Galectin-3 is a major driver of tissue inflammation and fibrosis. It is produced by activated macrophages and secreted in the extracellular matrix where it interacts with macromolecules and cells to form a fibrosome. In chronic liver inflammation, peripheral macrophages invade the organ and may lead to cirrhosis, a life-threatening fibrotic disorder. Belapectin, a large molecule captured by macrophages, is a galectin-3 inhibitor in development for cirrhosis.

I will present how our pan-PPAR agonist, lanifibranor, improves steatosis, hepatitis and fibrosis in patients with NASH.

I will highlight the discovery and development of Bexotegrast, a dual selective integrin inhibitor for pulmonary fibrosis. I will also describe Pliant’s translational approach and successful Phase 2 results in IPF.

We used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophage population to which we assign a profibrotic role across species and tissues, which are defined by expression of SPP1, GPNMB,FABP5, and CD63.  GM-CSF, IL-17A or TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers, and blockade of these cytokines reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis in mice.

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 and liver fibrosis. Galecto has developed several galectin-3 clinical candidates with disease-tailored administration for lung and liver fibrosis. This talk will focus on:

• an introduction to the Galecto portfolio of galectin inhibitors
• bioinformatic analysis constructing pathway maps depicting the role of galectin-3 in fibrosis with confirmatory overlaid inhibitor profiles
• translational pharmacology of inhaled and oral clinical candidates in IPF and cirrhosis including Phase II clinical data

Fibrosis is an intrinsic response to chronic injury and can progress toward excessive tissue scarring and organ failure, such as idiopathic pulmonary fibrosis (IPF) and liver cirrhosis. TGF-ß1 and 3 are key cytokines involved in the pathogenesis of tissue fibrosis. Targeting avb6 for IPF and biliary liver fibrosis is supported by preclinical pharmacological inhibition and genetic ablation data. However, TGF-ß inhibition is also linked to epithelial cell proliferation and inflammation. 

Evidence is accumulating that there are abnormalities in the pulmonary endothelium of patients with idiopathic pulmonary fibrosis (IPF), such as increased vascular permeability, loss of capillaries, and expansion of bronchial vessels. Single-cell RNA sequencing (scRNAseq) of IPF lung tissue suggests a loss of capillary endothelial cells (EC) in the fibrotic lung, and expansion of other EC. Defining the EC abnormalities present in IPF may identify opportunities for therapeutic intervention.

LTI-03 is a caveolin-1 scaffolding domain (CSD) peptide formulated for dry powder inhalation in idiopathic pulmonary fibrosis (IPF) patients. The anti-fibrotic and lung-regenerative effects of LTI-03 were confirmed in several experimental and translational studies including IPF precision-cut lung slices (PCLS). In PCLS studies, LTI-03 matched the potent anti-fibrotic effects of nintedanib without the toxicity and necrosis observed with the standard-of-care drug. LI-03 also enhanced alveolar epithelium viability. Inhaled LTI-03 was well tolerated in normal volunteers (NCT04233814) and a Phase 1b clinical trial is now underway in IPF patients. Together, LTI-03 is an exciting new IPF therapy.

I will discuss the role of RIP1 in inflammatory bowel disease as well its role in tissue damage for other related diseases. Progress on RIP1K inhibitors will also be included. 

TLC-3595 is a first-in-class, potent, systemically-distributed, oral, allosteric acetyl-CoA carboxylase 2 (ACC2)-selective inhibitor. TLC-3595 has pleiotropic benefits in multiple cell types that contribute to anti-fibrotic effects in murine models of hepatic fibrosis, and also reduces cardiac fibrosis and improves mortality in a genetic model of heart failure by restoring impaired fatty acid oxidation. These observations support the evaluation of TLC-3595 in patients with metabolic disease, including diabetes, NASH and cardiovascular disease.