MM-003: Human Protein Inhibitor of Galectin-3 for Cardiac Fibrosis

MandalMed’s lead product is MM-003, a human protein that is an inhibitor of galectin-3, which is being developed to prevent and treat harmful remodeling after myocardial infarction (MI; heart attack) and, thereby, improve cardiac function and reduce mortality from subsequent heart failure. Secondly, MandalMed intends to develop MM-003 for chronic use in heart failure by performing biomarker-directed clinical studies. Elevated levels of galectin-3 in the serum have identified a subset of individuals with heart failure that have more progressive disease.

MI is the most common cause of heart failure and cardiac morbidity in the Western world. The incidence in the United States is approximately 610,000 new attacks and 325,000 recurrent attacks annually. Fibrosis is triggered by the physiological response to injury or infection and leads to the deposition of extracellular matrix proteins such as collagen and the formation of new connective tissue. Excessive or dysregulated fibrosis reduces the functioning of the heart by reducing contractility, elasticity, and distensibility, which exacerbate processes that lead to heart failure.

 Although therapeutic agents currently used after MI such as the mineralocorticoid receptor antagonists (MRAs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) are efficacious and have shown anti-fibrotic effects in animal studies, the health burden from MI and subsequent heart failure remain very significant.

Galectin-3 is a key mediator of cardiac fibrosis and timely inhibition of galectin-3 after MI could improve the functionality of the heart and patient outcomes.

Section (left) of the entire myocardium of a rat at 28 days post-injury in an ischemia-reperfusion model with Masson’s trichrome staining (dark blue) for collagen deposition, which reveals the large primary lesion (black arrow). Section of a portion (right) of a rat myocardium at 28 days post-injury in an ischemia-reperfusion model with staining with Picro Sirius red to reveal collagen fiber accumu­la­tion (blue arrow) in the interstitial space between myocytes.

MM-003 for Liver Fibrosis

Chronic liver disease affects approximately 3 million people and leads to more than 42,000 deaths each year in the United States. Fibrosis is the outcome of almost all chronic liver diseases. It is due to a dynamic scarring process caused by the response of the body to liver injury in a similar way that injury causes scarring in the skin or other organs through the deposition of collagen and other extracellular matrix components. Fibrosis that is so extensive that the liver is no longer functional results in cirrhosis – the main cause of death from chronic liver disease. Resolution of liver fibrosis has been shown in animal models and in patients after treatment and/or removal of a causative agent but there are no approved agents that act to prevent or reverse fibrosis.

Mounting data implicate galectin-3 as a causal factor in liver fibrosis. Compared to wild type mice, galectin-3 deficient mice were protected from liver fibrosis from carbon tetrachloride exposure or bile duct ligation despite equivalent injury. Inhibition of galectin-3 expression with small interfering RNA had a therapeutic effect in the carbon tetrachloride mouse model of acute liver disease. In a bile duct ligation mouse model of chronic liver disease, galectin-3 expression was found to be induced in hepatic stellate cells that give rise to the fibrogenic myofibroblasts. Systemic and hepatic vein levels of galectin-3 were increased in patients with alcoholic liver cirrhosis and the levels were found to be negatively correlated with liver function.

MandalMed scientists and collaborators are testing MM-003, a dominant negative protein inhibitor of galectin-3, in animal models of liver disease to determine whether treatment can prevent and reverse liver fibrosis.