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

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A Randomised Controlled Trial of the Pharmacology of Omipalisib November 2018TM.docxFile embargoed until 18 September 20201.63 MBMicrosoft Word    Request a copy
Title: A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis
Authors: Lukey, PT
Harrison, SA
Yang, S
Man, Y
Holman, BF
Rashidnasab, A
Azzopardi, G
Grayer, M
Simpson, JK
Bareille, P
Paul, L
Woodcock, HV
Toshner, R
Saunders, P
Molyneaux, PL
Thielemans, K
Wilson, FJ
Mercer, PF
Chambers, RC
Groves, AM
Fahy, WA
Marshall, RP
Maher, TM
Item 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.
Issue Date: 1-Mar-2019
Date of Acceptance: 11-Dec-2018
URI: http://hdl.handle.net/10044/1/68165
DOI: https://dx.doi.org/10.1183/13993003.01992-2018
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
Keywords: 11 Medical And Health Sciences
Respiratory System
Publication Status: Published
Conference Place: England
Embargo Date: 2020-09-18
Article Number: 1801992
Online Publication Date: 2019-03-18
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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