A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy
| Autor: | Lisa Zarantonello, Hannes Hagström, Bruce F. Scharschmidt, Irina Kozlova, Lars-Erik Lins, Joe Mauney, Igor A. Zupanets, Maja Johansson, Martin Schalling, Krzysztof Tomasiewicz, Sara Montagnese, Torbjörn Bäckström, Elena Bunkova, Sergey Fitilev, Fredrik Thunarf, Masoud Mokhatarani, Dag Nilsson, Mette Munk Lauridsen, Maria Månsson, Fredrik Rorsman, Hendrik Vilstrup, Jan Erik Berglund, Stergios Kechagias, Eva Arlander, Carin Edmark Ocklind, Per Samuelson, Magnus Doverskog, Geza Lakner |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology Liver Cirrhosis Male Cirrhosis Sleepiness Allopregnanolone GR3027 neurosteroids cirrhosis vigilance Pilot Projects Neuropsychological Tests chemistry.chemical_compound 0302 clinical medicine Cognition Activities of Daily Living Attention Hepatic encephalopathy media_common Epworth Sleepiness Scale Electroencephalography Middle Aged Treatment Outcome 030211 gastroenterology & hepatology Female Arousal Neurosteroids Vigilance (psychology) medicine.medical_specialty Neuroactive steroid media_common.quotation_subject Gastroenterology and Hepatology Placebo 03 medical and health sciences Double-Blind Method Internal medicine medicine Gastroenterologi Humans Effects of sleep deprivation on cognitive performance GABA-A Receptor Antagonists Hepatology business.industry Drugs Investigational Phenanthrenes medicine.disease 030104 developmental biology chemistry Hepatic Encephalopathy business |
| Zdroj: | Montagnese, S, Lauridsen, M, Vilstrup, H, Zarantonello, L, Lakner, G, Fitilev, S, Zupanets, I, Kozlova, I, Bunkova, E, Tomasiewicz, K, Berglund, J E, Rorsman, F, Hagström, H, Kechagias, S, Ocklind, C E, Mauney, J, Thunarf, F, Mokhatarani, M, Bäckström, T, Doverskog, M, Lins, L-E, Månsson, M, Samuelson, P, Nilsson, D, Schalling, M, Johansson, M, Arlander, E & Scharschmidt, B F 2021, ' A pilot study of Golexanolone, a new GABA-A receptor modulating steroid antagonist, in patients with covert hepatic encephalopathy ', Journal of Hepatology, vol. 75, no. 1, pp. 98-107 . https://doi.org/10.1016/j.jhep.2021.03.012 Montagnese, S, Lauridsen, M, Vilstrup, H, Zarantonello, L, Lakner, G, Fitilev, S, Zupanets, I, Kozlova, I, Bunkova, E, Tomasiewicz, K, Berglund, J E, Rorsman, F, Hagström, H, Kechagias, S, Ocklind, C E, Mauney, J, Thunarf, F, Mokhatarani, M, Bäckström, T, Doverskog, M, Lins, L E, Månsson, M, Samuelson, P, Nilsson, D, Schalling, M, Johansson, M, Arlander, E & Scharschmidt, B F 2021, ' A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy ', Journal of Hepatology, vol. 75, no. 1, pp. 98-107 . https://doi.org/10.1016/j.jhep.2021.03.012 |
| DOI: | 10.1016/j.jhep.2021.03.012 |
| Popis: | 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. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. Funding Agencies|Umecrine Cognition AB |
| Databáze: | OpenAIRE |
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