Efficacy, safety, and tolerability of adjunctive brivaracetam for secondarily generalized tonic-clonic seizures: Pooled results from three Phase III studies

Purpose: Secondarily generalized tonic-clonic seizures (SGTCS) are among the most devastating types of seizures, contributing to increased morbidity and mortality. Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle 2A (SV2A), has been shown to be useful for the adjunctive treatment of focal seizures. We sought to determine its specific efficacy in treating SGTCS. Methods: Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 antiepileptic drugs (AEDs) who received placebo or BRV 50-200 mg/day without titration over a 12-week treatment period. We report efficacy and safety/tolerability data for the BRV therapeutic dose range (50-200 mg/day) in patients with focal seizures including baseline SGTCS. Results: Patients (efficacy population, N=409) had been diagnosed with epilepsy for a mean I standard deviation duration of 22.2 +/- 13.1 years. Baseline median SGTCS frequency was 3.0 per 28 days. The majority (293, 71.6%) had failed >= 2 AEDs prior to study enrollment. The median percent reduction from baseline in SGTCS frequency/28 days was: placebo, 33.3%; BRV 50 mg/day, 66.6% (p < 0.001); BRV 100 mg/day, 61.2% (p = 0.002); and BRV 200 mg/day, 82.1% (p < 0.001). The >= 50% responder rate for SGTCS was: placebo, 33.0%; BRV 50 mg/day, 61.3% (p = 0.003); BRV 100 mg/day, 55.0% (p < 0.001); and BRV 200 mg/day, 64.0% (p < 0.001). Freedom from SGTCS was achieved by: placebo, 14.8%; BRV 50 mg/day, 22.6%; BRV 100 mg/day, 31.0%; and BRV 200 mg/day, 36.0% of patients. Time to first SGTCS during the treatment period was longer in patients receiving BRV than placebo (26 days vs 8 days, hazard ratio 0.55, p < 0.001). In the SGTCS safety population (N=487), treatment-emergent adverse events (TEAEs) were reported by 60.6% of patients receiving placebo vs 65.0% of patients receiving BRV >= 50 mg/day. Serious TEAEs were reported by 3.1% placebo vs 3.9% BRV >= 50 mg/day. Discontinuations due to TEAEs were 3.9% placebo vs 6.3% BRV >= 50 mg/day. Conclusions: In patients with drug-resistant focal seizures, adjunctive BRV is effective in reducing the frequency of SGTCS. Almost one-third (30.4%) of patients were rendered completely free of SGTCS during the 12-week treatment period when taking BRV >= 50 mg/day. BRV was well tolerated, with a TEAE profile consistent with that of the overall study population. (C) 2016 UCB, Brussels, Belgium. Published by Elsevier B.V.