Soluble Epoxide Hydrolase Inhibitor GSK2256294 for Acute Ischemic Stroke

Project Summary
The proposed translational studies will determine the cereroprotective efficacy of GSK2256294, an FDA-
approved soluble epoxide hydrolase (sEH) inhibitor. Inhibition of sEH increases the endogenous levels of its
substrate epoxyeicosatrienoates (EETs), which are endogenous brain lipid mediators with multiple mechanisms
of action that are beneficial in stroke, including vasodilation, cytoprotection, anti-inflammation and suppression
of platelet aggregation. Ample evidence from our group and others demonstrate that sEH inhibition and gene
deletion reduce infarct size and improve functional outcomes after experimental ischemia-reperfusion injury in
brain. The benefits of sEH inactivation in experimental ischemic stroke have been demonstrated in young and
old male and female mice with diabetes and hypertension. Importantly, gain of function mutations in the sEH
gene, called EPHX2, are associated with increased risk of ischemic stroke and worse outcome in humans,
whereas carriers of a loss-of-function mutation have reduced risk of stroke and improved outcome. We have
recently completed a Phase Ib clinical trial using GSK2256294 in patients with aneurysmal subarachnoid
hemorrhage (SAH). The trial demonstrated that GSK2256294, administered orally for 10 days, is safe and well
tolerated in critically ill patients with SAH. Although not powered for efficacy, the trial also showed trends for
improvement in relevant functional outcomes. The proposed studies will test the efficacy of GSK2256294 in the
NINDS Stroke Preclinical Assessment Network (SPAN) using the transient MCAO occlusion (tMCAO) model in
young adult and aged mice with type 2 diabetes. PI will participate on the SPAN Steering Committee, attend all
SPAN meetings and work collaboratively with all awarded sites, the Coordinating Center (CC) and NINDS
Program staff to achieve the goals of the SPAN program. GSK2256294 will be synthesized by a highly
experienced contract research organization (BOC Sciences) and will be provided in a sufficient amount to be
tested in parallel by the entire SPAN network. PI will work with the CC to validate activity, concentration and
solubility of GSK2256294 and test its efficacy in the tMCAO model in a randomized and blinded fashion. The
long-term goal is to support the use of GSK2256294 in a clinical trial for acute ischemic stroke (AIS) and advance
its use in AIS patients. Because GSK2256294 is already approved by the FDA and has an established safety
record in humans including in hemorrhagic stroke patients, it can be advanced rapidly for testing in clinical trials
of AIS if efficacy is confirmed through rigorous testing by the SPAN network.

Grant Number: 5U01NS132345-03
NIH Institute/Center: NIH
Principal Investigator: Nabil Alkayed