Fibrosis is insidious
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 novel orally available small molecules with wide therapeutic windows to treat fibrotic diseases. While these molecules have shown remarkable efficacy in animal models of fibrosis diseases, some of them have unique properties for the treatment of cancer. The initial targeted indication for these compounds is Triple Negative Breast Cancer(TNBC). In addition to providing an efficacious and safe treatment, these lead candidates have the potential to significantly improve long-term prognosis of breast cancer survivors by preventing heart failures that commonly arise from delayed and progressive chemotherapy-induced cardiomyopathy.
Triple Negative Breast Cancer (TNBC)
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.
Cardio-Oncology is an emerging subspecialty that addresses the profound effects of malignancies and oncological treatments on the cardiovascular system that often lead to heart failure mortality. While cardiovascular damage can occur with numerous cancer therapies, anthracyclines like doxorubicin (DOX, Adriamycin), the frontline treatment for TNBC, are best known to cause dose-dependent, delayed, and progressive cardiomyopathy, often years after treatment. Therefore, the leading cause of death in breast cancer survivors is cardiovascular disease, caused by the same treatment that once saved their lives. Additionally, many patients cannot endure cancer treatments due to reduced cardiovascular health.NovoMedix has developed oral drugs that co-target key pathways with anti-cancer as well as cardioprotective properties. This first-in-class therapy would be ideal in combination with anthracycline chemotherapeutic for the treatment of TNBC. Preclinical data shows that these molecules have synergistic properties in killing cancer cells when used in combination with chemotherapic agents as well as protecting cardiomyocytes from damage. Potential clinical benefit is reducing the culmulative exposure of patients to chemotherapeutic agents to prevent cardiomyopathy and minimize other adverse events while directly protecting and decreasing sensitivity of cardiomyocytes to chemo-damage. This unique property derived from the co-targeting activity of NovoMedix's drug candidates should significantly improve the longevity and quality-of-life of breast cancer survivors.
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).