Consensus meeting on the use of perampanel▼ as adjunctive therapy in clinical practice: recommendations from an expert panel

Posted in Sponsored Feature,Supplements on 15th Apr 2015

Summary

page19-1Perampanel has a novel mode of action based on a rational hypothesis of seizure initiation and spread. This can be considered when discussing the possibility of initiating perampanel treatment in patients with partial onset seizures who have failed to gain control with other AEDs.

Perampanel is an easy to use antiepileptic treatment that, based on the results of phase 3 placebo-controlled studies, has an efficacy profile comparable to other recently-introduced treatments. Currently-available data demonstrate a reduction of secondarily generalised seizures with perampanel treatment.

Data from ‘real-world’ studies and clinical experience support the evidence from randomised controlled studies and confirm that perampanel is effective and generally well tolerated in clinical practice. No new safety signals or concerns have emerged to date.

All patients with refractory partial-onset seizures should be reviewed by an epilepsy specialist when possible. Perampanel may be initiated by an epilepsy specialist, appropriately-qualified epilepsy nurse specialist or general neurologist. Ongoing perampanel prescribing may be undertaken in primary care with support from a consultant neurologist or epilepsy nurse specialist if required. Perampanel can be considered a 2nd-line adjunctive therapy option in patients aged 12 years and older with partial-onset seizures.

Perampanel may be combined with other AEDs  with good efficacy outcomes. A higher dose of perampanel may be required in patients taking enzyme-inducing AEDs.

Perampanel should be initiated at a dose of 2 mg/ day, taken at bedtime, and titrated by increments of 2 mg every 4 weeks according to clinical need to achieve the maximum tolerated dose (MTD) (up to 12 mg/day). Consider withdrawing perampanel if there is no evidence of clinical benefit once the MTD has been reached.

Introduction
Perampanel (Fycompa®, Eisai Ltd.) is a first-in-class antiepileptic drug (AED) that was introduced into the UK in September 2012 for the adjunctive treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 12 years and older.1 By November  2014, over 7500 patients had been treated with perampanel in the UK and Ireland.2 In light of the increasing experience of using perampanel in clinical practice, a panel of epilepsy experts met in December 2014 to review their experiences of using the treatment and to develop consensus recommendations on its appropriate use in clinical practice. This report provides an overview of the latest clinical research findings with perampanel and summarises the group’s feedback and consensus recommendations.

Mode of action of perampanel
Perampanel is a selective, non-competitive antagonist of the ionotropic ∝-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor on post-synaptic neurons.1 These receptors are localised at excitatory synapses in the central nervous system, where they are essential for the generation and spread of epileptic activity.3 Perampanel selectively and potently inhibits AMPA receptors and reduces neuronal hyperexcitability, demonstrating a broad-spectrum of activity in animal models used to identify AEDs.4

The group agreed that the novel and rational mode of action of perampanel was one of the considerations when developing an individual’s treatment plan and discussing the possibility of initiating perampanel in relevant patients. For some patients, the novel mode of action of perampanel may be an attractive feature of the treatment that helps to explain the rationale for its use as an adjunctive AED.

Consensus statement 1: Perampanel has a novel mode of action based on a rational hypothesis of seizure initiation and spread. This can be considered when discussing the possibility of initiating perampanel treatment in patients with partial onset seizures who have failed to gain control with other AEDs.

Figure 1. Median percentage change in seizure frequency per 28 days reported in a pooled analysis of phase 3 studies9 and individual studies5–7 of adjunctive perampanel. Data shown are the differences between baseline and the double-blind treatment phase (ITT analysis set).

Figure 1. Median percentage change in seizure frequency per 28 days reported in a pooled analysis of phase 3 studies9 and individual studies5–7 of adjunctive perampanel. Data shown are the differences between baseline and the double-blind treatment phase (ITT analysis set).

Figure 2. Percentage of patients reporting a ≥50% reduction from baseline in seizure frequency in a pooled analysis of phase 3 studies9 and individual studies5–7 of adjunctive perampanel (ITT analysis set).

Figure 2. Percentage of patients reporting a ≥50% reduction from baseline in seizure frequency in a pooled analysis of phase 3 studies9 and individual studies5–7 of adjunctive perampanel (ITT analysis set).

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Figure 3. Median percentage change in seizure frequency per 28 days according to seizure type in a pooled analysis of phase 3 studies of adjunctive perampanel.9

Figure 4. Seizure outcomes in ‘difficult-to-treat’ patients receiving adjunctive perampanel in clinical practice: results of an observational study conducted in Austria and Germany.10

Figure 4. Seizure outcomes in ‘difficult-to-treat’ patients receiving adjunctive perampanel in clinical practice: results of an observational study conducted in Austria and Germany.10

Efficacy and safety of perampanel

The efficacy and safety of perampanel have been evaluated in a clinical development programme that included three phase 3, double-blind, placebo-controlled studies: study 304,5 study 3056 and study 3067 and a recently-reported long-term extension study 307.8 1480 patients aged ≥12 years who were receiving one, two or three AEDs and experienced at least five partial-onset seizures during a 6-week baseline period were enrolled into the phase 3 studies. Perampanel doses of 2, 4, 8 and 12 mg taken once-daily were assessed. Doses were titrated up by 2 mg each week over a 6-week period, followed by a 13-week, double-blind maintenance phase. Primary efficacy endpoints were median % change from baseline in seizure frequency per 28 days and the percentage of patients achieving a ≥50% reduction in the frequency of all seizures per 28 days (50% responder rate; baseline versus maintenance).

Pooled analysis of phase 3 studies
This pooled analysis included data from 1480 patients who took part in the three phase 3 studies.9 These were treatment-refractory patients who experienced a median of 10–13 partial-onset seizures per 28 days during the pre-randomisation phase of the studies, despite most individuals (86%) receiving two or three AEDs. The most common concomitant AEDs were carbamazepine, valproic acid, lamotrigine and levetiracetam. The key findings from this analysis are outlined below:9

Efficacy:

  • Adjunctive therapy with perampanel 4, 8 and 12 mg/day significantly reduced the frequency of partial-onset seizures (Figure 1) and improved responder rates (Figure 2) compared with placebo.
  • Perampanel 4, 8 and 12 mg/day also significantly reduced the frequency of secondarily generalised seizures compared with placebo (Figure 3).
  • At the recommended initial maintenance doses of 4–8 mg/day, up to 17% of patients achieved ≥75% reduction in seizure frequency.
  • Seizure-freedom rates during maintenance therapy were higher with perampanel 4–12 mg/day (3.5–4.4%) than with placebo (1.0%) (p<0.05 for each dose, completer analysis).

Safety and tolerability:

  • Perampanel was generally well tolerated. The most frequently-reported treatment-emergent adverse events (TEAEs) were dizziness and somnolence (Table 1).
  • Psychiatric and behavioural TEAEs (e.g. irritability, hostility, aggression) were observed more frequently in perampanel-treated patients than in placebo-treated patients – the frequency of these events increased with increasing perampanel doses.
  • Serious AEs were reported by a similar proportion of patients taking placebo (5.0%) and perampanel (5.5%).

This pooled analysis augments the findings from the individual studies demonstrating the efficacy and tolerability of perampanel as an adjunctive treatment for patients with partial-onset seizures. The group agreed that, in this highly treatment-refractory study population – which is typical of the populations now entering AED clinical trials – seizure freedom is not always a realistic goal. The efficacy profile of perampanel was considered by the group to be comparable to that of other recently-introduced AEDs.

Long-term extension study
Study 307 was designed as the long-term, open-label extension to the three phase 3 double-blind, placebo-controlled studies of adjunctive perampanel in partial-onset seizures to validate the initial registration study findings: 96% of eligible patients who completed the phase 3 trials entered this study.8 The study was designed with a 16-week, blinded conversion period, during which all participants were up-titrated by 2 mg every 2 weeks to 12 mg/day or their maximum tolerated dose (MTD). This was followed by a long-term (~5 years) follow-up period during which dose adjustments of perampanel and concomitant AEDs could be made at the investigator’s discretion.

At the time of latest reporting, 1216 patients had received perampanel for a median duration of 1.5 years (range 1 week to 3.3 years), with more than 300 patients having received treatment for >2 years.8 The mean daily dose of perampanel achieved was 10.6 mg, with 92% of patients taking a maximum daily dose of 10 or 12 mg. Fifty-eight percent of patients were retained on perampanel treatment at the data cut-off point for this analysis. The key findings from this study were as follows:8

  • Long-term adjunctive perampanel was generally well tolerated, with a safety and tolerability profile consistent with that reported in phase 2 and 3 studies.
  • Most AEs reported were mild or moderate in intensity. The most frequently-reported adverse events were dizziness, somnolence, headache, fatigue, irritability and weight increase. Only dizziness and irritability led to treatment discontinuation in >1% of patients (3.9% and 1.3%, respectively).
  • No new safety signals were observed with over 1803 patient-years of exposure to perampanel.
  • Treatment efficacy in terms of seizure response was maintained over 2 years of perampanel treatment, indicating sustained benefits.
  • Responder rates consistently remained above 40% after titration and reached 58% in the 337 patients treated for 2 years.
  • In patients with secondarily generalised seizures at baseline, the frequency of these seizures was reduced by 77% at 9 months (n=422) and by 90% at 2 years (n=141).
  • Long-term seizure freedom was achieved in some of these highly treatment-refractory patients (5% of patients treated for 1 year (n=694) and 3% of patients treated for 2 years (n=141)).

Consensus statement 2: Perampanel is an easy to use antiepileptic
treatment that, based on the results of phase 3 placebo-controlled studies, has an efficacy profile comparable to other recently-introduced treatments. Currently-available data demonstrate a reduction of secondarily generalised seizures with perampanel treatment.

Perampanel in the ‘real-world’: results from European and UK studies

Data are now emerging from ‘real-world’ observational studies conducted in clinical practice. One recently-reported study involved 281 ‘difficult-to-treat’ patients with partial epilepsy being managed in epilepsy centres and neurology departments in Austria and Germany.10 Data from consecutively-treated patients receiving adjunctive perampanel were collected for a minimum of 6 months. The mean dose of perampanel in this study was 7.7 mg/day.

After 6 months of follow-up, 169 patients (60%) were still receiving perampanel treatment and 43 patients (15%) had been seizure-free during the preceding 3 months at a mean dose of 8.7 mg/day (Figure 4). Half the patients had experienced at least a 50% reduction in their seizure frequency (all seizure types) (Figure 4). As in the phase 3 clinical trials, the most commonly reported AEs were somnolence and dizziness. Other AEs reported were ataxia, aggression, nausea and irritability.

The results from a number of other ‘real-world’ studies conducted in Spain,11 the UK12–19 and Ireland20 have also been published or presented. These observational studies involving almost 500 patients who had taken adjunctive perampanel for up to 14 months in clinical practice confirm relatively high rates of treatment retention and good seizure response rates – typically at lower doses than were used in the controlled clinical trials. A seizure freedom rate of 17% was reported in one study.13 In the view of the group the tolerability profile of perampanel in these ‘real-world’ studies reflected that observed in clinical trials, with dizziness, somnolence and irritability the most commonly-reported AEs.

The group reviewed their own experiences of using perampanel in clinical practice, reporting that the treatment is easy to use in a broad range of patients; it has a manageable tolerability profile and has been very effective in some patients. Cases were presented demonstrating sustained seizure-freedom in some previously intractable patients, early responses to perampanel treatment, frequent improvements in seizure severity, more rapid post-ictal recovery, and improved quality of life. Members of the group reported that, in some patients, it had been possible to reduce or withdraw other AEDs after initiation of perampanel treatment. Other cases were presented in which patients had a less favourable response, with an increase in irritability/aggression and/or mood disturbances leading to treatment withdrawal.

The panel members agreed that, in their experience, perampanel was generally well tolerated by most patients, with predictable early side-effects (e.g. dizziness), an acceptable neurocognitive profile, and manageable levels of headache and irritability. Treatment retention rates were reported to be generally high.

Consensus statement 3: Data from ‘real-world’ studies and clinical experience support the evidence from randomized controlled studies and confirm that perampanel is effective and generally well tolerated in clinical practice. No new safety signals or concerns have emerged to date.

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Optimising use of perampanel in clinical practice

Clinical guidelines from the National Institute for Health and Clinical Excellence (NICE) relating to the diagnosis and treatment of epilepsy were published in January 201221 and do not, therefore, include recommendations for the adjunctive use of perampanel in partial-onset seizures. The guidelines currently recommend that all patients with newly diagnosed partial-onset seizures are offered monotherapy with carbamazepine or lamotrigine as a first-line treatment (Table 1).21 Alternative monotherapies for patients in whom these treatments are unsuitable or not tolerated are levetiracetam, oxcarbazepine and sodium valproate.21 NICE-recommended adjunctive treatments are shown in Table 1. The NICE guidelines recommend that if standard adjunctive treatment is ineffective or not tolerated, advice should be sought from a tertiary epilepsy specialist.

When to consider initiating perampanel
There are currently no clear-cut, evidence-based guidelines to assist in the selection and sequencing of AED treatment. Treatment decisions are made empirically based on the seizure type and/or syndrome, the patient’s age and gender, comorbidities and learning status, the side-effect profile of the drug, personal preferences, cost and affordability. The group agreed that, based on its ease of use and efficacy and tolerability profile, perampanel could be considered a 2nd-line adjunctive therapy option in patients with partial-onset seizures (Table 1). The group recommended that perampanel may be considered before pregabalin, gabapentin, tiagabine, phenytoin, phenobarbital, vigabatrin and retigabine in most patients. There are currently no specific predictive factors for the efficacy and tolerability of perampanel treatment – patients aged 12 years and older whose partial seizures are uncontrolled on monotherapy could therefore be potential candidates to receive adjunctive perampanel.

In-line with NICE guidance, the meeting participants concurred that all patients with refractory partial-onset seizures should be reviewed by an epilepsy specialist when possible. They agreed that perampanel may be initiated by an epilepsy specialist, appropriately-qualified epilepsy nurse specialist or general neurologist. Ongoing perampanel prescribing may be undertaken in primary care with support from a consultant neurologist or epilepsy nurse specialist if required.

Consensus statement 4: All patients with refractory partial-onset seizures should be reviewed by an epilepsy specialist when possible. Perampanel may be initiated by an epilepsy specialist, appropriately-qualified epilepsy nurse specialist or general neurologist. Ongoing perampanel prescribing may be undertaken in primary care with support from a consultant neurologist or epilepsy nurse specialist if required. Perampanel can be considered a 2nd-line adjunctive therapy option in patients aged 12 years and older with partial-onset seizures.

Combining perampanel with other AEDs
Perampanel is rapidly absorbed after oral administration (Cmax at 0.25–2.0 hours) with an average half-life of 105 hours.1 The drug is primarily metabolised by cytochrome P450 3A4 (CYP3A4)-mediated oxidation followed by sequential glucuronidation. At clinically-relevant doses, perampanel is neither a potent inhibitor nor an inducer of cytochrome P450 isoenzymes. However, since it is metabolised via CYP3A4, concomitant administration of AEDs that are CYP3A4 inducers (e.g. carbamazepine, oxcarbazepine, phenytoin and topiramate) will increase perampanel clearance and reduce perampanel plasma concentrations.

Pharmacokinetic/pharmacodynamic modelling using data from the phase 3 studies suggests a significant association between increases in perampanel plasma concentrations and reductions in seizure frequency,22 indicating that patients taking enzyme-inducing AEDs may require higher doses of perampanel to optimise their clinical outcomes. This is supported by the results from the pooled analysis of the phase 3 studies,9 which reported reduced efficacy when perampanel 12 mg/day was added to carbamazepine (median % change in frequency of all partial seizures –20.3%; 50% responder rate for all partial seizures 31.3%) than when added to sodium valproate (–37.2%; 36.5%, respectively), lamotrigine (–31.2%; 30.6%, respectively) or levetiracetam (–34.7%; 43.0%, respectively). The analysis confirmed, however, that perampanel is effective in all AED combinations assessed.

Consensus statement 5: Perampanel may be combined with other AEDs with good efficacy outcomes. A higher dose of perampanel may be required in patients taking enzyme-inducing AEDs.

Perampanel dosing and titration
Perampanel should be taken once-daily before bedtime.1 Treatment should be initiated at a dose of 2 mg/day and titrated in 2 mg/day increments to a maintenance dose of 4–8 mg/day according to individual response.1 Depending on individual response and tolerability, the dose may be increased to a maximum recommended dose of 12 mg/day.1

In clinical trials, perampanel doses were titrated in 1- to 2-weekly intervals, however, ‘real-world’ data and experience in clinical practice suggests improved tolerability and treatment retention with a slower dose titration schedule. The group confirmed that, in their experience, perampanel doses should be increased every 4 weeks according to clinical need to achieve the MTD (up to a maximum dose of 12 mg/day). If there is no evidence of clinical benefit once the MTD has been reached, treatment withdrawal should be considered.

Consensus statement 6: Perampanel should be initiated at a dose of 2 mg/day, taken at bedtime, and titrated by increments of 2 mg every 4 weeks according to clinical need to achieve the maximum tolerated dose (MTD) (up to 12 mg/day). Consider withdrawing perampanel if there is no evidence of clinical benefit once the MTD has been reached.

Summary and conclusions

Perampanel is a valuable addition to the armamentarium for treating partial-onset seizures and preventing secondary generalisation. Its unique mode of action, ease of use, and good efficacy and tolerability profile make it potentially suitable for use as an adjunctive therapy in most treatment-refractory patients aged 12 years and older with partial epilepsy. Clinicians should consider perampanel as a 2nd-line adjunctive therapy option in patients who have not responded adequately to other AEDs.

Perampanel treatment may be initiated by an epilepsy specialist, appropriately-qualified epilepsy nurse specialist or general neurologist. Experience in clinical practice suggests that perampanel should be titrated slowly to the MTD (up to 12 mg/day) to enhance tolerability and treatment retention. Ongoing prescribing of perampanel may be undertaken in primary care with support from a consultant neurologist or epilepsy specialist nurse if required.

Acknowledgements

This report was initiated, supported and funded by Eisai Ltd. Medical writing support was provided by Ali Jordan and Innervate Ltd, and funded by Eisai Ltd.

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This publication was initiated and funded by Eisai Ltd.
Fycompa-UK0174, April 2015.  Prescribing information is on the last page.

ACNR 2015;15(1);19-24.  Online 15/04/15

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