Drugs DOI 10.1007/s40265-015-0465-z

ADIS DRUG EVALUATION

Perampanel: A Review in Drug-Resistant Epilepsy James E. Frampton1

Ó Springer International Publishing Switzerland 2015

Abstract Perampanel (FycompaÒ), an orally-active, selective, noncompetitive a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor antagonist, is a first-in-class antiepileptic drug (AED) offering the convenience of once-daily administration. In the EU and US, perampanel is approved in patients with epilepsy aged C12 years for the adjunctive treatment of primary generalized tonic-clonic seizures (GTCS) and partial-onset seizures (POS; with or without secondary generalization). In phase III trials of 17 or 19 weeks’ duration, add-on perampanel B12 mg/day significantly improved seizure control in patients aged C12 years who were experiencing either primary GTCS or POS (with or without secondary generalization), despite ongoing treatment with stable dosages of one to three AEDs. Improvements in seizure control were maintained for up to 2 years in extensions of these core studies. Perampanel also provided sustained seizure control for up to &4 years in an extension of two phase II studies in patients aged C18 years with drug-resistant POS. Adjunctive perampanel therapy was generally well tolerated. Treatment-emergent adverse events were most commonly CNS-related (e.g. dizziness, somnolence, fatigue and irritability) and dose-related; however, most

The manuscript was reviewed by: M.J. Brodie, Epilepsy Unit, Western Infirmary, Glasgow, Scotland, UK; G. Krauss, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; P.N. Patsalos, Department of Clinical and Experimental Epilepsy, UCL-Institute of Neurology, London, UK; D. Schmidt, Epilepsy Research Group, Berlin, Germany. & James E. Frampton [email protected] 1

Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand

were of mild to moderate intensity. Clinical experience with perampanel is accumulating, although comparative studies and pharmacoeconomic data that could assist in positioning it relative to other AEDS that are approved and/or recommended as adjunctive therapy are lacking. Nonetheless, on the basis of its overall clinical profile and unique mechanism of action, perampanel is a useful additional adjunctive treatment option for patients with drug-resistant POS, with or without secondary generalization, and primary GTCS.

Adjunctive perampanel therapy in drug-resistant epilepsy: a summary Novel mode of action (AMPA receptor antagonist) Convenient once-daily oral administration at bedtime Specifically evaluated in patients with drug-resistant POS (with or without secondary generalization) and drug-resistant primary GTCS in pivotal studies Dosed to clinical effect, regardless of concomitant (enzyme- or non-enzyme-inducing) AEDs Main tolerability concerns relate to the potential risk of falls and (as with other AEDS) of neuropsychiatric adverse events, including aggressive/hostile behaviours and, uncommonly, suicidality

1 Introduction Epilepsy is the most common serious neurological disorder; it affects [50 million people worldwide, mostly in developing countries [1–3]. Epileptic seizures are divided

J. E. Frampton

into two broad categories: generalized seizures, including primary (idiopathic) generalized tonic-clonic seizures (GTCS), which involve both hemispheres of the brain from the outset of the seizure; and partial-onset seizures (POS), which are initially limited to one hemisphere [4]. POS, which may account for up to &60 % of all epilepsies in the EU and USA [5], can be further divided into three categories: simple partial seizures that are not associated with impairment of consciousness; complex partial (CP) seizures that are associated with impairment of consciousness; and simple or complex partial seizures that evolve into secondary generalized (SG) seizures, including secondary GTCS [4]. Together, primary and secondary GTCS account for up to 50 % of all epilepsy diagnoses [6]; because of related complications, including increases in the risks of seizure-related injuries and sudden unexpected death, prevention of (primary or secondary) GTCS is an important aspect of the therapeutic management of epilepsy [7]. Anti-epileptic drug (AED) therapy forms the mainstay of treatment for most patients with epilepsy [8]; the number of commercially available agents has increased fourfold (to more than 20) over the past two decades [5]. AED monotherapy is the preferred first-line approach [9], with combination (adjunctive or add-on) therapy recommended when two (typically three [5]) adequate trials of AEDs as monotherapy have failed to result in seizure freedom [10]. However, despite the introduction of numerous new AEDs with varying mechanisms of action and improved tolerability, between 15 and 35 % of all patients with epilepsy still fail to achieve long-term remission; this highlights an ongoing need for additional agents with novel modes of action [2, 11, 12]. Moreover, while all newer second- or third-generation AEDs have been evaluated as adjunctive therapy in patients with drug-resistant POS, including those with secondary GTCS, only a small subset have been specifically studied in patients with drug-resistant primary GTCS [7]. Perampanel (FycompaÒ) is a first-in-class, potent, selective, orally-active, noncompetitive a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist [1]. Briefly, AMPA receptors are ligand-gated ion channels activated by glutamate, the major excitatory neurotransmitter in the CNS, which is thought to have an important role in inducing seizures. Although there are other ionotropic glutamate receptors in the CNS (N-methyl-D-aspartate, kainate), AMPA receptors appear to be the predominant mediator of excitatory neurotransmission and are involved in the generation and spread of seizure activity [1]. Perampanel is approved for the adjunctive treatment of POS (with or without SG seizures) in patients aged C12 years with epilepsy in the EU [13] and USA [14]. It is also approved for the adjunctive treatment of

primary GTCS in patients aged C12 years with idiopathic generalized epilepsy (IGE) in the EU [13] and patients aged C12 years with epilepsy in the USA [14]. This article summarizes the pharmacological properties of perampanel and reviews its clinical efficacy and tolerability as an adjunctive therapy in the management of drug-resistant POS and primary GTCS.

2 Pharmacological Properties of Perampanel The pharmacological properties of perampanel have been reviewed in detail previously [1, 15, 16]; only a very brief overview is provided here. The preclinical pharmacodynamic profile of perampanel is characterized by selective and noncompetitive antagonism of AMPA-type glutamate receptors in vitro and the demonstration of anticonvulsant activity in vivo (Table 1). However, the precise mechanism(s) underlying its antiepileptic effect in humans have not been fully elucidated [13, 14]. The pharmacokinetic profile of oral perampanel is characterized by rapid and complete absorption (negligible first-pass effect), extensive metabolism [primarily by cytochrome P450 (CYP)] and slow elimination (Table 1). However, the clearance of perampanel can be markedly increased (and hence its half-life markedly shortened) with concurrent administration of potent inducers of CYP3A enzymes, notably the enzyme-inducing AEDs (EIAEDs) carbamazepine, oxcarbazepine and phenytoin (Table 1). Perampanel is not considered to be a potent inducer or inhibitor of CYP or uridine diphosphoglucose-glucuronosyltransferase enzymes [13, 14].

3 Therapeutic Efficacy of Perampanel The efficacy of adjunctive perampanel therapy has been evaluated in four randomized, double-blind, placebo-controlled, multicentre, phase III trials: one in patients with drug-resistant primary GTCS (study 332 [13, 17, 18]; Sect. 3.1) and three in patients with drug-resistant POS, with or without secondary generalization (studies 304 [19], 305 [20] and 306 [21]; Sect. 3.2). All trial participants were aged C12 years [17–21]. 3.1 Drug-Resistant Primary Generalized Tonic-Clonic Seizures 3.1.1 Short-Term Efficacy To be eligible to enter study 332, patients had to have a clinical diagnosis of primary GTCS in the setting of IGE

Perampanel: A Review Table 1 Key pharmacological properties of oral perampanel Pharmacodynamic profile [1, 13–15] Selectively blocks AMPA receptor-mediated synaptic excitation (e.g. no effect on N-methyl-D-aspartate receptor responses) Displaced from AMPA receptors by other noncompetitive AMPA receptor antagonists (e.g. GYKI 52466), but not by AMPA Exhibits broad-spectrum antiseizure activity in diverse animal seizure models General pharmacokinetic profile [1, 13, 14, 16] Demonstrates dose-proportional increases in exposure over dosage range of 1–12 mg once daily Bioavailability &100 %; peak plasma concentration achieved &0.5–2.5 h after dosing; Css achieved in &2–3 weeks Plasma protein binding is &95 % Extensively metabolized via primary oxidation (mediated by CYP3A4 and/or 3A5, and possibly other CYP isoenzymes) and subsequent glucuronidation 70 and 30 % [13] (48 and 22 % [14]) of dose eliminated in the faeces and urine, respectively (primarily as oxidative and conjugated metabolites)a Apparent clearance is 12 mL/min and average elimination half-life is &105 h Special patient populations [1, 13, 14, 16] Pharmacokinetics not significantly affected by age or ethnicity Exposureb increased (by 1.8-fold) and elimination half-life prolonged (&2.5-fold) in mild hepatic impairment; exposure increased (3.3-fold) and elimination half-life prolonged (&2.1-fold) in moderate hepatic impairment; PER not studied in severe hepatic impairmentc PER not formally studied in renal impairment; however, plasma clearance not influenced by creatinine clearance over range 39–160 mL/minc,d Drug interactions [1, 13, 14, 16] EIAEDs: average Css of PER decreased with concurrently administered EIAEDse CYP3A inducers other than EIAEDs: PER plasma concentrations may be decreased with concurrently administered potent CYP inducers CYP3A inhibitors: average Css of PER increased (by 20 %) with concurrently administered ketoconazole OC: PER 12 mg/day may decrease efficacy of progestative-containing OCs; use of additional reliable methods of contraception is recommended CNS depressants: concomitant use of PER and CNS depressants, including alcohol, may increase CNS depression AMPA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, Css plasma steady-state concentration, CYP cytochrome P450, EIAEDs enzymeinducing anti-epileptic drugs, OC oral contraceptive, PER perampanel, POS partial-onset seizures a

Only trace amounts of PER metabolites are observed in plasma

b

Exposure to free PER, as opposed to exposure to total (free and protein-bound) PER

c

Consult local prescribing information for dosage and administration recommendations in patients with hepatic or renal impairment

d

In patients with refractory POS who received PER B12 mg/day in clinical trials

e

Threefold reduction with carbamazepine; twofold reduction with phenytoin and oxcarbazepine; 20 % reduction with topiramate

(confirmed by external Epilepsy Study Consortium review), with or without other subtypes of primary generalized seizures. They also had to experience at least three primary GTCS during the 4- to 8-week baseline phase of the trial (prior to randomization), despite ongoing treatment with fixed dosages of one to three AEDs (only one of which could be an EIAED) [13, 17, 18]. Patients were randomized to double-blind adjunctive therapy with once-daily perampanel or placebo for 17 weeks (4 weeks’ titration; 13 weeks’ maintenance). During titration, the initial perampanel dosage of 2 mg/day was up-titrated to 8 mg/day or, if this could not be reached, to the maximum tolerated dosage. During maintenance, patients continued on the dosage achieved during titration [17, 18]. Add-on perampanel at dosages of up to 8 mg/day was significantly more effective than placebo in controlling

seizures in patients with drug-resistant primary GTCS, both in terms of the reduction from baseline in primary GTCS frequency, as assessed over the entire double-blind treatment period, and the 50 % responder rate, as assessed over the double-blind maintenance period (co-primary endpoints; Table 2). Improvements in these endpoints were seen regardless of age, gender or race (abstract [23]). Almost one-quarter of perampanel recipients were free of all seizures during the double-blind maintenance period (Table 2); nearly one-third (30.9 %) were free of primary GTCS. In comparison, \5 % of placebo-treated patients were free of all seizures during the double-blind maintenance period (Table 2); only 12.3 % were free of primary GTCS [18]. Among patients with primary GTCS and concomitant myoclonic seizures, 4 (16.7 %) of 24 perampanel recipients versus 3 (13.0 %) of 23 placebo recipients were free of

J. E. Frampton Table 2 Main efficacy findings from phase III trials with perampanel as adjunctive therapy in patients (aged C12 years) with drug-resistant primary generalized tonic-clonic seizures or drug-resistant partial-onset seizures (with or without secondary generalization) Study

Regimen (mg od) [no. of ptsa]

Median BL seizure frequencyb/28 days

Median % change from BL in seizure frequencyb over entire DB treatment periodc,d

50% responder ratee over DB maintenance periodf

Percentage of pts free of all seizures over DB maintenance periodg

23.5

Primary GTCS Study 332 [17, 18]

PER 2–8 [81]

2.6

-76.5***

64.2**

PL [81]

2.5

-38.4

39.5

4.9

PER 8 [133]

14.3

-26.3*

37.6

2.6

PER 12 [133]

12.0

-34.5*

36.1

2.0

PL [121]

13.7

-21.0

26.4

0.0

PER 8 [129]

13.0

-30.5***

33.3**

2.8

PER 12 [121]

13.7

-17.6*

33.9***

6.5

PL [136] PER 2 [180]

11.8 10.1

-9.7 -13.6

14.7 20.6

1.7 1.9

PER 4 [172]

10.0

-23.3**

28.5*

4.4

PER 8 [169]

10.9

-30.8***

34.9***

4.8

9.3

-10.7

17.9

1.2

POS (with or without secondary generalization) Study 304 [19]

Study 305 [20]

Study 306 [21]

PL [184] Pooled analysis [22]

PER 2 [180]

10.1

-13.6

20.6

1.9

PER 4 [172]

10.0

-23.3**

28.5*

4.4*

PER 8 [431]

12.2

-28.8***

35.3***

3.5*

PER 12 [254]

13.0

-27.2***

35.0***

4.1*

PL [441]

11.1

-12.8

19.3

1.0

BL baseline, DB double blind, GTCS generalized tonic-clonic seizures, od once daily, PER perampanel, POS partial onset seizures, PL placebo, pts patients * p \ 0.05, ** p \ 0.01, *** p \ 0.001 vs. PL a

Intent-to-treat analysis set

b

Frequency of primary GTCS in study 332; frequency of all POS in studies 304–306

c

17 weeks (including 4 weeks’ titration) in study 332; 19 weeks (including 6 weeks’ titration) in studies 304–306

d

Co-primary endpoint in study 332; the primary endpoint for the USA in studies 304–306

e

Percentage of pts who experienced C50 % reduction in seizure frequency (primary GTCS in study 332; POS in studies 304–306)

f

Co-primary endpoint in study 332; the primary endpoint for the EU in studies 304–306

g

Where stated, among pts who completed the maintenance period (study 304, study 306, pooled analysis)

all seizures [13]. Among patients with primary GTCS and concomitant absence seizures, 6 (22.2%) of 27 perampanel recipients versus 4 (12.1 %) of 33 placebo recipients were free of all seizures.

baseline in the core study) was generally stable over time from about week 26 through to the end of year 2; it was 65.9 % at the end of year 1 [13]. 3.2 Drug-Resistant Partial-Onset Seizures

3.1.2 Long-Term Efficacy 3.2.1 Short-Term Efficacy The ongoing 142-week, open-label extension (OLE) of study 332 consisted of a conversion period (6 weeks) followed by a maintenance period [17, 18]. Of the 114 patients who entered this extension, 73.7 and 16.7 % had a modal daily perampanel dosage of [4 to 8 and [8 to 12 mg/day, respectively [13]. The 50% responder rate (i.e. the percentage of patients experiencing a C50 % reduction in primary GTCS frequency relative to the pre-perampanel

Studies 304–306 were conducted at centres throughout Europe, Asia, North America, Central/South America, South Africa and Australia. To be eligible to enter one of these similarly designed trials. They also had to experience at least five POS during the 6-week baseline phase (and could not have a seizure-free period C25 days), despite ongoing treatment with stable dosages of one to three

Perampanel: A Review

AEDs (only one of which could be an EIAED). Patients were also required to have failed at least two AEDs in the previous 2 years [19–21]. Patients were randomized to double-blind adjunctive treatment with once-daily perampanel or placebo for 19 weeks (6 weeks’ titration; 13 weeks’ maintenance). During titration, the initial perampanel dosage of 2 mg/day was up-titrated to the assigned target dosage of 2, 4 or 8 mg/day [19, 21], 8 or 12 mg/day [20] or, if this could not be reached, to the maximum tolerated dosage. During maintenance, patients continued on the dosage achieved during titration [19–21]. Patients completing these core studies were eligible to enter a long-term OLE study (study 307 [24]; Sect. 3.2.2). The main findings of the individual studies are presented in Table 2. The primary endpoint data, together with the secondary and exploratory endpoint data, have previously been reviewed in detail [1]; therefore, this section focuses primarily on results from pooled analyses of all three trials that have been published or presented since the earlier article [22, 25–29]. Add-on perampanel at dosages of 4, 8 and 12 mg/day was significantly more effective than placebo in controlling seizures in patients with drug-resistant POS, both in terms of the reduction from baseline in POS frequency over the entire double-blind treatment period and the 50 % responder rate over the double-blind maintenance period (primary endpoints; Table 2) [22]. In subgroup analyses, the efficacy of perampanel in adolescents aged 12–17 years [n = 143 (&10 % of the treated cohort in the pooled analysis)] was consistent with that of the drug in the overall study population [27]. Similarly, the efficacy of perampanel in elderly patients aged C65 years [n = 28 (&2 % of the treated cohort)] was consistent with that of the drug in adults aged C18 to \65 years [n = 1307 (&88 % of the treated cohort)] [28]. The efficacy of perampanel appeared somewhat more pronounced in women than men [29]. There was a significant (p = 0.042) treatment-by-region interaction reflecting high placebo responses in patients from Central/South America who were enrolled in study 304 [n = 160 (&11 % of the treated cohort)] [19, 30]. However, despite the acknowledged confounding, Latin American patients were not excluded from the pooled efficacy dataset that underlies the results presented in Table 2 and Fig. 1 [22]. Among the various secondary and exploratory endpoints, the reduction in the frequency of CP plus SG seizures significantly favoured perampanel 4, 8 and 12 mg/day over placebo (Fig. 1a), as did the reduction in the frequency of SG seizures alone (Fig. 1c). Similarly, the 50 % responder rate for CP plus SG seizures significantly favoured perampanel 4, 8 and 12 mg/day over placebo (Fig. 1b), while the 50 % responder rate for SG seizures

alone significantly favoured perampanel 8 and 12 mg/day over placebo (Fig. 1d) [22]. Seizure-freedom rates during the double-blind maintenance period were also significantly higher in perampanel 4, 8 and 12 mg/day recipients compared with placebo recipients [22] (Table 2). Of note, post hoc analyses of pooled actual (last) dosage data from the phase III trials provided evidence that the efficacy of perampanel was more pronounced when it was coadministered with non-EIAEDs compared with EIAEDs [25]. For perampanel 4, 8 and 12 mg/day recipients (excluding those from Latin America because of confounding; see above), the respective reductions from baseline in POS frequency over the entire double-blind treatment period were 20.1, 36.2 and 47.5 % in those receiving non-EIAEDs compared with 29.0, 26.3 and 17.6 % in those receiving EIAEDs (carbamazepine, oxcarbazepine or phenytoin). The corresponding 50 % responder rates were 35.1, 45.3 and 54.3 % compared with 27.1, 32.4 and 32.9 % [25]. Both the reduction in seizure frequency and increase in responder rate were significant (p \ 0.05 vs. placebo) with perampanel 4 mg/day in patients receiving non-EIAEDs, but not in those receiving EIAEDs. Moreover, the reductions in seizure frequency and increases in responder rates with perampanel 8 and 12 mg/day were significantly (p \ 0.05) greater in patients receiving non-EIAEDs compared with those receiving EIAEDs [25]. Data pooled from studies 304–306 also provides evidence that adjunctive perampanel therapy can improve seizure control without worsening health-related quality of life; moreover, it may reduce cognitive decline (abstract [26]). The distribution of patients with improved, stable or worsened scores (n = 801) was similar between the placebo and perampanel groups for all Quality of Life in Epilepsy Inventory (QOLIE-31-P) scale scores except cognition, where significantly fewer perampanel than placebo recipients experienced worsening (19.3 vs. 27.0 %; p = 0.043) [26]. 3.2.2 Long-Term Efficacy Data regarding the long-term efficacy of adjunctive perampanel therapy in patients with drug-resistant POS are available from interim analyses of two OLEs: one (study 207 [31]) that enrolled patients aged 18–70 years who completed a 12- or 16-week, phase II dose-escalation study [32]; and another (study 307 [24]) that enrolled patients who completed one of the three 19-week, phase III studies described in Sect. 3.2.1. Both OLEs included a titration/conversion period (12 weeks in study 207; 16 weeks in study 307) followed by a maintenance period (up to 424 weeks in study 207; 256 weeks in study 307). During the conversion period

J. E. Frampton

a

b 0 -5 -10 -15 -20 -25 -30 -35

** ** **

-40

50 % responder rate (% of patients)

Median % change from baseline in seizure frequency/28 days

Complex partial plus secondarily generalized seizures Perampanel 2 mg/day (n = 167)

45 40

**

**

*

Perampanel 4 mg/day (n = 157) Perampanel 8 mg/day (n = 393)

35

Perampanel 12 mg/day (n = 233)

30

Placebo (n = 405)

25 20 15 10 5 0

Secondarily generalized seizures

d

0

-10 -20 -30 -40 -50

* **

-60 -70

**

50 % responder rate (% of patients)

Median % change from baseline in seizure frequency/28 days

c

Perampanel 2 mg/day (n = 68)

70

Perampanel 4 mg/day (n = 71)

** 60

Perampanel 8 mg/day (n= 157)

* 50

Perampanel 12 mg/day (n = 95) Placebo (n = 173)

40 30 20 10 0

Fig. 1 Effect of adjunctive perampanel therapy on complex partial plus secondarily generalized seizures and secondarily generalized seizures only in a pooled analysis of three phase III trials [22]. *p \ 0.01, **p \ 0.001 vs. placebo

(which was blinded in study 307, but not in study 207), patients who received perampanel \12 mg/day or placebo in a core study were up-titrated to the maximum tolerated dosage (up to 12 mg/day); those who received perampanel 12 mg/day in a core study were maintained on this dosage. During the maintenance period, dose adjustments of perampanel and concomitant AEDs were permitted at the investigator’s discretion [24, 31]. In both OLEs, long-term treatment with add-on perampanel at dosages B12 mg/day maintained improvements in seizure control seen during the core studies [24, 31]. In the analysis of study 207 (performed after &4 years), approximately half (46 %) of the 138 patients achieved a maximum tolerated dosage of 8–12 mg/day. The respective median reductions from pre-perampanel baseline in 28-day seizure frequency at 1, 2, 3 and 4 years in patients with C1, 2, 3 and 4 years of perampanel exposure were 43.7, 52.0, 49.7 and 48.4 %; the respective 50 % responder rates were 43.8, 51.5, 49.0 and 50.0 % (n = 89, 66, 52 and 18) [31].

In the analysis of study 307, nearly all (92.3 %) of the 1216 patients in the safety population reached a maximum tolerated dosage of 10 or 12 mg/day; the mean dosage over the maintenance period only was 10.6 mg/day. For all POS, as well as for SG seizures alone, seizure reductions and responder rates in the four patient cohorts analyzed (i.e. those with C26, 39, 52 and 104 weeks of exposure to perampanel) were similar at similar time points. For all POS, the respective median reductions from pre-perampanel baseline in 28-day seizure frequency at 14–26, 27–39, 40–52 and 92–104 weeks in patients with C26, 39, 52 and 104 weeks of peramapanel exposure were 40, 46, 48 and 60 %; the respective 50 % responder rates were 42, 46, 48 and 58 % (n = 1090, 980, 874 and 337). For SG seizures alone, the respective median reductions from preperampanel baseline in 28-day seizure frequency were 67, 77, 80 and 90 % [24]; the respective 50 % responder rates were 60, 65, 68 and 73 % (n = 458, 422, 381 and 141) [33].

Perampanel: A Review

3.2.3 Dose-Response Relationship Analyses of perampanel efficacy based on randomized assignment to a target dosage in phase III studies have clearly demonstrated a positive dose-response relationship between the 4 and 8 mg/day dosages, but not between the 8 and 12 mg/day dosages [30]. However, such analyses may have underestimated the effect of higher dosages due to confounding that occurs as a result of (some) patients being unable to reach the target dosage (e.g. due to poor tolerability). Pharmacokinetic/pharmacodynamic analyses of pooled actual (last) dosage data from the phase III core trials suggested that seizure frequency decreased linearly with increasing perampanel plasma concentration (i.e. exposure) over the 2–12 mg/day dosage range [34]. Furthermore, ad hoc analyses of integrated pooled actual (last) dosage data from the phase III core trials and their OLE suggested that increasing the perampanel dosage from 8 to 12 mg/day could provide additional benefits in seizure control in at least some patients able to tolerate the higher dosage [30]. Excluding patients from Latin America (because of the confounding treatment-by-region effect; see Sect. 3.2.1), a total of 372 patients were randomly assigned to a target dosage of perampanel 8 mg/day in studies 304–306. In the subset of 217 patients who completed the core study maintenance period at 8 mg/day and then had an actual (last) dosage of perampanel 12 mg/day during the OLE blinded titration/conversion period, there was an approximately onethird improvement in the median reduction from baseline in 28-day seizure frequency (from 32.4 % on 8 mg/day during the core study maintenance period to 44.2 % on 12 mg/day during the OLE titration/conversion period) and a slight increase in the 50 % responder rate (from 37.3 to 42.9 %). Similarly, in the subset of 181 patients who completed the core study maintenance period at 8 mg/day and then had an actual (last) dose of perampanel 12 mg/day during the first 13 weeks of the OLE maintenance period, there was an approximately one-third improvement in the median reduction from baseline in 28-day seizure frequency (from 34.1 to 46.0 %) and an increase in the 50 % responder rate (from 39.2 to 46.4 %). Corresponding analyses of subsets of patients who completed the core study maintenance period at 12 mg/day and continued on this dosage during the OLE showed that seizure control was at least maintained in these individuals [30].

4 Tolerability of Perampanel 4.1 Short-Term Tolerability Adjunctive use of perampanel was generally well tolerated across the phase III core POS studies (see Sect. 3.2.1), with

treatment-emergent adverse events (TEAEs) being largely mild or moderate in severity [1]. Pooled data from these three trials showed that the reporting of at least one TEAE was dose-related: 64.5, 81.2 and 89.0 % of perampanel 4, 8 and 12 mg/day recipients (n = 172, 431 and 255) compared with 66.5 % of placebo recipients (n = 442) reported any TEAE [22, 35]. The overall incidence of TEAEs in perampanel 2–12 mg/day recipients was generally similar in the presence and absence of EIAEDs [25], while that in perampanel 12 mg/day recipients was similar, regardless of the number of concomitant AEDs at baseline (abstract [36]). The four most common TEAEs considered to be adverse drug reactions (ADRs) were dizziness (16.3, 31.8 and 42.7 % with perampanel 4, 8 and 12 mg/day vs. 9 % with placebo), somnolence (9.3, 15.5 and 17.6 vs.7.2 %), fatigue (7.6, 8.4 and 12.2 vs. 4.8 %) and irritability (4.1, 6.7 and 11.8 vs. 2.9 %) [22]; most of these events occurred during initial titration [37]. Other common ADRs included nausea (2.9, 5.8 and 7.8 vs. 4.5 %) and falls (1.7, 5.1 and 10.2 vs. 3.4 %) [22]. Of note, dizziness (45.0 vs. 28.6 %), fatigue (25.0 vs. 8.7 %) and fall (25.0 vs. 4.9 %), occurred at a numerically higher rate in elderly (n = 20) versus adult (n = 920) perampanel-treated patients [28]. The most common TEAE not considered to be an ADR was headache (11.0, 11.4 and 13.3 % with perampanel 4, 8 and 12 mg/day vs. 11.3 % with placebo) [22]. Serious TEAEs were reported by 3.5, 5.6 and 8.2 % of perampanel 4, 8 and 12 mg/day recipients compared with 5.0 % of placebo recipients; serious psychiatric disorder TEAEs were reported by 1.2 % of perampanel recipients versus 0.9 % of placebo recipients [22, 35, 38]. The rate of TEAEs leading to early withdrawal was clearly related to dose: 2.9, 7.7 and 19.2 % of perampanel 4, 8 and 12 mg/day recipients compared with 4.8 % of placebo recipients prematurely discontinued because of TEAEs (most frequently dizziness, convulsion and somnolence) [22, 35]. A post hoc analysis of data pooled from the phase III core POS studies suggested that falls were related to perampanel exposure, both in patients having concurrent seizures and those not having concurrent seizures, albeit (as expected) falls occurred more frequently in the former (abstract [39]). Overall, more perampanel 2–12 mg/day recipients than placebo recipients experienced falls (5.1 vs. 3.4 %); one perampanel 12 mg/day recipient had a serious fall [22, 39]. Another post hoc analysis of data pooled from the phase III core POS studies that used ‘narrow-and-broad’ MedDRA Standardized Medical Query (SMQ) terms to identify TEAEs suggestive of hostility/aggression indicated the presence of a dose-response relationship: 5.2, 12.3 and 20.4 % of perampanel 4, 8 and 12 mg/day recipients

J. E. Frampton

compared with 5.7 % of placebo recipients reported events within this SMQ [most frequently irritability (4.1, 6.7 and 11.8 vs. 2.9 %; see above) and aggression (0.6, 1.6 and 3.1 vs. 0.5 %)] [38]. Two patients receiving perampanel 12 mg/day and one receiving perampanel 2 mg/day (compared with none receiving placebo) reported a serious TEAE of aggression, while no perampanel 4–12 mg/day (or placebo) recipient reported a serious TEAE of irritability [22, 38]. Psychic and behavioural TEAEs generally occurred within the first 6 weeks of treatment with perampanel [38]. Among perampanel 2–12 mg/day recipients, suiciderelated TEAEs occurred with a similar frequency to that in placebo recipients, according to a retrospective review of data pooled from the phase II and III core POS studies and their OLEs (abstract [40]). The exposureadjusted rate of these events was 0.008 patients/patientyear for perampanel (n = 1651; overall exposure 2281 patient-years) versus 0.012 patients/patient-year for placebo (n = 510; overall exposure 165 patient-years). 18 perampanel recipients (1.1 %) reported a suicide-related TEAE, with 13 events being considered serious and 11 leading to study discontinuation, although none resulted in patient death. In comparison, two placebo recipients (0.4 %) reported a suicide-related TEAE; neither event led to study discontinuation or patient death. The incidence of suicide-related TEAEs in the phase III core POS studies was 0.3 % (3 of 1038 patients) with perampanel versus 0.5 % (2 of 442 patients) with placebo [40]. Clinically significant weight gain ([7 % increase in bodyweight) occurred in 14.0, 15.3 and 15.4 % of perampanel 4, 8 and 12 mg/day recipients compared with 7.1 % of placebo recipients [22]. There were no clinically important mean changes in laboratory parameters or vital signs in perampanel-treated patients [22]. In addition, and consistent with the results of a thorough QT study [41], there was no evidence that perampanel at dosages B12 mg/day increased QT interval duration [41] or the risk of cardiac or ECG-related TEAEs compared with placebo (abstract [42]). The adverse event profile of perampanel at dosages of up to 8 mg/day in patients with drug-resistant primary GTCS was similar to that of the drug at dosages of up to 12 mg/day in patients with drug-resistant POS [18]. 4.2 Long-Term Tolerability In general, the tolerability profile of adjunctive perampanel therapy in OLEs of phase II or III trials has been similar to that reported in the core studies; no new safety signals have emerged during long-term treatment for up to 3 [24] or &4

Table 3 Main tolerability findings from an open-label extension of phase III trials with perampanel as adjunctive therapy in patients (aged C12 years; n = 1216) with drug-resistant partial-onset seizures (with or without secondary generalization) [24] C1 AEs occurred in 91 % of pts; AEs mild to moderate in intensity in 80 % of these pts AEs led to study discontinuation in 16 % of pts; only AEs leading to discontinuation in [1% of pts were dizziness and irritability AEs occurring in C10 % of pts were dizziness, somnolence, headache, fatigue, irritability and (unspecified) weight increase SAEs occurred in 18.7 % of pts; only SAEs occurring in [1 % of pts were epilepsy-related [convulsion (3.0 %) and status epilepticus (1.1 %)] An SAE of aggression occurred in 1.0 % of pts; none of the 12 patients had a medical history of aggression Suicidal ideation occurred in 0.5 % of pts; suicide attempt occurred in 0.3% of pts No clinically relevant changes in vital signs, ECG parameters or laboratory values Clinically significant weight gain ([7 % :) occurred in 37.8 % of pts; clinically significant weight loss ([7 % ;) occurred in 11.0 % of pts (S)AEs (serious) adverse events, pts patients, : increase, ; decrease

[31] years. At the time of the interim analysis of study 307 [24] (see Sect. 3.2.2), the median duration of exposure to perampanel was &1.5 years; total exposure to perampanel was [1803 patient-years. The main findings from study 307 are summarized in Table 3.

5 Dosage and Administration of Perampanel In the EU and US, perampanel should be taken orally once daily at bedtime, with or without food, and titrated based upon individual clinical response and tolerability. In the event of a single missed dose, the patient should wait and take their next dose as scheduled [13, 14]. Perampanel therapy should be initiated at a dosage of 2 mg/day (or 4 mg/day in patients receiving EIAEDs in the US [14]); the dosage may be increased by increments of 2 mg/day to a maintenance dosage appropriate for the indication (maximum 12 mg/day) [13, 14]. Upward dosage titration should occur no more frequently than at 2-week intervals (or at 1-week intervals in patients receiving concomitant drugs that shorten the elimination half-life of perampanel, e.g. EIAEDs) in the EU [13], and no more frequently than at weekly intervals in the US [14]. Some other aspects of dosage and administration recommendations vary between the EU [13] and the US [14]; local prescribing information should be consulted for more detailed information on posology (including use and any dosage adjustments required in special patient populations), warnings and precautions, and drug interactions.

Perampanel: A Review

6 Place of Perampanel in the Management of Drug-Resistant Epilepsy For the clinician treating a patient with epilepsy who has failed initial monotherapy, the choice of which AED to use as the first adjunctive therapy primarily rests on individual patient and drug characteristics, such as the patient’s age, gender and weight, the efficacy of the AED against the seizure type, the tolerability profile of the AED, the AED dosing regimen and propensity for drug interactions with concomitant medications, and the presence of concomitant diseases. Cost can also be a consideration [5, 43–45]. An almost complete lack of head-to-head comparative data compounds the challenge of selecting an appropriate adjunctive agent from among the many available possibilities. Furthermore, despite (or because of) the highly systematic, regulatory-driven process underlying the development of newer AEDs, these agents cannot be differentiated from one another in terms of efficacy and tolerability, based on indirect comparisons [5, 7, 43, 46]. Against this background, perampanel is a first-in-class AMPA receptor antagonist (Sect. 1) that offers a unique mechanism of action compared with other currently available AEDs. Advocated for more than two decades, the concept of ‘rational’ polytherapy (i.e. adding an AED with a different mechanism of action to the one that is already being given—and failing—as this may improve efficacy compared with adding an AED with the same mechanism of action) has been adopted by many physicians [5, 43], albeit this principle has not been unequivocally demonstrated [43]. In the EU and US, adjunctive use of perampanel is indicated in adolescent and adult patients with POS, with or without secondary generalization, and those with primary GTCS (Sect. 1). These approvals are based on the results of short-term phase III trials in which peramapanel dosages B8 mg/day significantly improved seizure control in patients aged C12 years who had drug-resistant primary GTCS (Sect. 3.1) and perampanel dosages between 4–12 mg/day significantly improved seizure control in patients aged C12 years who had drug-resistant POS, with or without secondary generalization (Sect. 3.2.1). As regards longer-term efficacy, interim results showed that add-on perampanel B12 mg/day maintained improvements in seizure control for up to 2 years in OLEs of these phase III core studies, and for up to &4 years in an OLE of two phase II studies in patients with drug-resistant POS (Sects. 3.1.2, 3.2.2). Pooled data from phase III studies in adolescent and adult patients with drug-resistant POS suggested that adjunctive perampanel therapy could improve seizure control without worsening health-related quality of life

(Sect. 3.2.1). Moreover, there was evidence of a positive effect of the drug on cognition, based on the QOLIE-31-P cognitive functioning subscale score (Sect. 3.2.1). In comparison, adjunctive perampanel had no overall impact on cognition in a short-term phase II study that only enrolled adolescents with drug-resistant POS, based on the Cognitive Drug Research system global cognition score [47]. Published prior to the availability of perampanel, a review of relevant data for other AEDs suggested that the effect of an agent on cognition (e.g. positive or negative) could vary depending on both patient characteristics and drug-related variables [48]. Adjunctive perampanel was generally well tolerated in short-term phase III studies in patients with drug-resistant primary GTCS or POS, and no new safety signals have been identified during long-term treatment (up to 4 years) in OLEs of phase II or III trials in patients with drugresistant POS (Sect. 4). Special warnings and precautions for use set out in the EU label for perampanel include those relating to the risks of aggression, suicidal ideation and falls [13]. In comparison, the US label for the drug includes a boxed warning about the risk of serious psychiatric and behavioural reactions; it also includes warnings and precautions relating to suicidal behaviour and ideation, and falls [14]. Nearly all AEDs cause some degree of cognitive, psychiatric or behavioural adverse reactions [49], and the association of these agents with increased suicide risk has been interpreted as likely representing a class effect [50, 51]. However, the reason underlying the apparent increased risk of falls, particularly in the elderly, with perampanel is unclear [13]. By virtue of its long half-life (Sect. 2), perampanel can be administered conveniently once daily (orally; at bedtime); this should aid patient compliance and, in the event of a missed dose, will have only minimal impact on seizure control [16]. Perampanel must be titrated based on clinical response and tolerability [13, 14]. Recommended maintenance dosages range from 4 to 12 mg/day [13, 14], the latter being the maximum recommended dosage (Sect. 5). According to perampanel labelling, patients able to tolerate an increase in their maintenance dosage from 8 to 12 mg/day may benefit further in terms of seizure control [13, 14]; this suggestion is substantiated by an analysis of perampanel dosages actually received by patients with drug-resistant POS in phase III studies (Sect. 3.2.3). Perampanel is dosed to clinical effect, regardless of concomitant AEDs [13]. In terms of its potential to interact with concomitantly prescribed AEDs, perampanel is neither a potent inducer nor inhibitor of CYP enzymes and, at the highest recommended dosage (12 mg/day), does not meaningfully affect the clearance of certain other AEDs, among them carbamazepine and lamotrigine [13, 14] (Sect.

J. E. Frampton

2). In contrast, the half-life of perampanel is markedly shortened with concurrent administration of potent inducers of CYP3A enzymes, including the EIAEDs carbamazepine, oxcarbazepine and phenytoin (Sect. 2). Therefore, in the presence of these EIAEDs, the EU label recommends uptitration of perampanel at 1-week rather than 2-week intervals (Sect. 5); the US label recommends a higher than usual starting dosage of perampanel (Sect. 5). Apart from perampanel, three of four additional AEDs that have already been evaluated as add-on therapy in drugresistant primary GTCS have demonstrated efficacy and are approved for this indication, namely topiramate (in patients aged C2 years in the US and EU), levetiracetam (in patients aged C6 and C12 years in the US and EU, respectively) and lamotrigine (in patients aged C2 and C13 years in the US and EU, respectively). Randomized clinical trials evaluating lacosamide and pregabalin are ongoing; however, the lack of efficacy of gabapentin (the fourth additional AED already evaluated) suggests that a2d calcium channel ligands lack efficacy in this setting [7]. Adjunctive perampanel, particularly at higher dosages, demonstrated efficacy against drug-resistant SG seizures, albeit this was a protocol-prespecified exploratory endpoint (Sect. 3.2.1) [22]. All AEDs approved in the US and/or EU for the treatment of POS, either as monotherapy or as addon therapy, are considered to be effective in preventing secondary GTCS [7]. Available evidence does not support there being differences between AEDs in terms of preventing secondary GTCS [7, 52]. However, although effective against secondary GTCS, some AEDs (carbamazepine, oxcarbazepine and phenytoin) may aggravate primary GTCS [7]. Additionally, it has been suggested that AEDs for which the impact on secondary GTCS has been formally evaluated and which have demonstrated greater efficacy than placebo (e.g. perampanel, topiramate and lacosamide) might preferentially be used [7]. Current UK guidance comprises recent recommendations issued by the Scottish Intercollegiate Guidelines Network (SIGN) [53] and earlier advice provided by the National Institute for Health and Care Excellence (NICE) [10]. According to the SIGN recommendations [53], perampanel is one of a number of AEDs—the others being carbamazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, sodium valproate and zonisamide—that may be used in the adjunctive treatment of POS. The NICE advice [10] takes into account efficacy, tolerability and cost-effectiveness (but not regulatory status) and recommends initially offering adjunctive clobazam, lamotrigine, levetiracetam, sodium valproate or topiramate both for drug-resistant POS and drug-resistant primary GTCS, and adjunctive carbamazepine, gabapentin and oxcarbazepine only for drugresistant POS. This guidance was published prior to the

approval of perampanel; clinical evidence (and opinion) pertaining to this agent is scheduled for inclusion in the next update [10]. US guidance (American Academy of Neurology [45]) that predates both UK guidelines by several years is also in the process of being updated. In the interim, real-world clinical experience with perampanel is accumulating [12, 54]; the availability of pharmacoeconomic data that may assist further in the positioning of the drug is awaited with interest. Thus, on the basis of its overall clinical profile and unique mechanism of action, perampanel offers a useful additional adjunctive treatment option for patients with drug-resistant POS (including secondary GTCS) and primary GTCS. Data selection sources: Relevant medical literature (including published and unpublished data) on perampanel was identified by searching databases including MEDLINE (from 1946), PubMed (from 1946) and EMBASE (from 1996) [searches last updated 18 August 2015], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Perampanel, Fycompa, E-2007, epilepsy, epileptic, seizure, partial, focal, frontal-lobe, tonic-clonic, grand-mal. Study selection: Studies in patients with partial epilepsy and tonic clonic seizures who received perampanel. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Acknowledgments During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Compliance with Ethical Standards Funding The preparation of this review was not supported by any external funding. Conflict of interest James Frampton is a salaried employee of Adis/ Springer, is responsible for the article content and declares no relevant conflicts of interest.

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