Abstracts

Rationale: Treatment-emergent adverse event (TEAE) and exposure data from three clinical efficacy and safety studies were pooled to assess safety of cenobamate in patients with uncontrolled focal seizures when titrated weekly (1W) or every other week (2W). YKP3089C013 (C013) and YKP3089C017 (C017) were double-blind, placebo-controlled, phase 2 studies with ongoing open-label extensions (OLEs). YKP3089C021 (C021) is a long-term, open-label, phase 3, safety study. Methods: In C013, a starting dose of 50 mg/day was increased by 50 mg/day every 2 weeks to a target dose of 200 mg/day (max OLE dose 400 mg/day). In C017, patients were randomized to cenobamate 100, 200, or 400 mg/day. A starting dose of 50 mg/day was increased in weekly increments of 50 mg/day until 200 mg/day was reached. Patients in the 400 mg/day group then received weekly incremental increases of 100 mg/day (max OLE dose 400 mg/day). In C021, a starting dose of 12.5 mg/day was increased at 2-week intervals (12.5, 25, 50, 100, 150, and 200 mg/day) to a target dose of 200 mg/day. The dose could then be increased by 50 mg/day every 2 weeks to a maximum of 400 mg/day. TEAEs, discontinuations due to TEAEs, and serious TEAEs were compared between pooled data for C013 & C021 (2W) and C017 (1W). Results: Of the total population (n=1525, 2W group; n=419, 1W group), mean age was 39.5 y, 50.3% were male, and patients took a mean 2.3 concomitant AEDs at baseline. Median (range) exposure in months was 9.1 (0.03-79.4) and 38.4 (0.2, 54.5) for 2W and 1W groups; median modal daily dose was 200 mg (2W) and 250 mg (1W). Fewer patients had >=1 treatment-related TEAE in the 2W (70.0%) vs 1W (83.8%) group, fewer patients reported >=1 serious TEAE in the 2W (9.6%) vs 1W group (20.5%), and fewer 2W patients discontinued due to a TEAE vs the 1W group (11.0% vs 19.3%). The most common TEAEs leading to discontinuation were dizziness (2W, 1.0%; 1W, 2.4%), somnolence (2W, 0.6%; 1W, 1.9%), and ataxia (2W, 0.4%; 1W, 1.9%). Severe TEAEs were also experienced by fewer 2W vs 1W patients, most common of which were dizziness (0.9%, 2W; 4.8% 1W), vertigo (0.0%, 2W; 1.7% 1W), ataxia, and balance disorder (each 0.3%, 2W; 1.4%, 1W). One patient in the 1W group (200 mg/day), experienced a serious TEAE of DRESS on treatment Day 24. Conclusions: The current pooled safety analysis indicates that a slower, 2-week titration schedule of cenobamate was better tolerated than a 1-week titration. Fewer patients in the 2W vs 1W titration group experienced treatment-related TEAEs, discontinuations due to TEAEs, and serious and severe TEAEs, particularly those related to CNS disorders such as vertigo, ataxia, and dizziness. No cases of DRESS were identified in the 2W group. Funding: SK Life Science, Inc.