Late Breaking Abstract - A PET imaging study to confirm target engagement in the lungs of patients with IPF following a single dose of a novel inhaled avß6 integrin inhibitor

Abstract

Rationale: GSK3008348 is an inhaled αvβ6 integrin inhibitor. Here we present the results of a randomised, placebo-controlled, single dose phase Ib study (204715, NCT03069989) to demonstrate pulmonary target engagement of GSK3008348 in IPF patients, assessed by dynamic positron emission tomography (PET) using a radiolabelled αvβ6-specific ligand, [18F]-FBA-A20FMDV2. Methods: Participants with IPF received 1mg of GSK3008348 or placebo in a ratio of 5:2. Safety, tolerability, PK and PET-derived target engagement were assessed. The primary endpoint was whole lung volume of distribution (VT) at ~30 mins post-dose compared to the pre-dose VT. The study success criterion was ‘the posterior probability (true % reduction in VT > 0%) ≥ 80%’. Assuming a within-subject standard deviation between two PET scans of 0.15 (PETAL study, NCT02052297), a sample of 5 patients was required to give a minimum detectable reduction of 6.2%. Results: 8 IPF patients (1 female, mean age 75 years) were enrolled into the study and 7 completed. GSK3008348 was well tolerated. The PK was generally consistent with a previous healthy volunteer study (NCT02612051). The mean % reduction of the PET signal (VT) observed 30 mins after inhalation of 1mg of GSK3008348 was 20% (95% CrI: -9% to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. Conclusions: This study demonstrated target engagement following nebulised dosing with GSK3008348 to individuals with IPF. To the best of our knowledge this is the first time a target specific radioligand has been used to assess target engagement in the lung.