Journal of Neurology https://doi.org/10.1007/s00415-017-8681-y

REVIEW

Efficacy and safety of perampanel in Parkinson’s disease. A systematic review with meta‑analysis Simona Lattanzi1 · Elisabetta Grillo2 · Francesco Brigo3,4 · Mauro Silvestrini1 Received: 13 September 2017 / Revised: 9 November 2017 / Accepted: 14 November 2017 © Springer-Verlag GmbH Germany, part of Springer Nature 2017

Abstract Background  L-Dopa represents the mainstay of therapy of Parkinson’s disease (PD), but its effectiveness is reduced with continued treatment and disease progression. Accordingly, there remains a need to explore novel treatment strategies to manage the signs and symptoms of the later disease stages. The aim of the study was to evaluate the efficacy and safety of adjunctive perampanel (PER) in patients with PD through a meta-analysis of existing trials. Methods  Randomized, placebo-controlled, double- or single-blind, add-on studies of PER in patients with PD were identified through a systematic literature search. The following outcomes were assessed: changes from baseline to final efficacy visit in total daily OFF time, activities of daily living during OFF time and motor function during ON time, incidence of adverse events (AEs), and treatment withdrawal. Results  Four trials were included involving 2266 participants, 1449 and 817 for PER and placebo treatment groups, respectively. Four PER daily doses were tested, namely 0.5, 1, 2 and 4 mg. There were no significant differences in any efficacy outcome between PER and placebo treated patients. The risk ratios (RRs) for AEs, severe AEs and treatment withdrawal were similar between placebo and PER at 0.5, 1 and 2 mg; the 4 mg daily dose was associated with an increased risk of AEs [RR 1.118 (1.047–1.193)], and withdrawal for AEs [RR 1.345 (1.034–1.749)] and for any reason [RR 1.197 (1.020–1.406)]. Conclusions  In PD patients experiencing motor fluctuations, adjunctive PER did not improve the motor state and was welltolerated at the lower doses. Keywords  Parkinson’s disease · Perampanel · Movement disorders · Dyskinesia

Introduction Parkinson’s disease (PD) is one of the most common neurodegenerative diseases and causes of progressive disability; it Electronic supplementary material  The online version of this article (https://doi.org/10.1007/s00415-017-8681-y) contains supplementary material, which is available to authorized users. * Simona Lattanzi [email protected] 1



Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Conca 71, 60020 Ancona, Italy

2



Medical Department Eisai s.r.l, San Donato Milanese, Italy

3

Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Verona, Italy

4

Division of Neurology, “Franz Tappeiner” Hospital, Merano, BZ, Italy



affects approximately 1% of people over the age of 60 years, and the prevalence is predicted to increase due to the aging of the population [1]. L-Dopa represents the mainstay of therapy, and it is usually associated with substantial symptomatic relief. Nonetheless, its effectiveness is reduced with continued treatment and disease progression, and motor fluctuations—including wearing-off and on–off phenomena—and dyskinesia become prominent and compromise the quality of life in up to twothirds of patients over time [2]. As such, there remains a need to explore novel treatment strategies to manage the signs and symptoms of the later disease stages. Perampanel (PER) is a first-in-class, orally administered, highly selective and non-competitive α-amino-3-hydroxy5-methyl-4-isoxazole-propionic acid (AMPA)-type glutamate receptor antagonist, which was found to improve motor symptoms in rodent and primate PD models [3–5] and reduce the total daily time spent in OFF state in patients

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with advanced PD in a post hoc analysis of an early, doseranging, clinical trial [6]. The aim of this study was to evaluate the efficacy, safety and tolerability of adjunctive PER in patients with PD.

Materials and methods Search strategy The study results were reported according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [7]. We systematically searched (June week 4, 2017) PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) (e-Appendix I). There were no date limitations or language restrictions. The manufacturer of PER was contacted for information about any unpublished or ongoing studies. The reference lists of retrieved studies were reviewed to search for additional reports of relevant trials. The protocol was not registered previously.

Eligibility criteria Studies were selected when they met the following entry criteria: randomized, placebo-controlled, double- or singleblind, parallel-group or cross-over, fixed-dose add-on studies, with active and control groups receiving oral PER and matched placebo, respectively, in addition to stable anti-parkinsonian treatment regimen. Adult (> 18 years) patients with a diagnosis of PD [8] were included, irrespective of sex and ethnicity.

Outcome measures The primary efficacy outcome was the change in total daily OFF time from baseline to final efficacy visit; secondary endpoints were the changes in activities of daily living (ADL) during OFF time (UPDRS Part II) and motor function during ON time (UPDRS part III). Duration/disability of levodopa-induced dyskinesia (UPDRS Part IV) at final efficacy visit was further considered. Safety and tolerability outcomes were the proportions of patients who experienced any treatment emergent adverse event (AE) and serious AEs, and withdrew the treatment for any reason and for AEs. The effects on laboratory tests, ECG and vital signs were narratively reviewed.

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Study selection, data extraction and assessment of the risk of bias Two review authors (S. L. and E. G.) independently assessed trials for inclusion and extracted the information from included trials. Any disagreement was resolved by discussion with a third review author (F. B.). The risk of bias of the identified studies was assessed in accordance with the recommendations of the Cochrane Collaboration [9]. Funnel plots and Egger statistical test were used to evaluate the publication bias risk.

Statistical analysis Heterogeneity among the trials was assessed by the Chisquared test and the I2 statistics for heterogeneity [9–11]. Provided no significant heterogeneity was present (p > 0.10), results were synthesized using a fixed effect model; if the probability value was  ≤  0.10, heterogeneity will determine the choice of a fixed- or random effects model for I2 < 40 or ≥ 40%, respectively [12–14]. Risk ratio (RR) and weighted mean difference (WMD), each with 95% confidence intervals (CIs), were the measures of associations between treatment and dichotomous/continuous outcomes. Analyses were performed according to PER daily dose. Reported probability values were two-sided, with significance set at < 0.05. Data analysis was performed using STATA/IC 13.1 statistical package (StataCorp LP, College Station, TX, USA).

Results Results of the search and characteristics of included studies Four studies [6, 15, 16] fulfilled the inclusion criteria and were included in the review and meta-analysis (Fig. 1). All studies were randomized, double-blind, placebo-controlled, multicentre, parallel-group, and tested four PER daily doses, namely 0.5 [6], 1 [6], 2 [6, 15] and 4 [15, 16] mg. They included 2266 participants, 1449 and 817 for PER and placebo treatment groups, respectively. Patients were enrolled if presented predictable motor fluctuations of the “wearingoff type”, including the presence of at least a 2-h OFF time during the waking day, and received optimized, stable antiparkinsonian treatment regimen including L-dopa for at least 4 weeks before the study entry. Details of the studies and participants are given in Table 1 and Supplement Table e-1, respectively. We rated all trials as having unclear risk of selection bias, since no details of sequence generation and allocation concealment were provided, and detection bias, since tests of blinding were not documented. The risk of

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Study outcomes

Fig. 1  Flow diagram of study selection process. CENTRAL Cochrane Central Register of Controlled Trials

performance and selective reporting bias was judged low in any case. The attrition bias risk was considered low in two trials [6, 16] and unclear in studies 301 [15] and 302 [15] since patients lost to follow-up and withdrawals were documented, but the exact reasons across the treatment arms were not clear. All trials were sponsored by the PER manufacturer. Summary of the risks of bias is shown in Supplement Table e-2. Despite the low number of included trials, funnel plots and Egger statistical test did not suggest publication bias (e-Appendix II).

Total daily OFF time during treatment with the lower PER dosages was assessed in one single trial [6]: the mean change difference from baseline to week 12 in comparison to placebo resulted − 0.36 (− 1.09 to 0.38; p = 0.342) and − 0.56 h (− 1.30 to 0.18; p = 0.136) hours for the 0.5 and 1 mg daily doses, respectively. No significant differences were found in changes of total daily OFF time, ADL during OFF time and motor function during ON time between 2 and 4 mg PER and placebo-treated patients (Figs. 2, 3). There were no differences in duration and disability of levodopa-induced dyskinesia at final efficacy visit between placebo and PER groups at any tested dose (Supplement Table e-3-4). No meaningful differences were found in the risk of AEs, severe AEs and treatment withdrawal between placebo and PER at 0.5, 1 and 2 mg a day; the 4 mg daily dose was associated with an increased risk of AEs [RR 1.118 (1.047–1.193)], withdrawal for AEs [RR 1.345 (1.034–1.749)] and for any reason [RR 1.197 (1.020–1.406)] (Table 2). There were no clinically meaningful changes from baseline in laboratory tests, vital signs, and ECG. Across all trials, fifteen deaths occurred (PER 2 mg n = 2, PER 4 mg n = 6 and placebo n = 7), but none was related to the study treatment.

Discussion The current systematic review and meta-analysis provide evidence that adjunctive PER at daily doses ranging from 0.5 to 4 mg did not improve the motor state in PD patients experiencing wearing-off motor fluctuations while on stable and optimized L-Dopa treatment. In addition, PER failed to affect duration and disability of L-Dopa-induced dyskinesia at any tested dose.

Table 1  Characteristics of included studies Reference study

Eggert et al. [6]

Study design

Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase II, multicenter Study 301 [15] Randomized, double-blind, placebo-controlled, parallel-group phase III, multicenter Study 302 [15] Randomized, double-blind, placebo-controlled, parallel-group phase III, multicenter Rascol et al. [16] Randomized, double-blind, placebo-controlled and active-controlled, parallelgroup, phase III, multicenter

Treatment duration (weeks)

Treatment arms

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Placebo PER: 0.5, 1 and 2 mg daily Placebo PER: 2 and 4 mg daily Placebo PER: 2 and 4 mg daily Placebo PER: 4 mg daily Entacapone: 200 mg daily

30 20 18

PER perampanel

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Fig. 2  Efficacy of adjunctive perampanel 2 mg daily dose versus placebo. ADL activities of daily living, CI confidence interval, WMD weighted mean difference

The neuro-degeneration of the substantia nigra is considered the main pathophysiological mechanism underpinning PD [17], and the early success in the development of effective treatments partly has so far relied mostly on the understanding of the prevalent role of dopamine deficiency. Nonetheless, neurotransmission represents a dynamic process and dopamine depletion results into widespread effects into the brain [18]: signs and symptoms of PD result from an imbalance in the excitatory and inhibitory drives of direct and indirect basal ganglia circuits, and they do not simply reflect the dopaminergic denervation [17]. This new perspective has led to a shift from strategies targeted to replace dopamine towards

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non-dopaminergic approaches directed to restore the neuro-signaling balance [19]. The gain in glutamatergic transmission in the striatum, which is related to either nigrostriatal denervation or nonphysiologic dopamine stimulation, has been shown to influence the basal ganglia output and contribute to the disease manifestations and therapy complications [20]. Additionally, glutamate-mediated excito-toxicity may represent a main cause of neuron loss, and aberrant glutamate regulation may contribute to neuro-degeneration [21]. Consequently, the reduction of the excitatory drive by blocking glutamate receptors could conceivably represent an alternative therapeutic strategy to control PD symptoms and

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Fig. 3  Efficacy of adjunctive perampanel 4 mg daily dose versus placebo. ADL activities of daily living, CI confidence interval, WMD weighted mean difference

dopaminergic treatment-induced side effects. The antagonism of these pathways may even reduce the loss of neural cells and have disease-modifying effects. The main receptors involved in glutamatergic transmission at the basal ganglia site are the N-methyl-d-aspartate (NMDA) and AMPA ionotropic subtypes. The enhancement of the indirect pathway can lead to the hyperactivity of the NMDA receptors expressed in neurons of the striatum and sub-thalamic nucleus [19]. Accordingly, NMDA antagonists would reduce excessive activation of these receptors in the indirect pathway and provide beneficial effects on PD symptoms [19]. In primate and rodent PD models, NMDA antagonists increased

the anti-parkinsonian effects of L-Dopa and reduced the motor complications related to chronic L-Dopa treatment [22–24]. The value of NMDA receptor blockade in clinical practice has been mostly demonstrated for L-Dopainduced dyskinesias. The non-competitive antagonism of NMDA receptors by amantadine decreased dyskinesia severity and motor fluctuations in L-Dopa treated patients [25]; memantine—a NMDA receptor antagonist currently licensed for the Alzheimer’s Disease treatment—improved LIDs and on–off timing [26]. Similarly, the inhibition of glutamate release through safinamide increased daily ON time in patients with mid-to-late stage PD and motor fluctuations [27].

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Table 2  Meta-analysis of tolerability and safety endpoints according to perampanel dose

Journal of Neurology Study outcome

Studies

Perampanel 0.5 mg  At least one AE  Serious AEs  Treatment withdrawal for any reason  Treatment withdrawal for AEs Perampanel 1 mg  At least one AE  Serious AEs  Treatment withdrawal for any reason  Treatment withdrawal for AEs Perampanel 2 mg  At least one AE  Serious AEs  Treatment withdrawal for any reason  Treatment withdrawal for AEs Perampanel 4 mg  At least one AE  Serious AEs  Treatment withdrawal for any reason  Treatment withdrawal for AEs

Patients

Risk ratio

95% CI

p

I2 (%)

1 1 1 1

134 134 134 134

1.398 0.243 0.794 0.693

0.954–2.047 0.028–2.115 0.352–1.791 0.232–2.076

0.086 0.200 0.578 0.513

– – – –

1 1 1 1

131 131 131 131

1.300 0.254 0.831 0.725

0.875–1.930 0.029–2.211 0.369–1.871 0.243–2.169

0.194 0.214 0.654 0.565

– – – –

3 3 3 3

1143 1143 1143 1143

0.986 0.700 1.008 0.902

0.912–1.066 0.465–1.055 0.816–1.245 0.665–1.223

0.718 0.089 0.939 0.508

0.0 0.0 0.0 0.0

3 3 3 3

1494 1494 1494 1494

1.118 1.028 1.197 1.345

1.047–1.193 0.715–1.478 1.020–1.406 1.034–1.749

0.001 0.882 0.028 0.027

19.6 0.1 0.0 0.0

AE adverse event, CI confidence interval, RR risk ratio

The AMPA receptors mediate the great majority of fast excitatory synaptic transmission and are key regulators of neural plasticity [28, 29]. Bearing in mind the importance to restore the excitatory balance of basal ganglia outputs in PD patients, the blockade of the AMPA receptors may have a meaningful therapeutic role [30, 31]. Indeed, the antagonists of the AMPA-type glutamate receptor showed anti-parkinsonian properties in preclinical setting: they prolonged the effect of L-dopa and reduced the “wearing-off” phenomenon associated to chronic dopaminergic therapy in parkinsonian rodents [3, 4], increased locomotor activity following L-dopa administration, and reduced peak-dose dyskinesia in nonhuman primate models [3–5]. Despite the highly promising experimental background, the selective antagonism of the AMPA transmission through PER failed, however, to significantly improve the motor status in PD patients, as by pooled analysis of all the available trials. These findings highlight how data coming from animal investigations may not necessarily translate into clinical evidence. Possible explanations include the incomplete understanding of the mechanisms underlying disease manifestations, or the inappropriateness of animal models. On this regard, however, the glutamatergic dysfunction has proven to be a valuable mechanistic hypothesis. The choice of drug dosages and trial endpoints may have been major contributors to the PER failure, and they should deserve further explorations. The single dosefinding, phase II, controlled study evaluated PER at three different dosages—ranging from 0.5 to 2 mg daily—but it

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did not determine the maximum tolerated dose. Although no differences emerged in the efficacy of PER compared to placebo, a dose–response trend was observed, and increase up to 4 mg was suggested for future clinical trials. It may not be excluded that this dose was sub-therapeutic, and further increments could have offered clinical benefit. Finally, different primary outcomes, like the mean change in motor function during ON time rather than variation in total daily OFF time, could have been more sensitive to reveal possible anti-parkinsonian effects. Taking into account all the above issues, there is enough evidence to still consider the glutamatergic system as a promising direction for future research trajectories in the field of PD therapy. One study objective was to evaluate the tolerability and safety of adjunctive PER. Perampanel was well-tolerated at daily doses ranging from 0.5 to 2 mg, and it was associated to higher incidence of AEs and treatment discontinuation at 4 mg in comparison to placebo. Adverse events were mostly mild to moderate in severity, and somnolence, dizziness and dyskinesia were those most frequently associated to PER. They all represent common side effects and substantially overlap the profile of the majority of the anti-parkinsonian medications, whereas not accompanied by any efficacy benefit. Although only one trial evaluated cognition, no detrimental effects on working memory and transcription tasks accuracy were observed with PER at the lower doses. Across phase II and phase III trials, the mortality rate was relatively

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high, as expected from the average age of the patient population, but none of the case was conducible to the study treatment. Our systematic review and meta-analysis is the first to evaluate the efficacy and safety of adjunctive PER in L-Dopa treated PD patients. Nonetheless, different caveats need to be considered while interpreting the findings. Few trials met the eligibility criteria, and they included relatively small patient samples in each arm; additionally, only low dosages of the study drug were tested. Although participants were allowed to take anti-parkinsonian medications other than L-Dopa, results were not stratified according to the class and dose of the concomitant therapies. Noteworthy, sensitivity analysis taking into account the use of anti-glutamatergic agents or catechol-O-methyltransferase inhibitors could detect potential confounding factors [32]. Furthermore, the pooled incidence rates of individual AEs could not be estimated since only the most frequently observed side effects were described in each single trial. Finally, despite the need of long-term therapy for PD patients, the treatment period of included trials ranged from 12 to 30 weeks, and the metaanalysis cannot provide information about the long-term safety of PER and the occurrence of rare adverse events in this population. Current pharmacological options for PD are mostly directed to restore, mimic or replace the dopamine deficiency. Although this approach remains the best way to alleviate the symptoms, motor fluctuations and hyperkinetic movements compromise its long-term effectiveness. In addition, the growing understanding of the molecular pathways and neurotransmitter signaling underlying the disease pathophysiology has resulted in increasing efforts to identify new therapeutic targets [33–35]. As a result, a variety of nondopamine centric strategies has been developed in the last decades, but only a minority has successfully translated from bench-to-bedside.

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7. 8.

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Compliance with ethical standards 

16.

Conflicts of interest  SL and MS declare that they have no conflict of interest. EG is an employee of Eisai s.r.l. FB has received speakers’ honoraria from Eisai and PeerVoice, payment for consultancy from Eisai, and travel support from Eisai, ITALFARMACO, and UCB Pharma.

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