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 7day 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, [ 18 F]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.

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

“…The aim of this study was to fully characterize GSK3008348 and generate translational drug discovery biomarkers that will facilitate the performance of future clinical trials. To date, GSK3008348 has been shown to be safe and well tolerated in phase I healthy volunteer studies 24 and has completed a phase Ib study, demonstrating target engagement of the αvβ6 integrin in IPF patients 25 .…”

“…NanoSPECT-CT imaging studies using A20FMDV2 in saline and bleomycin-treated mice demonstrated the dose-and time-dependent engagement of GSK3008348 with αvβ6 in an in vivo model of lung fibrosis. The quantification of αvβ6 integrin upregulation in IPF and the profiling of GSK3008348 binding to the integrin in diseased tissue will allow this pre-clinical work to be translated to clinical studies in IPF 25,28 .…”

“…All the data generated as part of this study have contributed to the design and clinical dose prediction used for GSK3008348 in phase Ib studies where the ability of this molecule to engage the αvβ6 integrin in IPF patients is currently under investigation 25 . Based on this translational data package the hypothesized mechanism of action of GSK3008348 post administration into an IPF patient's lung is as follows: (1) nebulized GSK3008348 would enter the lung and bind to αvβ6 with high affinity and fast association kinetics.…”

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

“…In a bleomycin-induced murine lung fibrosis model, GSK300834 was used as an inhalable therapeutic and reduced lung collagen deposition and fibrosis progression [ 475 ]. The results of a small phase Ib study (eight patients) indicate that nebulized dosing with GSK300834 was safe and led to successful target engagement [ 478 ]. Future clinical studies with GSK300834 are eagerly awaited.…”

Consensus Recommendations on the Use of18F-FDG PET/CT in Lung Disease

“…18 F-Fluorodeoxyglucose ( 18 F-FDG) is the most widely available and commonly used PET tracer and is predominantly employed to assess lung inflammation and fibrosis-related processes for both research and clinical purposes. New molecularly-targeted PET tracers are also being developed to support the respiratory drug development process, with a recent publication demonstrating the additional potential for PET imaging to assess drug target engagement in the lungs (5).…”