Glibenclamide Likely Prevents and Treats Severe Cerebral Edema in Patients with Large Hemisphere Infarction and Traumatic Brain Injury

Based on data from previous and current clinical trials, a group of researchers led by J. Marc Simard, MD, PhD, Dr. Bizhan Aarabi Professor in Neurotrauma at the University of Maryland School of Medicine and Chief of the Neurosurgical Service at the Baltimore VA Hospital, have evaluated the efficacy of intravenous glibenclamide in preventing and treating severe cerebral edema arising from large hemisphere infarction (LHI) and contusion-caused traumatic brain injury (TBI).¹ Also known as Glyburide, a common diabetes mellitus drug, in intravenous form glibenclamide is now referred to as BIIB093 (brand name Cirara; Biogen, Cambridge, MA) and is well-tolerated by patients at 3 mg/day infused over 72 hours. The agent causes no interference – and even demonstrates synergy in terms of neurological function outcomes – with tissue plasminogen activator (tPA), potentially making it an ideal complement for patients with ischemic stroke.

In cases of LHI and TBI, cerebral edema of 11 mL or greater in volume is strongly linked to neurological damage and, in many cases, death. Currently, decompressive craniectomy is the only clinically proven treatment for cerebral edema that both reduces mortality and leads to improvements in neurological function, but that treatment is not without its own risks. Osmotic and corticosteroid approaches to reducing cerebral edema have proven to be inadequate and lack clinical evidence for their efficacy.

However, glibenclamide inhibits five sub-regulated ion channels, the most significant of which is sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1-TRPM4). In earlier research, Dr. Simard discovered this SUR1-TRPM4 channel (formerly the SUR1-regulated NCCa-ATP channel) and its role in causing cerebral edema after ischemic stroke.² He holds a patent for “A novel non-selective cation channel in neural cells and methods for treating brain swelling” for the use of SUR1 antagonists such as glibenclamide and tolbutamide that target this channel to reduce cerebral edema.³

The presence of elevated SUR1 in cerebral spinal fluid has been shown to serve as a biomarker for clinical outcome for TBI⁴. High levels of SUR1-TRPM4 result in microvascular dysfunction that leads to edema and, later, secondary hemorrhage.5 SUR1-TRPM4 has also been linked at the molecular level to necrotic cell death.⁵

Under normal circumstances, BIIB093 does not accumulate in the brain; however, LHI and TBI compromise the blood-brain barrier and cause a low brain pH, promoting the uptake of BIIB093, a weak acid. BIIB093 binds to SUR1-TRPM4, causing cells to retain potassium and repel sodium, resulting in less depolarization. The exact mechanism for this is not yet fully understood, but this process reduces leaks in the blood-brain barrier and prevents edema. In animal models, glibenclamide suppresses the hemorrhagic progression of a contusion (HPC)⁶, which not only expands outwards, but is a disease process in which hemorrhages also develop independently in new areas of injured tissue. In contusion-TBI, glibenclamide reduces HPC as well as edema and leads to improved neurological outcomes.⁷

Dr. Simard and his fellow researchers reviewed the data from previous and current trials exploring the agent now known as BIIB093:

NCT01268683 | GAMES-Pilot and GAMES-RP: Glyburide Advantage in Malignant Edema and Stoke | The randomized phase of the GAMES trial found that BIIB093 significantly reduced the “median midline shift at the level of the septum pellucidum.” At 72-96 hours, this midline shift was 4.6 mm in the BIIB093-treated group compared with 8.5 mm in the placebo group (P=0.0006). BIIB093 also reduced plasma matrix metalloproteinase (MMP)-9 levels – a marker of inflammation – at 24 – 72 hours: 211 ng/mL vs. 346 ng/mL with placebo, P=0.006. Moreover, subjects younger than 70 who had been treated with BIIB093 had reduced mortality at all time points.
NCT02864953 | CHARM: Cirara in large Hemispheric infarction Analyzing modified Rankin and Mortality: A Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction | The primary objective of this currently ongoing trial for LHI is to determine if BIIB093 improves functional outcomes at day 90. Secondary outcomes include time to all-cause death, portion of patients who achieve modified Rankin scores of 0-4 by day 90, reduction in midline shift at 72 hours and incidence of adverse events.
NCT014554154 | Glyburide (RP-1127) for Traumatic Brain Injury (TBI) | This completed small, phase 2, randomized, placebo-controlled trial revealed that lesion (hemorrhage plus edema) volumes increased 136% with BIIB093 (then RP-1127; Remedy Pharmaceuticals, New York) compared to 1,036% with placebo; moreover, hemorrhage volumes increased with placebo (+11.6%) but decreased with BIIB093 (-29.6%), P = 0.62. This trial’s lack of statistical significance is attributable to small group sizes, each with a wide variety of contusions.
NCT03954041 | ASTRAL: Antagonizing SUR1-TRPM4 to Reduce the progression of intracerebral hematoma And edema surrounding Lesions | The primary objective of this currently open trial is to determine if BIIB093 reduces edema at hour 96 in patients with contusion-TBI. The secondary objectives are to evaluate the agent’s effect on neurological outcomes, 90-day survival, and differential effects on edema and hematoma expansion.

After reviewing these trials, the researchers concluded that “important treatment effects of BIIB093 were observed in patients with LHI and TBI.” While, to date, favorable data on BIIB093 for TBI is limited to only seven study participants, in LHI “robust effects of drug were observed on objective biological variables including midline shift, plasma MMP-9 levels, and net water uptake.” The researchers concluded that these effects directly translated to improved outcomes such as better alertness and National Institute of Health Stroke Scale scores and fewer deaths caused by edema. Moreover, in LHI subjects younger than 70, BIIB093 was associated with better functional outcomes and improved survival. While more data is still necessary before BIIB093 can become FDA-approved for the treatment of severe cerebral edema, it is a promising agent that has the potential to save many lives and preserve the quality of those lives.

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