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Translational pharmacology of an inhaled small molecule ?v?6 integrin inhibitor for idiopathic pulmonary fibrosis.

ABSTRACT: The ?v?6 integrin plays a key role in the activation of transforming growth factor-? (TGF?), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule ?v?6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to ?v?6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGF? signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the ?v?6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages ?v?6, induces prolonged inhibition of TGF? signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

SUBMITTER: John AE

PROVIDER: S-EPMC7494911 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis.

John Alison E AE Graves Rebecca H RH Pun K Tao KT Vitulli Giovanni G Forty Ellen J EJ Mercer Paul F PF Morrell Josie L JL Barrett John W JW Rogers Rebecca F RF Hafeji Maryam M Bibby Lloyd I LI Gower Elaine E Morrison Valerie S VS Man Yim Y Roper James A JA Luckett Jeni C JC Borthwick Lee A LA Barksby Ben S BS Burgoyne Rachel A RA Barnes Rory R Le Joelle J Flint David J DJ Pyne Susan S Habgood Anthony A Organ Louise A LA Joseph Chitra C Edwards-Pritchard Rochelle C RC Maher Toby M TM Fisher Andrew J AJ Gudmann Natasja Stæhr NS Leeming Diana J DJ Chambers Rachel C RC Lukey Pauline T PT Marshall Richard P RP Macdonald Simon J F SJF Jenkins R Gisli RG Slack Robert J RJ

Nature communications 20200916 1

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK300 ...[more]

PMID: 32938936

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Project description:BackgroundIdiopathic 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.MethodsThis 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%.ResultsEight 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.ConclusionsThis 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 registrationclinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.

Dataset Information

Translational pharmacology of an inhaled small molecule ?v?6 integrin inhibitor for idiopathic pulmonary fibrosis.

Publications

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis.

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