7 CLINICAL NEUROSCIENCES UPDATE SUMMER 2018 aquaporin-4, a water channel long implicated in brain edema. Moreover, new work in stroke has shown that the SUR1-TRPM4 channel is activated not only by ischemia/reperfusion, but also by the very drug used to treat stroke patients—recombinant tissue plasminogen activator (rtPA). Early on, it also was recognized that the channel is potently blocked by glyburide. At the time, glyburide was known only as an antidiabetic drug that caused the release of insulin through its ability to block ATP- sensitive potassium channels. When it was discovered that the SUR1- TRPM4 channel is transcriptionally upregulated in cerebral ischemia and TBI, it became evident that glyburide might have other uses beyond diabetes, particularly for LHI and brain contusions. Preclinical studies on animal models of LHI quickly showed that pharmacological blockade of SUR1-TRPM4 with glyburide reduces edema, brain swelling and death. One preclinical study found that, left untreated, LHI in an animal model resulted in 67% mortality, similar to that in untreated humans with LHI. In this model, both glyburide and decompressive craniectomy prevented mortality, but glyburide-treated rats were significantly better off in terms of brain tissue preservation, recovery of neurological function and general wellbeing. This study exemplified the axiom that “preventing brain swelling is better than decompressing the already swollen brain.” A natural experiment suggested itself—what happens to diabetic patients when they have a stroke? What happens if they are already on glyburide or a similar sulfonylurea drug, as compared to being on a non-sulfonylurea drug for their diabetes? Retrospective studies showed that, indeed, patients who were taking a sulfonylurea drug for diabetes and who stayed on it after stroke fared better than those who were not taking a sulfonylurea. Patients on a sulfonylurea recovered better, were less likely to have hemorrhagic transformation, and were less likely to die. A Problem Remedied Although the preclinical and retrospective clinical data were promising, there was one problem: the oral form of glyburide was not suitable for non-diabetics, who would be at risk of developing hypoglycemia, or for critically ill patients, who usually cannot take pills. In response, a New York-based pharmaceutical company called Remedy Pharmaceuticals was formed for the explicit purpose of developing and testing an intravenous formulation of glyburide, dubbed RP-1127. Designed for use in stroke and TBI, RP-1127 would be the first therapy for acute CNS disease that specifically targets edema. Remedy Pharmaceuticals sponsored two early-stage clinical trials called: “Glyburide Advantage in Malignant Edema and Stroke” (GAMES), focused on patients with LHI, i.e., those at highest risk of dying or needing a decompressive craniectomy. The GAMES-Pilot study was conducted at just two sites, University of Maryland and Mass General Hospital. The study was largely to determine the logistics of whether we could even contemplate a realistic study of RP-1127 in humans, not just patients with stroke, but those with the most severe, life-threatening stokes, those with LHI? The GAMES- Pilot study showed that indeed it is possible to recruit appropriate LHI patients, complete an MRI evaluation, obtain informed consent, and begin an infusion of RP-1127 within 10 hours of stroke onset. When the GAMES-Pilot outcome data were compared with historical controls, subjects treated with RP-1127 were found to have more favorable clinical outcomes, with reduced death and less need for decompressive craniectomy. GAMES-Pilot led to a modest-sized Phase 2 clinical trial, GAMES-RP, a double-blind, randomized, placebo- controlled trial conducted at 17 medical centers in the USA. The primary endpoint of GAMES-RP was not met, largely because it stipulated less use of decompressive craniectomy, which many patients underwent, some perhaps needlessly. Nevertheless, the findings were quite promising, with significant reductions in midline-shift (linked to brain swelling) and serum MMP-9 (linked to edema and hemorrhagic transformation), a reduction in all- cause mortality by half, and a very favorable shift in functional outcomes (mRS) at 90 days and one year. Adjudicated neurological deaths were highly significantly reduced with drug, compared to placebo. “The story of glyburide (also known as glibenclamide) in ischemic stroke and TBI is a classic example of ‘bench to bedside’ research.” CONTINUED ON PAGE 8