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

Pauline T Lukey1, Stephen A Harrison1, Shuying Yang1

  • 1GlaxoSmithKline Research and Development, Stevenage, UK.

The European Respiratory Journal
|February 16, 2019
PubMed

Insights

Omipalisib, a PI3K/mTOR inhibitor, showed acceptable safety and target engagement in the lungs of idiopathic pulmonary fibrosis (IPF) patients. This study confirms systemic and lung exposure correlates with pharmacodynamic activity in IPF.

Area of Science:

  • Pharmacology
  • Pulmonary Medicine
  • Oncology

Background:

  • Idiopathic pulmonary fibrosis (IPF) pathogenesis involves phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR).
  • Omipalisib (GSK2126458) is a potent inhibitor targeting the PI3K/mTOR pathway.

Purpose of the Study:

  • To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of omipalisib in IPF patients.
  • To confirm target engagement and assess pharmacodynamic effects in the lungs.

Main Methods:

  • A randomized, placebo-controlled, double-blind, dose-escalation study (NCT01725139) involving 17 IPF subjects.
  • Omipalisib administered at 0.25mg, 1mg, and 2mg twice daily for 8 days.
  • Pharmacokinetic analysis, target engagement markers (pAKT, PIP3), and 18F-FDG PET/CT scans were utilized.

Main Results:

  • Omipalisib was generally well-tolerated, with diarrhea as the most common adverse event.
  • Dose-related increases in insulin and glucose were observed.
  • Pharmacokinetics indicated blood exposure predicts lung exposure, with confirmed target engagement in both.
  • 18F-FDG PET/CT demonstrated exposure-dependent reduction in lung 18F-FDG uptake, confirming pharmacodynamic activity.

Conclusions:

  • Omipalisib demonstrates acceptable tolerability in IPF patients at effective exposure levels.
  • Target engagement and pharmacodynamic effects were confirmed systemically and within lung tissue.
  • These findings support further investigation of omipalisib in IPF treatment.

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