Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin αvβ6 inhibitor, in healthy participants

Abstract

PurposeInhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the αvβ6 integrin for the treatment of IPF. The phase 1 first-time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants.MethodsSingle ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1–3000 mcg given by nebulisation.ResultsA total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half-lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100–3000 mcg). Dose normalised geometric mean Cmax increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety.ConclusionsIn summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300–3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF.Electronic supplementary materialThe online version of this article (10.1007/s00228-018-2435-3) contains supplementary material, which is available to authorized users.

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

“…A single nebulised 1000 mcg dose of GSK3008348 inhibited the uptake of the specific PET ligand [ 18 F]FB-A20FMDV2 in the lung at~30 min post-dose, providing evidence of target engagement with the αvβ6 integrin receptor, but not at~24 h, indicating that the duration of target engagement was less than 24 h, consistent with a priori PK/PD modelling. Single doses of 1000 mcg of GSK3008348 were well tolerated, and PK was generally consistent with that observed for healthy volunteers [8].…”

“…In an in vivo mouse model of lung fibrosis, inhaled GSK3008348 inhibited the activation of TGFβ [7]. GSK3008348 has previously been demonstrated to be well tolerated at single doses up to 3000 mcg in healthy human participants, with a pharmacokinetic (PK) profile that was dose proportional at potentially clinically relevant doses [8].…”

The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression

“…This antibody, STX-100 (BG00011), is currently in clinical trials for treatment of idiopathic pulmonary fibrosis and for nephropathy [157]. Likewise, the first small molecule inhibitor of αvβ6 integrin, GSK3008348, was produced by GlaxoSmithKline Research as an inhaled compound for the treatment of idiopathic pulmonary fibrosis [163].…”

Late‐Stage Functionalization by Chan–Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors

“…Recently, an α v β 6 antibody and the GSK candidate GSK3008348 3 have both been evaluated clinically, and inhibition of the α v β 6 integrin with 3 did not cause any adverse effects in healthy volunteers when dosed at 3–3000 μg . Inhibitor 3 , and structurally similar compounds, are RGD mimetics, and such structures form the basis of our current work.…”