Research Project
9142025
? DESCRIPTION (provided by applicant): The overall goal for this project is the development of safer, more effective drugs for the treatment of heart failure. Heart disease is the number one cause of death worldwide and the #1 killer of women - more than all forms of cancer combined. One in 9 deaths in the US are heart failure related. The prevalence of heart failure has risen dramatically as a result of the reduction in mortality from acute myocardial infarction. About half of the people who develop heart failure die within 5 years of diagnosis. Clearly, there is a significant need for therapies to treat the devastating effects of heart failure. Cardiac hypertrophy is a major predictor of heart failure. Initially, the heart adapts to stress by inducin hypertrophic growth of cardiomyocytes in order to withstand the increased myocardial wall stress. However, periods of prolonged stress result in maladaptive changes, including increased fibrosis and remodeling as a result of persistent cardiac myofibroblasts. Over time cardiac function decreases, which ultimately results in heart failure. A key component of both the initial response to stress (myocardial infarct or pressure overload) is TGF-?. Although elevated levels of TGF-? are initially important for tissue repair and remodeling after injury, sustained overproduction of TGF-? leads to the development of myocardial fibrosis and maladaptive cardiac hypertrophy. NovoMedix has developed a novel series of small molecules that prevent the conversion of normal fibroblasts to the myofibroblast phenotype. One of the compounds in this series, NM922, was tested in a mouse transverse aortic constriction (TAC) model of heart failure. NM922 was administered daily for 10 weeks starting at 6 weeks post constriction. Chronic treatment with NM922 following the onset of cardiac hypertrophy and heart failure resulted in reduced myocardial collagen formation and attenuated adverse remodeling with preservation of left ventricular ejection fraction. The specific aims for this project are: 1) complete additional safety testing and identify at least one back-up candidate; 2) select vehicle/formulation for oral dosing; and 3) define optimal dosing window and demonstrate in vivo efficacy in a mouse TAC model when administered orally. Optimized drug candidates that are effective orally in the TAC mouse model will advance to Phase II, where they will undergo additional testing in both small and large animal models of heart failure as well as additional pre clinical toxicology testing.
