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.

Lanifibranor is a balanced agonist of PPAR α, β/δ and γ, nuclear receptors that together modulate a continuum of upstream to downstream pathways of NASH from insulin resistance to liver fibrosis. Correspondingly, lanifibranor therapy improves histological NASH activity and liver fibrosis as well as markers of cardiometabolic health, incl. lipid profile, glycemia control and systemic inflammation. Based on its target profile, lanifibranor addresses the broad spectrum of NASH disease biology.

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 organ fibrosis. Galecto have developed several galectin-3 clinical candidates with disease-tailored administration for different organ 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 clinical candidates in 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 emerging that there are changes in the microvascular cells in lungs of patients with pulmonary fibrosis. In addition, factors associated with development of persistent and progressive fibrosis, including aging and repetitive injury, have been found to also cause persistent vascular dysfunction. Studies that induce vascular dysfunction increase experimental pulmonary fibrosis, and those that improve vascular function reduce the fibrotic response to lung injury. Thus, the endothelium is increasingly being recognized as an active player in fibrogenesis, and thus a potential target for antifibrotic therapies.

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.

Growth Hormone (GH) deficiency correlates with the development and progression of NAFLD to NASH and fibrosis. GH and Insulin-like Growth Factor 1 (IGF-1) regulate metabolic, immune, and hepatic stellate cell function. Alterations in GH production and function is associated with visceral adiposity and NAFLD/NASH. Treatment with GH or GHRH improves liver histologic, imaging, and biochemical parameters. However, GHRH—or the analog, tesamorelin—induces endogenous GH secretion with an improved safety profile vs. exogenous GH administration.

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.

I will describe the cell surface membrane proteome we have identified on the fibrotic liver. This proteome is notoriously difficult to isolate because membrane proteins are hydrophobic and limited in abundance. I will present how Peptidisc captures the membrane proteome in a water-soluble state amenable to biochemical assays. I will present the results obtained with healthy and fibrotic organs, plus our efforts toward drug discovery assays.