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, Scharschmidt BF.
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.