Abstracts

Rationale: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand, which also displays inhibitory activity at neuronal voltage-dependent sodium channels. Efficacy and tolerability results from BRV Phase II studies in adults provided the necessary information to progress to confirmatory trials. The purpose of these Phase III trials was to evaluate the efficacy, safety and tolerability of adjunctive BRV in adults with refractory partial-onset seizures. Methods: Two prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trials (N01253 and N01252) enrolled adults (16-70 years) with well-characterized focal epilepsy not fully controlled despite treatment with 1 or 2 AEDs. Patients experiencing at least 8 partial-onset seizures whether or not secondarily generalized during the 8-week prospective baseline period were randomized (1:1:1:1) to receive twice-daily BRV (N01253: 5, 20 or 50 mg/day; N01252: 20, 50 or 100 mg/day) or placebo without titration. The primary efficacy endpoint was the partial-onset seizure frequency/week over the 12-week treatment period. Tolerability and safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests, ECGs, vital signs, physical and neurological examinations. Results: Of 400 patients randomized to study N01253, 396 were included in the ITT population (placebo n=98, BRV5 n=97, BRV20 n=100, BRV50 n=101) and 362/396 (91.4%) completed the 12-week treatment period. Of 399 patients randomized to study N01252, 398 were included in the ITT population (placebo n=100, BRV20 n=99, BRV50 n=99, BRV100 n=100) and 367/398 (92.2%) completed the 12-week treatment period. Patients’ characteristics were similar across both studies (N01253/N01252): mean (SD) age 38.13 (12.45)/37.24 (13.05) years; median (Q1-Q3) baseline partial-onset seizure frequency/week 2.53 (1.54-6.05)/1.95 (1.28-3.78); 78.3%/78.9% patients were on 2 concomitant AEDs, most frequently carbamazepine (40.4%/46.5%). Study N01253 achieved statistical significance in its primary efficacy endpoint, the percent reduction over placebo during the 12-week treatment period of the BRV50 arm (12.8%, p=0.025). Study N01252 did not achieve statistical significance on the primary efficacy endpoint, the percent reduction over placebo of the BRV50 arm (6.5%, p=0.261), however, statistical significance was achieved for BRV100 at the nominal 0.05 level (11.7%, p=0.037). Data from both studies showed that BRV was generally well tolerated, with the majority of TEAEs being mild to moderate in intensity. Conclusions: Adjunctive BRV was associated with a reduction in weekly partial-onset seizure frequency over placebo in one pivotal study. In both trials BRV was generally well tolerated with a low discontinuation rate. Further analysis of the primary and secondary endpoints of these Phase III trials will provide a better understanding of the potential of BRV in epilepsy. *Both authors contributed equally Studies sponsored by UCB (NCT00464269; NCT00490035)