Abstracts

Rationale: Oxcarbazepine (OXC) is a twice-daily, immediate-release (IR) antiepileptic drug (AED) with broad-spectrum efficacy in children and adults. Adverse events (AEs) associated with OXC appear to be dose-related. Nervous and ophthalmologic system AEs (defined by Medical Dictionary for Regulatory Activities [MedDRA]) are among the most troubling and commonly lead to discontinuation. Supernus Pharmaceuticals, Inc is developing SPN-804, a novel, once-daily, extended-release (ER) formulation of OXC that may reduce the dose- and peak-related AEs that occur with OXC IR and may facilitate adherence to therapy. Methods: This multicenter, randomized, double-blind, placebo-controlled, 3-arm (SPN-804 2400 mg/d, SPN-804 1200 mg/d, or placebo) study enrolled adults 18-65 years old with refractory partial epilepsy despite 1-3 concomitant AEDs. Titration to target dosing occurred over 4 weeks and then target dosing was maintained for 12 weeks thereafter. Standard safety assessments were conducted. This subanalysis examined the incidence and impact of nervous and ophthalmologic system AEs with SPN-804 and compared them to those observed with OXC IR using historical data from a similarly designed trial.Results: Of 369 patients randomized, 366 (99.2%) took ?1 dose of study drug and comprised the safety population. Mean age was 39 (range: 18-66); 164 (44.8%) were male. Overall, AEs occurred in 69.1%, 56.6%, and 54.5% and discontinuations due to AEs occurred in 30.1%, 15.6% and 11.6% of those taking SPN-804 2400 mg/d, SPN-804 1200 mg/d, or placebo, respectively. Nervous system AEs occurred in 56.1%, 38.5%, and 30.6% of those taking SPN-804 2400 mg/d, SPN-804 1200 mg/d, or placebo, respectively, while ophthalmologic AEs occurred in 14.6%, 14.8%, and 5.8%. The majority of AEs were mild to moderate in intensity. Severe AEs with a higher incidence in both SPN-804 groups vs placebo were dizziness (2%, 2400 mg/d; 3%, 1200 mg/d; 0.8%, placebo) and diplopia (0.8%, 0.8%, and 0%, respectively). Conclusions: Although long-term head-to-head clinical studies evaluating the AE profile of SPN-804 and OXC IR would be the ideal comparison, no such data are available. Using an historical comparison, the Barcs et al study revealed higher overall AE rates (90.4% and 97.7%), and discontinuations due to AEs (36.2% and 66.7%) with OXC IR 1200 mg/d and 2400 mg/d, respectively, than with corresponding doses of SPN-804. Nervous and ophthalmologic AEs including dizziness, somnolence, headache, tremor, nystagmus, and diplopia were markedly lower with either dose of SPN-804 vs comparative OXC IR doses. This randomized, double-blind study suggests that SPN-804 may provide a marked tolerability improvement in overall AE rates, and for the particularly troubling nervous and ophthalmologic system AEs at both doses, especially as it relates to the SPN-804 2400 mg/d dose, compared to historical data for OXC IR. If this advantage proves true, SPN-804 may lead to improved effectiveness and patient adherence.