1. A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.
- Author
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Montagnese S, Lauridsen M, Vilstrup H, Zarantonello L, Lakner G, Fitilev S, Zupanets I, Kozlova I, Bunkova E, Tomasiewicz K, Berglund JE, Rorsman F, Hagström H, Kechagias S, Ocklind CE, Mauney J, Thunarf F, Mokhatarani M, Bäckström T, Doverskog M, Lins LE, Månsson M, Samuelson P, Nilsson D, Schalling M, Johansson M, Arlander E, and Scharschmidt BF
- Subjects
- Activities of Daily Living, Arousal drug effects, Attention drug effects, Double-Blind Method, Drugs, Investigational, Electroencephalography methods, Female, Humans, Liver Cirrhosis complications, Male, Middle Aged, Neuropsychological Tests, Neurosteroids administration & dosage, Neurosteroids adverse effects, Neurosteroids pharmacokinetics, Pilot Projects, Sleepiness drug effects, Treatment Outcome, Cognition drug effects, GABA-A Receptor Antagonists administration & dosage, GABA-A Receptor Antagonists adverse effects, GABA-A Receptor Antagonists pharmacokinetics, Hepatic Encephalopathy diagnosis, Hepatic Encephalopathy drug therapy, Hepatic Encephalopathy etiology, Hepatic Encephalopathy metabolism, Phenanthrenes administration & dosage, Phenanthrenes adverse effects, Phenanthrenes pharmacokinetics
- Abstract
Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by 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. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone 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 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (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 patients 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 patients 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. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone., Lay Summary: Many patients with 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 this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug., Clinical Trial Registration Number: EudraCT 2016-003651-30., Competing Interests: Conflict of interest Torbjörn Bäckström, Mette Lauridsen, Maria Månsson, Joe Mauney, Masoud Mokhatarani, Sara Montagnese, Dag Nilsson, Lars-Erik Lins, Per Samuelson, Martin Schalling, Bruce F. Scharschmidt, Fredrik Thunarf, Hendrik Vilstrup and Lisa Zarantonello are current or recent consultants to Umecrine Cognition, AB. Torbjörn Bäckström and Bruce F. Scharschmidt are also Board members and shareholders of Umecrine Cognition AB. Magnus Doverskog and Maja Johansson, and Eva Arlander are current or recent employees of Umecrine Cognition AB. Géza Lakner, Sergey Fitilev, Igor Zupanets, Irina Kozlova, Elena Bunkova, Krzysztof Tomasiewicz, Jan Erik Berglund, Fredrik Rorsman, Hannes Hagström, Stergios Kechagias and Carin Edmark Ocklind have received investigator grants from Umecrine Cognition AB to support the cost of performing the clinical study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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