OBJECTIVE:Assess the relationship between subjective daytime sleepiness and therapeutic effect of adjunctive perampanel in a post hoc analysis of AMPA (NCT04257604), a prospective, observational study in Italy. METHODS:AMPA included people with epilepsy (PWE) aged ≥ 12 years with insufficiently controlled focal-onset seizures, with/without focal to bilateral tonic-clonic seizures, on 1-3 baseline anti-seizure medications, who were prescribed adjunctive perampanel. Full Analysis Set (FAS) included PWE (≥ 18 years) who received ≥ 1 perampanel dose, with baseline Epworth Sleepiness Scale (ESS) scores. ESS was administered at baseline and each study visit for ≤ 12 months. Excessive daytime sleepiness was defined as ESS ≥‍ 11 points. Quality of life (QoL) was assessed using QOLIE-31-P. RESULTS:FAS included 202 PWE. Mean (SD) ESS was 6.3 (4.5) at baseline (N = 202) and 6.2 (4.4) at end of treatment (EoT; n = 177); 29 PWE reported ≥‍ 4-point decreases from baseline ESS at EoT, while 31 reported ≥‍ 4-point increases. Median percent reductions in seizure frequency/28 days from baseline were 85.6% in improved ESS group and 77.6% in worsened ESS group (n = 14 each). At EoT, 14 PWE with no excessive daytime sleepiness reported a mean (SD) QOLIE-31-P score change of + 7.9 (12.9) points while 11 PWE with excessive daytime sleepiness had a mean (SD) change of -3.4 (18.6). Overall incidence of treatment-emergent adverse events was 56.9%; most commonly, dizziness/vertigo (22.8%) and somnolence (8.4%). CONCLUSION:In the FAS, adjunctive perampanel did not worsen daytime sleepiness for ≤ 12 months. In a small subset of patients, seizure frequency was reduced, regardless of ESS changes, and mean QoL at EoT was improved for those without excessive daytime sleepiness but declined for those with excessive daytime sleepiness. No new safety signals emerged.

OBJECTIVE:The AMPA study (Study 501; NCT04257604) was a multicenter, prospective, 12-month observational study in Italy that evaluated the effectiveness and safety of adjunctive perampanel in patients with focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS). METHODS:Patients aged ≥12 years with insufficiently controlled FOS, with or without FBTCS, receiving 1-3 anti-seizure medications (ASMs) were prescribed adjunctive perampanel per the approved indication. The primary endpoint was the median percent change in total seizure frequency per 28 days from baseline at Month 6. Baseline seizure frequency per 28 days was calculated using seizure diaries and/or medical records of seizures occurring in the 8 weeks prior to the baseline visit while patients were receiving 1-3 ASMs. Treatment-emergent adverse events (TEAEs), including serious TEAEs, were monitored for up to 12 months. RESULTS:Of the 240 patients enrolled in the study, 234 were included in the Full and Safety Analysis Sets. Median age (minimum, maximum) was 36.0 years (12, 84) and 51.3% (n = 120/234) were female. The majority of patients (77.8% [n = 182/234]) received ≥2 concomitant ASMs at baseline, with the most common being carbamazepine (33.8% [n = 79/234]). The median percent reduction in total seizure frequency per 28 days from baseline (95% confidence interval) was 55.4% (46.7%-66.7%) at Month 6. Overall, the retention rate was 57.3% (n = 134/234) following 12 months of treatment. During the study, the overall incidence of TEAEs was 56.4% (n = 132/234), with the most frequently reported TEAE being dizziness/vertigo (21.8% [n = 51/234]). Serious TEAEs were experienced by 6.0% (n = 14/234) of patients and no deaths were reported during the 12-month treatment period. SIGNIFICANCE:Data from the AMPA study suggest that adjunctive perampanel is associated with improvement in seizure control and with good retention rates and tolerability in a real-world clinical setting. These findings further support the use of adjunctive perampanel as a suitable treatment option for adolescent and adult patients with epilepsy. PLAIN LANGUAGE SUMMARY:Our study looked at teenage and adult patients with epilepsy in Italy who took the study drug, called perampanel, as well as the epilepsy treatments they had already been prescribed. After 12 months, 134 out of 234 patients were still using perampanel. Patients taking perampanel had fewer seizures than they did before they started taking perampanel. Side effects occurred in 132 patients (most commonly dizziness/vertigo, irritability, and sleepiness) and caused 45 of them to withdraw from the study. Perampanel was a suitable treatment option for teenage and adult patients with epilepsy.

OBJECTIVE:Early response to anti-seizure medication (ASM) is associated with a favorable prognosis in patients with epilepsy. Research is required to confirm existing data on the clinical use of perampanel as first adjunctive therapy in different patient groups and different regions. Here, we present a post hoc analysis of four post-marketing studies to examine side by side the efficacy and safety of perampanel administered as the first adjunctive ASM across different geographic settings. METHODS:Data from patients receiving first adjunctive perampanel were included in this post hoc analysis from Study 412 (NCT02726074, South Korea), Study 410 (NCT03288129, US), Study 509 (NCT04202159, Germany), and Study 501 (NCT04257604, Italy). Assessments included the median percent reduction from baseline/screening in seizure frequency, seizure-freedom rate, retention rate, and safety. RESULTS:A total of 170 patients who received first adjunctive perampanel were included in this study, including 102 patients from Study 412, 44 from Study 410, 13 from Study 509, and 11 from Study 501. At the latest time point in each study, 50% responder rates were ≥62.5% (range, 62.5%-100.0%) across seizure types, while seizure-freedom rates ranged from 25.0% to 100.0% (median, 51.6%). Retention rates were ≥61.8% at Month 6 in all studies and ≥54.5% at Month 12 in Studies 410 and 501 where these data were available. Overall, 46.2%-90.9% of patients experienced ≥1 treatment-emergent adverse event (TEAE) and 13.7%-27.3% discontinued perampanel due to TEAE(s). The most common TEAEs reported across each study were dizziness (≤50.0%), somnolence (≤36.4%), and fatigue (≤13.6%). SIGNIFICANCE:The results from this post hoc analysis demonstrated that perampanel as first adjunctive therapy had a good treatment response with no new safety signals observed. Limitations included the post hoc nature of the analysis and the inability to pool data due to study design differences. Overall, these data support the use of perampanel as an early-line treatment in patients with epilepsy. PLAIN LANGUAGE SUMMARY:This analysis looked at a medicine called perampanel and how well it works for people with epilepsy when it was one of the first medicines added to their regular seizure treatment. Data were collected from four separate studies that were done in South Korea, the United States, Germany, and Italy. Most patients had fewer seizures across all four studies after 6 months of treatment. The most common side effects reported in patients included dizziness and sleepiness. Perampanel worked well when used early during treatment, and most people were able to keep taking perampanel without significant difficulties.

IntroductionStudy 512 aimed to assess the efficacy and safety of perampanel (PER) as the first add-on therapy.MethodsIn this 12-month, prospective, observational, multicenter study, people with epilepsy (PWE) aged ≥12 years with focal-onset seizures or generalized tonic–clonic seizures (GTCS) associated with idiopathic generalized epilepsy received PER as the first add-on therapy to antiseizure medication (ASM) monotherapy. The primary efficacy endpoint was the retention rate at 12 months. Other endpoints included change in seizure frequency from baseline; pragmatic seizure freedom rate (proportion of PWE in the full analysis set achieving freedom from all seizures); responder rate (≥50% seizure frequency reduction from baseline), changes from baseline in the 10-item Quality of Life in Epilepsy questionnaire (QOLIE-10) total score, the Epworth Sleepiness Scale (ESS), and the age-corrected EpiTrack and EpiTrack Junior total score; safety/tolerability (treatment-emergent adverse events [TEAEs]); and PER dose.ResultsOf 184 PWE (Safety Set, n = 182; Full Analysis Set, n = 174), 135 (73.4%) completed the 12-month study. The mean PER dose was 4.7 mg/day. Retention rate at 12 months was 74.2% in the overall population, 81.8% in the 12 to <18 years age group, 74.3% in the 18 to <65 years age group, and 66.7% in the ≥65 years age group. Retention rates were similar between PWE with focal-onset seizures (74.5%) and GTCS (75.0%). The median reduction in monthly seizure frequency per 28 days from baseline to 12 months was 78.6% in the overall population, 92.3% in the 12 to <18 age group, 75.0% in the 18 to <65 years age group, and 87.5% in the ≥65 years age group. In the overall population, pragmatic seizure freedom rates at 12 months were 36.2% (all seizures), 34.1% (all focal seizures), and 45.5% (GTCS); the responder rate at 12 months was 64.4% in the overall population. In total, 52.7% of PWE experienced TEAEs, and 12.1% discontinued due to TEAEs. No significant changes were identified from baseline to 12 months in QOLIE-10, ESS, and the age-corrected EpiTrack and EpiTrack Junior scores.ConclusionPER was efficacious for focal and generalized seizures across all age groups and was generally well-tolerated, as demonstrated by the high retention rates at 12 months.

Examine long-term findings from two Phase III open-label extension (OLEx) studies of adjunctive perampanel in patients aged ≥60 years experiencing focal seizures (FS), with/without focal to bilateral tonic-clonic seizures (FBTCS), with/without enzyme-inducing anti-seizure medications (EIASMs). METHODS:Study 307 (NCT00735397) included a Conversion Period (16 weeks; blinded) and a Maintenance Period (256 weeks). Study 335 OLEx (NCT01618695) included Pre-conversion (4 weeks), Conversion (6 weeks), and Maintenance Periods (≥46 weeks). Perampanel (2-12 mg/day) was given alongside 1-3 concomitant ASMs, of which ≤2 (Study 307) and ≤1 (Study 335) were EIASMs. Efficacy and safety outcomes were analyzed. RESULTS:Seventy-one patients aged ≥60 years were included in the Full and Safety Analysis Sets. Over 4 years, seizure frequency decreased regardless of EIASM use; seizure-freedom rates for FS were 0.0 % (n = 0/71) for Year 1, 2.6 % (n = 1/38) Year 2, 5.3 % (n = 1/19) Year 3, and 0.0 % (n = 0/14) Year 4. For FBTCS, these rates were 26.3 % (n = 5/19) for Year 1, 22.2 % (n = 2/9) Year 2, 40.0 % (n = 2/5) Year 3, and 0.0 % (n = 0/4) Year 4. The 90 % responder rates were ≥14.0 % for FS and ≥40.0 % for FBTCS. Incidence of treatment-emergent adverse events (TEAEs) was highest during Year 1 (87.3 % [n = 62/71]) but decreased across Years 2-4 (47.4 %-60.4 %). The most commonly reported TEAE during Years 1/2 was dizziness (47.9 % [n = 34/71] and 12.5 % [n = 6/48], respectively) and during Years 3/4 was fall (15.8 % [n = 3/19] and 14.3 % [n = 2/14]). SIGNIFICANCE:Adjunctive perampanel conferred long-term seizure control in older patients with epilepsy; safety was aligned with established perampanel safety profile.

BACKGROUND:Lecanemab 10 mg/kg every 2 weeks (Q2W) intravenously was shown in the Clarity AD trial to slow the progression of Alzheimer's disease (AD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrated that lecanemab average steady-state concentrations (Cav, ss) are associated with amyloid plaque lowering and efficacy, while maximum steady-state concentrations (Cmax, ss) are correlated with ARIA-E. A subcutaneous lecanemab formulation was hypothesized to have similar or better safety profile, with lower rates of systemic administration reactions. Herein, we provide an update on the clinical results from the subcutaneous lecanemab development program. METHODS:Clarity AD is a phase 3, double-blind, placebo-controlled study of 18-month treatment duration with an ongoing open-label extension (OLE) in patients with early AD. Eligible patients were randomized to placebo or 10 mg/kg lecanemab biweekly. Subcutaneous dosing is under development based on pharmacokinetic (PK) and pharmacodynamic (PD) modeling, bioavailability data, as well as clinically in a substudy of the OLE. A subset of participants in the subcutaneous substudy were lecanemab naïve. Validated anti-drug antibodies (ADA) and neutralizing antibody (Nab) assays were performed using a tiered approach. RESULTS:In the Clarity AD phase 3 study, lecanemab subcutaneous weekly dosing with a single 360 mg autoinjector has low rate of ADA (2%) with low titers and maintains plasma biomarkers at levels consistent with inhibition of AD pathology and neuroinflammation; PK was not affected by immunogenicity. From modeling data, initiating subcutaneous maintenance dosing of 360 mg weekly at 18- or 24-months results in similar effect on amyloid PET and CDR-SB compared to biweekly dosing for 4 years. There was no ARIA-E, ARIA-H, or deaths reported in participants receiving 360 mg subcutaneous lecanemab. Injection site reactions were infrequent and mostly of mild or moderate severity. Systemic reactions to subcutaneous treatment were uncommon. Among dosing options tested, lecanemab subcutaneous 360 mg autoinjector was selected as the optimal formulation for maintenance therapy. CONCLUSIONS:Subcutaneous lecanemab has low-risk for immunogenicity. Lecanemab, administered subcutaneously, has a safety, tolerability, and pharmacodynamic profile that favorably compares to the approved 10mg/kg biweekly intravenous dose, and autoinjector administration provides greater patient convenience.

OBJECTIVE:Study 311 (NCT02849626) Extension A assessed long-term outcomes of adjunctive perampanel treatment in children (ages 4 to <12 years) with uncontrolled focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS). METHODS:Patients completing the 23-week Core Study could enter Extension A (29-week Maintenance and 4-week Follow-up Periods) to receive perampanel at the dose achieved during the Core Study. Dose adjustments were permitted per the investigator's discretion during Extension A. The maximum dose was 12 mg/day for patients enrolled in Japan and without enzyme-inducing anti-seizure medications (EIASMs), or 16 mg/day with EIASM(s). Safety and tolerability were monitored throughout Extension A. Efficacy assessments included median percent change in seizure frequency per 28 days from baseline and 50% responder rates. Outcomes were analyzed by seizure type, age (4 to <7 vs 7 to <12 years), and EIASM use. RESULTS:Of 180 patients enrolling in the Core Study, 136 entered (FOS, n = 116 [including 43 with FBTCS]; GTCS, n = 20) and 122 completed Extension A. Treatment-emergent adverse events (TEAEs) were the most common reason for discontinuation (4%). The mean (standard deviation) dose during Extension A was 8.3 (3.2) mg/day. Incidences of TEAEs in Extension A were 69% overall and 62%-89% across subgroups; TEAEs led to dose adjustment in 10% of patients. No changes of clinical concern in cognition, growth, development, or quality of life were identified over 52 weeks. At Weeks 40-52, median percent reductions in seizure frequency per 28 days from baseline were 69% (FOS, n = 108), 74% (FBTCS, n = 41), and 100% (GTCS, n = 13); 50% responder rates were 62% (FOS and GTCS) and 81% (FBTCS). Efficacy outcomes were comparable across age and EIASM groups. SIGNIFICANCE:These findings support long-term (≤52 weeks) use of adjunctive perampanel in children with epilepsy, irrespective of seizure type, age, or EIASM use.

OBJECTIVE:In traditionally designed randomized clinical trials of antiseizure medications, participants take a blinded treatment for a prespecified number of weeks, irrespective of continued seizures. The alternative design time to prerandomization monthly seizure count (T-PSC) allows participants to end the blinded treatment after an individually prespecified number of seizures, which shortens exposure to placebo and ineffective treatment. Previous reanalyses have shown that T-PSC replicated the efficacy conclusions of trials; therefore, we evaluated whether T-PSC also could replicate tolerability and safety conclusions. METHODS:We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from three blinded, placebo-controlled trials of perampanel for focal onset seizures (NCT00699972, NCT00699582, NCT00700310). We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs that prompted medication adjustment compared to those observed during the full-length trial. RESULTS:Of the 1480 participants in the three trials, 1093 experienced any TEAE, of whom 1006 (92%) had onset prior to T-PSC. When evaluating the differences in each type of TEAE for each dose of perampanel from placebo within each trial, there was no consistent pattern of under- or overestimation. Across the three studies, 23 of 79 (29%) serious TEAEs, most requiring hospitalization, occurred after T-PSC. SIGNIFICANCE:Almost all TEAEs occurred before T-PSC. Similar conclusions regarding the tolerability and safety of perampanel would have been reached if the T-PSC design had been used. This suggests that the T-PSC design may potentially benefit participants by allowing earlier change from an ineffective treatment to an alternate treatment, which could reduce the risk of serious consequences of ineffective treatment, such as hospitalization.

The Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients ≥2 years of age with uncontrolled seizures associated with Lennox–Gastaut syndrome (LGS). Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18-week double-blind, randomized, placebo-controlled Core Study and ≥52-week open-label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure-freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures. Seventy patients were randomized into the Core Study (perampanel, n  = 34; placebo, n  = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments ( p  = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs −.7%, respectively, p  = .001) or all countable motor seizures (44.0% vs −.6%, respectively, p  = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment-emergent adverse events occurred in 85.3% of perampanel-treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo-treated patients. This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long-term efficacy and safety of perampanel in the LGS population.

INTRODUCTION:The non-interventional Phase IV PROVE study (NCT03208660) assessed retention, efficacy, safety and tolerability, and perampanel dosing in patients with epilepsy during routine clinical care. This analysis evaluated final data from patients aged <4 years and 4-<12 years. METHODS:Data were obtained retrospectively from medical/pharmacy records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinician recommendations. Retention rate was the primary endpoint. Secondary assessments included median percent changes in seizure frequency, seizure-freedom rates, investigator impression of seizure effect, and safety and tolerability. RESULTS:The Safety Analysis Set (SAS) included 41 patients (<4 years; mean maximum dose, 3.5 mg/day) and 203 patients (4-<12 years; mean maximum dose, 5.3 mg/day); 24-month retention rates were 35.7% (n = 5/14) and 42.0% (n = 47/112), respectively. In the Full Analysis Set, during Months 1-3, median percent reductions in seizure frequency were 33.3% (n = 8 [<4 years]) and 26.0% (n = 32 [4-<12 years]), and seizure-freedom rates were 12.5% in both groups (n = 1/8 and n = 4/32); patient numbers were low at later time points. Most patients showed improvements in seizure control (45.9% [<4 years] versus 52.4% [4-<12 years]) or no change (45.9% versus 34.5%) (SAS). Treatment-emergent adverse events (TEAEs) were reported in 12 (<4 years: 29.3%; most common, irritability [7.3%]) and 64 patients (4-<12 years: 31.5%; most common, aggression [6.9%]). CONCLUSIONS:Perampanel was generally well tolerated with <21% of TEAEs leading to withdrawal at 24 months, had favorable retention rates (≥50% and >35% at 12 and 24 months, respectively), and sustained efficacy in pediatric patients during routine clinical care.

Abstract Objective To evaluate the long‐term efficacy, safety, and tolerability of adjunctive perampanel for the treatment of patients with refractory focal‐onset seizures (FOS), with or without focal to bilateral tonic–clonic seizures (FBTCS), from the Asia‐Pacific region. Methods Study 335 (NCT01618695) was a randomized, double‐blind, placebo‐controlled, Phase III study. Patients aged ≥12 years with refractory FOS who completed the Core Study could enter an open‐label extension (OLEx) Phase (6‐week Conversion and ≥46‐week Maintenance Period). Endpoints included median percent reduction in seizure frequency per 28 days, 50% responder and seizure‐freedom rates, and treatment‐emergent adverse events (TEAEs). Results The Intent‐to‐Treat Analysis Set included 704 patients (529 received perampanel and 175 received placebo during the Core Study; all patients received perampanel during OLEx). The median percent reduction in seizure frequency and 50% responder rates in patients who received perampanel during the Core Study were maintained throughout the OLEx Phase (Week 64–75: 55.9% and 54.3%, respectively). Seizure freedom for ≥12 consecutive months at any time during perampanel treatment was achieved by 4.1% of patients with FOS and 14.2% of patients with FBTCS. Among patients treated with perampanel 4 mg/day (n = 83), median reduction in seizure frequency was lower in those who received concomitant enzyme‐inducing anti‐seizure medications (EIASMs) than those who received non‐EIASMs. The most common TEAE was dizziness (n = 318; 46.8%); 141 (20.8%) patients had TEAEs that led to study/drug withdrawal. Significance Overall, long‐term seizure control was achieved with adjunctive perampanel in patients with refractory FOS, with or without FBTCS, in an Asia‐Pacific population.

OBJECTIVE:Static assignment of participants in randomized clinical trials to placebo or ineffective treatment confers risk from continued seizures. An alternative trial design of time to exceed prerandomization monthly seizure count (T-PSC) has replicated the efficacy conclusions of traditionally designed trials, with shorter exposure to placebo and ineffective treatment. Trials aim to evaluate efficacy as well as safety and tolerability; therefore, we evaluated whether this T-PSC design also could replicate the trial's safety and tolerability conclusions. METHODS:We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from a blinded, placebo-controlled trial of perampanel for primary generalized tonic-clonic seizures (NCT01393743). The safety analysis set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs of special interest that occurred before T-PSC relative to those observed during the full-length trial. RESULTS:Of the 67 and 59 participants who experienced TEAEs in the perampanel and placebo arms during full-length trial, 66 (99%) and 54 (92%) participants experienced TEAEs with onset occurring before T-PSC, respectively. When limited to treatment-related TEAEs, 55 of 56 (98%) and 32 of 37 (86%) participants reported treatment-related TEAEs that occurred before T-PSC in the perampanel and placebo arms, respectively. There were more TEAEs after T-PSC with placebo as compared to perampanel (Fisher exact odds ratio = 8.6, p = .035), which resulted in overestimation of the difference in TEAE rate. There was a numerical reduction in serious TEAEs (3/13 occurred after T-PSC, one in placebo and two in perampanel). SIGNIFICANCE:Almost all TEAEs occurred before T-PSC. More treatment-related TEAEs occurred after T-PSC for participants randomized to placebo than perampanel, which may be due to either a shorter T-PSC or delayed time to TEAE for placebo.

ObjectivesThe Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients >= 2 years of age with uncontrolled seizures associated with Lennox-Gastaut syndrome (LGS).MethodsEligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18-week double-blind, randomized, placebo-controlled Core Study and >= 52-week open-label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure-freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures.ResultsSeventy patients were randomized into the Core Study (perampanel, n = 34; placebo, n = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs -.7%, respectively, p = .001) or all countable motor seizures (44.0% vs -.6%, respectively, p = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment-emergent adverse events occurred in 85.3% of perampanel-treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo-treated patients.SignificanceThis study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for <= 71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long-term efficacy and safety of perampanel in the LGS population.

Objective: To assess efficacy of perampanel monotherapy by seizure type in a post hoc analysis of the FREEDOM Study (Study 342; NCT03201900). Background: FREEDOM demonstrated long-term (52 weeks) efficacy and tolerability of perampanel monotherapy (4–8mg/day) in patients aged ≥12 years with newly diagnosed or currently untreated recurrent focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS) in Japan and Korea. Design/Methods: The Core Study comprised a 4-week Pretreatment Phase and a 32-week Treatment Phase (6-week Titration; 26-week Maintenance) during which patients received perampanel 4mg/day. Patients who experienced seizure(s) during the 4-mg/day Maintenance Period could be transitioned to an additional 30-week 8-mg/day Treatment Phase (4-week Titration; 26-week Maintenance). Patients could also enter a 26-week Extension Phase to continue treatment with perampanel monotherapy after completion of the Core Study. The 52-week seizure-freedom rates were stratified by prior history of the following subtypes of FOS: focal impaired awareness seizures (FIAS), FBTCS, and FIAS plus FBTCS. Results: Overall, 89 patients received ≥1 dose of perampanel (Safety Analysis Set [SAS]) and 73 patients entered the 4-mg/day Maintenance Period (modified Intent-to-Treat [mITT] Analysis Set), of whom 21 patients transitioned to the 8-mg/day Treatment Phase. In the SAS, the mean (standard deviation [SD]) duration of perampanel exposure was 66.5 (52.0) weeks across the Core Study and Extension Phase. In the mITT population, the mean (SD) age was 41.7 (18.5) years, and most patients had newly diagnosed epilepsy (95.9% [n=70/73]). The 52-week seizure-freedom rates were 34.1% for FIAS, 31.3% for FBTCS, and 32.9% for FIAS plus FBTCS; these rates at last evaluated dose (4 or 8mg/day) were 41.5% (FIAS), 43.8% (FBTCS), and 42.9% (FIAS plus FBTCS). Conclusions: These results suggest that seizure freedom can be achieved and sustained with perampanel monotherapy treatment (4–8mg/day) long-term (≤52 weeks) regardless of seizure type. Disclosure: Sung Chul Lim has nothing to disclose. Anna Patten, 14934 has received personal compensation for serving as an employee of Eisai Ltd. An immediate family member of Dr. Morita-Sherman has received personal compensation for serving as an employee of Forrester Research. Dr. Morita-Sherman has received personal compensation for serving as an employee of Eisai Inc.. An immediate family member of Dr. Morita-Sherman has stock in Forrester Research. The institution of Dr. Morita-Sherman has received research support from Cleveland Clinic. Dr. Ngo has received personal compensation for serving as an employee of Eisai Inc.. Dr. Yamamoto has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Eisai. Dr. Yamamoto has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Daiichi-Sankyo.