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Randomized Controlled Trial
. 2019 Mar 18;53(3):1801992.
doi: 10.1183/13993003.01992-2018. Print 2019 Mar.

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

Pauline T Lukey  1 , Stephen A Harrison  1 , Shuying Yang  1 , Yim Man  1 , Beverley F Holman  2 , Alaleh Rashidnasab  2 , Gabrielle Azzopardi  2 , Michael Grayer  1 , Juliet K Simpson  1 , Philippe Bareille  1 , Lyn Paul  3 , Hannah V Woodcock  4 , Richard Toshner  3 , Peter Saunders  3 , Philip L Molyneaux  3   5 , Kris Thielemans  2 , Frederick J Wilson  1 , Paul F Mercer  4 , Rachel C Chambers  4 , Ashley M Groves  2 , William A Fahy  1 , Richard P Marshall  1 , Toby M Maher  6   5
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Free article
Randomized Controlled Trial

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

Pauline T Lukey et al. Eur Respir J. .
Free article

Abstract

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.

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Conflict of interest statement

Conflict of interest: P.T. Lukey was a GSK employee at the time of the study and is still a shareholder. P.T. Lukey now works or has worked as an independent consultant to GSK R&D, the Francis Crick Institute, Syncona, Mereo BioPharma, Peptinnovate, BerGenBio, Morphic Therapeutics and LifT BioSciences. Conflict of interest: S.A. Harrison reports that the study was funded by GlaxoSmithKline; and is an employee of and holds shares in GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Yang reports that the study was funded by GlaxoSmithKline; and is an employee of and holds shares in GlaxoSmithKline, outside the submitted work. Conflict of interest: Y. Man has nothing to disclose. Conflict of interest: B.F. Holman reports grants from EPSRC, during the conduct of the study. Conflict of interest: A. Rashidnasab reports grants from GSK, during the conduct of the study. Conflict of interest: G. Azzopardi has nothing to disclose. Conflict of interest: M. Grayer reports that the study was funded by GlaxoSmithKline; and received personal fees as a contractor on assignment at GSK to complete statistical analyses, from GlaxoSmithKline, outside the submitted work. Conflict of interest: J.K. Simpson is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: P. Bareille is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: L. Paul has nothing to disclose. Conflict of interest: H.V. Woodcock reports grants from GlaxoSmithKline, during the conduct of the study. Conflict of interest: R. Toshner has nothing to disclose. Conflict of interest: P. Saunders has nothing to disclose. Conflict of interest: P.L. Molyneaux has nothing to disclose. Conflict of interest: K. Thielemans reports grants from GSK, during the conduct of the study; grants from GE Healthcare, outside the submitted work. Conflict of interest: F.J. Wilson is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: P.F. Mercer was funded through a collaborative framework agreement with GlaxoSmithKline. Conflict of interest: R.C. Chambers reports grants from GlaxoSmithKline (GSK), during the conduct of the study; and R.C. Chambers’ spouse is an employee of GSK. Conflict of interest: A.M. Groves has nothing to disclose. Conflict of interest: W.A. Fahy is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: R.P. Marshall is an employee of and holds shares in GlaxoSmithKline, outside the submitted work. Conflict of interest: T.M. Maher has, via his institution, received industry-academic funding from GlaxoSmithKline R&D and UCB and has received consultancy or speaker's fees from Apellis, Astra Zeneca, aTyr Pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, ProMetic, Roche, Sanumed and UCB.

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