BIIB093 (IV glibenclamide): an investigational compound for the prevention and treatment of severe cerebral edema

ABSTRACT

Introduction: Brain swelling due to edema formation is a major cause of neurological deterioration and death in patients with large hemispheric infarction (LHI) and severe traumatic brain injury (TBI), especially contusion-TBI. Preclinical studies have shown that SUR1-TRPM4 channels play a critical role in edema formation and brain swelling in LHI and TBI. Glibenclamide, a sulfonylurea drug and potent inhibitor of SUR1-TRPM4, was reformulated for intravenous injection, known as BIIB093.

Areas covered: We discuss the findings from Phase 2 clinical trials of BIIB093 in patients with LHI (GAMES-Pilot and GAMES-RP) and from a small Phase 2 clinical trial in patients with TBI. For the GAMES trials, we review data on objective biological variables, adjudicated edema-related endpoints, functional outcomes, and mortality which, despite missing the primary endpoint, supported the initiation of a Phase 3 trial in LHI (CHARM). For the TBI trial, we review data on MRI measures of edema and the initiation of a Phase 2 trial in contusion-TBI (ASTRAL).

Expert opinion: Emerging clinical data show that BIIB093 has the potential to transform our management of patients with LHI, contusion-TBI and other conditions in which swelling leads to neurological deterioration and death.

KEYWORDS:

• Glibenclamide
• BIIB093
• SUR1-TRPM4
• large hemispheric infarction
• stroke
• traumatic brain injury
• contusion
• cerebral edema

Article highlights

• Edema-associated brain swelling is a major cause of neurological deterioration and death in patients with large hemispheric infarction (LHI), severe traumatic brain injury (TBI) and other CNS conditions.

• The only proven treatment for severe brain swelling is decompressive craniectomy but this procedure has significant drawbacks.

• SUR1-TRPM4 channels play a critical role in edema formation and brain swelling in LHI and TBI.

• Emerging clinical data show that SUR1-TRPM4 inhibitor BIIB093 may transform the management of patients with LHI and contusion-TBI.

Box 1. Drug summary box.

Declaration of interest

WT Kimberly and KN Sheth received grants from Remedy Pharmaceuticals during the conduct of GAMES-Pilot and GAMES-RP, and also receive research grants from Biogen. JM Simard holds a US patent (7,285,574), ‘A novel non-selective cation channel in neural cells and methods for treating brain swelling.’ JM Simard is a member of the Board of Directors and holds shares in Remedy Pharmaceuticals and is a paid consultant for Biogen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded. N Badjatia is supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS105503). WT Kimberly is supported by grants from NINDS (R01NS099209) and AHA (AHA 17CSA 33550004). KN Sheth is supported by grants from NINDS (U01NS106513; U24NS107136; U24NS107215; R03NS112859; R01NR018335). JM Simard is supported by grants from the Department of Veterans Affairs (I01BX002889), the Department of Defense (SCI170199), the National Heart, Lung and Blood Institute (R01HL082517) and the NINDS (R01NS060801; R01NS102589; R01NS105633).