Oasis Pharmaceuticals, LLC

Lipid Receptor GPR31 as a Target for Anti-thrombotic and Stroke Therapy - Despite Prevalent Use of Anti-platelet and Anti-lipid Therapies, Stroke Remains the Third Major Cause of Death and Is the Leading Cause of Adult Disability in the Us With an Estimated Cost in the Range of $34 Billion Annually. Approximately 20% of the Annual 795,000 Stroke Patients Die Within One Year and 15-30% Are Permanently Disabled. Antiplatelet Therapy Is Mainly Used for Primary Prevention of Acute Ischemic Stroke in Cerebrovascular Disease. Bioactive Fatty Acids Are a New Class of Molecular Targets That Hold Great Therapeutic Potential Because of Their Diverse Role as Signaling Molecules That Regulate Metabolism and Inflammation. the Oxidation of Arachidonic Acid by 12-LOX Results in the Production of a Number of Bioactive Lipids Including the Metabolite 12(S)-HETE. the Lipid Receptor GPR31, an Orphan Class a GPCR, Is a 12(S)- Hete Receptor Recently Shown to Be Involved in Inflammatory Signaling. We Recently Discovered That GPR31 Mediates 12(S)-HETE Prothrombotic Signaling in Platelets and Promotes Glutamate-induced Oxidative Toxicity in Neuronal Cells. Therefore, We Propose That Targeting GPR31 May Provide a Therapeutic Path Towards Development of a Safe and Effective Antiplatelet Therapy That Is Coupled With Secondary Neuroprotective Effects for Mitigating Against the Acute Neurologic Sequela of Stroke to Provide a More Effective and Safer Alternative Option or Adjunct to Fibrinolytic Therapy. We Have Recently Succeeded in Identifying the First Effective GPR31 Antagonist Using Our Cell-penetrating, Membrane-tethered, Pepducin Technology to Be Validated in These Preclinical Ind-enabling Studies as an Anti-platelet and Anti-stroke Agent. We Show Here That This I3-LOOP Derived GPR31 Lipopeptide Has Potent Antiplatelet Activity and Nearly Completely Suppresses Arterial Thrombosis Without an Effect on Hemostasis in Mice. Preliminary Data With the GPR310 Pepducin Shows a Highly Significant Reduction in Stroke Infarct Area in Mice Similar to the Protective Effect of GPR31-DEFICIENCY. Furthermore, We Provide Evidence for a Direct Neuroprotective Effect of the GPR310 Pepducin on HT22 Neuronal Cells Subjected to Glutamate Mediated Oxidative Stress. the Goal of This Phase 2 STTR Project Is to Develop the GPR310 Pepducin as a Collaborative Effort Between Oasis Pharmaceuticals (lexington, Ma), Tufts Medical Center (boston, Ma) That Would Provide a Robust Ind Data Package Required to Advance the Initial Commercial Development of the First GPR31 Inhibitor as a Dual Antiplatelet, Anti-stroke Drug. This Drug Development Program Would Establish the Scientific Merit of the GPR31 Target by Accomplishing the Major Milestones at the End of 2 Years of GLP Safety/pharmacology and Efficacy in Stroke Models ± Thrombolytic Therapy to Support a Phase I First-in-human Clinical Trial.