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. 2020;21(1):1-9 DOI 10.1186/s12931-020-01339-7

 

Journal Homepage

Journal Title: Respiratory Research

ISSN: 1465-9921 (Print); 1465-993X (Online)

Publisher: BMC

LCC Subject Category: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the respiratory system

Country of publisher: United Kingdom

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Toby M. Maher (Royal Brompton Hospital)

Juliet K. Simpson (GlaxoSmithKline Research and Development)

Joanna C. Porter (University College London Hospital)

Frederick J. Wilson (GlaxoSmithKline Research and Development)

Robert Chan (GlaxoSmithKline Research and Development)

Rhena Eames (GlaxoSmithKline Research and Development)

Yi Cui (GlaxoSmithKline Research and Development)

Sarah Siederer (GlaxoSmithKline Research and Development)

Simon Parry (GlaxoSmithKline Research and Development)

Julia Kenny (GlaxoSmithKline Research and Development)

Robert J. Slack (GlaxoSmithKline Research and Development)

Jagdeep Sahota (University College London Hospital)

Lyn Paul (Royal Brompton Hospital)

Peter Saunders (Royal Brompton Hospital)

Philip L. Molyneaux (Royal Brompton Hospital)

Pauline T. Lukey (GlaxoSmithKline Research and Development)

Gaia Rizzo (Invicro, A Konica Minolta Company)

Graham E. Searle (Invicro, A Konica Minolta Company)

Richard P. Marshall (GlaxoSmithKline Research and Development)

Azeem Saleem (Invicro, A Konica Minolta Company)

Arthur R. Kang’ombe (GlaxoSmithKline Research and Development)

David Fairman (GlaxoSmithKline Research and Development)

William A. Fahy (GlaxoSmithKline Research and Development)

Mitra Vahdati-Bolouri (GlaxoSmithKline Research and Development)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 17 weeks

 

Abstract | Full Text

Abstract 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.