The av integrins (avb1, avb3, avb5, avb6, avb8) are a subset of a family of heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix signaling. In this talk, we will describe the development of our integrin inhibitor library as well as discuss the challenges in targeting integrins with small molecule drugs.

Galectin-3 is a ß-galactoside-binding lectin highly expressed in fibrotic tissue of diverse etiologies and has been shown to play a key role in lung, liver and kidney fibrosis. Galecto, Inc. have developed a number of high affinity and selective galectin-3 inhibitors currently undergoing clinical investigation in fibrotic diseases of the lung and liver. This talk will focus on the translational pharmacology of these galectin-3 inhibitors and their potential as anti-fibrotics.

Tissue fibrosis is a driver of end-stage organ failure and cancer. Using highly specific monoclonal antibodies and patient-derived models, we uncovered Claudin-1 as a target for treatment of liver fibrosis. Targeting Claudin-1 reverted inflammation-induced hepatocyte perturbation and suppressed the pro-fibrogenic differentiation of Kupffer cells and myofibroblasts. Safety studies of a fully humanized antibody in non-human primates did not reveal any significant adverse events. Antifibrotic effects in lung and kidney fibrosis models indicate a role of Claudin-1 as a candidate target for fibrosis across organs. Our data pave the way for therapeutic exploration of Claudin-1-targeting therapies for fibrotic diseases in patients.

Fibrosis covers a collection of progressive, chronic diseases with poor prognoses and significant unmet need. These diseases display cellular complexity, and heterogeneity in their progression and severity. Collectively, these features have hindered the development of new candidates. Here, we describe current preclinical efforts in anti-fibrotic candidates based on their mechanism, as we approach our goal to guide successful translation of novel therapies to the clinic.

Integrins are heterodimeric membrane proteins that participate in a number of cellular functions, including migration, adhesion, ECM remodeling, and TGFß activation. In human NASH samples as well as rodent models, expression levels of several integrins are elevated. Inhibition of integrins demonstrated anti-fibrotic effects in mouse NASH model. Furthermore, in a model of NASH fibrosis-induced HCC model, treatment of integrin inhibitors led to a reduction of tumor formation likely as a result of improved fibrosis. Taken together, integrins are key receptors implicated in fibrosis and targeting Integrins complements other mechanisms in NASH and confers a unique strategy to treat liver fibrosis. 

Seladelpar, a selective and potent PPARd agonist, has been studied for the treatment of nonalcoholic steatohepatitis (NASH) and primary biliary cholangitis. PPARd has ubiquitous tissue expression unlike the selective tissue expression of PPARa and PPARg. Seladelpar addresses key features of NASH by exerting its effects through regulation of lipid metabolism, inflammation, and fibrosis. The efficacy of seladelpar was evaluated in diet-induced NASH mouse models and a NASH clinical trial.

The biology of NASH is characterized by altered energy metabolism, inflammation and fibrogenesis, underlying progressive liver disease and other manifestations of metabolic syndrome, notably T2D and cardiovascular disease. PPAR nuclear receptors are master regulators of immune-metabolic and fibrosis pathways and promising targets for pharmacological therapy. Lanifibranor, a pan-PPAR agonist in late-stage development with a balanced PPARα, β/δ and γ profile and thereby modulating distinct effects of PPAR subtypes, has shown significant efficacy on both NASH resolution and fibrosis regression in the phase 2b NATIVE study. Lanifibranor also improved T2D markers, lipid profile and other cardiovascular risk factors.

By leveraging a unique chemical scaffold, we have developed a proprietary FXR platform, resulting in an improved therapeutic profile. Our two candidates, MET409 and MET642, are being investigated in patients with NASH. MET409 has completed a 12-week monotherapy trial and is being evaluated in a 12-week trial in combination with empagliflozin. MET642 has completed a 14-day trial in healthy volunteers and is being evaluated in a 16-week monotherapy trial. Our potentially best-in-class FXR agonists can address unmet needs of patients with NASH, either as front-line monotherapy or in combination with other agents.  

Semaglutide (glucagon-like peptide-1 receptor agonist), firsocostat (acetyl CoA carboxylase inhibitor) and cilofexor (farnesoid X receptor agonist) are being investigated in patients with advanced fibrosis due to NASH. Combinations of the 3 agents are more efficacious than the monotherapies to improve liver TG and NASH, and halt fibrosis progression preclinically. The combinations are also more efficacious at reducing non-invasive measures of liver TG and stiffness in NASH subjects.

FASN is a key enzyme of lipid synthesis. We will present the translational story of our lead FASN inhibitor, which is in clinical development for NASH.

NASH (or Non-Alcoholic Steatohepatitis) is a form of Non-Alcoholic Fatty Liver Disease (NAFLD) that is one of the leading causes of liver disease worldwide. Selecting the appropriate preclinical model to recapitulate this disease requires an in depth understanding of clinical endpoints and therapeutic targeting. The Diet Induced NASH B6 is a metabolically-driven NASH mouse model relevant to the investigation of steatotic, inflammatory and fibrotic mechanisms. Its use in testing clinically-relevant therapeutics targeting FXR and PPAR signaling will be discussed.

I will discuss some of the translational challenges, including developing good biomarkers, for lung fibrosis.

Interstitial lung diseases are characterized by relentless scarring of the lung parenchyma resulting in respiratory failure and death. IPF is particularly notorious for a variable and lethal disease course. Despite the recent success of antifibrotic therapies, IPF remains a high-risk disease area for drug development. This session will discuss the several challenges that have hampered drug development in IPF and other progressive fibrosing ILDs and potential strategies to mitigate them.