Assessment of Ganaxolone's Anticonvulsant Activity Using a Randomized, Double‐Blind, Presurgical Trial Design

Abstract

Summary:Purpose: A double-blind, randomized, placebocontrolled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed.Methods: Fifty-two eligible patients were withdrawn from antiepileptic drugs and randomized to receive ganaxolone (24 patients) or placebo (28 patients) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: immediately after breakfast, lunch, and dinner.Results: The primary measure of antiepileptic activity was duration of treatment before withdrawal from the trial. KaplanMeier curves depicted a clear separation between treatment groups, with 50% of the ganaxolone-treated patients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward efficacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revealed a significant treatment effect on survival time in men (p = 0.03). Post-hoc x' probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse events being reported by 79% of patients in the ganaxolone group and 68% of patients in the placebo group.Conclusions: Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that ganaxolone does have antiepileptic activity. Key Words: Ganaxolone-Epilepsy-Presurgical trial-Partial seizures-y-Aminobutyric acid A modulator.Ganaxolone is a member of a novel class of neuroactive steroids called epalons, which allosterically modulate the y-aminobutyric acid type A receptor complex via a unique recognition site (1). The compound was developed after it was observed that endogenously occurring metabolites of progesterone and deoxycorticosterone, such as 3a-hydroxy-501-pregnan-2O-one and 501-tetrahydrodeoxycorticosterone, had substantial anticonvulsant effects in animal models of epilepsy (24). Ganaxolone (3au-hydroxy-3~-methyl-5a-pregnan-20-one) is the 3P-methylated, synthetic analog of 301-hydroxy-501-pregnan-20-one and possesses no detectable hormonal acAccepted May 12, 2000. Dr. Morrell is now with The Neurological Institute, Columbia Presbyterian Medical Center, New York, NY.Address correspondence to Dr. Edward P. Monaghan at Serono, Inc., 700 Longwater Dr, Norwell, MA 02061. E-mail: edward.monaghan. us-bos0 1 @ serono.com tivity (5). In vivo pharmacology studies demonstrated that ganaxolone provides protection in a wide variety of animal models, including pentylenetetrazol-, bicuculline-, aminophylline-, t-butylbicyclophosphorothionate-, and corneal kindling-induced seizure models, suggesting that it may have utility in the treatment of a broad range of seizure types (6-8).Traditionally, early clinical trials in epilep...

Neurosteroids modulate epileptiform activity and associated high-frequency oscillations in the piriform cortex

“…In epileptic patients, finasteride, which inhibits neurosteroid synthesis, was recently shown to enhance seizure susceptibility (Pugnaghi et al, 2013). Moreover, the synthetic analog of anti-convulsant neurosteroids, ganaxolone, significantly reduced seizure frequency in patients with medically refractory partial epilepsy (Laxer et al, 2000).…”

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

“…Ganaxolone is a C3-β-methyl derivative of allopregnanolone, and was developed as an orally effective neurosteroid, presumably because of the inhibition of C3-hydroxyl oxidation due to the presence of the methyl group (Beekman, et al, 1998,Carter, et al, 1997,Gee, 1996. Pharmacokinetic and in vivo studies have shown that ganaxolone has greater efficacy than allopregnanolone at GABA A receptors (Beekman, et al, 1998,Carter, et al, 1997,Gee, 1996,Kerrigan, et al, 2000,Laxer, et al, 2000,Monaghan, et al, 1997,Robichaud and Debonnel, 2005. We treated mice at postnatal day 7, using the same dose of ganaxolone as we used for allopregnanolone (25 mg/kg).…”

Hormonal Therapy for Epilepsy

“…As previously mentioned, positive modulation of the GnRH-gonadotropin-releasing hormone; TID-three times a day GABA A receptors by allopregnanolone has anticonvulsant effects. Laxer et al [28] completed a multicenter, doubleblind, randomized, placebo-controlled monotherapy clinical trial that evaluated the safety, tolerability, and antiepileptic activity of ganaxolone. The study population consisted of 52 inpatients with medically refractory complex partial seizures who had undergone complete withdrawal from all AEDs during or after video-electroencephalographic evaluations to assess their suitability for surgical intervention.…”