Rationale: Epilepsy is most prevalent in older adults (65 and older). Changes in metabolism, absorption, and pharmacokinetic competition can lead to differences in the safety, tolerability, and efficacy of antiseizure medications (ASMs). Cenobamate is an ASM approved in the U.S. and EU for focal seizures in adults. Safety and efficacy data were analyzed for the older adult subset in a post-hoc analysis of a global, phase 3, long-term, open-label safety study (Sperling et al. 2020).
Methods: Adults 18 to 70 years old with uncontrolled focal seizures taking stable doses of 1-3 ASMs were enrolled in the phase 3 trial. Adjunctive cenobamate dosage was initiated at 12.5 mg/day, increasing at 2-week intervals (25, 50, 100, 150, and 200 mg/day) to the target dose of 200 mg/day. The dose could be further increased by 50 mg/day at 2-week intervals (maximum, 400 mg/day). Safety and efficacy were analyzed post-hoc for a subset of patients aged 65-70. Safety was assessed by documenting treatment-emergent adverse events (TEAEs). Post-hoc efficacy assessments were conducted on a subset of 240 patients with adequate seizure data available (n=18, ≥ 65 years). Efficacy was measured as the percentage of patients achieving 100% seizure reduction within 3-month intervals during the maintenance phase. Concomitant ASM drug load changes from baseline to 1 year were measured, with drug load defined as the ratio of actual drug dose per day to the defined daily dose by the World Health Organization.
Results: Of 1340 patients (mean age, 39.7 years) who received ≥ 1 dose of study medication, 42 were older adults aged 65 to 70 years (mean age 67.0 years). The median duration of exposure was 36.1 and 36.9 months for the overall population and older patients. The median last available dose was 200 mg/day. 80%, 72%, and 68% of patients overall, and 76%, 71%, and 69% of older patients remained on cenobamate at 1, 2, and 3 years, respectively. Rates of discontinuation due to TEAEs were 13.6% (183/1340) in the overall population and 26.2% (11/42) in older patients. TEAEs reported in 20% or more of older patients were dizziness (42.9%), somnolence (38.1%), fall (31.0%), fatigue (28.6%), balance disorder (21.4%), and upper respiratory tract infection (21.4%) (Table). TEAEs listed under psychiatric disorders, including anxiety (4.1% vs. 7.1%) and insomnia (4.1% vs. 4.8%), were comparable between the overall population and older adults, respectively. In the efficacy subset, the rate of 100% seizure reduction within a 3-month interval increased over time for the overall population and older adults, reaching 52% and 77%, respectively by 24 months (Figure). Concomitant ASM drug load, not including cenobamate, was reduced in the overall population (baseline: 3.57, -29.44% mean change) and older patients (baseline: 2.68, -31.18% mean change).
Conclusions: Results from this post-hoc analysis indicated comparable tolerability in older patients and the overall study population when treated with adjunctive cenobamate. Efficacy, measured by 100% seizure reduction, and concomitant ASM drug load also indicated a similar response to adjunctive cenobamate.
Funding: Funded by SK Life Science, Inc.