Abstracts

Rationale: Oxcarbazepine (OXC) is a twice-daily antiepileptic drug (AED) with broad-spectrum efficacy. Supernus Pharmaceuticals, Inc. is developing SPN-804, a novel, extended-release (ER) formulation of OXC that may provide convenient, once-daily epilepsy treatment, reduce the dose- and peak-dose-related side effects of the original OXC formulation and facilitate adherence to therapy. Adjunctive treatment with SPN-804 in adults with refractory partial seizures is evaluated. Methods: Adults aged 18-65 with refractory partial epilepsy enrolled in this multicenter, randomized, double-blind, placebo-controlled, 3-arm study. Seizure frequency was assessed at baseline over 4-8 weeks (minimum 3 seizures/28 days for inclusion). Randomized adjunctive treatment included SPN-804 (1200 mg/d or 2400 mg/d) vs placebo; stable AEDs were continued. Drug titration occurred over 4 weeks (600 mg/wk) and then was maintained for 12 weeks. The primary endpoint was the median percentage change from baseline in partial seizure frequency per 28 days (PCH_T). Secondary endpoints included treatment response (ie, ?50% reduction in partial seizure frequency), seizure-free rates, Subject Global Impression of Change (SGIC), and change scores from the Quality of Life in Epilepsy-31 survey (QOLIE-31). Safety assessments were conducted.Results: Of 369 patients randomized, 366 (99.2%) made up the intent-to-treat population. Mean age was 38.9 (range: 18-66); 164 (44.8%) were male. The median PCH_T was -38.20 for 1200 mg/d (P=0.077 vs placebo), -42.90 for 2400 mg/d (P=0.003 vs placebo), and -28.70 for placebo. At 2400 mg/d, SPN-804 provided significant treatment response (P=0.018) and seizure-free rates during treatment (P=0.013) and maintenance (P=0.008) periods vs placebo. SGIC and QOLIE-31 revealed few treatment group differences. Adverse events (AEs) occurred in 69.1%, 56.6%, and 54.5% of those on SPN-804 2400 mg/d, SPN-804 1200 mg/d, and placebo, respectively; the most frequently reported AEs with SPN-804 were dizziness, somnolence, headache, nausea, diplopia, and vomiting. Serious AEs occurred in 9.8%, 6.6%, and 6.6% of those on SPN-804 2400 mg/d, SPN-804 1200 mg/d, and placebo, respectively. One death (ovarian cancer) occurred on placebo; no deaths occurred during SPN-804 therapy. Conclusions: SPN-804 2400 mg/d significantly reduced partial seizure frequency from baseline vs placebo. Seizure frequency reduction with SPN-804 1200 mg/d exhibited a strong trend toward statistical significance (P=0.077) vs placebo. This finding may be explained by the high placebo response rate noted here and is consistent with a general trend of higher placebo response rates observed in pivotal studies of other new AEDs. Both SPN-804 doses were generally well tolerated; no new safety signals were observed. The improved tolerability of SPN-804, a new OXC formulation, especially at doses up to 2400 mg/d, may translate to improved tolerability, adherence, and better patient outcomes. This study was funded by Supernus Pharmaceuticals, Inc.