Biogen Inc. has enrolled the first patient in a global phase III study of BIIB-093 (I.V. glibenclamide) for the prevention and treatment of severe cerebral edema in large hemispheric infarction, one of the most severe types of ischemic stroke. The trial, governed by an FDA special protocol assessment, will measure the fast-tracked drug's effect on a rating of functional outcomes at 90 days following treatment.

Biogen acquired the asset, formerly known as Cirara, from Remedy Pharmaceuticals Inc. in May 2017 for $120 million up front, plus potential milestone and royalty payments. Its advancement is part of the company's efforts to leverage what R&D chief Michael Ehlers, during a recent company conference call, called Biogen's "core strengths in neuroinflammation, neurovascular biology and clinical neurology."

It was unclear exactly why the phase III study of BIIB-093, first posted by Malvern, Pa.-based Remedy in ClinicalTrials.gov in August 2016, took so long to start and whether enrollment of the first patient triggered a milestone payment from Biogen to Remedy. Biogen spokeswoman Nina Varghese did not respond to questions about either topic.

Cambridge, Mass.-based Biogen's approach to stroke, however, is better known, having begun with its failed bid to apply its blockbuster Tysabri (natalizumab) to acute ischemic strokes. While that effort didn't prove effective, "we gained valuable experience through the execution of these clinical studies, providing us with deeper knowledge of the use of novel imaging and clinical endpoints, patient stratification and regulatory paths," Ehlers said during the June 28 call. (See BioWorld, Feb. 8, 2018.)

Large hemispheric infarction (LHI), a type of ischemic stroke primarily affecting the middle cerebral artery, is one of the most severe types of ischemic stroke. It's associated with the development of severe cerebral edema and often leads to mortality, at rates of between 40 percent to 80 percent, according to Biogen.

Each year about 1.7 million ischemic strokes occur in the U.S., Europe and Japan. About 15 percent of those events are classified as LHI. Current evidence-based guidelines for management of such strokes recommend intensive care treatment focused on ensuring airway support, providing pain and sedation medications, screening for swallowing abnormalities, controlling glucose levels and blood pressure, using osmotic therapy, and other supportive measures, Varghese said.

Surgical management, such as decompressive hemicraniectomy, has been shown to reduce mortality in LHI. But the effect of the procedure on functional outcomes in survivors is limited, an issue that played an important role in shaping I.V. glibenclamide's development.

In preclinical studies, the drug has been shown to inhibit SUR1-TRPM4 channels that mediate stroke-related brain swelling. But a phase II study muddied the waters. In that 86-patient study, called GAMES-RP, Remedy ran a double-blind, randomized, placebo-controlled test designed to assess the effects of early and continuous administration of I.V. glibenclamide for the prevention and treatment of severe cerebral edema following LHI. The unmet primary endpoint was the proportion of patients with a modified Rankin score of 0 to 4 at 90 days without undergoing decompressive craniectomy.

"Although the GAMES-RP study failed to meet the primary endpoint, we believe the results were confounded by patients undergoing decompressive craniectomy," Ehlers said in June.

Now, in the phase III study, called Charm, Biogen will run an international, multicenter, randomized, double-blind, placebo-controlled trial that aims to enroll 680 patients with LHI in about 20 countries. It will evaluate the efficacy and safety of I.V. glibenclamide treatment within 10 hours following stroke onset. The primary endpoint is, again, a modified Rankin Scale score, assessed at 90 days. Notably, "commitment to decompressive craniectomy prior to enrollment" is one of the key exclusion criteria for the trial. The estimated primary completion date of the study is Sept. 28, 2020.

I.V. glibenclamide is a high-affinity inhibitor of Sur1-Trpm4 channels, which are up-regulated following ischemia and trauma. Opening of those channels can lead to cerebral edema, midline shift, increased intracranial pressure and brain herniation, resulting in permanent disability or death, Biogen said. As a member of the sulfonylurea class, its oral form has been an established treatment for diabetes mellitus for more than 30 years, giving it a well-understood safety profile in that context.

Shares of Biogen (NASDAQ:BIIB) closed Tuesday at $346.72, down $6.77.