Abstracts

Rationale: YKP3089, a tetrazole alkyl carbamate derivative, is a new investigational antiepileptic drug (AED) with a potentially unique mechanism of action. YKP3089 displayed activity in a broad array of screening models, including the LTG-resistant amygdala-kindled rat and the 6 Hz model. The exact mechanism of action is unclear, although it appears to enhance GABA-induced currents without binding to GABAA subunits. It is an inhibitor of the inactivated state of Na+ channels. In early clinical studies, YKP3089 demonstrated a PK profile suited to clinical use, including once-daily dosing. Plasma concentrations correlated with PD effect in the human photosensitivity model. This is the first Phase 2 randomized, double-blind, placebo-controlled study of YKP3089 to assess efficacy and tolerability in patients with partial-onset seizures.Methods: Design: After an 8-wk baseline, patients were randomized to either placebo or YKP3089 titrated over 6 wks to 200 mg (50 mg increments at 2-wk intervals), followed by a 6-wk maintenance phase. Population: Adults with inadequately controlled partial-onset seizures ( 3 seizures/month in baseline) despite therapy with 1-3 AEDs. Population for primary analyses was ITT. The primary endpoint was median % reduction from baseline 28-day seizure frequency. Secondary endpoints included 50% responder rate; % of study completers with no seizures in maintenance phase; and median % seizure reduction by seizure type. Results: ITT population: YKP3089, N=113; placebo, N=108. Mean ages: 36 yr (YKP3089) and 37 yr (placebo); gender: 51% female (YKP3089) and 46% female (placebo). At baseline, median 28-day seizure frequency was 7.5 (YKP3089) and 5.5 (placebo). In patients receiving YKP3089, median % seizure reduction was 55.6% vs 21.5% (P<0.0001) with placebo. The 50% responder rates were 50.4% and 22.2% (P<0.0001), for YKP3089 and placebo, respectively. Among study completers, 27.5% receiving YKP3089 and 9.1% receiving placebo had no seizures during the maintenance phase. Median % seizure reductions according to baseline seizure type for YKP3089 vs placebo were 77% vs 33% (P<0.05) for SGTCS; 56% vs 21% (P<0.001) for CPS; and 76% vs 28% (P<0.05) for simple partial seizures with motor component. Most common AEs occurring in 10% of patients (YKP3089 vs placebo) were somnolence (22% vs 12%), dizziness (21% vs 17%), fatigue (11% vs 6%), headache (11% vs 11%) and nystagmus (10% vs 0). Nervous system and GI AEs occurring in 5% included balance disorder (8% vs 1%), tremor (6% vs 2%), constipation (5% vs 0), diarrhea (5% vs 0), and vomiting (5% vs 2%). In the YKP3089 arm, 3.5% discontinued due to AEs vs. 3.7% in the placebo arm.Conclusions: In this randomized double-blind placebo-controlled trial in patients with refractory partial epilepsy, YKP3089 200 mg was highly effective compared to placebo in reducing the frequency of partial-onset seizures. No major or unexpected safety or tolerability concerns were identified. Additional studies are ongoing. Study sponsored by SK Life Sciences.