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Perampanel monotherapy for the treatment of epilepsy: Clinical trial and real-world evidence

Open AccessPublished:September 21, 2022DOI:https://doi.org/10.1016/j.yebeh.2022.108885

      Highlights

      • Perampanel is approved for use as monotherapy in approximately 48 countries.
      • This review examines the use of perampanel monotherapy in patients with epilepsy.
      • Perampanel monotherapy use offered favorable seizure freedom and retention rates.

      Abstract

      Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration’s (FDA’s) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs.

      Abbreviations:

      AE (adverse event), ASM (anti-seizure medication), CI (confidence interval), FAS (focal aware seizures), FBTCS (focal to bilateral tonic-clonic seizures), FDA (Food and Drug Administration), FIAS (focal impaired awareness seizures), FOS (focal-onset seizures), GTCS (generalized tonic-clonic seizures), IGE (idiopathic generalized epilepsy), ILAE (International League Against Epilepsy), ITT (Intent-to-Treat), max (maximum), min (minimum), mITT (modified ITT), N/A (not applicable), NR (not reported), OP (observation point), OR (odds ratio), SD (standard deviation), TEAE (treatment-emergent adverse event), TCS (tonic-clonic seizures)

      Keywords

      1. Introduction

      Perampanel is an orally active, non-competitive, selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist [
      • Hanada T.
      • Hashizume Y.
      • Tokuhara N.
      • Takenaka O.
      • Kohmura N.
      • Ogasawara A.
      • et al.
      Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.
      ,

      Food and Drug Administration (FDA). FYCOMPA® Prescribing Information. Available at: https://www.fycompa.com/-/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed February 28, 2022.

      ], which received initial US Food and Drug Administration (FDA) approval in 2012 for use as adjunctive therapy for focal-onset seizures (FOS; previously partial-onset seizures), with or without focal to bilateral tonic-clonic seizures (FBTCS; previously termed secondarily generalized seizures), in patients with epilepsy aged ≥12 years. This approval was based on data from three pivotal, randomized, double-blind, placebo-controlled, Phase III clinical trials (Studies 304, 305, and 306) [

      Food and Drug Administration (FDA). FYCOMPA® Prescribing Information. Available at: https://www.fycompa.com/-/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed February 28, 2022.

      ,
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ]. In 2015, perampanel also received FDA approval for the adjunctive treatment of generalized tonic-clonic seizures (GTCS; previously termed primary generalized tonic-clonic seizures) in patients with epilepsy aged ≥12 years, based on data from a randomized, double-blind, placebo-controlled, Phase III clinical trial (Study 332) in patients with idiopathic generalized epilepsy (IGE) with GTCS [
      • French J.A.
      • Krauss G.L.
      • Wechsler R.T.
      • Wang X.-F.
      • DiVentura B.
      • Brandt C.
      • et al.
      Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: A randomized trial.
      ]. Of note, during the Baseline Period of Study 332, 29% of patients who were randomized and treated also had myoclonic seizures and 37% had absence seizures. While the study was not powered to evaluate the efficacy of perampanel for myoclonic and/or absence seizures, no patients discontinued due to worsening of these seizure types [
      • Brandt C.
      • Wechsler R.T.
      • O’Brien T.J.
      • Patten A.
      • Malhotra M.
      • Ngo L.Y.
      • et al.
      Adjunctive perampanel and myoclonic and absence seizures: Post hoc analysis of data from study 332 in patients with idiopathic generalized epilepsy.
      ].
      In 2017, perampanel received FDA approval for use as monotherapy for the treatment of FOS, with or without FBTCS, based on the FDA’s policy allowing extrapolation of data from adjunctive trials to the monotherapy setting in the absence of randomized controlled monotherapy trials. While initial monotherapy approval was for use in patients aged ≥12 years, this was subsequently expanded in 2018 to include pediatric patients aged ≥4 years. In addition, perampanel has since received approval in Japan for use as monotherapy in patients aged ≥4 years with FOS, with or without FBTCS, and is currently approved in approximately 48 countries for use as monotherapy for FOS, with or without FBTCS [
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ,

      Eisai News Release. Approval of antiepileptic drug Fycompa® in Japan for monotherapy and pediatric indications for partial-onset seizures, as well as a new formulation. Available at: https://www.eisai.com/news/2020/pdf/enews202004pdf.pdf. Accessed December 20, 2021.

      ].
      Although data from randomized clinical trials are clearly useful, there are some key differences between doses and titration schedules used in adjunctive therapy clinical trials designed for regulatory approval compared with real-world use as initial therapy for patients who have not previously received any anti-seizure medications (ASMs). In particular, titration of perampanel in the pivotal Phase III clinical trials occurred weekly [
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ], which, considering the long half-life of perampanel (∼105 h), may be faster than titration schedules used in routine clinical practice, and could potentially lead to higher rates of adverse events (AEs). In addition, the perampanel doses of up to 12 mg/day utilized in the Phase III trials, in which patients had refractory epilepsy [
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ], are likely to be higher than required to achieve seizure control in ASM-naïve patients or in patients whose seizures are less refractory. Indeed, 4-mg/day perampanel has been shown to control seizures during clinical trials and so may be appropriate for ASM-naïve patients [
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ,
      • Steinhoff B.J.
      • Patten A.
      • Williams B.
      • Malhotra M.
      Efficacy and safety of adjunctive perampanel 4 mg/d for the treatment of focal seizures: A pooled post hoc analysis of four randomized, double-blind, phase III studies.
      ]. Moreover, the incidence of AEs may increase with increasing dose, as has been observed in adjunctive therapy trials [
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ]. As such, real-world studies are critical to inform appropriate clinical use of perampanel in ASM-naïve patients, particularly in relation to dosing and titration schedules.
      This review summarizes the clinical evidence for the efficacy and safety of perampanel administered as primary monotherapy (in the absence of any concomitant ASMs) or secondary monotherapy (conversion from adjunctive therapy to monotherapy by withdrawing concomitant ASMs).

      2. Literature search and selection strategies

      A literature search using PubMed was conducted to identify any studies that described the use of perampanel monotherapy for treating epilepsy across geographic areas and ethnic populations. The search and selection strategies are presented in Fig. 1. Articles published between 2010 and 2021 were identified if “perampanel” OR “E-2007” OR “E2007” OR “Fycompa” AND “monotherapy” were included in the title or abstract. Articles were removed before screening if effects of perampanel in non-clinical studies, practice guidelines, treatment of seizures resulting from other medical conditions (such as brain tumors and essential tremor), or as an adjunctive therapy for epilepsy were reported. Reviews, case reports, post hoc analyses, and meta-analyses were excluded during the screening.
      Figure thumbnail gr1
      Fig. 1Flow diagram of literature search and selection strategies. aArticles were shortlisted if they were published between 2010 and 2021. bThe titles and abstracts of articles fulfilling the search criteria were examined, and articles were included if they reported safety and efficacy outcomes for patients receiving perampanel monotherapy for the treatment of epilepsy. ASMs, anti-seizure medications.

      3. Study designs and primary endpoints

      Eight studies were identified and have been included in this review. Three studies were sponsored by Eisai, including one prospective, open-label, Phase III study of patients with newly diagnosed epilepsy (Study 342 [FREEDOM; NCT03201900]) and two retrospective, real-world, Phase IV studies of patients with epilepsy (Studies 504 [NCT02736162] and 506 [PROVE; NCT03208660]). Of the remaining five retrospective real-world studies, four were non-sponsored, independent studies and one was sponsored by Eisai. The full designs of the eight studies have been previously published [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ,
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ,
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ,
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ,
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      ,
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ,
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      ], and the key details are summarized in Table 1. Efficacy and safety of perampanel were assessed in the overall population (including patients who received perampanel as monotherapy or adjunctive therapy) in all studies included in this review; efficacy data are only discussed here for patients who were included in the Efficacy Analysis Sets (defined as patients who had seizure-frequency data available and received perampanel monotherapy).
      Table 1Overview of studies including perampanel monotherapy.
      Study 342 (NCT03201900)
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      Study 504 (NCT02736162)
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      Study 506 (NCT03208660)
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      Wehner et al.
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      Heyman et al.
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      Toledano Delgado et al.
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      Chinvarun
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      Macrohon et al.
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      Study typeProspective, multicenter, open-label, uncontrolled, Phase III clinical trialRetrospective, multicenter, real-world, non-interventional, Phase IV clinical studyRetrospective, multicenter, real-world, noninterventional, Phase IV clinical studyRetrospective, single-center, observational studyRetrospective, single-center studyRetrospective, multicenter, real-world studyRetrospective, single-center, real-world studyRetrospective, cross-sectional, descriptive study
      PatientsPreviously untreated patients aged 12–74 years with a diagnosis of FOS, with or without FBTCSPatients with a diagnosis of epilepsy and receiving perampanel monotherapyPatients with a diagnosis of epilepsy initiating perampanel treatment after January 1, 2014Patients who initiated perampanel treatment at the age of ≥17 years during the prespecified datesPatients aged 1–17 years with refractory epilepsy receiving perampanelPatients aged ≥12 years with a diagnosis of FOS or IGE and receiving perampanel monotherapyPatients aged ≥15 years with newly diagnosed FOS, with or without FBTCS, and received perampanel monotherapyPatients initiated perampanel treatment at the age of <18 years with ≥1 follow-up visit
      RegionJapan and South KoreaEuropeUSUKIsraelSpainThailandPhilippines
      Study datesJune 2017 – February 2019January 2013 – March 2016April 2017 – April 2019October 1, 2012 – March 31, 2015October 2015 (study cut-off date)March 1, 2019 (study cut-off date)July 2015 – March 2020June 2019 – June 2020
      TreatmentMonotherapyMonotherapyMonotherapy and adjunctive therapyMonotherapy and adjunctive therapyMonotherapy and adjunctive therapyMonotherapyMonotherapyMonotherapy and adjunctive therapy
      Dosage4 or 8 mg/day
      For patients who experienced seizure(s) on 4 mg/day, the perampanel dose could be up-titrated to 8 mg/day during an additional 30-week 8-mg/day Treatment Phase (comprising a 4-week Titration Period and 26-week Maintenance Period).
      Any dose permitted as per investigator’s discretion based on patients’ clinical responses and tolerability
      ObjectivesThe efficacy and safety of perampanel monotherapy for newly diagnosed epilepsy with FOSThe dosage, efficacy, and safety of perampanel monotherapy in routine clinical careThe dosage, efficacy, and safety of perampanel in routine clinical careThe effectiveness and safety of perampanel in routine clinical care of epilepsyThe tolerability and efficacy of perampanel for refractory epilepsyThe effectiveness and safety of perampanel monotherapy for FOS and GTCS during the first year of treatment in routine clinical careThe efficacy and tolerability of perampanel monotherapy for newly diagnosed epilepsy with FOS in routine clinical careThe efficacy and safety of perampanel
      Primary endpointSeizure-freedom rate for FOS during the 4- or 8-mg/day 26-week Maintenance PeriodRetention rate
      Retention rates are calculated as the proportion of patients who remained on perampanel monotherapy after conversion from perampanel adjunctive therapy/the number of patients who could have been exposed at each time point. FBTCS, focal to bilateral tonic-clonic seizures; FOS, focal-onset seizures; GTCS, generalized tonic-clonic seizures; IGE, idiopathic generalized epilepsy; NA, not applicable.
      at 3, 6, 12, 18, and 24 months
      Retention rate
      Retention rates are calculated as the proportion of patients who remained on perampanel monotherapy after conversion from perampanel adjunctive therapy/the number of patients who could have been exposed at each time point. FBTCS, focal to bilateral tonic-clonic seizures; FOS, focal-onset seizures; GTCS, generalized tonic-clonic seizures; IGE, idiopathic generalized epilepsy; NA, not applicable.
      at 3, 6, 12, 18, and 24 months
      NANARetention rate
      Retention rates are calculated as the proportion of patients who remained on perampanel monotherapy after conversion from perampanel adjunctive therapy/the number of patients who could have been exposed at each time point. FBTCS, focal to bilateral tonic-clonic seizures; FOS, focal-onset seizures; GTCS, generalized tonic-clonic seizures; IGE, idiopathic generalized epilepsy; NA, not applicable.
      at 3, 6, and 12 months, and last follow-up
      Retention rate
      Retention rates are calculated as the proportion of patients who remained on perampanel monotherapy after conversion from perampanel adjunctive therapy/the number of patients who could have been exposed at each time point. FBTCS, focal to bilateral tonic-clonic seizures; FOS, focal-onset seizures; GTCS, generalized tonic-clonic seizures; IGE, idiopathic generalized epilepsy; NA, not applicable.
      at 3, 6, and 12 months
      NA
      a For patients who experienced seizure(s) on 4 mg/day, the perampanel dose could be up-titrated to 8 mg/day during an additional 30-week 8-mg/day Treatment Phase (comprising a 4-week Titration Period and 26-week Maintenance Period).
      b Retention rates are calculated as the proportion of patients who remained on perampanel monotherapy after conversion from perampanel adjunctive therapy/the number of patients who could have been exposed at each time point.FBTCS, focal to bilateral tonic-clonic seizures; FOS, focal-onset seizures; GTCS, generalized tonic-clonic seizures; IGE, idiopathic generalized epilepsy; NA, not applicable.
      Only study 342 was a prospective study, enrolling patients aged 12–74 years with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ]. Patients received once-daily oral perampanel 4 mg/day as monotherapy during a 32-week Treatment Phase (comprising a 6-week Titration Period [where patients received 2 mg/day for the first 2 weeks] and a 26-week Maintenance Period). Patients who experienced seizure(s) during the Maintenance Period could be up-titrated to 8 mg/day. In the remaining studies, perampanel was administered per clinicians’ discretion and patients’ therapeutic response and tolerability.
      Four of the eight studies included patients receiving perampanel as monotherapy or adjunctive therapy (Table 1); we will focus on monotherapy data from these studies but some of the adjunctive data will be discussed as a comparison for the purpose of this review. Seven of the studies reported efficacy outcomes for perampanel initiated in the absence of any concomitant ASMs (defined as primary monotherapy) or transitioned from adjunctive therapy to monotherapy by withdrawing concomitant ASMs (defined as secondary monotherapy).

      4. Clinical experience with perampanel monotherapy in patients with epilepsy

      4.1 Patients

      An overview of the baseline demographics and clinical characteristics of patients from the eight studies is presented in Table 2. All 89 patients in Study 342 received perampanel monotherapy and are included in this review [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ]. In Study 504, 69 patients received perampanel as monotherapy, and 60 of these patients had data available and are therefore included in this review [
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ]. Of the 1703 patients included in Study 506, 47 patients received perampanel as monotherapy [
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ]. It should be noted that of the 33 patients who received perampanel as primary monotherapy, 6 patients later added a secondary ASM, meaning that 27 patients received primary monotherapy only. A total of 98 patients were included in the Toledano Delgado et al. study (primary monotherapy, n = 20; secondary monotherapy, n = 78) [
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ]. Of note, four patients in the Toledano Delgado et al. study were also included in Study 504. In the real-world Studies 504 and 506, and the Toledano Delgado et al. study, the majority of patients had been diagnosed with epilepsy for ≥5 years and received continuous ASM treatment, suggesting that the majority of patients receiving perampanel monotherapy in these three studies may have refractory disease.
      Table 2Overview of patient demographics and clinical characteristics at baseline in studies of perampanel.
      Study 342
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      Study 504
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      Study 506
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      Wehner et al.
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      Heyman et al.
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      Toledano Delgado et al.
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      Chinvarun
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      Macrohon et al.
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      (N = 89)(N = 60)(N = 47)
      Only the subgroup of patients who received perampanel monotherapy is reported.
      (N = 376)
      Includes patients receiving perampanel as monotherapy and adjunctive therapy, percentages are based on the overall patient population.
      (N = 24)
      Includes patients receiving perampanel as monotherapy and adjunctive therapy, percentages are based on the overall patient population.
      (N = 98)(N = 41)(N = 65)
      Includes patients receiving perampanel as monotherapy and adjunctive therapy, percentages are based on the overall patient population.
      Age, years
       Mean (SD)42.1 (18.2)NR31.5 (18.2)NR (NR)
      Age at the initiation of perampanel treatment.
      10 (4.4)49.6 (21.7)46.1 (21.8)
      Age at the initiation of perampanel treatment.
      9.1 (5.2)
      Age at the initiation of perampanel treatment.
       Median (min, max)43.0 (15, 72)NR27.0 (7, 71)42 (17, 82)NR (1, 17)NR (14, 91)NR (15, 88)9.0 (NR)
      Age range, n (%)
       <12 yearsN/A8 (13.3)5 (10.6)NA15 (62.5)NR28 (68)
      The cut-off age was 60 years of age.
      39 (60.0)
       12 to <18 years7 (7.9)6 (10.0)7 (14.9)NA9 (37.5)NR26 (40.0)
       18 to <65 years71 (79.8)44 (73.3)31 (66.0)NRNANRNA
       ≥65 years11 (12.4)2 (3.3)4 (8.5)NRNA32 (32.5)13 (32)
      The cut-off age was 60 years of age.
      Female, n (%)44 (49.4)38 (63.3)25 (53.2)219 (58.2)15 (62.5)50 (51.0)24 (59)24 (36.9)
      Race,
      Percentages are calculated based on patients with available data and exclude those with missing or unknown data.
      n (%)
       White0 (0.0)58 (100.0)35 (74.5)NR
       Black or  African American0 (0.0)0 (0.0)2 (4.3)
       Asian89 (100.0)0 (0.0)2 (4.3)
       Other0 (0.0)0 (0.0)8 (17.0)
       Unknown/missing020
      Age at epilepsy diagnosis/onset
      Percentages are calculated based on patients with available data and exclude those with missing or unknown data.
       Mean (SD), years42.0 (18.2)NR19.3 (19.8)NR (NR)NR31.5
      Median age at epilepsy onset was reported in the study by Toledano Delgado et al.
      (NR)
      NR4.2 (4.4)
       <12 years, n (%)N/A18 (30.5)24 (53.3)NANRNRNRNR
       12 to <18 years, n (%)8 (9.0)19 (32.2)5 (11.1)
       18 to <65 years, n (%)71 (79.8)22 (37.3)15 (33.3)NRNANA
       ≥65 years, n (%)10 (11.2)0 (0.0)1 (2.2)
      Time since diagnosis
       Mean (SD)2.1 (12.8) monthsNR
      The majority (68.3% [n = 41/60]) of patients had been diagnosed with epilepsy for at least 5 years prior to the Study 504.
      12.8 (12.6) yearsNR6.5 (4.0) years11.5 (13.9) yearsNR4.6 (4.2) years
       Median (min, max)0.2 (0.0, 119.9) months7.0 (0.0, 47.0) yearsNR (1, 14) years6.5 (2, 65) years3.5 (0, 60) months3 (0.1, 17) years
      Seizure type,
      Percentages are calculated based on patients with available data and exclude those with missing or unknown data.
      n (%)
       FOS89 (100)
      Based on the 1981 ILAE Classification.
      48 (80.0)21 (55.3)314 (83.5)20 (83.3)71 (72.4)41 (100)11 (16.9)
       IGENA8 (14.3)11 (28.9)7 (1.9)2 (8.3)23 (23.5)NANR
       OtherNA0 (0.0)6 (15.8)NANR0 (0.0)NANR
       Unknown/missingNA494 (1.1)2 (8.3)3 (3.1)NANR
      Patients receiving monotherapy, N8960475298415
      Based on the data provided in the Macrohon et al. study, it is not clear whether one out of the five patients received perampanel as primary or secondary monotherapy. FOS, focal-onset seizures; IGE, idiopathic generalized epilepsy; ILAE, International League Against Epilepsy; max, maximum; min, minimum; N/A, not applicable; NR, not reported; SD, standard deviation.
       Primary,
      Primary monotherapy was defined as the administration of perampanel in the absence of any concomitant ASMs.
      n (%)
      89 (100)9 (15.0)33 (70.2)2 (100)20 (20.4)41 (100)NR
       Secondary,
      Secondary monotherapy was defined as conversion from adjunctive therapy to monotherapy by withdrawing concomitant ASMs.
      n (%)
      51 (85.0)14 (29.8)5 (100)78 (79.6)NR
      a Only the subgroup of patients who received perampanel monotherapy is reported.
      b Includes patients receiving perampanel as monotherapy and adjunctive therapy, percentages are based on the overall patient population.
      c Age at the initiation of perampanel treatment.
      d The cut-off age was 60 years of age.
      e Percentages are calculated based on patients with available data and exclude those with missing or unknown data.
      f Median age at epilepsy onset was reported in the study by Toledano Delgado et al.
      g The majority (68.3% [n = 41/60]) of patients had been diagnosed with epilepsy for at least 5 years prior to the Study 504.
      h Based on the 1981 ILAE Classification.
      i Primary monotherapy was defined as the administration of perampanel in the absence of any concomitant ASMs.
      j Secondary monotherapy was defined as conversion from adjunctive therapy to monotherapy by withdrawing concomitant ASMs.
      k Based on the data provided in the Macrohon et al. study, it is not clear whether one out of the five patients received perampanel as primary or secondary monotherapy.FOS, focal-onset seizures; IGE, idiopathic generalized epilepsy; ILAE, International League Against Epilepsy; max, maximum; min, minimum; N/A, not applicable; NR, not reported; SD, standard deviation.
      In addition, out of the 376 adult patients who were prescribed perampanel in the Wehner et al. study, five patients received secondary monotherapy by discontinuing concomitant ASMs [
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      ]. In the pediatric studies by Heyman et al. and Macrohon et al. 2/24 and 5/65 patients received perampanel monotherapy, respectively [
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      ,
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      ]. In the study by Chinvarun, 41 patients aged ≥15 years with newly diagnosed epilepsy for FOS, with or without FBTCS, received perampanel monotherapy [
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ]. As such, a total of 347 pediatric and adult patients who received perampanel monotherapy are presented and discussed in this review.

      4.2 Perampanel dosage and exposure

      The dosages and extent of exposure to perampanel monotherapy reported in each study are summarized in Table 3. Although different perampanel dosages were reported across studies, the most common doses of perampanel monotherapy were 4 and 8 mg/day, and a maximum dose of 20 mg/day, which is higher than the maximum recommended dose (12 mg/day) [

      Food and Drug Administration (FDA). FYCOMPA® Prescribing Information. Available at: https://www.fycompa.com/-/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed February 28, 2022.

      ], was reported in Study 504. The median maximum doses of perampanel were similar between the primary monotherapy (8 mg/day) and secondary monotherapy (7 mg/day) in Study 506. Treatment duration of perampanel monotherapy varied across studies, with a maximum cumulative duration of exposure to perampanel monotherapy up to 57.0 months as reported by Toledano Delgado et al.
      Table 3Dosages and the treatment durations of perampanel monotherapy.
      Study 342
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      Study 504
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      Study 506
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      Wehner et al.
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      Heyman et al.
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      Toledano Delgado et al.
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      Chinvarun
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      Macrohon et al.
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      Dose of perampanel monotherapy, mg/day
      Median
      The maximum dose is presented for Studies 342, 504, and 506. The maintenance dose is presented for the Delgado et al. study. The daily dose is presented for the Chinvarun study. The last perampanel dose is presented for the Macrohon et al. study.
      (min, max)
      4 (2, 8)8 (4, 20)Primary: 8 (2, 12)NRNR (4, 12)4 (2, 10)4 (2, 8)NR (1, 8)
      Secondary: 7 (4, 12)
      Cumulative duration of exposure to perampanel monotherapy
      Mean (SD)41.0 (25.5) weeks6.1 (NR)
      In Study 504, the median cumulative duration of exposure to perampanel was reported. NR, not reported; SD, standard deviation.
      months
      13.5 (11.8) monthsNRNR14.8 (9.1) monthsNRNR
      Range1.1–85.4 weeks0.5–44.1 months0.6–41.7 months4–27 monthsNR1.0–57.0 months3–12 months1–>12 months
      a The maximum dose is presented for Studies 342, 504, and 506. The maintenance dose is presented for the Delgado et al. study. The daily dose is presented for the Chinvarun study. The last perampanel dose is presented for the Macrohon et al. study.
      b In Study 504, the median cumulative duration of exposure to perampanel was reported.NR, not reported; SD, standard deviation.

      4.3 Efficacy outcomes of perampanel monotherapy

      Although the approaches of efficacy assessments varied across studies, retention rate was the most commonly reported efficacy endpoint and was the primary endpoint for four of the eight studies (Table 1). Retention rates at 3, 6, 12, 18, and 24 months from perampanel initiation are shown in Fig. 2 for Studies 504 and 506, and Toledano Delgado et al. and Chinvarun studies. After 12 months, 55.6% (n = 15/27), 48.7% (n = 19/39), 81.0% (n = 68/84), and 61.0% (n = 25/41) of patients remained on the treatment of perampanel monotherapy in these four studies [
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ,
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ,
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ]. For patients with newly diagnosed epilepsy, it is important to achieve seizure freedom with early-line treatments, particularly ASM monotherapy [
      • Brodie M.J.
      • Barry S.J.E.
      • Bamagous G.A.
      • Norrie J.D.
      • Kwan P.
      Patterns of treatment response in newly diagnosed epilepsy.
      ]. As shown in Fig. 3, the seizure-freedom rates for newly diagnosed FOS were comparable at 74.0% (n = 54/73; at the end of the 4 or 8 mg/day Maintenance Period; primary endpoint) in Study 342 and 76.5% (n = 13/17; 12 months) in the Chinvarun study. Secondary efficacy outcomes, including the median percentage reductions in seizure frequency and 50% and 75% responder rates, from Studies 342, 504, and 506, and the study by Toledano Delgado et al. are presented in Fig. 4, Fig. 5, Fig. 6. Overall, the secondary efficacy outcomes were also comparable across these four studies, although the number of patients who received perampanel monotherapy and had seizure data documented was small (<10 patients) in Study 506.
      Figure thumbnail gr2
      Fig. 2Retention rates of perampanel monotherapy for Studies 504 and 506, and Toledano Delgado et al. and Chinvarun studiesa,b. aRetention rates for the nine patients who received primary monotherapy in Study 504 were as follows: eight were still taking perampanel monotherapy at 3 months and 6 months, six were still taking perampanel monotherapy at 12 months, three were still taking perampanel monotherapy at 18 months, and two at 24 months. bBased on the Safety Analysis Sets from Studies 504 and 506 (PROVE) and the Effectiveness Analysis Set in the Toledano Delgado et al. post-registry study.
      Figure thumbnail gr3
      Fig. 3Seizure-freedom rates of perampanel monotherapy in the (A) Phase III Study 342a and (B) real-world studiesb. aBased on the modified Intent-to-Treat Analysis Set. bIncludes seizure groups with ≥2 patients only. CI, confidence interval; FAS, focal aware seizures; FBTCS, focal to bilateral tonic-clonic seizures; FIAS, focal impaired awareness seizures; GTCS, generalized tonic-clonic seizures; TCS, tonic-clonic seizures.
      Figure thumbnail gr4
      Fig. 4The median percent reductions in seizure frequency per 28 days with perampanel monotherapya. aBased on the Full Analysis Sets from Studies 504 and 506 (PROVE) and the Effectiveness Analysis Set in the Toledano Delgado et al. study.
      Figure thumbnail gr5
      Fig. 5Responder rates in real-world studies of perampanel monotherapy: (A) 50% responder rates and (B) 75% responder ratesa. aBased on the Full Analysis Sets from Studies 504 and 506 (PROVE) and the Effectiveness Analysis Set in the Toledano Delgado et al. study.
      Figure thumbnail gr6
      Fig. 6Additional seizure outcomes with perampanel monotherapy: (A) cumulative probability of time to first seizure or withdrawal in Study 342a and (B) seizure worsening in the Toledano Delgado et al. study. aBased on the modified Intent-to-Treat Analysis Set. CI, confidence interval.
      The remaining four studies included in this review also reported efficacy outcomes, albeit for small populations that are not easily compared to the larger studies. In the Heyman et al. study, one of the two pediatric patients with FOS who received perampanel became seizure free during the study (mean [standard deviation; SD] duration of follow-up, 8.1 [5.2] months) [
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      ], while the other patient had no change in seizure frequency. In the Macrohon et al. study, all five pediatric patients who received monotherapy were seizure free at the time of data collection, although the duration of treatment was not provided for this cohort. Efficacy outcomes for patients who received perampanel monotherapy in the Wehner et al. study were not reported.

      4.4 Safety outcomes of perampanel monotherapy

      The incidences of all treatment-emergent adverse events (TEAEs) and the most common TEAEs reported in ≥5% of patients in any study are shown in Table 4. In Study 342, the majority (75.3% [n = 67/89]) of patients receiving perampanel monotherapy for newly diagnosed FOS reported TEAEs [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ], whereas in the four retrospective, real-world studies [
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ,
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ,
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ], the incidences of TEAEs for perampanel monotherapy were relatively low (20.0–45.9%) and comparable across studies. Moreover, all reported TEAEs were considered mild to moderate in severity in Study 342, and the majority of observed TEAEs were deemed mild in nature in the Chinvarun study [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ]; severity of TEAEs were not reported in the remaining studies. Overall, serious TEAEs were not common (<11%) among patients receiving perampanel monotherapy. In Study 506, one death with an unknown cause was reported in a 71-year-old patient while receiving monotherapy (relationship to perampanel treatment was not recorded) [
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ]. As shown in Table 4, the rates of discontinuation due to TEAEs ranged from 6.7–16.3% among patients receiving perampanel monotherapy. Dizziness, somnolence, and irritability were among the most frequently reported TEAEs, irrespective of study design. In addition, nasopharyngitis and headache occurred in >10% of patients in Study 342 but were not commonly reported in the four real-world studies [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ,
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ,
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ,
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ]. In the remaining three studies, safety outcomes were not specifically reported for patients who received perampanel monotherapy [
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      ,
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      ,
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      ].
      Table 4Incidences of TEAEs and the most common TEAEs (occurring in ≥5% of patients) across studies of perampanel.
      Study 342
      A patient with ≥2 TEAEs is counted only once for that event.
      ,
      Reports patients receiving perampanel as primary or secondary monotherapy.
      ,
      Reports the Core Study data only.
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      Study 504
      A patient with ≥2 TEAEs is counted only once for that event.
      ,
      Reports patients receiving perampanel as primary or secondary monotherapy.
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      Study 506
      A patient with ≥2 TEAEs is counted only once for that event.
      ,
      Reports patients receiving perampanel as primary or secondary monotherapy.
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      Wehner et al.
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      Heyman et al.
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      Toledano Delgado et al.
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      Chinvarun
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      Macrohon et al.
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      (N = 89)(N = 60)(N = 47)(N = 376)
      Reports patients receiving perampanel as monotherapy and adjunctive therapy.
      (N = 24)
      Reports patients receiving perampanel as monotherapy and adjunctive therapy.
      (N = 98)
      Reports patients receiving perampanel as primary or secondary monotherapy.
      (N = 39)
      Reports patients receiving perampanel as primary or secondary monotherapy.
      (N = 65)
      Reports patients receiving perampanel as monotherapy and adjunctive therapy.
      TEAEs, n (%)67 (75.3)12 (20.0)17 (36.2)197 (52.4)16 (66.7)45 (45.9)16 (41.0)35 (53.8)
      Serious TEAEs, n (%)9 (10.1)0 (0.0)2 (4.3)NRNR0NR
      TEAEs leading to discontinuation, n (%)9 (10.1)4 (6.7)7 (14.9)156 (41.5)13 (54.2)16 (16.3)6 (15.4)NR
      The most common TEAEs (occurring in ≥5% of patients)
      Dizziness28 (31.5)3 (5.0)6 (12.8)NRNR
      One of the two pediatric patients who received perampanel monotherapy reported events of nervousness and behavioral deterioration, and the other patient reported restlessness.
      8 (8.1)11 (28.2)6 (9.2)
      Nasopharyngitis13 (14.6)0 (0.0)0 (0.0)NRNRNR
      Somnolence12 (13.5)1 (1.7)2 (4.3)10 (10.2)4 (10.3)13 (20.0)
      Headache10 (11.2)1 (1.7)1 (2.1)NRNRNR
      Irritability3 (3.4)2 (3.3)0 (0.0)17 (17.3)NR4 (6.2)
      Gait disturbance1 (1.1)0 (0.0)3 (6.4)NR6 (15.4)
      Six of the 39 patients who received perampanel monotherapy and had safety assessments reported events of ataxia during the treatment duration of the Chinvarun study. NR, not reported; TEAE, treatment-emergent adverse event.
      8 (12.3)
      Depression1 (1.1)0 (0.0)1 (2.1)10 (10.2)1 (2.6)NR
      Ataxia0 (0.0)0 (0.0)0 (0.0)NR6 (15.4)NR
      a A patient with ≥2 TEAEs is counted only once for that event.
      b Reports patients receiving perampanel as primary or secondary monotherapy.
      c Reports the Core Study data only.
      d Reports patients receiving perampanel as monotherapy and adjunctive therapy.
      e One of the two pediatric patients who received perampanel monotherapy reported events of nervousness and behavioral deterioration, and the other patient reported restlessness.
      f Six of the 39 patients who received perampanel monotherapy and had safety assessments reported events of ataxia during the treatment duration of the Chinvarun study.NR, not reported; TEAE, treatment-emergent adverse event.
      TEAEs related to psychiatric and behavioral disorders, except for irritability, were not consistently reported among patients receiving perampanel monotherapy across studies. In Study 342, no patients experienced TEAEs related to hostility and/or aggression [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ]. In the study by Toledano Delgado et al. 28 (28.5%) patients reported psychiatric TEAEs, of whom 14 patients discontinued due to psychiatric TEAEs (including three patients who experienced events of depression and one patient who experienced an event of irritability that were deemed severe by the treating physician). It was found in that study that women/girls and younger patients were found to be at a significantly higher risk of psychiatric AEs (odds ratio [OR] = 2.85, 95% confidence interval [CI]: 1–8.33; p ≤ 0.046 and OR = 0.97, 95% CI 0.93–1; p ≤ 0.034, respectively) [
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ]. In the study by Heyman et al. the two pediatric patients who received perampanel monotherapy experienced psychiatric and behavioral TEAEs; one patient reported nervousness and behavioral deterioration, the other patient experienced restlessness [
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      ].

      5. Discussion

      Historically, new ASMs were initially licensed as adjunctive therapy rather than monotherapy, due to ethical concerns around placebo-controlled monotherapy trials [
      • Mintzer S.
      • French J.A.
      • Perucca E.
      • Cramer J.A.
      • Messenheimer J.A.
      • Blum D.E.
      • et al.
      Is a separate monotherapy indication warranted for antiepileptic drugs?.
      ]. Following the publication of a white paper in 2015, which advocated a unified indication for ASMs, irrespective of concomitant ASM use [
      • Mintzer S.
      • French J.A.
      • Perucca E.
      • Cramer J.A.
      • Messenheimer J.A.
      • Blum D.E.
      • et al.
      Is a separate monotherapy indication warranted for antiepileptic drugs?.
      ], the FDA determined that it is acceptable to extrapolate efficacy and safety data from adjunctive trials to the monotherapy setting for FOS. Despite challenges in trial design, a number of ASMs, which have demonstrated good efficacy during adjunctive therapy, have subsequently had their original indications expanded to include use in monotherapy settings and have since demonstrated efficacy as monotherapies [

      Food and Drug Administration (FDA). FYCOMPA® Prescribing Information. Available at: https://www.fycompa.com/-/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed February 28, 2022.

      ,

      Food and Drug Administration (FDA). VIMPAT® (lacosamide) Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022253s049,022254s039,022255s031lbl.pdf. Accessed February 28, 2022.

      ]. These monotherapy indications were approved based on studies during which concomitant ASMs were withdrawn (i.e., conversion to monotherapy), or studies that included a ‘pseudo-placebo’ arm in which the comparator included a suboptimal dose of an established active control [
      • Mintzer S.
      • French J.A.
      • Perucca E.
      • Cramer J.A.
      • Messenheimer J.A.
      • Blum D.E.
      • et al.
      Is a separate monotherapy indication warranted for antiepileptic drugs?.
      ].
      The aim of this review was to report evidence of perampanel efficacy and safety in patients with epilepsy who received perampanel as primary or secondary monotherapy (Table 1). This included the prospective, open-label Study 342, which enrolled patients with newly diagnosed FOS, with or without FBTCS, who received perampanel monotherapy at 4 or 8 mg/day [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ], and seven retrospective, real-world studies, including patients with epilepsy who received perampanel as monotherapy or adjunctive therapy during routine clinical care [
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ,
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ,
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ,
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      ,
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ,
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      ]. For the purposes of this review, only patients who received perampanel as monotherapy are presented and discussed here. Due to the differing study designs (Table 1), data from these studies were summarized side-by-side to provide an overview of the efficacy, tolerability, and safety of perampanel monotherapy (Table 2, Table 3, Table 4, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6). Together they show that perampanel monotherapy may be a suitable treatment option for patients with newly diagnosed epilepsy with FOS, or other patients with epilepsy with FOS or IGE who have not responded to treatment with previous ASMs.
      A total of 347 patients receiving perampanel monotherapy were included in this review (Table 2), across geographic regions, age cohorts, ethnic backgrounds, and seizure types. Overall, the most common doses of perampanel monotherapy were 4 and 8 mg/day across studies. In routine care settings, perampanel monotherapy was administered up to 20 mg/day, (the maximum recommended dose is 12 mg/day [

      Food and Drug Administration (FDA). FYCOMPA® Prescribing Information. Available at: https://www.fycompa.com/-/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed February 28, 2022.

      ]), and the maximum doses were similar between primary and secondary monotherapy.
      Following the initiation of, or conversion to perampanel monotherapy, a good proportion (45.0–80.9%) of patients who received perampanel monotherapy were able to maintain the treatment for long periods of time (up to 12 months), irrespective of primary or secondary monotherapy (Fig. 2). Furthermore, the efficacy outcomes in the perampanel monotherapy studies included in this review, including seizure-freedom rates, responder rates, and median percentage reductions in seizure frequency per 28 days, suggest that perampanel monotherapy is efficacious and in line with expected responses from clinical trials of adjunctive perampanel [
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ,
      • French J.A.
      • Krauss G.L.
      • Wechsler R.T.
      • Wang X.-F.
      • DiVentura B.
      • Brandt C.
      • et al.
      Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: A randomized trial.
      ]. The seizure-freedom rate of perampanel monotherapy for newly diagnosed epilepsy with FOS was approximately 63–80% from Study 342 and the Chinvarun study [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ], in which perampanel was received as primary monotherapy in similar patient populations. However, it is important to note that assessment methods varied across studies. Moreover, as reported in the Toledano Delgado et al. study, the seizure-freedom rates were numerically higher in patients who received primary monotherapy relative to those reported in patients receiving secondary monotherapy. These findings are similar to the trend that seizure-freedom rates of lacosamide and eslicarbazepine acetate as primary monotherapy were broadly greater than those reported for secondary monotherapy [
      • Villanueva V.
      • Giráldez B.G.
      • Toledo M.
      • De Haan G.J.
      • Cumbo E.
      • Gambardella A.
      • et al.
      Lacosamide monotherapy in clinical practice: A retrospective chart review.
      ,
      • Villanueva V.
      • Bermejo P.
      • Montoya J.
      • Massot-Tarrús A.
      • Galiano M.L.
      • Toledo M.
      • et al.
      MONOZEB: Long-term observational study of eslicarbazepine acetate monotherapy.
      ]. Continuous monitoring of clinical outcomes is warranted to further evaluate the efficacy of perampanel monotherapy, as there are no notable differences or characteristics in therapeutic response between primary and secondary monotherapy in our analysis.
      In addition, two case series articles were identified during our literature search but were not included due to the methodology used in this review. The case series by Kwan et al. included nine patients with uncontrolled FOS or GTCS who converted to perampanel monotherapy during a Phase II or Phase III open-label extension study of adjunctive perampanel, of whom, seven patients remained on secondary monotherapy and the remaining two patients received perampanel monotherapy for ≥91 days before transitioning back to adjunctive perampanel [
      • Kwan P.
      • Mintzer S.
      • Laurenza A.
      • Patten A.
      • Cartwright K.
      Evaluation of perampanel as monotherapy for focal seizures: Experience from open-label extension studies.
      ]. Out of these seven patients, three patients achieved seizure freedom, and the remaining four patients all reported reductions in seizure frequency from baseline. In a retrospective, single-center, real-world study from the United Arab Emirates, Alsaadi et al. reported that seven patients with genetic generalized epilepsy received perampanel monotherapy at the study cut-off date [
      • Alsaadi T.
      • Kassie S.
      • Servano R.
      Efficacy and tolerability of perampanel in patients with genetic generalized epilepsy (GGE): A retrospective, single-center study from the United Arab Emirates (UAE).
      ]; two patients, who had not been exposed to adjunctive perampanel, who both had juvenile myoclonic epilepsy, had no seizures reported during the study. These seizure-freedom results could lend further support that perampanel monotherapy may provide therapeutic benefits for multiple types of seizures.
      Although direct comparisons cannot be made, these results are somewhat consistent with monotherapy studies of other ASMs in patients with primarily newly diagnosed epilepsy [
      • Brodie M.J.
      • Perucca E.
      • Ryvlin P.
      • Ben-Menachem E.
      • Meencke H.-J.
      • Levetiracetam Monotherapy Study Group
      Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy.
      ,
      • Alsaadi T.M.
      • Thieman C.
      Levetiracetam monotherapy for newly diagnosed epilepsy patients.
      ]. In particular, a small retrospective analysis of 13 patients with newly diagnosed epilepsy with FOS, with or without FBTCS, treated with levetiracetam monotherapy, found that 84.6% of patients remained on treatment at 6 months and 54.5% achieved seizure-free status at 6 months after treatment initiation [
      • Alsaadi T.M.
      • Thieman C.
      Levetiracetam monotherapy for newly diagnosed epilepsy patients.
      ]. In another study of patients with newly diagnosed FOS or GTCS, 73.0% and 72.8% of patients were seizure free for ≥6 months at the last evaluated dose with levetiracetam or carbamazepine, respectively [
      • Brodie M.J.
      • Perucca E.
      • Ryvlin P.
      • Ben-Menachem E.
      • Meencke H.-J.
      • Levetiracetam Monotherapy Study Group
      Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy.
      ]. Lamotrigine monotherapy has been shown to result in a seizure-freedom rate (in the 24-week Maintenance Period) of 43.1% in patients with newly diagnosed or recurrent FOS (including FBTCS) or GTCS [
      • Yamamoto T.
      • Hong S.B.
      • Shimizu M.
      • Sato K.
      • Numachi Y.
      Lamotrigine monotherapy in newly diagnosed epilepsy or recurrent epilepsy: a multi-center, open-label study.
      ]. A prospective, randomized, pragmatic trial also assessed the efficacy of phenobarbitone, phenytoin, carbamazepine, and sodium valproate in patients with newly diagnosed FOS, with or without FBTCS, or tonic-clonic seizures. At 6 months, 51% of patients overall were seizure free (phenobarbitone: 49%; phenytoin: 51%; carbamazepine: 56%; valproic acid: 50%) [
      • Heller A.J.
      • Chesterman P.
      • Elwes R.D.
      • Crawford P.
      • Chadwick D.
      • Johnson A.L.
      • et al.
      Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.
      ]. Finally, the International League Against Epilepsy (ILAE) reviewed the evidence for use of ASMs as initial monotherapy and reported 26-week seizure-freedom rates of 83.7% and 79.4% for carbamazepine and zonisamide, respectively, in adults with new-onset FOS [
      • Glauser T.
      • Ben-Menachem E.
      • Bourgeois B.
      • Cnaan A.
      • Guerreiro C.
      • Kälviäinen R.
      • et al.
      Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.
      ,
      • Baulac M.
      • Brodie M.J.
      • Patten A.
      • Segieth J.
      • Giorgi L.
      Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.
      ].
      As approximately 80% of patients with epilepsy are maintained on a single ASM in the first year after diagnosis [
      • Kwan P.
      • Brodie M.J.
      Early identification of refractory epilepsy.
      ,
      • Groth A.
      • Wilke T.
      • Borghs S.
      • Gille P.
      • Joeres L.
      Real life pharmaceutical treatment patterns for adult patients with focal epilepsy in Germany: a longitudinal and cross-sectional analysis of recently approved anti-epileptic drugs.
      ], and often continue the treatment which they were initially prescribed, the ability to use an effective ASM as initial monotherapy is critical. In a previous study of 470 patients with previously untreated epilepsy, it was found that 47.2% of patients achieved seizure freedom with the first ASM they received, compared with 14.3% and 2.6% of patients who achieved seizure freedom with the second or third/multiple ASMs [
      • Kwan P.
      • Brodie M.J.
      Early identification of refractory epilepsy.
      ]. These results suggest that achieving seizure control with monotherapy is a reasonable goal for most patients and response to the first ASM is an important prognostic factor. As such, the observed seizure-freedom rates in Study 342 and the retrospective studies are promising and suggest that perampanel may be a suitable first-line ASM treatment in some patients.
      Across all studies, perampanel monotherapy was generally well tolerated and no new safety concerns were observed as compared with adjunctive perampanel studies [
      • French J.A.
      • Krauss G.L.
      • Biton V.
      • Squillacote D.
      • Yang H.
      • Laurenza A.
      • et al.
      Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304.
      ,
      • French J.A.
      • Krauss G.L.
      • Steinhoff B.J.
      • Squillacote D.
      • Yang H.
      • Kumar D.
      • et al.
      Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305.
      ,
      • Krauss G.L.
      • Serratosa J.M.
      • Villanueva V.
      • Endziniene M.
      • Hong Z.
      • French J.
      • et al.
      Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures.
      ,
      • French J.A.
      • Krauss G.L.
      • Wechsler R.T.
      • Wang X.-F.
      • DiVentura B.
      • Brandt C.
      • et al.
      Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: A randomized trial.
      ]. The most commonly reported TEAEs across studies included dizziness, somnolence, and irritability (Table 4), which are consistent with the known safety profile of perampanel [

      Food and Drug Administration (FDA). FYCOMPA® Prescribing Information. Available at: https://www.fycompa.com/-/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed February 28, 2022.

      ]. For studies that reported such data, the incidences of serious TEAEs ranged from 0.0 to 10.1% for perampanel monotherapy. Overall, these data are in line with expectations, since TEAEs tend to be less frequent and often less severe with ASM monotherapy compared with adjunctive therapy due to the absence of pharmacokinetic or pharmacodynamic interactions with adjunctive ASMs [
      • Mintzer S.
      • French J.A.
      • Perucca E.
      • Cramer J.A.
      • Messenheimer J.A.
      • Blum D.E.
      • et al.
      Is a separate monotherapy indication warranted for antiepileptic drugs?.
      ]. However, direct comparisons between real-world observational studies and randomized clinical trials cannot be made due to inherent differences in study design and analysis methods. For example, in Study 342, most patients received perampanel 4 mg/day, whereas in the pivotal adjunctive therapy trials the majority of perampanel-treated patients were randomized to receive higher perampanel doses (up to 12 mg/day), and higher doses may be associated with a greater incidence of TEAEs [
      • Ko D.
      • Yang H.
      • Williams B.
      • Xing D.
      • Laurenza A.
      Perampanel in the treatment of partial seizures: Time to onset and duration of most common adverse events from pooled Phase III and extension studies.
      ]. Meanwhile, in real-world studies, TEAEs were only reported if they had been recorded in patient notes during routine clinical care, which may have led to an underrepresentation of TEAEs in these studies.
      The most frequently reported TEAE related to behavior and/or psychiatric disorders was irritability; however, no events of irritability were reported during Study 506 in patients receiving perampanel monotherapy. Although the reason for this is unclear, the higher proportion of patients receiving primary monotherapy in Study 506 (70.2%) may have resulted in greater tolerability compared with Study 504, in which the majority of patients received secondary monotherapy (85.0%). In Study 504, it is possible that the decision to convert to secondary monotherapy may have been made to reduce side effects associated with adjunctive treatment [
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ]. The duration of epilepsy and that of perampanel dosage were otherwise similar between both studies. In the Chinvarun study, only one patient reported an event of depression and no events of irritability were reported; the relatively low incidence of psychiatric TEAEs in this study is in line with what has been reported in Studies 342, 504, and 506 [
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ]. Interestingly, in the Toledano Delgado et al. study, 28.5% of patients had psychiatric AEs, and severe psychiatric AEs were reported in 4.1% of patients [
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ]. The most common psychiatric AEs among patients who received perampanel in the study were irritability (17.3%) and depression (10.2%) [
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ]. These rates are slightly higher than what has been reported in the studies discussed above as well as regulatory trials [
      • Ettinger A.B.
      • LoPresti A.
      • Yang H.
      • Williams B.
      • Zhou S.
      • Fain R.
      • et al.
      Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel.
      ]. This discrepancy could be due to the short-term Follow-up Periods or the exclusion of patients with antecedent psychiatric comorbidities in regulatory trials, which could limit the interpretation of the increased incidence of behavioral/psychiatric TEAEs reported by Toledano Delgado et al. Despite incidences of psychiatric TEAEs (of any severity) varying across studies, the totality of clinical evidence presented here suggests that severe psychiatric TEAEs may not be common with perampanel monotherapy.
      The data presented here indicate favorable retention rates and robust efficacy in patients receiving perampanel monotherapy and are similar to those reported for other ASMs when administered as monotherapy [
      • Yamamoto T.
      • Hong S.B.
      • Shimizu M.
      • Sato K.
      • Numachi Y.
      Lamotrigine monotherapy in newly diagnosed epilepsy or recurrent epilepsy: a multi-center, open-label study.
      ,
      • Heller A.J.
      • Chesterman P.
      • Elwes R.D.
      • Crawford P.
      • Chadwick D.
      • Johnson A.L.
      • et al.
      Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.
      ,
      • Glauser T.
      • Ben-Menachem E.
      • Bourgeois B.
      • Cnaan A.
      • Guerreiro C.
      • Kälviäinen R.
      • et al.
      Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.
      ,
      • Trinka E.
      • Ben-Menachem E.
      • Kowacs P.A.
      • Elger C.
      • Keller B.
      • Löffler K.
      • et al.
      Efficacy and safety of eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: A phase III double-blind, randomized, parallel-group, multicenter study.
      ]. ASM monotherapy may offer advantages over polytherapy, such as increased treatment compliance [
      • St Louis E.K.
      Monotherapy to polytherapy: antiepileptic drug conversions through the spectrum of epilepsy care.
      ]. Moreover, perampanel has the advantage of once-daily dosing due to the relatively long half-life of ∼105 h [

      Food and Drug Administration (FDA). FYCOMPA® Prescribing Information. Available at: https://www.fycompa.com/-/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf. Accessed February 28, 2022.

      ]. ASM formulations with a long half-life or extended-release formulations may offer particular benefits to patients as initial therapy by reducing the risk of a seizure after missed doses. Perampanel may be a particularly valuable monotherapy option in cases where patients are struggling to adhere to their treatment regimens and for adolescent patients who may find it difficult to comply with more complex treatment regimens. However, further studies investigating the efficacy and safety of perampanel monotherapy across different seizure types and in different patient populations, such as adolescents and the elderly, may be required.
      It should be noted that the studies summarized in this review have certain limitations. For example, Study 342 was a prospective Phase III trial, but there was no placebo control arm due to ethical concerns regarding using a placebo in monotherapy trials, and the use of fixed doses of perampanel may not necessarily reflect clinical practice [
      • Yamamoto T.
      • Lim S.C.
      • Ninomiya H.
      • Kubota Y.
      • Shin W.C.
      • Kim D.W.
      • et al.
      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).
      ]. Furthermore, given that Study 342 was an open-label clinical trial, investigators and patients might have inherent bias on the clinical outcomes. Studies 504 and 506, the Toledano Delgado et al. study, and the Chinvarun study were retrospective in design, which by design makes it difficult to determine any causal relationship between clinical outcomes and the treatment. Hence, there is room for a variety of unknown biases, such as variable data-collection and follow-up approaches across study sites, and a lack of complete and detailed efficacy data in patient-reported seizure diaries; such bias could limit interpretation of clinical outcomes from retrospective studies [
      • Wechsler R.T.
      • Wheless J.
      • Zafar M.
      • Huesmann G.R.
      • Lancman M.
      • Segal E.
      • et al.
      PROVE: Retrospective, non‐interventional, Phase IV study of perampanel in real‐world clinical care of patients with epilepsy.
      ,
      • Gil-Nagel A.
      • Burd S.
      • Toledo M.
      • Sander J.W.
      • Lebedeva A.
      • Patten A.
      • et al.
      A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy.
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ,
      • Toledano Delgado R.
      • García‐Morales I.
      • Parejo‐Carbonell B.
      • Jiménez‐Huete A.
      • Herrera‐Ramirez D.
      • González‐Hernández A.
      • et al.
      Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.
      ]. Notably, in Study 506, the Full Analysis Set included only 11/47 patients who were on perampanel monotherapy at baseline, and only five of these patients had efficacy data at end of treatment. In the studies by Wehner et al. Heyman et al. Chinvarun, and Macrohon et al. the number of patients who received perampanel monotherapy was relatively small (n = <100) compared with typical Phase III studies of adjunctive perampanel [
      • Wehner T.
      • Mannan S.
      • Turaga S.
      • Vallabhaneni K.
      • Yip H.M.
      • Wiggans C.
      • et al.
      Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center.
      ,
      • Chinvarun Y.
      A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.
      ,
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Epstein O.
      • Lazinger M.
      • Berkovitch M.
      • et al.
      Tolerability and efficacy of perampanel in children with refractory epilepsy.
      ,
      • Macrohon B.
      • Janette Resurreccion-De La Calzada J.
      • Sanchez-Gan B.
      Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.
      ]. Moreover, patients who received perampanel monotherapy at clinics, which were not involved in the studies selected for this review, were not being analyzed or discussed here; it is possible that the patient cohorts included in this review may not represent the overall population of patients who received perampanel monotherapy during routine clinical care. As such, the population sizes of perampanel monotherapy studies were generally small, which could limit the interpretation of efficacy data, especially at later time points.
      Although there are limitations, the studies included in this review contribute important information on the use of ASMs as monotherapy. Real-world studies, in particular, provide valuable information on the use of ASMs outside the confines of randomized controlled trials. For example, although the number of patients receiving perampanel monotherapy during Studies 504 and 506 was relatively small, these results provide important insights into the use of perampanel monotherapy in real-life clinical practice settings and demonstrate that seizure control with perampanel monotherapy may be achievable in some patients with epilepsy, irrespective of prior ASM use. Furthermore, given that a high proportion of patients in these studies had refractory disease, the retention rates reported with perampanel monotherapy are particularly encouraging.

      6. Conclusions

      Overall, the clinical experience reported to date supports the use of perampanel monotherapy in both newly diagnosed patients and those who have been unable to control their seizures with other ASMs. The data reported here support the use of perampanel as a treatment option when initiated as first-line treatment, and when conversion to perampanel monotherapy requires withdrawing other ASMs. In both cases, these results suggest that seizure freedom may be achieved following treatment with perampanel received as primary or secondary monotherapy in newly diagnosed patients and in patients whose seizures were refractory. Since seizure freedom was observed in over 60% of newly diagnosed patients receiving perampanel 4 mg/day, this may suggest that patients who are earlier on in their epilepsy journey and/or have less refractory epilepsy may achieve seizure control with lower perampanel doses than are commonly used in patients whose seizures are very refractory, resulting in better tolerability. As suggested for the ASM class, and in line with the recommendations in the prescribing information, psychiatric symptoms should be monitored upon the initiation of perampanel treatment, especially when increasing perampanel dose. As studies of perampanel monotherapy to date are limited, more data are expected to be accumulated in the future.

      Acknowledgments

      Medical writing support, under the direction of the authors, was provided by Laura George, PhD, Adele Edwards, PhD, and Can Huang, PhD, of CMC AFFINITY, a division of IPG Health Medical Communications, funded by Eisai Inc., in accordance with Good Publication Practice (GPP3) guidelines.

      Declaration of conflicting interests

      Takamichi Yamamoto has received speaker's honoraria from Daiichi-Sankyo, Eisai, LivaNova, Otsuka Pharmaceutical, and UCB Japan; has participated in advisory boards for Eisai; and has served as the Sponsor's Responsible Medical Officer for the FREEDOM Trial (Study 342).
      Antonio Gil-Nagel has served in speakers bureau and advisory boards for Arevelle, Bial, Biocodex, Esteve, Eisai, GW Pharmaceutical, PTC Therapeutics, Stoke, UCB Pharma, and Zogenix.
      James Wheless has received grant support from Aquestive, Eisai, Greenwich, INSYS Inc., LivaNova, Mallinckrodt, Neurelis, NeuroPace, the Shainberg Foundation, and West; has served as a consultant for Aquestive, BioMarin, Eisai, Greenwich, Mallinckrodt, Neurelis, NeuroPace, Shire, Supernus, and Zogenix; and has received speaker bureau honoraria from BioMarin, Eisai, Greenwich, LivaNova, Mallinckrodt, and Supernus.
      Ji Hyun Kim has no real or apparent conflicts of interest to disclose in relation to this work.
      Robert T Wechsler has been a clinical trial investigator for Aquestive, Biogen, Cavion, Cerevel, Eisai, Engage Pharma, Greenwich Biosciences, Lundbeck, Otsuka, Pfizer, SK Life Science, Sunovion, UCB Pharma, Xenon, and Zogenix; has served on advisory boards and/or carried out consulting work for Brain Sentinel, Cerevel, Eisai, Engage Pharma, Greenwich Biosciences, Lundbeck, Otsuka, SK Life Science, Sunovion, and UCB Pharma; has received speaker bureau honoraria for Aquestive, Eisai, Greenwich Biosciences, LivaNova, Neurelis, SK Life Science, Sunovion, and UCB Pharma; and is a member of the Epilepsy Study Consortium.

      Funding

      The author(s) disclose receipt of the following financial support for the research, authorship, and/or publication of this article: Study 504 was funded by Eisai Ltd. and Eisai Inc. Study 506 was funded by Eisai Inc. Study 342 was funded by Eisai Co., Ltd. The study by Toledano Delgado et al. was funded by an unrestricted grant from Eisai (RTD-PER-2018-01).

      Author contributions

      Takamichi Yamamoto served as Sponsor’s Responsible Medical Officer for Study 342 (NCT03201900), and contributed to the study design and protocol development.
      Antonio Gil-Nagel coordinated recruitment of patients into Study 504 (NCT02736162) and contributed to the acquisition of the data.
      James Wheless coordinated recruitment of patients into Study 506 (NCT03208660) and contributed to the acquisition of the data.
      Ji Hyun Kim coordinated recruitment of patients into Study 342 (NCT03201900).
      Robert T Wechsler contributed to the conception, design, and acquisition of the data for Study 506 (NCT03208660), and coordinated recruitment of patients into the study.
      All authors had access to the data, were involved in the decision to submit this article for publication, contributed to data interpretation, reviewed the manuscript, and approved the final version for submission.

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