Cirara (glybenclamide) / Remedy Pharma - LARVOL DELTA

Intravenous Glyburide in Medical and Endovascular-Treated Large-Core Stroke: A Subgroup Analysis of the CHARM Randomized Clinical Trial. (PubMed, Ann Neurol) - "This post-hoc analysis of the CHARM trial provides hypothesis-generating evidence that i.v. glyburide may improve outcome in large-core stroke <125 ml, especially among endovascular thrombectomy-treated patients. These results require confirmation in a prospective randomized clinical trial. ANN NEUROL 2025."

Clinical • Journal • Cardiovascular

Remedy Pharmaceuticals Secures Key U.S. Patent Allowance for CIRARA in Treating Large Hemispheric Infarction, Including Wake-Up Strokes (PRNewswire) - "Remedy Pharmaceuticals...today announced that the U.S. Patent and Trademark Office (USPTO) has allowed two additional patents covering its large hemispheric infarction (LHI) drug, CIRARA (IV glyburide)...The allowances include a claim covering the use of CIRARA's active pharmaceutical ingredient, glyburide, or any other SUR1-TRPM4 inhibitor, to treat patients with a LHI and a lesion volume of 50-125 mL who undergo endovascular therapy (EVT), a minimally invasive mechanical procedure used to remove blood clots from large arteries in the brain...The allowances also relate to the use of CIRARA's active pharmaceutical ingredient, glyburide, or any other SUR1-TRPM4 inhibitor, to treat wake-up stroke patients undergoing EVT....Both patents provide coverage through June 2044, with the possibility of extending one to June 2049."

Patent • CNS Disorders

Sulfonylurea drugs for people with severe hemispheric ischemic stroke. (PubMed, Cochrane Database Syst Rev) - "Compared to placebo, intravenous glyburide may have little to no effect on functional outcomes, assessed with the modified Rankin Scale, or mortality. It may also have little to no effect on neurological deterioration within three days, and probably has little to no effect on cardiac events or pneumonia. However, intravenous glyburide probably results in a large increased risk of hypoglycemia. This review includes only two RCTs at overall high risk of bias. We do not have sufficient evidence to determine the effects of sulfonylureas in people with ischemic stroke. More large studies, which include more sulfonylurea drugs with different routes of administration and dosages, and different age groups with ischemic stroke, would help to reduce the current uncertainties."

Clinical • Journal • Review • Cardiovascular • CNS Disorders • Hypoglycemia • Infectious Disease • Ischemic stroke • Pneumonia • Respiratory Diseases

International Stroke Conference 2025: Remedy Pharmaceuticals Unveils Landmark CIRARA Data Demonstrating Significant Improvements in Stroke Outcomes (PRNewswire) - "The pooled analysis of patients from the Phase 2b (GAMES-RP) and Phase 3 (CHARM) studies was consistent with the findings in CHARM, with CIRARA exhibiting an effect size of 2.42 (1.3 - 4.6), p=0.007 at 90 days."

Retrospective data • CNS Disorders • Ischemic stroke

International Stroke Conference 2025: Remedy Pharmaceuticals Unveils Landmark CIRARA Data Demonstrating Significant Improvements in Stroke Outcomes (PRNewswire) - P3 | N=535 | CHARM (NCT02864953) | Sponsor: Remedy Pharmaceuticals, Inc. | "Key findings were as follows: In the CHARM ≤ 125 mL subgroup, baselines were well-balanced between the CIRARA and placebo groups, and the overall OR for drug effect at 90 days was 2.11 (1.1-4.01), p=0.02. The effect of CIRARA was durable, and the OR for drug effect at 12-months using multiple imputations for missing data was 2.21 (1.13-4.31), p=0.02; In the CHARM ≤ 125 mL undergoing EVT subgroup, baseline variables of the CIRARA and placebo groups were again well-balanced and the overall Odds Ratio (OR) for drug effect at 90 days was 8.19 (1.60-42.0), p=0.01. Ninety days post stroke, twice as many patients treated on drug were able to walk independently (p=0.02), a critical measure of functional recovery that directly impacts quality of life, long-term care needs, and overall independence."

P3 data • CNS Disorders • Ischemic stroke

Long Term Outcomes in the CHARM Trial Evaluating Intravenous Glyburide for the Treatment of Large Hemispheric Infarction (ISC 2025) - "This effect was also present among those treated with endovascular thrombectomy at baseline (n=34, cOR 5.52, 95% CI 1.05-28.9, p=0.043).CONCLUSIONS Long term outcomes in the CHARM trial suggests a potential for durable improvement in functional outcome in patients treated with IV glyburide among those with a baseline stroke volume ≤125 mL. Demonstration of clinical efficacy requires a dedicated trial focusing on this patient population."

Cardiovascular

Intravenous Glyburide in Large Core, Endovascular-Treated Stroke Patients: An Analysis of the CHARM Trial (ISC 2025) - "The mean midline shift was 4.2 ± 2.5 mm in IV glyburide-treated subjects and 7.6 ± 5.5 mm among placebo-treated subjects (P=0.024).CONCLUSIONS There is evidence of benefit for IV glyburide in large core EVT treated subjects with a baseline stroke volume ≤125 mL. Although IV glyburide may also have benefit among non-EVT treated subjects, the evolving standard of care of EVT for large core stroke indicates that an efficient, feasible trial design should focus on EVT patients."

Clinical • Cardiovascular • Ischemic stroke

Glyburide for Large Hemispheric Infarcts ≤125 mL: a Meta-Analysis of Individual Patient Data from the GAMES-RP and CHARM Trials (ISC 2025) - "Among these patients at 90 days, IV Glyburide was associated with better functional outcome (cOR 2.56, 95% CI 1.28-5.11, p=0.008).CONCLUSIONS Individual patient data meta-analysis of 138 subjects enrolled in the GAMES-RP and CHARM trials show that IV Glyburide was associated with an improvement in functional outcome compared to placebo when the baseline stroke volume was ≤125 mL. This finding requires confirmation in a future clinical trial."

Retrospective data • Cardiovascular

Intravenous glibenclamide for cerebral oedema after large hemispheric stroke (CHARM): a phase 3, double-blind, placebo-controlled, randomised trial. (PubMed, Lancet Neurol) - P3 | "Intravenous glibenclamide did not improve functional outcome in patients aged 18-70 years after large hemispheric infarction, although the trial was underpowered to make definitive conclusions because it was stopped early. Future prospective evaluation could be warranted to identify a possible benefit of intravenous glibenclamide in specific subgroups."

Clinical • Journal • P3 data • Cardiovascular • CNS Disorders • Hypoglycemia • Infectious Disease • Ischemic stroke • Novel Coronavirus Disease

Remedy Pharmaceuticals Announces FDA Orphan Drug Designation Granted for the Treatment of Large Territory Acute Ischemic Stroke with CIRARA (PRNewswire) - "Remedy Pharmaceuticals...announced that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Division (OOPD) has granted Orphan Drug Designation for CIRARA for the treatment of 'large territory acute ischemic stroke,' which includes large hemispheric infarctions (LHI)."

Orphan drug • CNS Disorders

GAMES-PILOT: Glyburide Advantage in Malignant Edema and Stroke Pilot (clinicaltrials.gov) - P1/2 | N=10 | Completed | Sponsor: Remedy Pharmaceuticals, Inc. | Phase classification: P2a ➔ P1/2

Phase classification • Cardiovascular • Hypoglycemia • Ischemic stroke

Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction (clinicaltrials.gov) - P3 | N=537 | Terminated | Sponsor: Biogen | Active, not recruiting ➔ Terminated; Early completed to operational challenges and other strategic considerations, not for efficacy or safety reasons

Trial termination • Cardiovascular • CNS Disorders

A Study to Evaluate the Efficacy and Safety of BIIB093 in Participants With Brain Contusion (clinicaltrials.gov) - P2 | N=90 | Terminated | Sponsor: Biogen | Trial completion date: Jun 2025 ➔ Jun 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2025 ➔ Jun 2023; Early completed due to strategic considerations, not for efficacy or safety reasons.

Trial completion date • Trial primary completion date • Trial termination

Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction (clinicaltrials.gov) - P3 | N=537 | Active, not recruiting | Sponsor: Biogen | Trial completion date: Sep 2024 ➔ Aug 2023 | Trial primary completion date: Dec 2023 ➔ Aug 2023

Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders

A Study to Evaluate the Efficacy and Safety of BIIB093 in Participants With Brain Contusion (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Biogen | Recruiting ➔ Active, not recruiting | N=160 ➔ 90

Enrollment change • Enrollment closed

Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction (clinicaltrials.gov) - P3 | N=537 | Active, not recruiting | Sponsor: Biogen | Recruiting ➔ Active, not recruiting | N=768 ➔ 537

Enrollment change • Enrollment closed • Cardiovascular • CNS Disorders

Glibenclamide for Brain Contusions: Contextualizing a Promising Clinical Trial Design that Leverages an Imaging-Based TBI Endotype. (PubMed, Neurotherapeutics) - "ASTRAL is an ongoing international multi-center double blind multidose placebo-controlled phase-II clinical trial evaluating the safety and efficacy of an intravenous formulation of glibenclamide (BIIB093)...In this narrative review, we contextualize the development and design of ASTRAL, including the need to address TBI heterogeneity, the scientific rationale underlying the focus on brain contusions and contusion-expansion, and the preclinical and clinical data supporting benefit of SUR1-TRPM4 inhibition in this specific endotype. Within this framework, we summarize the current study design of ASTRAL which is sponsored by Biogen and actively enrolling with a goal of 160 participants."

Journal • Review • CNS Disorders • Hematological Disorders

Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide. (PubMed, Cell Rep Med) - "Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment...Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment."

Journal • PK/PD data • Cardiovascular • CNS Disorders • Immunology • Inflammation • MMP9

Intravenous Glibenclamide For Large Hemispheric Infarction: Baseline Data From Initial Enrollees In The Charm Phase 3 Study (ISC 2022) - P3 | "OBJECTIVE To present baseline data from initially enrolled participants in CHARM, a Phase 3 study evaluating whether intravenous (IV) glibenclamide (BIIB093) improves functional outcomes at 90 days in individuals with large hemispheric infarction (LHI) compared with placebo...Ages 71-85 years have completed enrollment; remaining enrollees in CHARM will be ≤70 years of age. Enrollment is ongoing."

P3 data • Cardiovascular • Ischemic stroke

A Study to Evaluate the Efficacy and Safety of BIIB093 in Participants With Brain Contusion (clinicaltrials.gov) - P2; N=160; Recruiting; Sponsor: Biogen; Trial completion date: May 2022 ➔ Jun 2025; Trial primary completion date: Dec 2021 ➔ Jan 2025

Clinical • Trial completion date • Trial primary completion date

Intravenous Administration of BIIB093 (Glibenclamide) in the Treatment of Severe Cerebral Edema After Massive Cerebral Infarction (clinicaltrials.gov) - P3; N=743; Recruiting; Sponsor: Peking University Third Hospital

New P3 trial • CNS Disorders • MRI

GAMES-RP: Glyburide Advantage in Malignant Edema and Stroke - Remedy Pharmaceuticals (clinicaltrials.gov) - P2; N=86; Completed; Sponsor: Biogen; Active, not recruiting ➔ Completed

Clinical • Trial completion • Cardiovascular • Ischemic stroke

Glyburide (RP-1127) for Traumatic Brain Injury (TBI) (clinicaltrials.gov) - P2; N=29; Completed; Sponsor: Biogen; Active, not recruiting ➔ Completed; N=100 ➔ 29

Clinical • Enrollment change • Trial completion • CNS Disorders • Vascular Neurology • MRI

Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction (clinicaltrials.gov) - P3; N=768; Recruiting; Sponsor: Biogen; Trial completion date: Nov 2022 ➔ Sep 2024; Trial primary completion date: Feb 2022 ➔ Dec 2023

Clinical • Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders

BIIB093 (intravenous glibenclamide) for the prevention of severe cerebral edema. (PubMed, Surg Neurol Int) - "Studies analyzing the GAMES-Pilot and GAMES-PR trials suggest that glibenclamide has a moderate, however, measurable effect on intermediate biomarkers and clinical endpoints. Meaningful conclusions are limited by the small sample size of patients studied."

Journal • Review • Cardiovascular • Ischemic stroke • MMP9