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

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 (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 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.

Keywords: Alpha-v beta-6; IPF, positron emission tomography; Idiopathic pulmonary fibrosis; Integrin; PET; [18F]FB-A20FMDV2, target engagement; αvβ6.

Fig. 1

Study schematic for cohort 1. HRCT: high-resolution computed tomography; PET: positron emission tomography; PK: pharmacokinetics; PET1: PET scan on day 1 at ~30 min post-dose; PET2: PET scan on day 2 at ~24 h post-dose

Fig. 2

Summary of adjusted medians of uncorrected VT, (mL/cm3) of [18F]FBA20FMDV2 and individual patient profiles. PET1: PET scan on day 1 at ~30 min post-dose; PET2: PET scan on day 2 at ~24 h post-dose. The adjusted medians (with 95% Cr I) were calculated from a Bayesian repeated measures model using data from participants on the GSK3008348 1000 mcg arm only and is indicated by a thicker line and filled triangles. Data for individual participants dosed with GSK300834 are shown with dotted lines linking the data. Individual subject data is shown for participants on GSK3008348 1000 mcg (red symbols) and placebo (green symbols). The PET data from the placebo participants are included on plots for reference, but were not included in the analysis.

Fig. 3

Median plasma GSK3008348 concentration-time plot