Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors play a key role in mediating glutamatergic transmission in the cortex. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile) is a potent, orally active, highly selective, non-competitive AMPA-type glutamate receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories. Development of perampanel as adjunctive therapy for the treatment of partial-onset seizures was planned in keeping with regulatory guidance and guidelines on antiepileptic drug (AED) development. This is the first AED with a specific action on glutamate-mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment-refractory partial-onset seizures in Phase III clinical trials. Perampanel (Fycompa®) has been approved in the EU and the United States for adjunctive treatment of partial-onset seizures.
Epilepsy is a common neurological disorder, affecting more than 50 million people worldwide . Despite the availability of numerous antiepileptic drugs (AEDs) , there remains a clinical need for novel and efficacious AEDs for use in the 20–30% of patients in whom current drug therapy is either ineffective or associated with intolerable side effects .
Glutamate is the principal excitatory neurotransmitter in the brain, and the glutamatergic system has been implicated in the pathogenesis of many neurological disorders, including epilepsy . In patients with epilepsy, sustained increases in extracellular glutamate concentrations have been observed in the hippocampus before and during seizure activity . Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a class of ionotropic glutamate receptors localized at excitatory synapses throughout the central nervous system (CNS) [6, 7]. AMPA glutamate receptors play a key role in glutamate-mediated excitatory neurotransmission and synaptic plasticity in the cortex and also appear critical to seizure generation and spread [7, 8]. As such, AMPA receptor antagonists may have therapeutic potential as novel AEDs.
Perampanel is a novel, orally active, highly selective, non-competitive AMPA receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories . This article provides an overview of the clinical development program for perampanel as adjunctive therapy for the treatment of refractory partial-onset seizures. Discovery and subsequent clinical evaluation of perampanel as a potential AED followed a rational process in keeping with recommendations to facilitate development of new AEDs .
AMPA receptor antagonists have been shown to have antiseizure activity in a range of preclinical epilepsy models [8, 9, 11]. The demonstrated efficacy of AMPA receptor antagonists in models of fully kindled seizures suggested potential therapeutic utility against partial seizures.
Non-competitive AMPA receptor antagonists are likely to be more efficacious than competitive antagonists under conditions of increased excitation, which may be expected to translate into clinical superiority in treating severe seizure conditions. Selectivity for AMPA receptors is also likely to be of clinical significance, as NMDA receptor antagonists are known to produce psychoactive effects, including schizophrenia-like symptoms and cognitive impairment .
Based on these data, Eisai continued the search for an orally active, potent, non-competitive AMPA receptor antagonist with a favorable pharmacokinetic and safety profile. Two high-throughput screening assays were used: the rat cortical neuron AMPA-induced cell death assay identified compounds with AMPA antagonist activity, while the tritiated AMPA binding assay allowed the detection and elimination of compounds acting as competitive AMPA receptor antagonists . A Ca2+ ion mobilization assay in rat primary neuron culture was used to screen for medicinal chemistry effects. The high-throughput screening approach identified 2,4-diphenyl-4H-[1,3,4]oxadiazin-5-one as a structurally novel, non-competitive AMPA receptor antagonist, and a suitable starting point for optimization . Optimization resulted in a series of novel 1,3,5-triaryl-1H-pyridin-2-one derivatives. The structure–activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile).
Preclinical studies showed perampanel to have potent activity in both in vitro AMPA-induced calcium influx assays and in vivo AMPA-induced seizure models. Furthermore, perampanel did not interact with either N-methyl-D-aspartate (NMDA) or kainate glutamate-type receptors [9, 13]. Preclinical data for perampanel also supported a favorable pharmacokinetic profile , warranting initiation of Phase I/II clinical trials.
Exploring the dose range: Phase I and Phase II clinical trials
Two Phase I clinical trials were undertaken to establish the pharmacokinetic and safety profile of perampanel in healthy volunteers . Perampanel displayed favorable pharmacokinetic properties, including good oral bioavailability and a long half-life (approximately 70–100 h). Due to the long half-life, drug concentrations would be expected to rise gradually with continuous use of the same dose, which could reduce adverse effects caused by rapid increases in concentration. Long half-lives also require slower titrations of dose, to avoid ‘overshooting’ the target dose, which can also therefore improve tolerability. The long half-life would also be expected to be beneficial in the event of patients missing a dose. In a multiple-dose study, steady-state plasma concentrations were reached by day 14 of once-daily dosing. These studies also showed perampanel to have acceptable tolerability.
As a result of these findings in healthy volunteers, a clinical trial program was initiated to establish the efficacy and tolerability of perampanel as adjunctive therapy in patients with refractory partial-onset seizures (Fig. 1). Proof-of-concept was provided by two dose-escalation Phase II clinical trials [16, 17]. These studies were designed to identify the effective dose range of perampanel for subsequent Phase III clinical trials (Fig. 2). In study 206, treatment with perampanel was initiated at 1 mg/day once or twice daily and titrated up to a maximum of 4 mg/day. Perampanel showed acceptable tolerability within this dose range, with adverse events in keeping with Phase I findings, and results suggested that doses in excess of 4 mg/day were likely to be tolerable in the target patient population. The tolerability of higher doses of perampanel (up to 12 mg/day) was therefore explored in study 208. Analyses showed that perampanel doses up to 12 mg/day had an acceptable tolerability profile. Neither of these dose-finding studies had been powered to discriminate from placebo for seizure endpoints. However, responder rates in study 206 were found to be similar to those reported for lower doses of some current AEDs [18, 19].
Population pharmacokinetic/pharmacodynamic (PK/PD) analyses provide important additional information for dose regimen optimization. Pooled PK/PD analysis of data from these two Phase II studies showed that seizure frequency decreased and the probability of response increased with increasing exposure to perampanel . Results of this analysis also showed co-administration of cytochrome P450 (CYP)-inducing AEDs to be associated with an increase in perampanel clearance and therefore a clinically relevant reduction in perampanel exposure.
These early clinical findings played a key role in guiding the dose selection and titration schedule of the perampanel Phase III epilepsy trial program. The preliminary signal of efficacy and the PK/PD model showing a continued log-linear response across the dose range studied (1–12 mg), combined with demonstration of tolerability of higher doses, supported initiation of treatment at doses of up to 12 mg/day in subsequent studies.
Phase III clinical trials
Three multicenter, double-blind, placebo-controlled Phase III trials were undertaken to assess the efficacy and safety of adjunctive once-daily perampanel at doses of up to 12 mg in adolescents and adults with uncontrolled partial-onset seizures despite current treatment with 1–3 AEDs [17, 21-23]. Study 306 was specifically designed to identify the minimal effective dose, as required in regulatory guidance and guidelines, and therefore has a larger sample size per arm than the other studies (approximately 170). Study 306 investigated lower doses of perampanel (2, 4, and 8 mg once daily). Studies 304 and 305 both evaluated higher doses of perampanel (8 and 12 mg once daily) to provide the replicate evidence required for confirmation of efficacy at the highest doses. In all studies, perampanel was titrated weekly in 2 mg increments for 6 weeks and then maintained at the dose achieved for 13 weeks (Fig. 3). Primary efficacy endpoints were median percentage change in seizure frequency and 50% responder rate.
The most frequently reported adverse events during treatment with perampanel were CNS related . Dizziness and somnolence were dose related and were therefore considered to be adverse drug reactions. The large majority of AEs were mild/moderate in severity, and there were no deaths during the Phase III studies.
Adjunctive therapy with perampanel at once-daily doses of 4–12 mg was found to significantly improve seizure control in patients with treatment-resistant partial-onset seizures, with profound improvements in secondarily generalized seizures (the most severe seizure types assessed) . A dose–response relationship for perampanel and the minimal effective dose was established in study 306, which evaluated doses of 2–8 mg/day . In studies 304 and 305, perampanel 8 and 12 mg/day consistently demonstrated efficacy over placebo.
A pooled analysis of PK/PD data from the Phase III studies showed that, as was observed in the Phase II studies, perampanel exposure was related to the actual dose achieved by patients, with increased exposure directly related to decreased seizure frequency and increased probability of response . The exposure/efficacy relationship for perampanel was not affected by demographic factors or by any concomitant AEDs, including known perampanel inducers. The relationship between treatment-emergent adverse events and perampanel exposure was similarly not altered by demographic factors or concomitant AED use. These findings suggest that potential inducer effects of concomitant AEDs can be overcome during perampanel treatment by titration to effect.
Long-term clinical studies
Extension studies were performed as part of the perampanel clinical development program . Patients who had completed the Phase II and Phase III trials were eligible for enrollment (Fig. 1). The Phase III extension (study 307) included a blinded conversion (titration) period. Both extension studies included a longer titration period than the initial trials—during which perampanel dosage was increased by 2 mg every 2 weeks to a maximum of 12 mg/day on the basis of individual tolerability and seizure control—followed by a period of long-term, open-label maintenance therapy. The slower titration period in these studies (blinded in study 307) was specifically intended to provide further information on the upper dose range of perampanel in routine practice.
Extension studies after the core studies, especially those with blinded conversion periods, provide essential information concerning AED efficacy, safety, and tolerability during long-term therapy that may not be obtained in shorter, randomized studies. Such studies are especially important where a new therapeutic target or novel mechanism of action is involved. Interim analyses of these studies at the time of writing this article showed the tolerability profile of perampanel during long-term therapy to be consistent with that seen in shorter, randomized trials, with seizure control also maintained during long-term treatment [27, 28]. In the extension study of the three pivotal Phase III trials, the vast majority of patients were titrated to perampanel doses of 10–12 mg/day .
To further explore the relationship between perampanel dose and efficacy, an additional dose–response analysis was undertaken using pooled data from the core Phase III studies and the blinded conversion period of the associated extension study [17, 29]. Results demonstrated that increased plasma levels of perampanel provided benefit to those patients who could tolerate dose escalation. Actual (last) dose data for change in seizure frequency and responder rate were consistent in showing improved efficacy of perampanel when patients’ doses were increased from 8 mg in the double-blind maintenance period of the core studies to 12 mg in the blinded conversion period of the extension study. An additional analysis of patients who received an actual (last) dose of 8 mg or 12 mg in studies 304 and 305 showed that 12 mg was consistently more efficacious than 8 mg for clinically severe secondarily generalized seizures. These findings suggest that while perampanel at once-daily doses of 4–8 mg is likely to be effective for most patients, the 12 mg dose may be an important option for those patients whose seizures are not adequately controlled at lower doses, and who can tolerate this higher daily dose.
Perampanel is the first AED with a specific action on glutamate-mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment-refractory partial-onset seizures in Phase III clinical trials. In keeping with earlier recommendations concerning AED development , the perampanel clinical trial program was designed not only to provide data on tolerability and efficacy, but also to include full exploration of the optimal dose range, randomized and actual dose investigations, an informative PK/PD model including investigation of potential interactions with other AEDs and efficacy in adolescent patients.
In Phase III studies, perampanel 4–12 mg significantly improved seizure control, with notable improvements in clinically severe secondarily generalized seizures. The most frequently reported adverse events were CNS related, as expected. The rapid titration to the highest tolerable dose required by the clinical trial design may have increased the likelihood of adverse events, which could be reduced in clinical practice by more gradual titration.
Subsequent papers in this supplement provide more detailed reviews of results from each stage of this innovative clinical development program. Available data suggest that perampanel is likely to prove a valuable addition to the epilepsy therapeutic armamentarium. Perampanel (Fycompa®) has now been approved in the EU and the United States for the adjunctive treatment of partial-onset seizures.
David Squillacote, MD, of Eisai Inc. assisted in the preparation of the article by providing up-to-date data access and editorial support. Editorial support was provided by Jennifer Coward, for Complete Medical Communications, and was funded by Eisai Inc.
Conflicts of interest and sources of funding statement
The studies described were funded by Eisai Inc. All authors are employees of Eisai Inc.