Efficacy and safety of perampanel monotherapy in patients with focal‐onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open‐label Study 342 (FREEDOM Study)

Abstract

Objective: Our study assessed perampanel monotherapy in patients (aged ≥12 years) with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures (FBTCS) in Japan and South Korea. Methods: Study 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study. Patients initially received perampanel in a 32-week 4-mg/d Treatment Phase (6-week Titration; 26-week Maintenance Periods). If they experienced a seizure during the 4-mg/d Maintenance Period, they could be up-titrated to 8 mg/d across an additional 30-week Treatment Phase (4-week Titration; 26-week Maintenance Periods). Primary endpoint was the seizure-freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment-emergent adverse events (TEAEs) were monitored. Results: At data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4-mg/d Titration Period, meaning 73 patients entered the 4-mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure-freedom rate in the 26-week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9-74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4-83.5) at 4 or 8 mg/d. | 275 YAMAMOTO eT Al.F I G U R E 1 Study design. a In the event of tolerability issues, the dose of perampanel could be reduced from 4 mg/d to 2 mg/d during Weeks 3 and 4 of the Titration Period, at the investigators' discretion. If the dose could not be up-titrated back to 4 mg/d, patients were discontinued from the study. b Patients experiencing seizures while receiving perampanel 4 mg/d could receive perampanel 8 mg/d at the investigators' discretion. If the 8-mg/d dose was not tolerated, patients could be down-titrated to 6 mg/d and continue the Maintenance Period. If patients experienced seizures while receiving perampanel 6 or 8 mg/d, or if the 6-mg/d dose was not tolerated, they ended the Treatment Phase. Abbreviation: QD, once daily

Optimal Use of Perampanel in Asian Patients with Epilepsy: Expert Opinion

“…Based on clinical trial data and real-world experience, perampanel is observed to have broad-spectrum efficacy in a range of seizure types when used as both monotherapy and adjunctive therapy. [7][8][9][10][11][12] Clinical studies and real-world evidence have demonstrated the benefits of initiating perampanel at low doses (≤6 mg) [7][8][9][10][11][12] and utilizing a slow titration strategy (increasing dose by 2 mg at ≥2-week intervals). 7,[14][15][16] Initiating perampanel at an early stage (as initial monotherapy or early adjunctive therapy) has also been shown to be associated with better patient outcomes; these data are described below.…”

“…Perampanel is a first-in-class AMPA receptor antagonist approved for the treatment of epilepsy and has broadspectrum efficacy. [7][8][9][10][11][12] Perampanel is indicated by the US Food and Drug Administration for treatment of focal onset seizures (FOS), with or without focal-to-bilateral tonicclonic seizures (FBTCS), in patients ≥4 years of age (monotherapy and adjunctive therapy) and as adjunctive therapy in the treatment of primary generalized tonicclonic seizures (GTCS) in patients with epilepsy ≥12 years of age. 13 In addition, perampanel has a once-daily dosing schedule that supports patient adherence.…”

Study protocol for a phase II randomised, double-blind, placebo-controlled trial of perampanel as an antiepileptogenic treatment following acute stroke

“…29 In this trial, a 76.5% reduction in seizure frequency was observed in the treatment group compared with 38.4% in the placebo group. While there have been no completed comparator-controlled monotherapy trials examining the efficacy of perampanel, an open-label study of those with newly diagnosed epilepsy or recurrence of epilepsy Open access demonstrated a seizure freedom rate of 74% in those on doses of 4 or 8 mg, 34 and a current trial is examining its role in the prevention and treatment of glioma-related seizures (ACTRN12617000078358, ACTRN12617000073303). Limited data extrapolated from patients discontinuing other antiepileptic drugs in clinical trials also support its feasibility as primary or secondary monotherapy for the treatment of focal seizures.…”

Corrigendum

“…In the article by Yamamoto et al, 1 the corresponding author’s contact information was published incorrectly. The correct email addresses are taka-yamamd@sis.seirei.or.jp and taka_mdms@icloud.com.…”