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Long-term tolerability, safety and efficacy of adjunctive perampanel in the open-label, dose-ascending Study 231 and extension Study 233 in Japanese patients with epilepsy
Corresponding author at: National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan.
1 Present address: International University of Health and Welfare, Narita, Japan. 2 Present address: Department of Epileptology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Studies 231/233 assessed perampanel tolerability in Japanese patients with POS.
•
33.3% of patients completing Study 231 achieved a maximum tolerated dose of 12 mg.
•
Median percent change in seizure frequency was –35.0% during Study 231.
•
In extension Study 233, 42.9% of patients received perampanel for ≤208 weeks.
•
Most treatment-related TEAEs were mild to moderate.
Abstract
Purpose
To evaluate long-term tolerability, safety and efficacy of adjunctive perampanel in a Phase II, multicentre, open-label, dose-ascending Study 231 (NCT00849212) and its extension (Study 233; NCT00903786) in Japanese patients with refractory partial-onset seizures (POS), with/without secondarily generalised seizures.
Methods
In Study 231, patients received adjunctive perampanel ≤12 mg/day during a 10-week treatment period. Patients completing Study 231 could enter Study 233 (≤316-week treatment period). Assessments included monitoring of treatment-related treatment-emergent adverse events (TEAEs), median percent change in seizure frequency per 28 days, 50% responder and seizure-freedom rates. During Study 231, a pharmacokinetic analysis assessed the effects of enzyme-inducing antiepileptic drugs.
Results
Overall, 23/30 (76.7%) patients completed Study 231; 21/30 (70.0%) received perampanel ≥8 mg/day and 10/30 (33.3%) achieved a maximum tolerated dose of 12 mg/day. Median percent change in seizure frequency per 28 days was –35.0%. 50% responder rate was 37.0%; 4 (13.3%) patients achieved seizure freedom. Twenty-one patients entered Study 233. Mean duration of exposure was 195 weeks; 9 (42.9%) patients received perampanel for ≤208 weeks. Seizure control was sustained for 316 weeks in 3/21 (14.3%) patients; 2 achieved seizure freedom. Treatment-related TEAEs were tolerable; the most common was dizziness (Study 231, 53.3%; Study 233, 14.3%). Mean perampanel plasma concentrations were lower with concomitant carbamazepine vs non-inducers (152.7 ng/mL vs 389.4 ng/mL across perampanel groups); small patient numbers for non-inducers (n = 2) should be considered when interpreting these data.
Conclusion
Adjunctive perampanel demonstrated a favourable safety profile and long-term tolerability in Japanese patients with refractory POS for ≤316 weeks.
Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE).
]. Multiple antiepileptic drugs (AEDs) have been developed to try to control seizures in patients with epilepsy; however, 20–30% of patients are still refractory to currently available drug treatments, thus, the development of novel AEDs is required [
Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
Perampanel is a selective, non-competitive, orally active antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which plays crucial roles in mediating fast excitatory synaptic transmission, and generating and spreading epileptic activity [
]. Perampanel is approved for the adjunctive treatment of partial-onset seizures (POS), with or without secondarily generalised (SG) seizures, and for primary generalised tonic-clonic (PGTC) seizures in patients with epilepsy aged ≥12 years in Japan, as well as in multiple other countries around the world (POS indication, >50 countries; PGTC seizures indication, >40 countries) [
Eisai Co., Ltd., Eisai’s in-house developed antiepileptic drug Fycompa® (perampanel hydrate) approved in Japan as adjunctive therapy for partial-onset and generalized tonic-clonic seizures. Available at: http://www.eisai.com/news/enews201616pdf.pdf. Accessed 14 August 2018.
Eisai Inc. Eisai Submits Supplemental Application for Partial Label Change for Antiepileptic Drug FYCOMPA® as Monotherapy for Treatment of Partial-Onset Seizures Based on New U.S. FDA policy. Available at: http://www.eisai.com/news/enews201665pdf.pdf. Accessed 14 August 2018.
The clinical programme for the development of perampanel included 4 Phase II studies that evaluated the tolerability and safety of adjunctive perampanel in non-Japanese patients with refractory POS: Studies 206 [
] and 203 (unpublished data on file, Eisai Europe Ltd., Hertfordshire, UK). Subsequently, 3 pivotal, randomised, double-blind, placebo-controlled, Phase III studies were conducted in a total of 1480 non-Japanese patients with refractory POS, with or without SG seizures, who were receiving 1–3 concomitant AEDs: Studies 304 [
Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.
]. These extension studies supported the favourable safety, tolerability and efficacy profile of adjunctive perampanel for up to 4 years in patients with POS [
Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.
Here, we report the results of Study 231, an open-label, dose-ascending study, and its extension study (Study 233), which explored the long-term tolerability, safety and efficacy of adjunctive perampanel in Japanese patients with refractory POS, with or without SG seizures. Since enzyme-inducing AEDs (EIAEDs), such as carbamazepine (CBZ), oxcarbazepine and phenytoin (PHT), have previously been shown to cause a 3-, 2- and 2-fold increase in perampanel clearance, respectively [
], a sub-analysis of Study 231 only, also investigated drug–drug interactions between perampanel and concomitant EIAED use.
2. Methods
2.1 Standard protocol approvals, registration and patient consents
Study 231 (ClinicalTrials.gov identifier: NCT00849212) was conducted between March and November 2009, and Study 233 (ClinicalTrials.gov identifier: NCT00903786) was conducted between June 2009 and October 2016 at 9 sites in Japan. Both studies were conducted in accordance with the ethical principles of the Declaration of Helsinki, and the standards specified in the articles of the Pharmaceutical Affairs Law and the Standards for the Conduct of Clinical Studies, as well as being consistent with Good Clinical Practice guidelines for studies conducted in Japan. The institutional review board approved the studies for each study centre, and all patients provided written informed consent.
2.2 Patients
Eligible patients for Study 231 were male or female, between ≥20 and <65 years of age and diagnosed with POS, with or without SG seizures, according to the International League Against Epilepsy classification of epileptic seizures [
International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy.
]. Patients had uncontrolled seizures for the previous 2 years, despite at least 12 weeks’ treatment with more than 1 standard AED. If ≥1 benzodiazepine was used for the treatment of anxiety, sleep disorders, etc., this was counted as 1 concomitant AED. Patients received stable doses of 1–3 concomitant AEDs for at least the 8 weeks before enrolment in the observation period, only 1 of which was permitted to be an EIAED (such as CBZ, PHT, phenobarbital [PB] or primidone). Finally, patients had to have ≥3 POS during the previous 4 weeks prior to observation start and no 21-day, seizure-free period during the previous 8 weeks before treatment start based on medical records. Simple POS without motor signs or auras only were not counted.
Patients were excluded from Study 231 if they had status epilepticus within the previous 12 months, a history of Lennox-Gastaut syndrome or psychogenic seizures, presence of generalised seizures (e.g. absence, myoclonic) or had seizure clusters in the 8 weeks before enrolment in the observation period when individual seizures could not be counted. Patients were also excluded if they had undergone surgery for epilepsy within the previous 2 years, received barbiturates within the previous 8 weeks (other than for seizure control) or had severe liver or kidney disease. Patients who were pregnant, likely to get pregnant or were lactating were also excluded. Full inclusion and exclusion criteria for Study 231 are shown in Supplementary Table 1.
2.3 Study designs and objectives
Study 231 was a Phase II, multicentre, open-label, exploratory study. The primary objective was to assess the tolerability and safety of adjunctive perampanel and define the maximum tolerated dose in Japanese patients. The preliminary efficacy of adjunctive perampanel in Japanese patients was also evaluated in this study.
Study 231 comprised a 4-week observation period and 10-week treatment period, consisting of 6-week titration and 4-week maintenance periods. During the observation period, patients were assessed to ensure that they met the inclusion criteria. During the titration period, perampanel was administered orally at bedtime at an initial once-daily dose of 2 mg, with weekly up-titration in 2-mg increments to a maximum once-daily dose of 12 mg. If the investigator considered that up-titration was not appropriate based on tolerability, the dose was maintained at the same level or one 2-mg down-titration was permitted. During the maintenance period, patients continued to receive the same perampanel dose achieved at the end of titration.
Study 233 was an open-label extension study designed for patients who were continuing to receive perampanel at the end of the maintenance period of Study 231. Study 233 comprised a treatment period (≤316 weeks) and 4-week follow-up period. The primary objective was to evaluate the long-term safety, tolerability and efficacy of adjunctive perampanel. During the treatment period, patients continued to receive perampanel at the same dose they achieved at the end of Study 231.
2.4 Tolerability and safety assessments
Tolerability and safety were assessed for patients with evaluable safety data who received at least 1 dose of perampanel during the titration and maintenance periods of Study 231 or during the treatment period of Study 233. Patients reported signs and symptoms of treatment-emergent adverse events (TEAEs), which were checked by the investigator at each visit and recorded on a case report form. The investigator also judged the causal relationship for all TEAEs as unrelated or related to the study drug. Treatment-related TEAEs included any TEAEs that were deemed to be possibly related or probably related to the study drug by the investigator. Regular visits were held during both studies and included assessment of treatment-related TEAEs, clinical laboratory parameters, vital signs and 12-lead electrocardiogram.
2.5 Maximum tolerated dose
Maximum tolerated dose was evaluated by an independent Tolerability and Safety Evaluation Committee and defined as follows:
•
If 10 weeks of treatment were completed: maximum tolerated dose was defined as the dose at last administration.
•
If the patient discontinued due to a treatment-related TEAE and had received the dose at discontinuation for <7 days: maximum tolerated dose was defined as 2 steps (4 mg) lower than the dose at discontinuation.
•
If the patient discontinued due to a treatment-related TEAE and had received the dose at discontinuation for ≥7 days: maximum tolerated dose was defined as 1 step (2 mg) lower than the dose at discontinuation.
•
If the patient discontinued due to a non–treatment-related TEAE and had received the dose at discontinuation for <7 days: maximum tolerated dose was defined as 1 step (2 mg) lower than the dose at discontinuation.
•
If the patient discontinued due to a non–treatment-related TEAE and had received the dose at discontinuation for ≥7 days: maximum tolerated dose was defined as the dose at discontinuation.
2.6 Efficacy assessments
Efficacy was assessed for patients with evaluable efficacy data using the last observation carried forward (LOCF) and observed case (OC) approaches during the titration and maintenance periods of Study 231 or the treatment period of Study 233. Patient diaries were used to record seizure frequency throughout both studies. Efficacy endpoints included percent change in seizure frequency per 28 days relative to baseline and 50% responder rate (defined as the proportion of patients with a reduction in seizure frequency per 28 days from baseline of ≥50%). Efficacy data from Study 231 were also used to evaluate the seizure freedom rate (defined as the proportion of patients with a reduction in seizure frequency per 28 days from baseline of 100%).
2.7 Pharmacokinetic (PK) assessments
In Study 231 only, PK was assessed for patients who received perampanel during the titration or maintenance periods and had evaluable drug-concentration data. Plasma concentrations of perampanel and the concomitant EIAEDs—CBZ, PHT and PB—were measured to assess drug–drug interactions. As noted in Section 2.3, perampanel was administered once-daily at bedtime during Study 231. Given the relatively long half-life of perampanel (approximately 105 h) [
], patient blood samples for PK assessment were collected during the day after bedtime administration at enrolment in the treatment period and then during Weeks 2, 4, 6, 8 and 10, as well as at discontinuation and follow-up (except for patients entering Study 233). PK was not assessed during Study 233.
3. Results
3.1 Patients
Patient disposition is summarised in Fig. 1. Overall, 32 patients were enrolled in Study 231 and 30 were treated. Of the 30 treated patients, 23 (76.7%) completed Study 231 and 21 (70.0%) entered Study 233. Thirty patients in Study 231 provided evaluable data for assessing safety and PK, and 21 patients in Study 233 provided evaluable data for assessing safety. Twenty-seven patients (LOCF) or 22 patients (OC) in Study 231, and 21 patients in Study 233 provided evaluable data for assessing efficacy. Discontinuations were due to adverse events (AEs), investigator request and patient choice (Study 231, n = 2, n = 1 and n = 4, respectively; Study 233, n = 0, n = 6 and n = 9, respectively).
Baseline demographics, including clinical characteristics and concomitant AED use, are shown in Table 1. Mean time since epilepsy onset was 22.8 years in Study 231. Most patients received concomitant EIAEDs (90.0% in Study 231 and 95.2% in Study 233), of which, the most commonly used was CBZ (56.7% in Study 231 and 61.9% in Study 233).
Table 1Demographics and baseline characteristics.
Study 231 (N = 30)
Study 233 (N = 21)
Mean age, years (SD)
35.4 (10.6)
36.5 (11.0)
Female, n (%)
14 (46.7)
10 (47.6)
Mean weight, kg (SD)
60.9 (15.5)
62.4 (16.0)
Mean BMI, kg/m2 (SD)
22.4 (4.1)
22.7 (4.0)
Epilepsy-specific characteristics
Mean time since epilepsy onset, years (SD)
22.8 (11.4)
22.2 (12.5)
Mean total seizure frequency per 28 days during baseline
EIAED indicates patients who used at least 1 of carbamazepine, phenytoin, phenobarbital or primidone; non-inducer indicates patients who only used concomitant AEDs other than those listed as EIAEDs.
AED, antiepileptic drug; BMI, body mass index; EIAED, enzyme-inducing antiepileptic drug; max, maximum; min, minimum; SD, standard deviation.
a Total seizure frequency per 28 days as recorded during the 4-week observation period of Study 231.
b Mean and median total seizure frequency per 28 days during baseline do not include auras only.
c AEDs used within 8 weeks before enrolment in the observation period of Study 231.
d For Study 233, this is derived from Study 231.
e EIAED indicates patients who used at least 1 of carbamazepine, phenytoin, phenobarbital or primidone; non-inducer indicates patients who only used concomitant AEDs other than those listed as EIAEDs.
The extent of perampanel exposure for the 30 patients treated in Study 231 and the 21 patients treated in Study 233 is summarised in Table 2. In Study 231, the mean (standard deviation [SD]) duration of exposure to perampanel was 8.7 (2.6) weeks. The maximum tolerated dose was ≥8 mg/day in 21 (70.0%) patients, ≥10 mg/day in 15 (50.0%) patients and 12 mg/day in 10 (33.3%) patients. The Tolerability and Safety Evaluation Committee judged that 1 (3.3%) patient was intolerant to perampanel after the maximum tolerated dose was lowered from 2 mg/day because adverse drug reaction (irritability) was likely to cause discontinuation of treatment.
Table 2Extent of exposure to perampanel in Studies 231 and 233.
One patient was judged to be intolerant to perampanel after the maximum tolerated dose was lowered from 2 mg/day because adverse drug reaction (irritability) was likely to cause discontinuation.
0 (0.0)
2 mg/day
1 (3.3)
0 (0.0)
4 mg/day
1 (3.3)
1 (4.8)
6 mg/day
6 (20.0)
2 (9.5)
8 mg/day
6 (20.0)
5 (23.8)
10 mg/day
5 (16.7)
4 (19.0)
12 mg/day
10 (33.3)
9 (42.9)
SD, standard deviation.
a One patient was judged to be intolerant to perampanel after the maximum tolerated dose was lowered from 2 mg/day because adverse drug reaction (irritability) was likely to cause discontinuation.
During the treatment period of Study 233, the mean (SD) duration of exposure to perampanel was 195.0 (123.0) weeks. Overall, 17 (81.0%) patients received perampanel for ≥52 weeks, 16 (76.2%) patients received perampanel for ≥112 weeks and 9 (42.9%) patients received perampanel for ≥208 weeks. Six (28.6%) patients were treated for ≥304 weeks (>5.8 years), and 3 (14.3%) patients continued receiving perampanel for 316 weeks. The maximum tolerated dose was 4 mg/day for 1 (4.8%) patient, 6 mg/day for 2 (9.5%) patients, 8 mg/day for 5 (23.8%) patients, 10 mg/day for 4 (19.0%) patients and 12 mg/day for 9 (42.9%) patients (Table 2).
3.3 Safety outcomes
TEAEs were reported in 27 (90.0%) patients in Study 231 and 21 (100.0%) patients in Study 233. The majority of TEAEs were mild (Study 231, 36.7%; Study 233, 57.1%) or moderate (Study 231, 53.3%; Study 233, 38.1%) in severity. Twenty-six (86.7%) patients in Study 231 and 11 (52.4%) patients in Study 233 experienced ≥1 treatment-related TEAE. Treatment-related TEAEs observed in ≥5% of patients in Studies 231 and 233 are shown in Table 3. The 2 most commonly reported treatment-related TEAEs were dizziness (Study 231, 53.3%; Study 233, 14.3%) and somnolence (Study 231, 46.7%; Study 233, 9.5%). Fewer patients in Study 233 experienced treatment-related TEAEs than in Study 231 (52.4% [n = 11] vs 86.7% [n = 26], respectively). There were no severe TEAEs, serious TEAEs, deaths or abnormal changes from baseline in laboratory test data resulting in discontinuation during Study 231 (data not shown). In Study 233, there were no deaths, but 1 severe TEAE was reported in 1 (4.8%) patient and 4 serious TEAEs were reported in 4 (19.0%) patients (pneumonia bacterial, gastric ulcer, joint dislocation and haemorrhoids; all n = 1); a causal relationship to the study drug was not found for any of these serious TEAEs.
Table 3Most common treatment-related TEAEs (occurring in ≥5% of patients) in Studies 231 and 233.
Study 231 (N = 30)
Study 233 (N = 21)
Any treatment-related TEAE, n (%)
26 (86.7)
11 (52.4)
Nervous system disorders
22 (73.3)
6 (28.6)
Dizziness
16 (53.3)
3 (14.3)
Somnolence
14 (46.7)
2 (9.5)
Headache
3 (10.0)
0 (0.0)
General disorders and administration-site conditions
In Study 231, 4 TEAEs led to discontinuation of perampanel in 2 patients: somnolence and asthenia in 1 patient, and epileptic aura and facial oedema in the other; a causal relationship with perampanel was not ruled out because both patients recovered after treatment discontinuation. No TEAEs led to discontinuation in Study 233 (data not shown).
3.4 Efficacy outcomes
In Study 231, median percent change in seizure frequency per 28 days increased in a dose-dependent manner in both the LOCF and OC analyses: median (range) percent changes in seizure frequency per 28 days for the LOCF analysis were –25.2% (265.2 to –100.0%) with perampanel ≤8 mg, –39.8% (312.8 to –66.7%) with perampanel 10 mg and –48.1% (13.3 to –100.0%) with perampanel 12 mg (Fig. 2A); and for the OC analysis were –35.0% (221.4 to –100.0%) with perampanel ≤8 mg, –39.8% (312.8 to –66.7%) with perampanel 10 mg and–48.1% (13.3 to –100.0%) with perampanel 12 mg (Fig. 2B). Fifty-percent responder rates in the LOCF analysis were 25%, 40% and 50% with perampanel ≤8, 10 and 12 mg, respectively (data not shown). Four patients achieved seizure freedom with perampanel ≥6 mg (perampanel 6 mg, n = 1; perampanel 8 mg, n = 1; perampanel 12 mg, n = 2).
Fig. 2Perampanel efficacy during Studies 231 and 233. Study 231: (A) median percent change in seizure frequency per 28 days for LOCF or (B) OC; Study 233: (C) median percent change in seizure frequency per 28 days at weeks 4, 8 and 16, and by 12 week intervals thereafter, for ≤316 weeks and (D) yearly average median percent changes in seizure frequency per 28 days for ≤6 years.
In (C), N = number of patients at risk; in (D), N = number of patients continuing treatment on the first day of the corresponding period (year). Error bars show SD.
LOCF, last observation carried forward; OC, observed case; SD, standard deviation.
During Study 233, median percent changes in seizure frequency per 28 days were evaluated at Weeks 4, 8 and 16, and every 12 weeks thereafter, and reductions in seizure frequency were maintained across the treatment period (Fig. 2C and D). Seizure control was sustained for 316 weeks in 3 patients (Fig. 2C), with 2 of these patients achieving seizure freedom. The yearly average median percent change in seizure frequency per 28 days was assessed for up to 6 years (Fig. 2D). During the first, second, third, fourth, fifth and sixth years of treatment, median percent changes in seizure frequency per 28 days were –35.5%, –45.5%, –44.2%, –48.0%, –68.6% and –91.6%, respectively.
3.5 Pharmacokinetic outcomes
Drug–drug interactions between perampanel and EIAEDs were evaluated in Study 231 only (Fig. 3). Among the 3 EIAEDs measured (CBZ, PHT and PB), coadministration of CBZ was associated with the greatest average reduction in perampanel plasma concentrations compared with patients who did not receive any EIAEDs (non-inducers; 152.7 ng/mL vs 389.4 ng/mL [60.8% reduction], respectively, across perampanel groups); average perampanel plasma concentrations were 261.9 ng/mL with coadministration of PHT and 299.0 ng/mL with coadministration of PB (32.7% and 23.2% reductions compared with non-inducers, respectively). On the other hand, plasma concentrations of the concomitant EIAEDs were not changed by any dose of perampanel (data not shown).
Fig. 3PK profiles of perampanel with/without EIAEDs in Study 231. Mean concentrations of perampanel are shown for patients treated with perampanel with/without EIAEDs (N = 29; error bars show SD). Plasma concentrations were plotted by maintenance dose of perampanel.
N = number of patients who were receiving coadministration of non-inducers only or coadministration of carbamazepine, phenytoin or phenobarbital during treatment with perampanel.
† = only 1 patient was included so SD was not reported.
EIAED, enzyme-inducing antiepileptic drug; PK, pharmacokinetics; SD, standard deviation.
This Phase II study and its extension phase explored the long-term tolerability, safety and efficacy of adjunctive perampanel in Japanese patients with refractory POS, with or without SG seizures.
Despite the baseline phase of Study 231 being 2 weeks shorter than previous Phase III POS studies (4 weeks in Study 231 vs 6 weeks in Studies 304, 305, 306 and 335 [
]), the median baseline total seizure frequency per 28 days recorded during Study 231 appeared to be similar to those recorded during the previous Phase III POS studies (Study 231, 9.9; Study 304, 12.0–14.3 across treatments [
]); this may indicate a more refractory patient population in Study 231. A more refractory patient population is further suggested by the high proportion of patients taking 3 concomitant AEDs during the 8 weeks before enrolment in the observation period in Study 231 (70.0%) as compared with the proportions of patients who were receiving 3 concomitant AEDs during the baseline phase of Studies 304 (28.9%) [
In terms of retention, the extension Study 233 showed that 81.0% of patients received perampanel for ≥52 weeks (1 year), 76.2% of patients received perampanel for ≥112 weeks (2 years) and 42.9% of patients received perampanel for ≥208 weeks (4 years). The 1- and 2-year retention rates of perampanel were comparable with those of lamotrigine (75.2% and 69.2%, respectively), levetiracetam (65.6% and 45.8%, respectively) and topiramate (51.7% and 38.3%, respectively) [
]. Furthermore, the tolerability of adjunctive perampanel in patients with POS has also been shown in 2 previous extension studies, during which 29.7% of patients received perampanel for >182 weeks (Study 207) and 10.7% of patients received perampanel for >124 weeks (Study 307) [
Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.
]. There were no TEAEs that led to discontinuation throughout Study 233. These results indicate that adjunctive perampanel (≤12 mg/day) is well tolerated for the long-term treatment (≤316 weeks) of Japanese patients with refractory POS.
The current study suggests that TEAEs with adjunctive perampanel are comparable with those reported with other currently available AEDs [
]. The safety analysis showed that the TEAE profile of perampanel remained consistent across both Studies 231 and 233, and was similar to that reported in previous studies of adjunctive perampanel, with the majority of TEAEs being mild to moderate [
Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.
]. The most frequently reported treatment-related TEAEs in Studies 231 and 233 were dizziness and somnolence. These TEAEs have also been observed in patients treated with other AEDs, such as lamotrigine, levetiracetam and topiramate [
], whereas in this study, aggressiveness was not reported following treatment with adjunctive perampanel. However, aggression has been previously reported with adjunctive perampanel [
In terms of efficacy, median percent changes in seizure frequency per 28 days with adjunctive perampanel in Study 231 were comparable with the previous dose-ascending Study 208 (–35.0% vs –39.6%, respectively), as were 50% responder rates (37.0% vs 39.5%, respectively) [
], suggesting that perampanel efficacy is similar in Japanese and non-Japanese populations. The greatest improvements in these seizure endpoints were achieved with perampanel doses of 8–12 mg/day. In this study, 4 patients achieved seizure freedom while receiving perampanel doses of 6 mg/day or higher. Although patient numbers were small in this study, efficacy data of the maximum tolerated dose suggested that the higher perampanel doses were associated with greater efficacy, which has also been observed in previous Phase III studies of adjunctive perampanel. For example, in Study 306, median percent change in seizure frequency per 28 days was –10.7% with placebo, –13.6% with perampanel 2 mg/day, –23.3% with perampanel 4 mg/day and –30.8% with perampanel 8 mg/day; statistically significant differences compared with placebo were observed with perampanel doses of ≥4 mg/day [
]. Furthermore, in Study 335, in which efficacy was evaluated in an Asia-Pacific population, the dose-dependent pattern of efficacy was also observed with median percent changes in seizure frequency per 28 days of –10.8%, –17.3%, –29.0% and –38.0% for placebo and perampanel 4, 8 and 12 mg/day, respectively; statistically significant differences compared with placebo were observed for perampanel doses of ≥8 mg/day [
Study 233 showed that seizure control was maintained for 316 weeks (>6 years) in 3 of 21 patients, and 2 of these patients achieved a 100.0% reduction in seizure frequency per 28 days following treatment with adjunctive perampanel for 6 years. Compared with Studies 207 and 307, perampanel efficacy was recorded for a longer time period during Study 233 (Study 207: a 48.4% reduction in seizure frequency was reported for ≤208 weeks [
Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.
Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, open-label extension study 307.
], PK data can provide valuable insights to support optimal dosing with perampanel. Once perampanel is orally administered, it is rapidly absorbed with almost 100% bioavailability [
]. Plasma concentrations of perampanel are significantly reduced by concomitant treatment of moderate and strong CYP3A4 inducers, including CBZ, PHT and oxcarbazepine, in patients as well as in preclinical models of epilepsy [
]. In our PK analysis, concomitant use of CBZ was shown to cause the greatest reduction in the plasma concentration of perampanel compared with concomitant use of PHT or PB; therefore, concomitant use of CBZ with perampanel requires careful consideration regarding perampanel dose. Consistent with these results, CBZ has also been shown to cause a greater reduction in perampanel exposure compared with PHT, PB or oxcarbazepine in previous population PK analyses in Japanese and non-Japanese patients with POS [
]. PK analyses of pooled data from 3 Phase III studies in non-Japanese patients indicated a relationship between perampanel plasma concentrations and its clinical effects [
]; however, this was not investigated in Study 231 due to the small number of patients. A limitation of this study is that the statistical analyses performed to evaluate the data cannot provide clear conclusions, due to the small patient sample sizes. In addition, given the small patient numbers in the non-inducers group (n = 2), firm conclusions cannot be made based on concomitant use of non-inducers vs EIAEDs with perampanel in Study 231.
5. Conclusion
Overall, Studies 231 and 233 demonstrate the long-term tolerability, safety and efficacy of adjunctive perampanel when administered at doses of up to 12 mg/day for ≤316 weeks (>6 years). These results support the use of perampanel for the adjunctive treatment of refractory POS, with or without SG seizures, in Japanese patients (aged ≥20 to <65 years).
Author contributions
All authors were involved in the study design, interpretation of the results, and the reviewing and approval of the manuscript, and in the decision to submit the article for publication. All authors also confirm accountability for the accuracy and integrity of the work.
Funding
This study was funded by Eisai Inc. and Eisai Co., Ltd., who contributed to the design and conduct of the study, as well as the management, analysis and interpretation of the data.
Disclosures and conflicts of interest
Naotaka Usui, Naoki Akamatsu, Akihiro Ohnishi, Sunao Kaneko and Yushi Inoue have no potential conflicts of interest to disclose.
Nobukazu Nakasato has received honoraria from Eisai for lecturing.
Hidetaka Hiramatsu, Kazunori Saeki and Hideaki Miyagishi are employees of Eisai Co., Ltd.
Ethical publication statement
We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Acknowledgements
Medical writing support, under the direction of the authors, was provided by David Pertab, PhD, of CMC AFFINITY, a division of Complete Medical Communications Ltd., Glasgow, UK, funded by Eisai Inc., in accordance with Good Publication Practice (GPP3) guidelines.
Appendix A. Supplementary data
The following is Supplementary data to this article:
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Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
Eisai Co., Ltd., Eisai’s in-house developed antiepileptic drug Fycompa® (perampanel hydrate) approved in Japan as adjunctive therapy for partial-onset and generalized tonic-clonic seizures. Available at: http://www.eisai.com/news/enews201616pdf.pdf. Accessed 14 August 2018.
Eisai Inc. Eisai Submits Supplemental Application for Partial Label Change for Antiepileptic Drug FYCOMPA® as Monotherapy for Treatment of Partial-Onset Seizures Based on New U.S. FDA policy. Available at: http://www.eisai.com/news/enews201665pdf.pdf. Accessed 14 August 2018.
Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.
International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy.
Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, open-label extension study 307.
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