The extracellular matrix is considered a common link in chronic diseases. Its physical and biochemical regulation are essential in normal tissue homeostasis and could also be the driving force in several diseases, including fibrosis and cancer. Herein, we explore and present recent findings in the ECM- immune system crosstalk in inflammatory skin diseases, such as psoriasis and hidradenitis suppurativa. 

Intestinal fibrosis is an area of increased attention and early activity in the pharmaceutical industry. It is defined as an excessive accumulation of scar tissue in the intestinal wall and is a common complication of inflammatory bowel diseases. I will review the biological pathways leading to intestinal fibrosis, including the different fibroblast subtypes in the intestine. I will also discuss points of intersection with other fibroproliferative diseases including potential targets, and touch upon the drug development landscape for intestinal fibrosis.

Caveolin-1 protein expression is decreased in IPF leading to the loss of caveolin-1-dependent regulation of cell membrane receptor localization and the amplification of intracellular signaling pathways, many of which drive organ fibrosis. To address this deficit in caveolin-1 in IPF, Lung Therapeutics has developed LTI-03, which is a seven amino acid sequence derived from the caveolin scaffolding domain (CSD) of caveolin-1 and is delivered by dry powder inhalation. LTI-03 targets multiple profibrotic signaling factors in primary IPF fibroblasts and basal-like cells. LTI-03 supports type II and type I alveolar epithelial cell survival in IPF precision cut lung slices. 

Liver cirrhosis and cardiovascular disease are major causes of mortality in patients with NASH. The pan-PPAR agonist lanifibranor has shown efficacy on NASH resolution and fibrosis improvement (NATIVE study). Lanifibranor also improved a broad panel of markers of cardiometabolic health, incl. insulin resistance, lipid and glucose metabolism, systemic inflammation, blood pressure and hepatic steatosis. Lanifibranor therapy addresses hepatic injury and fibrosis as well as the metabolic-immune disease biology of NASH.

TGFß inhibition remains a promising anti-fibrotic approach. However, inhibition of all 3 TGFß isoforms is associated with safety liabilities. Scholar Rock has identified a selective antibody that inhibits matrix-associated TGFß1 complexed with LTBP1 and 3, spares TGFß1 presented by immune cells, and reduces TGFß signaling and fibrosis in preclinical models of kidney disease. This LTBP-TGFß1 antibody may offer a safety profile that is better suited to treating chronic fibrotic indications.

TGFß isoforms, 1, 2, and 3, are master profibrogenic cytokines in many tissues. However, they are pleiotropic factors that are involved in development, immune homeostasis, and cell cycle regulation, which poses safety challenges to develop successful therapies for fibrosis indications. Recently, inhibition of TGFß via isoform-specific antibodies or local inhibition of TGFß activation have demonstrated the therapeutic potential of the selective targeting of TGFß family members.

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, Inc. has developed several high affinities and selective galectin-3 inhibitors including the inhaled small molecule GB0139 that is currently undergoing clinical investigation in IPF. This talk will focus on the translational pharmacology of GB0139 and its potential as an anti-fibrotic therapy.

I will discuss Madrigal’s lead candidate, resmetirom, a once daily, oral, thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of NASH in the liver. Resmetirom is currently being evaluated in two Phase 3 clinical studies (MAESTRO-NASH and MAESTRO-NAFLD-1) designed to demonstrate multiple benefits in patients with NASH. MAESTRO-NAFLD-1 has completed with positive results.

Belapectin is a polycarbohydrate candidate drug for liver cirrhosis due to NASH and, in combination with a PD-1 inhibitor, for advanced/metastatic head and neck cancers. Belapectin is in Phase 2b/3 and Phase 2, respectively. Belapectin is a galectin-3 inhibitor and disrupts the galectin-3 fibrosome that plays a major role in these diseases. Belapectin targets and acts primarily on activated macrophages that invade the liver in cirrhosis and the tumor microenvironment in advanced cancers.

We identified ten novel MOAs with predicted efficacy in NASH and twenty novel MOAs for IPF. This process took 15 weeks and 12 weeks, respectively, from program start to in vivo results, identifying lead molecule TXR-612 for NASH and TXR-1002 and TXR-1007 for IPF. Preclinical results have demonstrated significant safety and efficacy in NASH and IPF.

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 non-junctional CLDN1 reverted inflammation-induced hepatocyte pro-fibrogenic signaling and cell fate and suppressed the pro-fibrogenic differentiation of myofibroblasts. Safety studies of a fully humanized antibody in non-human primates did not reveal any significant adverse events. Antifibrotic effects across lung and kidney fibrosis models have confirmed a role of Claudin-1 as a target for fibrosis across organs. The clinical development of Claudin-1-targeting therapies for fibrotic diseases in patients is ongoing.