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

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 medi...

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Bibliographic Details
Published in:	The European respiratory journal Vol. 53; no. 3; p. 1801992
Main Authors:	Lukey, Pauline T, Harrison, Stephen A, Yang, Shuying, Man, Yim, Holman, Beverley F, Rashidnasab, Alaleh, Azzopardi, Gabrielle, Grayer, Michael, Simpson, Juliet K, Bareille, Philippe, Paul, Lyn, Woodcock, Hannah V, Toshner, Richard, Saunders, Peter, Molyneaux, Philip L, Thielemans, Kris, Wilson, Frederick J, Mercer, Paul F, Chambers, Rachel C, Groves, Ashley M, Fahy, William A, Marshall, Richard P, Maher, Toby M
Format:	Journal Article
Language:	English
Published:	England 01-03-2019
Subjects:	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
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Summary:	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. F-2 fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in F-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.
ISSN:	0903-1936 1399-3003
DOI:	10.1183/13993003.01992-2018