Glibenclamide for Brain Contusions: Contextualizing a Promising Clinical Trial Design that Leverages an Imaging-Based TBI Endotype.

ABSTRACT

TBI heterogeneity is recognized as a major impediment to successful translation of therapies that could improve morbidity and mortality after injury. This heterogeneity exists on multiple levels including primary injury, secondary injury/host-response, and recovery. One widely accepted type of primary-injury related heterogeneity is pathoanatomic-the intracranial compartment that is predominantly affected, which can include any combination of subdural, subarachnoid, intraparenchymal, diffuse axonal, intraventricular and epidural hemorrhages. Intraparenchymal contusions carry the highest risk for progression. Contusion expansion is one of the most important drivers of death and disability after TBI. Over the past decade, there has been increasing evidence of the role of the sulfonylurea-receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel in secondary injury after TBI, including progression of both cerebral edema and intraparenchymal hemorrhage. Inhibition of SUR1-TRPM4 with glibenclamide has shown promising results in preclinical models of contusional TBI with benefits against cerebral edema, secondary hemorrhage progression of the contusion, and improved functional outcome. Early-stage human research supports the key role of this pathway in contusion expansion and suggests a benefit with glibenclamide inhibition. 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). ASTRAL is a unique and innovative study that addresses TBI heterogeneity by limiting enrollment to patients with the TBI pathoanatomic endotype of brain contusion and using contusion-expansion (a mechanistically linked secondary injury) as its primary outcome. Both criteria are consistent with the strong supporting preclinical and molecular data. 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.