Director Arkansas Epilepsy Program Little Rock, Arkansas
Rationale: Cenobamate is an antiseizure medication (ASM) approved in the U.S. for treatment of focal (partial-onset) seizures in adults. Adjunctive cenobamate significantly reduced seizure frequency in two Phase 2 randomized, double-blind, placebo-controlled studies in patients with uncontrolled focal seizures. A global, Phase 3, long-term, open-label safety study (C021) used start-low, go-slow titration, designed to mitigate the risk of DRESS, to assess safety in a larger sample (N=1347 enrolled). In this post-hoc analysis, seizure reduction in cenobamate-treated patients was assessed during titration in C021, using data from ten eligible U.S. study sites. Methods: Adults 18-70 years old with uncontrolled focal seizures taking stable doses of one to three ASMs were initiated on adjunctive cenobamate 12.5 mg/day for two weeks (wks), with increasing daily doses (25, 50, 100, 150, and 200 mg) at 2-wk intervals. Further increases to a maximum of 400 mg/day (using biweekly increments of 50 mg/day) were permitted during a dose-optimization/maintenance phase. A protocol amendment permitted the post-hoc collection of seizure data. Seizure reduction up to the cenobamate dose of 100 mg/day was compared with the predicted change in seizure frequency for the C021 titration. Results: Seizure data were available for 249 patients and 183 were still receiving cenobamate (retention rate 73%) as of the last reported 3-month clinic visit. After excluding patients with < 1 focal to bilateral tonic-clonic (FBTC) seizure/yr or missing data, 173 were included in the analysis. At the 100 mg/day cenobamate dose (wks 7-8) compared with screening seizure frequency, 32% (7/22) of patients with focal aware motor (FAM), 60% (96/160) of patients with focal impaired awareness (FIA), 85% (55/65) of patients with FBTC, and 54% (94/173) of patients with all focal seizures were seizure-free (SF) at that visit. Sixty-two patients were SF for ≥12 months at the last clinic visit. Among these 62 at the 50 mg/day dose (wks 5-6) the percent reduction in 28-day seizure frequency was: 87% FAM, 64% FIA, 78% FBTC, and 74% all focal seizures (Figure 1A). Among these 62, reduction in total seizures was seen with the initial 12.5 mg/day dose (wks 1-2). Further reduction occurred at a dose of 25 mg/day (wks 3-4) and 50 mg/day (wks 5-6) (Figure 1B). These results exceed the predictions in seizure reduction during cenobamate titration in the NDA submission (Figure 2). The most common treatment-emergent adverse events were sleepiness, somnolence, and dizziness. No cases of DRESS were reported. Conclusions: Patients with uncontrolled focal seizures who received adjunctive cenobamate with the start-low, go-slow titration started to have seizure reduction as early as the first one to two wks of therapy with the initial 12.5 mg/day dose. Reduction in seizure frequency across all focal seizure subtypes appeared most consistent from 50 mg/day onward. Early seizure reduction appears to be a good predictor of response. Patients without early reduction, however, may also have a response as additional seizure reduction, including seizure freedom, occurred with continued increases in cenobamate dose during titration. Funding: Please list any funding that was received in support of this abstract.:
