Perampanel Study 207: long-term open-label evaluation in patients with epilepsy

Abstract

Objectives -Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel a-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures. Materials and methods -Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70 years) who completed one of two randomized, placebocontrolled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2 mg increments of perampanel every 2 weeks to 12 mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424 weeks (~8 years). Interim analysis data cut-off date was 1 December, 2010. Results -Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4 years after study start), over a third (n = 53, 38.4%) remained on perampanel; 41.3% (n = 57) of patients had >3 years of exposure; and 13.0% (n = 18) had at least 4 years' exposure. Mean ± standard deviation (SD) duration of exposure was 116 ± 75 weeks and mean ± SD dose during the OLE Maintenance Period was 7.3 ± 3.3 mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28 days during open-label treatment was À31.5% (À99.2 to 512.2). Conclusions -Long-termup to 4 years -adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

Perampanel, an Antagonist of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors, for the Treatment of Epilepsy: Studies in Human Epileptic Brain and Nonepileptic Brain and in Rodent Models

“…Low-dose margins of efficacy over motor effects have been reported before in rodents (Hanada et al, 2011). Although it is well tolerated, perampanel has shown motor impairments in human studies and in phase III data Krauss et al, 2012Krauss et al, , 2013Rektor et al, 2012). Thus, although protective indices in rodents are not always fully translatable into human motor side-effect liabilities (Löscher and Nolting, 1991), the data with perampanel in the current study and in Hanada et al (2011) have uncovered the dose-dependent motor consequences of perampanel in humans.…”

“…Given the motor impairments observed in rodents (Hanada et al, 2011;Rogawski and Hanada, 2013; present study) and the ataxia and dizziness reported in epileptic patients at higher doses of perampanel Krauss et al, 2012Krauss et al, , 2013Rektor et al, 2012), it is suggested that cerebellar AMPA receptor blockade is a primary mediator of the main side effects of perampanel. Our results showing that both rodent and human cerebellar AMPA receptors are equally inhibited by perampanel further corroborate this hypothesis.…”

“…Perampanel has been investigated in several phase III clinical studies Krauss et al, 2012Krauss et al, , 2013Rektor et al, 2012). The key clinical trials were conducted on a global level as randomized, double-blind, placebo-controlled, dose-escalation studies that examined 1480 patients with partial-onset seizures.…”

Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy

“…In addition, treatment was associated with an acceptable and consistent safety profile. Two long-term extension trials were also carried out to investigate the long-term efficacy and safety of perampanel [42,43], and interim analyses have so far shown consistent results with the Phase III trials.…”

Use of Perampanel in the Treatment of Epilepsy: A Review of Literature and a Case Report

“…Перампа-нел -мощный высокоселективный неконкурентный ингибитор ионотропных AMPA-рецепторов постсинап-тических мембран нейронов на уровне неокортекса и гиппокампа [6,9,26,41]. По мнению многих авторов, перампанел -первый АЭП со специфическим дейст-вием на обмен глутамата (опосредованное глутаматом возбуждение в ЦНС), эффективность и переносимость которого при резистентных фокальных приступах были доказаны в клинических исследованиях III фазы [13, 17-21, 27, 28, 31].…”