Targeting LRRC8 signaling to prevent and treat arterial thrombosis in type 2 diabetes

Project SummaryCardiovascular disease (CVD) including stroke and myocardial infarction (MI), and Type 2 diabetes (T2D) areoverlapping global pandemics. CVD is the most common cause of death in patients with T2D and the economicburden of stroke and myocardial ischemia in patients with T2D is staggering. While newer glycemic controlagents 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 rupturedatherosclerotic plaque, occluding the vessel lumen, and resulting in downstream ischemia. There are at leastfour 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, theirtherapeutic potential is limited by major bleeding. Thus, there is a large unmet clinical and commercial needfor a drug that improves glycemic control in T2D and also safely prevents cerebral and coronary vascularthrombosis. Senseion Therapeutics Inc. has been developing novel glycemic control agents derived from a toolcompound 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. Wethen 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-classtherapeutic approach with dual glycemic control and antithrombotic activity. We anticipate these drugsto fill a large unmet clinical need to improve glycemic control in T2D and also safely prevent cerebraland 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 vivodose range-finding toxicity studies. · AIM 2: Perform pre-clinical SN-4XX dose-response, head-to-head efficacy, combination therapy andreversibility for antithrombotic activity versus bleeding. · AIM 3: Manufacture the lead SN-4XX compound under cGMP conditions required for all IND-enablingstudies, at least Phase I clinical studies, and all 24-month stability studies.