Development of PAR Pepducins as a Novel Antithrombotic Treatment

Coronary artery disease remains the leading cause of death in the United States Platelets play an important role in the pathogenesis of acute coronary syndrome ACS as platelet activation aggregation and secretion are key components of arterial thrombus formation Despite dual anti platelet therapy for ACS and percutaneous coronary interventions PCI many patients sustain a high incidence up to at years of major adverse events such as death myocardial infarction MI or stroke and would benefit from new therapeutics that interfere with the other important pathways that regulate primary platelet activation These findings underscore the fact that platelet activation requires multiple receptors and that receptor interactions play an important role in hemostasis while contributing to pathological thrombosis Protease activated receptor PAR and are activated by thrombin and trigger platelet activation aggregation Compared to heparin the bleeding risk by targeting thrombin with bivalirudin is lower with similar reductions in cardiac events but is accompanied by an increase in the rate of acute stent thrombosis The two downstream thrombin receptors have distinct roles in platelet activation and each of these represents an independent therapeutic target An oral drug targeting PAR is already in the clinic not approved for acute indications due to bleeding risk however there are no drugs yet approved for PAR Furthermore PAR was recently shown to be a critical contributing factor for high thrombotic risk with potential differences in human platelet PAR reactivity that are found frequently in African Americans as compared to Caucasians Individuals with `highandapos PAR reactivity include those that carry a single nucleotide polymorphism SNP in TM Therefore PAR is an attractive anti platelet target that may show extra benefit in preventing life threatening arterial thrombosis in individuals with `highandapos PAR reactivity while sparing the essential hemostatic effects of PAR collagen and thrombin Oasis Pharmaceuticals has developed a potent fast acting injectable PAR pepducin inhibitor OA to prevent acute ischemic complications of arterial thrombosis in high risk PCI patients that are not treatment candidates for a slow onset oral PAR inhibitor The goal of the proposed IND enabling Phase I STTR studies is to generate an FDA approved subcutaneous formulation for clinical testing for a PAR lipidated peptide inhibitor with i stability profile characterized from accelerated and long term stability andgt months ii a rapid onset andlt min of PAR platelet inhibition with a half life that is optimal h for acute prevention of ischemic events during PCI in ACS patients Optimal subcutaneous formulation for the PAR pepducin will be used to demonstrate efficacy in rodent and primate models favorable PK and rapid delivery to platelets in non human primates and rodents The ultimate goal of this STTR proposal is to rapidly advance the pre clinical development of this highly promising parenteral PAR inhibitor into the therapeutic arena to potentially dramatically improve cardiovascular disease outcomes in high risk patients Project Narrative Platelets play a pivotal role in causing heart attacks and despite current antiplatelet therapies heart attacks continue to be a leading cause of death in the United States The occurrence of life threatening arterial thrombotic events during acute coronary syndromes ACS and percutaneous coronary interventions PCI are critically dependent on reactive platelets Given the high prevalence of atherothrombotic disease and high MI and death rates there remains a high unmet need for new therapeutics as exemplified by the Oasis PAR pepducin program that can target thrombin dependent activation of platelets without affecting hemostasis