Authors :
Brenda Porter, MD, PhD – Stanford University; Ryutaro Kira, MD, PhD – Fukuoka Children's Hospital; Jeehun Lee, MD, PhD – Department of Pediatrics – Samsung Medical Center; Alec Aeby, MD, PhD – Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles; Anna Patten, PhD – Eisai Ltd.; Leock Ngo, PhD – Eisai Inc.
Rationale: LGS is a severe refractory childhood-onset epilepsy characterized by a triad of multiple seizure types (including drop seizures), intellectual disability, and distinct electroencephalographic (EEG) abnormalities. We report the results from a Phase III study (Study 338; NCT02834793) that evaluated the long-term efficacy and safety of adjunctive perampanel in patients aged ≥ 2 years with inadequately controlled seizures with LGS.
Methods: Study 338 enrolled patients with clinical and EEG confirmation of LGS who were < 11 years of age at LGS onset, were receiving 1–4 concomitant ASMs at stable doses for ≥ 30 days before screening, and had an average of ≥ 2 drop seizures/week during the Baseline Period (≥ 4 weeks). The study comprised a randomized, double-blind, placebo-controlled Core Study (4–8-week screening/baseline, 6-week Titration [2 to ≤ 8 mg/day based on response/tolerability], 12-week Maintenance), and open-label Extension A (52 weeks) and Extension B (patients in Japan or countries without an Extended Access Program). 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: Of 70 patients randomized in the Core Study (perampanel, n=34; placebo, n=36), 58 patients entered Extension A; 13/32 patients who completed Extension A entered Extension B. In the Core Study, the median percent reduction in drop seizure and all seizure frequency/28 days was numerically higher for perampanel (23.1% and 18.2%, respectively) vs placebo (4.5% and 6.5%, respectively). The median percent reduction in drop seizure and all seizure frequency/28 days in the Extension Phase (perampanel only) was 29.5% and 26.1%, respectively.
The 50% and 75% responder and seizure-freedom rates for drop and all seizures were higher with perampanel compared with placebo in the Core Study (Table 1). Responder rates and reductions in seizure frequency were maintained through the Extension Phase for drop seizures and all seizures. Table 2 summarizes treatment-emergent adverse events, and perampanel exposure and dosage. Overall, the most common TEAEs in patients receiving perampanel were somnolence, irritability, upper respiratory tract infection, and decreased appetite. Few patients in the Core Study discontinued due to TEAEs (Core Study, n=3; Extension, n=8; Table 2). There were no deaths during the Core Study, but two deaths (unrelated to perampanel) occurred during the Extension Phase.
Conclusions: Adjunctive perampanel reduced drop- and total-seizure frequency and was well tolerated in patients aged ≥ 2 years with LGS in the Core Study. Findings from the Extension Phase demonstrate long-term efficacy and good tolerability of perampanel in this patient population.
Funding: Eisai Co., Ltd., Eisai Inc., and Eisai Ltd.