Development of Oral Small Molecule PCSK9 Antagonist

Project Summary AbstractThe epidemic of cardiovascular diseaseCVDis a global phenomenon that remains the number one cause of
death throughout the worldkilling nearlymillion people per yeara number that is expected to grow tomillion byA high cholesterol level is well known risk factors for heart diseaseAlthough blood
cholesterol can be lowered using a number of marketed drugsof which statins are the leading drugsonlyof patients taking these drugs are achieving the low density lipoprotein cholesterol goals set by the
National Cholesterol Education ProgramNCEPFurthermorepatients with homozygous familial
hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapyand are at very high risk of premature cardiovascular diseaseThese and other patients will dramatically
benefit from an aggressive treatment of hypercholesterolemiaThe long term goal of this work is to develop
novel orally bioavailable drugs for cholesterol loweringOur therapeutic target is the protease proprotein
convertase subtilisin like kexin typePCSKPCSKcontrols the degradation of the LDL receptorLDLRin
the liver and thereby contributes to cholesterol homeostasisPCSKis synthesized as a precursor protein that
undergoes processingSecreted PCSKbinds to the LDL receptorLDLRand chaperones it to the
degradation pathwayTo achieve our goalwe identified nanomolar orally active small molecule PCSKLDLR
antagonists and demonstrated its efficacy in animal modelAs part of this Phase II proposalwe will undertake
all the work required to characterize these compounds in multiple animal models for the proof of concept and
conduct safety assessment in order to advance the lead compound toward IND enabling studies and clinical
trials