A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy

Abstract

Enters the CNS and reverses the inhibitory effects of neuroactive steroids on brain function in humans 9 Normalizes an elevated GABAergic tone, independent of ammonia 9 Improves cognitive function Cirrhosisis a growing problem and an end-stage disease Current drugs are targeting elevated ammonia levels Increased production of allopregnanolone Ammonia, inflammation Golexanolone: the only HE drug directly targeting CNS Golexanolone in HE CNS-related disorders Excessive GABAergic inhibition is a central driver of HE Excessive GABAergic tone Cirrhosis HighlightsHerein, we report findings from a pilot phase IIa study of golexanolone, a GABA-A receptor-modulating steroid antagonist, in clinical development for HE.Golexanolone was generally well tolerated and seemed to improve neuropsychiatric performance.These findings support a role for neurosteroids in the pathogenesis of HE-related sleepiness and vigilance.The results also suggest a role for golexanolone in the treatment of neurosteroid-mediated vigilance and cognitive disorders including HE.

Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments

“…Golexanolone treatment resulted in favorable changes vs. placebo in Epworth Sleepiness Scale, mean dominant frequency and delta + theta/alpha + beta ratio. Post hoc analyses showed an improvement in continuous reaction time, psychometric hepatic encephalopathy score and animal naming test, which suggests an efficacy signal by cognitive measures as well 115 …”

Review article: current and emerging therapies for the management of cirrhosis and its complications

“…Finally, the ammonia and glutamine scavenger, intravenous ornithine phenylacetate did not improve the resolution of overt HE compared to lactulose 62 . Adjunctive therapies such as faecal microbiota transplantation and golexanolone (a neurosteroid antagonist) have been evaluated but not in phase 3 trials 63,64 . Case series have suggested a potential role for the closure of spontaneous portosystemic shunts, however, recurrence rates remain high 65 …”

“…62 Adjunctive therapies such as faecal microbiota transplantation and golexanolone (a neurosteroid antagonist) appear promising but not in phase 3 trials. 63,64 Case series have suggested a potential role for the closure of spontaneous portosystemic shunts, however, recurrence rates remain high. 65…”

Hepatic Encephalopathy: Current and Emerging Treatment Modalities

“…Galexanolone is a small molecule GABA-A receptor-modulating steroid antagonist that has been shown to improve spatial learning and motor coordination in rat models of HE. 85,86 In a recent randomized trial including 45 patients with cirrhosis, galexanolone was associated with improved neuropsychiatric performance indicated by improvement on daytime sleepiness scores and favorable changes in electroencephalogram. Furthermore, it was welltolerated with satisfactory safety profile.…”