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

Active Project Grant Awarded Last action

Award ID
R44HL169181
Recipient
Awarding agency
Obligated
$4,317,925

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 78% complete
Originally
Place of performance
Clayton, MO 63105, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Obligated Date
Amendment $0
Amendment $1,015,058
Amendment $1,015,058
Amendment $96,412
Amendment -$96,412
Amendment $0
Amendment $0
Amendment $982,162
Amendment $982,162
Original award $323,485

Quick answers

Who received award R44HL169181?

R44HL169181 was awarded to Senseion Therapeutics Inc. by National Heart Lung and Blood Institute (National Institutes of Health) on September 1, 2023.

How much is award R44HL169181 worth?

$4,317,925 has been obligated on R44HL169181.

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