GSK3008348 / GSK - LARVOL DELTA

Core Modifications of GSK3335103 toward Orally Bioavailable αvβ6 Inhibitors with Improved Synthetic Tractability. (PubMed, J Med Chem) - "Strategies to reduce the basicity of the central ring nitrogen present in GSK3008348 were employed, while avoiding the synthetic complexity of the chiral, fluorine-containing quaternary carbon center contained in GSK3335103. Following initial PK studies, this series was optimized, aided by analysis of the physicochemical and in vitro PK properties, to deliver lead molecules (S)-20 and 28 as potent and orally bioavailable αvβ6 inhibitors with improved synthetic tractability."

Journal • Fibrosis • Immunology • TGFB1

Integrin αVβ1 Regulates Procollagen I Production through a Non-canonical Transforming Growth Factor β Signaling Pathway in Human Hepatic Stellate Cells. (PubMed, Biochem J) - " Extensive evidence has established the concept that αV integrins are involved in the activation of latent transforming growth factor β (TGF-β), a master regulator of the fibrotic signaling cascade.  Based on mRNA and protein expression profiling data, we found that αVβ1 integrin is the most abundant member of the αV integrin family in either quiescent or TGF-β1-activated primary human HSCs.  Unexpectedly, either a selective αVβ1 inhibitor, Compound 8 (C8), or a pan-αV integrin inhibitor, GSK3008348, decreased TGF-β1-activated procollagen I production in primary human HSCs, in which the role of β1 integrin was confirmed by ITGB1 siRNA...Furthermore, a selective inhibitor of MEK1/2 blocked TGF-β1 induced phosphorylation of ERK1/2 and decreased TGF-β1 induced procollagen I production, while a specific inhibitor of STAT3 had no effect on TGF-β1 induced procollagen I production.  Taken together, current data indicate that αVβ1 integrin can regulate TGF-β..."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • SMAD3 • STAT3 • TGFB1

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis. (PubMed, Nat Commun) - "In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin αvβ6 inhibitor, in healthy participants. (PubMed, Eur J Clin Pharmacol) - P1; "In 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."

Clinical • Journal • PK/PD data • Biosimilar • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

GSK3008348: Data from P1 trial (NCT03069989) for IPF in H2 2020 (GSK) - Q2 2018 Results

P1 data • Fibrosis • Immunology

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. (PubMed, Respir Res) - P1 | "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."

Clinical • Journal • P1 data

INTEGRIN αvβ6 EXPRESSION CORRELATES WITH FIBROSIS IN HUMAN NASH AND DRIVES PROGRESSION OF STEATOHEPATITIS IN MICE (AASLD 2019) - "Furthermore, delayed therapy with selective αvβ6 inhibitor MR-1882 (20 and 50mg/kg/day) or pan-αv integrin inhibitor, GSK3008348 (100mg/kg/day) delivered via osmotic minipumps was assessed in HF-CDAA model of pre-established fibrosis (week 6 through 11 of HF-CDAA)... Integrin αvβ6 is expressed on cells comprising ductular reaction and parallels the fibrosis progression in human NASH. Genetic or pharmacological αvβ6 targeting lead to remarkable suppression ductular reaction and fibrosis in murine NASH. Our data support αvβ6 integrin as a promising therapeutic target in NASH."

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 (ERS 2019) - P1; "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."

Clinical • Late-breaking abstract

Single Doses of GSK3008348 in Idiopathic Pulmonary Fibrosis (IPF) Participants Using Positron Emission Tomography (PET) Imaging (clinicaltrials.gov) - P1; N=8; Terminated; Sponsor: GlaxoSmithKline; Trial completion date: May 2019 ➔ Jul 2018; Active, not recruiting ➔ Terminated; Sufficient information was gathered from cohort 1 to terminate the study without proceeding to optional cohort 2.

Clinical • Trial completion date • Trial termination