Fibrosis can affect virtually all organs and tissues. In the case of physical or vascular trauma, reparative fibrosis such as wound healing is critical for survival. However, when the fibrotic response becomes dysregulated either as an extended response to injury (e.g. cardiac fibrosis) or as a secondary response to proinflammaory cytokines/growth factors (e.g. cancer stroma) it will result in diseases that account for an estimated 45% of deaths in the western world. NovoMedix has developed a platform technology that enables the development of orally available small molecules with wide therapeutic windows to treat fibrotic diseases. The initial targeted indications are Heart Failure and Triple Negative Breast Cancer (TNBC).
Heart disease is the leading cause of death worldwide. One of the major contributors to heart disease, and a predictor of poor clinical outcome, is cardiac fibrosis (scarring of the heart tissue) which leads to heart failure. Most people with heart failure die within 5 years of diagnosis. Therefore, a drug that stops or reverses cardiac fibrosis and prevents heart failure could save millions of lives annually.
Cardiac fibroblasts are the main cell type in the heart and respond to myocardial injury by transforming into hyperactive cells known as myofibroblasts which deposit connective tissue (collagen and other matrix proteins) to form a scar to heal wounds. Under normal circumstances, myofibroblasts disappear once the wound is healed. In hypertensive heart disease, the injury is chronic, leading to persistence of myofibroblasts. This results in cardiac fibrosis, the buildup of scar tissue in the heart muscle and valves. The scar tissue is thicker and stiffer than regular tissue, making it difficult for the heart to work properly. The increased load on the heart results in increased heart size and ventricle wall thickness and decreased pumping ability leading to heart failure.
NovoMedix has developed a novel drug that inhibits the conversion of normal fibroblasts to hyperactive myofibroblasts. In a mouse model of heart failure, our drug has been shown to decrease collagen formation in the heart by 50% (p ‹ 0.05) and to preserve heart structure and function. Specifically, our drug significantly attenuated left ventricular dilation (p ‹ 0.01), preserved left ventricular ejection fraction (p ‹ 0.001), and resulted in reduced heart (p ‹ 0.01) weight compared to vehicle when administered 6 weeks after injury (transaortic constriction).
Cancer - Triple Negative Breast Cancer
One in 8 women in the US will develop breast cancer during her lifetime. Breast cancer is the second most commonly diagnosed form of cancer and the second leading cause of cancer deaths in women. Survival rates for breast cancer are dependent on the stage at diagnosis. Triple negative breast cancer (TNBC – estrogen, progesterone, and Her2Nu receptor negative) is a highly aggressive form of breast cancer that is generally diagnosed at an advanced stage and has higher rates of recurrence, resistance, metastasis, and death than other subtypes. Unlike other forms of breast cancer, no targeted therapies exist for TNBC. There is a clear need to develop more effective therapies for TNBC.
There are two strategies that can be used to kill tumors. The standard approach is the direct killing of tumor cells using a chemotherapeutic agent that kills rapidly dividing tumor cells faster than it kills normal cells. Another approach is to cut off the nutrient supply to the tumor. The initial focus of this approach was to prevent the creation of new blood vessels (angiogenesis). Unfortunately, these approaches have met with limited success. Another approach that is gaining traction is blocking the conversion of adjacent normal cells (fibroblasts) to activated cells (cancer associated fibroblasts) that drive the growth, invasion, drug resistance, and metastasis of tumor cells.
NovoMedix has developed an oral drug that is effective in treating TNBC in animal models. This drug treats cancer in both ways by: 1) direct inhibition of tumor cell replication (inhibition of translation initiation), and 2) preventing the formation of cancer associated fibroblasts. This drug is in pre-clinical toxicology studies to support an IND. Results to date show that it is very safe and effective.
While we are focused on TNBC and Heart Failure, the underlying biology (the inhibition and potential reversal of activated myofibroblasts) is relevant in the pathophysiology of numerous diseases such as hepatic, pulmonary, and renal fibrosis as well as solid tumors that are particular dependent on the stroma; such as pancreatic cancer. With the potential of a novel clinical lead candidate for each new indication, we welcome potential licensing partners to advance this class of novel anti-fibrotic compounds to bring new drugs to patients with unmet medical needs.