Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial.

Commentary Despite the availability of multiple AEDs, many patients with epilepsy continue to have refractory seizures as well as debilitating side effects. As such, there continues to be a need to explore and investigate new AEDs. Brivaracetam is a novel compound that has been studied extensively in preclinical, phase II, and now phase III trials. The results of three phase III, prospective multicenter randomized, double-blind placebo-controlled, parallel-group trials have recently been published (1–3) and yield mixed results. Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand. It is not entirely clear how SV2A affects neuro-transmission, but animal studies suggest that it is potentially a good target for seizure control. Mice deficient in SV2A have seizures (4). Among animal models of epileptogenesis as well PURPOSE: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial-onset (focal) seizures. METHODS: This was a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trial (N01253; NCT00464269). Adults aged 16–70 years with well-characterized partial epilepsy not fully controlled despite treatment with one or two antiepilep-tic drugs (AEDs) were enrolled. Patients who experienced eight or more 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 placebo (PBO) or BRV (5, 20, or 50 mg/day) without titration. The primary efficacy endpoint was percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/week during the 12-week treatment period. Comparison of BRV with PBO was sequential (50, 20 mg/day, then 5 mg/day). Secondary endpoints included ≥50% responder rate and median percent reduction from baseline in partial-onset seizure frequency/week. Post hoc analyses included the primary efficacy endpoint evaluated over 28 days and exploratory subanalyses of efficacy by seizure subtype. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), laboratory tests, electrocardiography, vital signs, and physical and neurologic examinations. KEY FINDINGS: Of 400 patients randomized, 396 were included in the intent-to-treat (ITT) population (PBO n = 98, BRV 5 mg/day n = 97, BRV 20 mg/day n = 100, BRV 50 mg/day n = 101) and 392 comprised the modified ITT (mITT) population. A total of 361 (91.2%) of 396 patients completed the study. Most patients (78.3%) were receiving two concomitant AEDs. Percent reduction in partial-onset seizure frequency/ week over PBO was …