TY - JOUR T1 - A Randomised, Placebo-Controlled Study of Omipalisib (PI3K/mTOR) in Idiopathic Pulmonary Fibrosis JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01992-2018 SP - 1801992 AU - Pauline T. Lukey AU - Stephen A. Harrison AU - Shuying Yang AU - Yim Man AU - Beverley F. Holman AU - Alaleh Rashidnasab AU - Gabrielle Azzopardi AU - Michael Grayer AU - Juliet K. Simpson AU - Philippe Bareille AU - Lyn Paul AU - Hannah V. Woodcock AU - Richard Toshner AU - Peter Saunders AU - Philip L. Molyneaux AU - Kris Thielemans AU - Frederick J. Wilson AU - Paul F. Mercer AU - Rachel C. Chambers AU - Ashley M. Groves AU - William A. Fahy AU - Richard P. Marshall AU - Toby M. Maher Y1 - 2019/01/01 UR - http://erj.ersjournals.com/content/early/2018/12/14/13993003.01992-2018.abstract N2 - 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Marshall reports other from GlaxosmithKline, outside the submitted work.Conflict of interest: Dr. Grayer reports other from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, outside the submitted work.Conflict of interest: Dr. Rashidnasab reports grants from GSK, during the conduct of the study.Conflict of interest: Dr. Azzopardi has nothing to disclose.Conflict of interest: Dr. Bareille reports other from GSK, during the conduct of the study.Conflict of interest: Dr. Groves has nothing to disclose.Conflict of interest: Dr. Man has nothing to disclose.Conflict of interest: Dr. Harrison reports other from GSK, during the conduct of the study; other from GSK, outside the submitted work.Conflict of interest: Dr. Thielemans reports grants from GSK, during the conduct of the study; grants from GE Healthcare, outside the submitted work.Conflict of interest: Dr. Paul has nothing to disclose.Conflict of interest: Dr. Chambers reports grants from GlaxoSmithKline (GSK), from null, during the conduct of the study; and My spouse is an employee of GSK.Conflict of interest: Dr. Fahy reports other from GSK, outside the submitted work.Conflict of interest: Dr. Holman reports grants from EPSRC, during the conduct of the study.Conflict of interest: Dr. Woodcock reports grants from GlaxoSmithKline, during the conduct of the study;Conflict of interest: Dr. Lukey reports other from GlaxoSmithKline R&D, outside the submitted work; and I was a GSK employee at the time of the study and am still a shareholder. I now work or have 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: Dr. Toshner has nothing to disclose.Conflict of interest: Mr. Wilson reports personal fees and other from GlaxoSmithKline, during the conduct of the study; personal fees and other from GlaxoSmithKline, outside the submitted work.Conflict of interest: Dr. Simpson reports personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work.Conflict of interest: Dr. Saunders has nothing to disclose.Conflict of interest: Dr. Yang reports other from GSK, during the conduct of the study; other from GSK, outside the submitted work.Conflict of interest: Dr. Molyneaux has nothing to disclose.Conflict of interest: TMM has, via his institution, received industry-academic funding from GlaxoSmithKline R&D and UCB and has received consultancy or speakers fees from Apellis, Astra Zeneca, aTyr Pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, ProMetic, Roche, Sanumed and UCB.Conflict of interest: Dr. Mercer reports other from GlaxoSmithKline, during the conduct of the study. 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