Project Summary/Abstract Heart disease has been the leading cause of death in the United States and the world for more than a century, ever since the early 1900s. About 610,000 people die of heart disease in the United States every year–that's 1 in every 4 deaths. The epidemic burden is enormous; in 2016, cardiovascular disease (CVD) cost $555 billion in the US alone, and by 2035, the cost will skyrocket to $1.1 trillion. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, more than 7M patients have high LDL-cholesterol and not responsive to statin, and an additional 4M statin intolerance and 1.3M are familial hypercholesteremic (FH). These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel orally bioavailable drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing. Secreted PCSK9 binds to the LDL-receptor (LDLR) and chaperones it to the degradation pathway. To achieve our goal, we identified a nanomolar orally active small molecule PCSK9/LDLR antagonist (P-21) that showed outstanding potency in mice fed high-fat diet. The LDL- cholesterol lowering effect of P-21 is as potent as the marketed monoclonal antibodies. As part of this Phase-II SBIR proposal, our goal is to advance the development of our lead compound (P-21) to Phase-I clinical trial. Our studies will focus on ensuring that P-21 adheres to the set of established criteria as a pre-clinical candidate and on undertaking the work required to obtain the safety and toxicology studies in two mammalian species required for a GLP-IND enabling study application submission.

Project Narrative Heart disease is the leading cause of death for both men and women in the US. A high cholesterol level is a well-known risk factor for heart disease. Our goal is to develop a new oral bioavailable cholesterol lowering drug that have an effect on all individuals with high cholesterol levels, including that segment of the population that do not respond to statin, who are statin intolerant and those who have very high cholesterol levels.