Cardiovascular disease (CVD) including stroke and myocardial infarction (MI), and Type 2 diabetes (T2D) are overlapping global pandemics. CVD is the most common cause of death in patients with T2D and the economic burden of stroke and myocardial ischemia in patients with T2D is staggering. While newer glycemic control agents like SGLT2 inhibitors and GLP1 agonists can help reduce CVD events in T2D, significant residual CVD risk remains. Stroke and MI most often occur when a platelet-rich thrombus form at the site of a ruptured atherosclerotic plaque, occluding the vessel lumen, and resulting in downstream ischemia. There are at least four classes of drugs available to inhibit platelet rich thrombi formation including aspirin, P2Y12 receptor inhibitors, and thrombin receptor inhibitors. While current antiplatelet drugs can reduce CVD events and death, their therapeutic potential is limited by major bleeding. Thus, there is a large unmet clinical and commercial need for a drug that improves glycemic control in T2D and also safely prevents cerebral and coronary vascular thrombosis. Senseion Therapeutics Inc. has been developing novel glycemic control agents derived from a tool compound SN-401 (SN-4XX) targeting LRRC8 proteins. In the course of developing these T2D therapeutics, we discovered human genetic evidence implicating LRRC8 regulation of platelet function in humans. We then validated LRRC8 proteins as a target for antiplatelet activity using targeted mouse genetics, and confirmed both in vitro and in vivo antiplatelet/antithrombotic activity of a novel SN-401 derived compound that also demonstrates glycemic control activity. We propose that SN-4XX compounds represent a first-in-class therapeutic approach with dual glycemic control and antithrombotic activity. We anticipate these drugs to fill a large unmet clinical need to improve glycemic control in T2D and also safely prevent cerebral and coronary vascular thrombosis, reducing the large residual risk of CVD events associated with T2D. Phase 1 AIMS: · AIM 1: Evaluate previously synthesized compounds for in vitro antiplatelet and in vivo antithrombotic activity. · AIM 2: Complete in vitro Absorption, Distribution, Metabolism, Excretion, Toxicity. Phase 2 AIMS: · AIM 1: Perform in vivo oral dosing pharmacokinetics, in vitro ion channel selectivity studies, and in vivo dose range-finding toxicity studies. · AIM 2: Perform pre-clinical SN-4XX dose-response, head-to-head efficacy, combination therapy and reversibility for antithrombotic activity versus bleeding. · AIM 3: Manufacture the lead SN-4XX compound under cGMP conditions required for all IND-enabling studies, at least Phase I clinical studies, and all 24-month stability studies.
Public Health Relevance Statement: Project Narrative Type 2 diabetes (T2D) and cardiovascular disease (CVD) are major overlapping health concerns in today's society. Therefore, developing novel drugs that treat both type 2 diabetes and thrombosis is a therapeutic priority. The proposed research is relevant to the mission of the NCATS because it proposes to develop LRRC8 complex modulators (SN-4XX) for to treat both T2D and thrombotic diseases to reduce stroke myocardial infarction in T2D patients. Exploring this therapeutic approach and testing a series of LRRC8 modulators will expand our understanding of novel therapeutic avenues and delineate an innovative target for the treatment and prevention of diabetes and cardiovascular disease.
Project Terms: absorption; inhibitor; Aspirin; Acetylsalicylic Acid; Biological Availability; Bioavailability; Physiologic Availability; Blood Platelets; Marrow platelet; Platelets; Thrombocytes; Blood Vessels; vascular; Cardiovascular Diseases; cardiovascular disorder; Cause of Death; Cells; Cell Body; Clinical Research; Clinical Study; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; Cessation of life; Death; Non-Insulin-Dependent Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Ketosis-Resistant Diabetes Mellitus; Maturity-Onset Diabetes Mellitus; NIDDM; Non-Insulin Dependent Diabetes; Noninsulin Dependent Diabetes; Noninsulin Dependent Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Stable Diabetes Mellitus; T2 DM; T2D; T2DM; Type 2 Diabetes Mellitus; Type 2 diabetes; Type II Diabetes Mellitus; Type II diabetes; adult onset diabetes; ketosis resistant diabetes; maturity onset diabetes; type 2 DM; type II DM; type two diabetes; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Human Genome; human whole genome; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Head; Health; Hemorrhage; Bleeding; blood loss; Hospitalization; Hospital Admission; Human; Modern Man; Human Genetics; In Vitro; Integrins; Integrins Extracellular Matrix; Ion Channel; Ionic Channels; Membrane Channels; Ischemia; Isoenzymes; Isozymes; Lead; Pb element; heavy metal Pb; heavy metal lead; Marketing; Metabolism; Intermediary Metabolism; Metabolic Processes; Mission; Mus; Mice; Mice Mammals; Murine; Myocardial Infarction; Cardiac infarction; Myocardial Infarct; cardiac infarct; coronary attack; coronary infarct; coronary infarction; heart attack; heart infarct; heart infarction; Patients; Permeability; Drug Kinetics; Pharmacokinetics; Proteins; Research; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Societies; Solubility; Stroke; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; stroked; strokes; Testing; Thrombosis; thrombotic disease; thrombotic disorder; Work; Thrombin Receptor; Antiplatelet Agents; Antiplatelet Drugs; Thrombus; Ischemic Heart; Ischemic Heart Disease; Ischemic myocardium; cardiac ischemia; coronary ischemia; heart ischemia; myocardial ischemia/hypoxia; myocardium ischemia; Myocardial Ischemia; Investigational New Drug Application; improved; Site; Clinical; Residual; Residual state; Phase; Series; Ensure; excretion; Excretory function; cerebral; Cerebrum; Agonist; Therapeutic; tool; Complex; Event; Oral; meter; cardiovascular disorder prevention; CVD prevention; cardiac disease prevention; cardiovascular disease prevention; cytotoxicity; Lytotoxicity; receptor; Receptor Protein; Toxic effect; Toxicities; multiple drug use; multidrug use; poly drug use; polydrug use; novel; Regulation; response; stroke therapy; stroke treatment; treating stroke; cardiovascular disease risk; cardiovascular disorder risk; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; prevent stroke; Stroke prevention; preventing; prevent; small molecule; GCG gene; GCG; GLP1; GLP2; Dose; Data; Direct Costs; Economic Burden; in vivo; Experimental Genetics; Leucine-Rich Repeat; Right-Handed Beta-Alpha Superhelix; Coronary; pandemic disease; pandemic; Diabetes prevention; pre-clinical; preclinical; glycemic control; glucose control; glucose homeostasis; glucose regulation; blood glucose regulation; diabetes mouse model; Diabetic mouse; innovate; innovative; innovation; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; nondiabetic; non-diabetic; lead series; phenome; Phase I Study; phase 1 study; phase II study; phase 2 study; efficacy study; care costs; atherosclerotic plaque rupture; platelet function; mouse genetics; thrombotic; National Center for Advancing Translational Sciences; NCATS; manufacture; manufacturing organization
