Abstracts

Rationale: LGS is a severe refractory childhood-onset epilepsy characterized by a triad of multiple seizure types (including drop seizures), intellectual disability, and certain electroencephalographic (EEG) abnormalities. Study 338 (NCT02834793) was a Phase III study that evaluated the efficacy and safety of adjunctive perampanel in patients aged ≥ 2 years with uncontrolled seizures with LGS. Here we present results from a post hoc analysis stratified by modal dose (≤ 4 mg/day, > 4 to ≤ 8 mg/day, and > 8 mg/day).

Methods: Study 338 enrolled patients with clinical and EEG confirmation of LGS diagnosis who were < 11 years of age at the onset of LGS, were receiving 1–4 concomitant anti-seizure medications at stable doses for ≥ 30 days before screening, and had an average of ≥ 2 drop seizures/week during baseline (at least 4 weeks). The study consisted of a randomized, double-blind, placebo-controlled Core Study (4–8-week screening/baseline, 6-week titration [2 to ≤ 8 mg/day based on response and tolerability], 12-week maintenance), and open-label Extension A (52 weeks) and Extension B (for patients in Japan or countries without an Extended Access Program). Perampanel could be up-titrated to 12 mg/day in the Extension Phase (except in Japan, where the maximum allowed dose remained at 8 mg/day). The primary endpoint was median percent change from baseline in drop seizure frequency/28 days during the Titration and Maintenance Periods (drop seizures included atonic, tonic, or myoclonic seizures that led or could have led to a fall). Secondary endpoints included 50% and 75% responder and seizure-freedom rates for drop seizures and all seizures, and safety outcomes.

Results: A total of 70 patients were randomized in the Core Study to receive either perampanel (≤ 4 mg/day, n=6; > 4 to ≤ 8 mg/day, n=28) or placebo (n=36); 58 patients entered Extension A and received perampanel at ≤ 4 mg/day (n=14), > 4 to ≤8 mg/day (n=37), or > 8 mg/day (n=7), 13 of whom entered Extension B. During the Core Study, the mean (standard deviation) modal doses were 3.5 (0.8) and 7.5 (0.9) mg for ≤ 4 mg/day and > 4 to ≤ 8 mg/day groups, respectively; for the Extension Phase, these were 3.7 (1.5), 7.5 (0.9), and 10.9 (1.1) mg for ≤ 4 mg/day, > 4 to ≤ 8 mg/day, and > 8 mg/day groups, respectively. Table 1 provides an overview of efficacy outcomes by modal dose. Median percent reductions in drop seizure frequency/28 days were 4.5% (placebo), 30.7% (≤ 4 mg/day), and 23.1% ( > 4 to ≤ 8 mg/day) during the Core Study; for the Extension Phase, these were 39.6% (≤ 4 mg/day), 27.8% ( > 4 to ≤8 mg/day), and 40.7% ( > 8 mg/day). Similar incidences of treatment-emergent adverse events were reported across all dose groups (Table 2).

Conclusions: Overall, efficacy was attained across all dose levels; however, interpretation of these data is limited due to small sample size and further research is warranted. Some patients may achieve efficacy at lower doses, and some may require a higher dose of perampanel. No new safety signals emerged.

Funding: Eisai Inc., Eisai Ltd., Eisai Co., Ltd.