UM Scientists Stroke Drug Research

University of Maryland School of Medicine scientists will be submitting a grant application to the National Institutes of Health to test a commonly used diabetes medication — which has shown great promise in preventing the often-fatal brain swelling accompanying large strokes — in a new nationwide clinical trial network. In preliminary research led by Kevin Sheth, M.D., assistant professor of neurology, an intravenous version of the diabetes drug glyburide, which blocks a channel in the brain that can lead to devastating cerebral edema in the hours after a sizable stroke occurs, was given to patients at high risk for 
brain swelling. The pilot study of IV glyburide, or RP-1127, was based on the discoveries of J. Marc Simard, M.D, Ph.D., a University of Maryland professor of neurosurgery, pathology and physiology. Dr. Simard’s research, published in leading journals such as Nature Medicine and Stroke, has shed light on the fundamental understanding of edema formation after acute brain injury. His novel discoveries in molecular medicine form the basis for the Glyburide Advantage in Malignant Edema and Stroke (GAMES) pilot study, as well as parallel work in traumatic brain injury. Dr. Sheth’s clinical group, which includes University of 
Maryland Professor of Neurology Barney J. Stern, M.D., partnered with Massachusetts General Hospital in Boston, Rush Medical Center in Chicago, the University of Pittsburgh, the Medical University of South Carolina and Remedy Pharmaceuticals to test IV glyburide in 10 patients in the pilot study. Remedy Pharmaceuticals is the exclusive licensee of Dr. Simard’s inventions and has previously demonstrated safety in a phase I study in health volunteers. 

Novel, safe and exciting

“We’re excited for a number of reasons: RP-1127 is a novel therapy, appears to be safe and the preliminary results are very encouraging,” says Dr. Sheth, the research’s principal investigator, who also holds faculty appointments in neurosurgery and emergency medicine. “All of a sudden, in less than a decade, as a direct result of Dr. Simard’s work, we have a new target for which there has previously been no effective drug therapy — brain edema. This work is exciting because we are hoping to translate a novel basic science discovery to a group of patients who otherwise have a dismal outcome.”

Indeed, cerebral edema strikes approximately 10% to 12% of the 795,000 Americans afflicted by stroke every year — a complication, when severe, with a 60% to 80% mortality rate. Until now, the only effective therapy leading to improved survival in this population has been the surgical removal of a portion of the skull, which can relieve internal pressure but may leave patients neurologically disabled. Brain swelling can complicate many serious conditions, such as traumatic brain injury (TBI), encephalitis or cerebral hemorrhage, all of which may someday benefit from IV glyburide’s effects, Dr. Sheth says.

Glyburide receptors appear to be present on many cell types involved in stroke, including neurons, glia and endothelial cells, and the drug blocks a sodium channel in the brain that allows water to permeate brain cells and blood vessel linings. Preventing this swelling, which can compromise blood flow to surrounding tissues, increase clot damage and cause death, is far preferable to performing invasive procedures to relieve brain pressure after the fact, Dr. Sheth says. 

The games pilot

In the GAMES pilot, Dr. Sheth and his team evaluated the safety and feasibility of a three-day infusion of IV glyburide on 10 patients under age 80 within 10 hours of stroke onset. Patients qualified if they presented with severe clinical deficits as measured by the NIH Stroke Scale and if an MRI calculated the size of their stroke infarct as 82 cubic centimeters or larger — patients considered at high risk for cerebral edema.

None of the patients developed low blood sugar from the diabetes drug — which could have been dangerous for brain function — and with one patient death, mortality has been lower than expected, Dr. Sheth says. Also, the majority of enrolled patients did not require surgical removal of the skull, ventilator assistance or the use of other anti-brain swelling medications. Daily MRI studies during treatment showed that patients experienced less swelling, smaller stroke size and less brain bleeding when compared to prior patients with similarly large strokes.

Patients were not excluded from participating if they had received the clot-busting drug tPA (tissue plasminogen activator) — which increases the risk of brain hemorrhage — and Dr. Sheth says glyburide may actually enhance the safety of tPA since it may also reduce the incidence of cerebral bleeding. “Then we’d be talking about a broad, major public health phenomenon,” he says. “Primarily (however), this study demonstrates feasibility and safety. Because the results are so dramatic to those of us who care for these critically ill patients, we’re very excited. But the study isn’t blinded and we have no comparison group.”

Big trials ahead

With that cautionary note in mind, Dr. Sheth is enthusiastic about the drug’s prospects during the next phase of trials. It is the first proposed stroke and neuro-critical care study accepted by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) new nationwide clinical trial network, NeuroNEXT, which aims to facilitate the rapid development and implementation of clinical studies in neurological disorders. Dr. Sheth and Dr. Stern will be co-principal investigators along with Gregory del Zoppo, M.D., of the University of Washington School of Medicine. The randomized, double-blinded NeuroNEXT trial of glyburide will enroll approximately 170 patients in 25 to 30 research centers across the country and focus on signs of clinical and neuroimaging efficacy, Dr. Sheth says. “These are incredibly sick patients and it requires a multidisciplinary approach with neurosurgeons, neurologists and critical care specialists,” he says. “It makes it more satisfying to have everyone at the table working together.”