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

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 (alpha v beta 6) 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 alpha v beta 6-specific ligand, [F-18]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V-T), 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 V-T > 0%) of >= 80%. Results Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V-T at 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in V-T > 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 alpha v beta 6 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.