Potential of αvβ6 and αvβ1 integrin inhibition for treatment of idiopathic pulmonary fibrosis

ABSTRACT

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown cause with a dismal prognosis. Nintedanib and Pirfenidone are approved worldwide for the treatment of IPF, but they only slow the rate of functional decline and disease progression. Therefore, there is an urgent need for more efficacious and better tolerated drugs.

Areas covered

αvβ6 and αvβ1 are two integrins overexpressed in fibrotic tissue, which play a critical role in the development of lung fibrosis. They act by converting transforming growth factor (TGF)-β, one of the most important profibrotic cytokine, in its active form. Here, we summarize and critically discuss the potential of a dual αvβ6/αvβ1 integrin inhibitor for the treatment of IPF.

Expert opinion

Bexotegrast, a dual αvβ6/αvβ1 integrin inhibitor, has the potential to slow or even halt disease progression in IPF. Indeed, the strong pre-clinical rationale and promising early phase clinical trial data have raised expectations.

KEYWORDS:

• αvβ1
• αvβ6
• Bexotegrast
• idiopathic pulmonary fibrosis
• integrins
• treatment

Article highlights

• Integrins αvβ6 and αvβ1 play a pivotal role in the development of fibrosis by activating TGF-β.

• Bexotegrats is a dual αvβ6/αvβ1 integrin inhibitor that has shown promising results in reducing collagen gene expression in animal models.

• INTEGRIS-IPF trial, a phase 2a study evaluating the safety and efficacy of Bexotegrast in individuals with IPF, has shown a reduction in FVC decline over 12 weeks compared to placebo.

• Additional anti-αvβ6 molecules are under examination among IPF investigated drugs: BG00011 a humanized anti-αvβ6 IgG1 monoclonal antibody and GSK 3335103 an orally available small molecule RGD-mimetic αvβ6 inhibitor.

• Since decades, integrin inhibitors have been considered a promising therapeutic target and they have already been approved in the treatment of several diseases like acute coronary syndrome and Crohn’s disease.

Declaration of interest

P Spagnolo reports consulting fees from Behring, Chiesi, Galapagos (during the conduct of this study), Glycocore, Lupin, Novartis, Pieris, and PPM services and institutional grants from Boehringer Ingelheim, PPM services, and Roche outside the submitted work.

PL Molyneaux reports receiving institutional grant funding from AstraZeneca and speaker fees from Hoffman-La Roche and Boehringer Ingelheim, and advisory board fees from AstraZeneca, Trevi Therapeutics, and Qureight.

TM Maher reports receiving consulting fees from Boehringer Ingelheim, Hoffman-La Roche, AstraZeneca, Bayer, Blade, Bristol Myers Squibb, CSL Behring, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pfizer, Pliant, Respivant, Sanofi, Theravance, Trevi Therapeutics, Veracyte, and Vicore and participating on a data safety monitoring or advisory board for Fibrogen, Blade, and Nerre Therapeutics.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.