A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis
Author(s)
Type
Journal Article
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.
Date Issued
2019-03-01
Date Acceptance
2018-12-11
Citation
European Respiratory Journal, 2019, 53 (3)
ISSN
0903-1936
Publisher
European Respiratory Society
Journal / Book Title
European Respiratory Journal
Volume
53
Issue
3
Copyright Statement
© 2019 ERS. https://www.ersjournals.com/user-licence
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30765508
PII: 13993003.01992-2018
Subjects
11 Medical And Health Sciences
Respiratory System
Publication Status
Published
Coverage Spatial
England
Article Number
1801992
Date Publish Online
2019-03-18