Background: Golexanolone is a novel small molecule GABA-A receptor modulating steroid antagonist under development for treatment of cognitive and vigilance disorders due to allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Here we report golexanolone safety, pharmacokinetics (PK) and effects on the electroencephalogram (EEG), subjective sleepiness and cognitive performance in adult patients with cirrhosis.
Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80mg bid) or placebo. CRT, Psychometric Hepatic Encephalopathy Score (PHES), Animal Naming Test (ANT), Epworth Sleepiness Scale (ESS) and EEG (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days.
Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 subjects randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p=0.047), MDF (p=0.142) and DT/AB (p=0.021). All subjects also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well.
Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. The results implicate GABA-A receptor modulating neurosteroids in the pathogenesis of HE and suggest that golexanolone deserves further study as a potential therapeutic.
Lay summary: Many patients with liver cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of the study suggest that golexanolone is well tolerated and may improve cognition as reflected by measures of sleepiness, attention span and brain wave activity and they pave the way for future larger studies of this promising experimental drug.
Clinical trial registration number: EudraCT 2016-003651-30.
Keywords: Allopregnanolone; GR3027; cirrhosis; neurosteroids; vigilance.
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.