Subgroup Analyses of Phase 3 CHARM Trial Show Potential Therapeutic Benefit of IV Glibenclamide in Large Hemispheric Infarction

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In a subgroup of patients who underwent endovascular thrombectomy in addition to IV glibenclamide, results showed improved functional outcomes favoring active treatment, coupled with greater reductions in mortality.

Taylor Kimberly, MD, PhD, chief of the Division of Neurocritical Care at Massachusetts General Hospital, and associate professor of neurology at Harvard Medical School

Taylor Kimberly, MD, PhD

Despite neutral top-line results, recently announced post-hoc data from the phase 3 CHARM trial (NCT02864953) showed that treatment with intravenous glibenclamide (CIRARA; Remedy Pharmaceuticals) resulted in meaningful improvements in functional outcomes among subgroups of patients with large hemispheric infarction (LHI).1

CHARM, a multinational, double-blind, randomized, placebo-controlled study comprised of 535 enrolled patients aged 18-85 with LHI, as indicated by an Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) value of 1-5 or an ischemic core volume of 80-300 ml by CT perfusion (CTP) or MRI diffusion weighted imaging. A pre-specified analysis of patients who received recombinant tissue plasminogen activator (rtPA) and underwent endovascular thrombectomy (EVT) highlighted the treatment benefits of CIRARA over placebo.

In a subgroup of patients with National Institute of Health Stroke Scale (NIHSS) less than 20 (n = 274), findings showed statistically significant improvements in functional outcomes on the modified Rankin Scale (mRS), indicated by odds ratio of 1.66 (P = .03). Of those enrolled, 431 were aged 18-70 (efficacy analysis population) and 81 were between 71-85 years of age. With EVT therapy increasingly used in LHI, investigators observed an odds ratio of 1.75 favoring CIRARA. While not statistically significant, the study authors noted these findings were particularly encouraging.

"These findings are very promising and suggest that CIRARA is complementary to current standard of care, such as tPA and endovascular therapy, and could be the next big advancement in the treatment of large hemispheric infarctions," principal investigator Taylor Kimberly, MD, PhD, chief of the Division of Neurocritical Care at Massachusetts General Hospital, and associate professor of neurology at Harvard Medical School, said in a statement.1

Currently, there are not medications available to specifically reduce brain swelling caused by LHI. In the modified intent-to-treat (mITT) population with CTP/MRI lesion volume less than 125 mL (n = 118), results showed an odds ratio of 2.15 in favor of CIRARA (P = .04). Mortality was numerically decreased from 22% in the placebo group to 14% in the CIRARA group without an increase in severe disability. In addition, the proportion of patients with an mRS between 0-3 was 36% in the CIRARA group vs 19% for those on placebo, otherwise representing a 89% increase.

"Mortality and long-term disability remain stubbornly high, especially in cases of severe stroke,” Kevin Sheth, MD, a professor of neurology and director of the Yale Center for Brain & Mind Health, and co-principal investigator on the CHARM study, said in statement.1 "CIRARA could help the tens of thousands of patients who fall victim to LHI each year have a fighting chance to live and enjoy productive lives."

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A subgroup of patients in the mITT who underwent EVT and had CTP/MRI lesion volume less than 125 mL (n = 34) experienced even greater benefit from CIRARA. All told, this group had an odds ratio of 7.13 favoring active treatment (P = .01) on mRS, with 62% having scores between 0-3 vs 31% of those on placebo. In addition, mortality was numerically decreased from 31% in the placebo group to 6% in the CIRARA group without an increase in severe disability.

Glibenclamide is a long-acting sulfonylurea that has been used safely for decades to treat type 2 diabetes. Over the past 20 years, the medication has been repeatedly shown to prevent brain edema and neuroinflammation and improve neurological outcomes in different animal models of stroke, presumedly by blocking a de novo synthesis ion channel called sulfonylurea receptor 1-transient receptor potential M4.

IV glibenclamide, previously known as BIIB093, was assessed in a pivotal phase 2 trial dubbed GAMES-RP (NCT01794182). GAMES-RP included 86 patients with LHI but was stopped early because of funding reasons. Although the study did not meet the primary end point of patients achieving mRS score of 0-4 at 90 days, IV glibenclamide demonstrated potential positive effects on functional outcomes and mortality, supported by biomarkers and imaging measures of brain swelling.2

Mortality at 30 days was reduced from 36% in the placebo group to 15% in IV glibenclamide-treated patients (P = 0.03). In addition, in patients 70 years of age and younger, 90-day functional outcomes were statistically significantly improved (P = 0.048) in the IV glibenclamide group versus placebo. These clinical effects correlated with a significant decrease in the concentration of metalloproteinase-9 (MMP-9), a biomarker associated with extracellular matrix breakdown following stroke, in the IV glibenclamide-treated group. The IV glibenclamide-treated group at approximately 72 hours showed a significant reduction in midline shift (p=0.0006), an imaging marker of neurological deterioration and poor outcomes including death.

REFERENCES
1. Remedy Pharmaceuticals Gets Rights To Acute Stroke Drug Back From Biogen; Announces Clinically Meaningful and Statistically Significant Results From Pre-specified Subgroup and Post Hoc Analyses of Phase 3 Study. Remedy Pharmaceuticals. May 29, 2024. Accessed June 7, 2024. https://www.prnewswire.com/news-releases/remedy-pharmaceuticals-gets-rights-to-acute-stroke-drug-back-from-biogen-announces-clinically-meaningful-and-statistically-significant-results-from-pre-specified-subgroup-and-post-hoc-analyses-of-phase-3-study-302157095.html
2. Biogen Enrolls First Patient in Global Phase 3 Study of BIIB093 (IV Glibenclamide) for Large Hemispheric Infarction. Biogen. September 4, 2018. Accessed June 7, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-enrolls-first-patient-global-phase-3-study-biib093-iv
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