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A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

Maher, Toby M.; Simpson, Juliet K.; Porter, Joanna C.; Wilson, Frederick J.; Chan, Robert; Eames, Rhena; Cui, Yi; Siederer, Sarah; Parry, Simon; Kenny, Julia; Slack, Robert J.; Sahota, Jagdeep; Paul, Lyn; Saunders, Peter; Molyneaux, Philip L.; Lukey, Pauline T.; Rizzo, Gaia; Searle, Graham E.; Marshall, Richard P.; Saleem, Azeem; Kang'Ombe, Arthur R.; Fairman, David; Fahy, William A.; Vahdati-Bolouri, Mitra

Authors

Toby M. Maher

Juliet K. Simpson

Joanna C. Porter

Frederick J. Wilson

Robert Chan

Rhena Eames

Yi Cui

Sarah Siederer

Simon Parry

Julia Kenny

Robert J. Slack

Jagdeep Sahota

Lyn Paul

Peter Saunders

Philip L. Molyneaux

Pauline T. Lukey

Gaia Rizzo

Graham E. Searle

Richard P. Marshall

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Dr Azeem Saleem A.Saleem@hull.ac.uk
Reader and Honorary Consultant in Clinical Oncology

Arthur R. Kang'Ombe

David Fairman

William A. Fahy

Mitra Vahdati-Bolouri



Abstract

© 2020 The Author(s). Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: Baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI:-9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration: Clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.

Citation

Maher, T. M., Simpson, J. K., Porter, J. C., Wilson, F. J., Chan, R., Eames, R., …Vahdati-Bolouri, M. (2020). A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor. Respiratory Research, 21(1), Article 75. https://doi.org/10.1186/s12931-020-01339-7

Journal Article Type Article
Acceptance Date Mar 18, 2020
Online Publication Date Mar 26, 2020
Publication Date Mar 26, 2020
Deposit Date Feb 10, 2021
Publicly Available Date Mar 28, 2024
Journal Respiratory Research
Print ISSN 1465-9921
Electronic ISSN 1465-993X
Publisher BioMed Central
Peer Reviewed Peer Reviewed
Volume 21
Issue 1
Article Number 75
DOI https://doi.org/10.1186/s12931-020-01339-7
Keywords Alpha-v beta-6; αvβ6; Integrin; Idiopathic pulmonary fibrosis; IPF, positron emission tomography; PET; [18F]FB-A20FMDV2, target engagement
Public URL https://hull-repository.worktribe.com/output/3630049

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Copyright Statement
© The Author(s). 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.






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