines
  • Quinolines / administration & dosage*
  • Sulfonamides / administration & dosage*
  • TOR Serine-Threonine Kinases / metabolism
  • Treatment Outcome


  • Pyridazines
  • Quinolines
  • Sulfonamides
  • Fluorodeoxyglucose F18
  • omipalisib
  • MTOR protein, human
  • TOR Serine-Threonine Kinases