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Review
. 2019 Dec;28(12):1031-1040.
doi: 10.1080/13543784.2019.1681967. Epub 2019 Oct 24.

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

Melissa Pergakis  1 , Neeraj Badjatia  1 , Seemant Chaturvedi  1 , Carolyn A Cronin  1 , W Taylor Kimberly  2 , Kevin N Sheth  3 , J Marc Simard  4
Affiliations
Review

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

Melissa Pergakis et al. Expert Opin Investig Drugs. 2019 Dec.

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: BIIB093; Glibenclamide; SUR1-TRPM4; cerebral edema; contusion; large hemispheric infarction; stroke; traumatic brain injury.

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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.
BIIB093 reduces midline shift in LHI. (a and b): MRI of BIIB093-treated (a) and placebo-treated (b) subjects. (c) Midline shift in BIIB093-treated and placebo-treated subjects; adapted with permission from Sheth et al. [72].
Figure 2.
Figure 2.
BIIB093 reduces plasma MMP-9 levels in LHI. (a and b) Plasma MMP-9 levels as a function of time (a) and overall levels (b) in BIIB093-treated and placebo-treated subjects; adapted with permission from Sheth et al. [72].
Figure 3.
Figure 3.
BIIB093 significantly improves mortality and trends toward improving functional outcome (mRS) in subjects <70 years of age with LHI. (a) Mortality at 3, 6 and 12 months in BIIB093-treated and placebo-treated subjects. (b) mRS shift at 3 and 12 months in BIIB093-treated and placebo-treated subjects; adapted from Sheth et al. [81].
Figure 4.
Figure 4.
BIIB093 reduces MRI measures of edema in contusion-TBI. Percent changes in mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular and intracellular water, respectively, were compared in uninjured white matter (WM) and in lesions for the two treatment arms. For each measure of edema, comparing the two placebo arms, there was a significant difference between uninjured white matter and lesions, whereas comparing the two BIIB093 arms, there was no significant difference between uninjured white matter and lesions; adapted from Eisenberg et al. [73].
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