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Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) approved for monotherapy (in the USA) and adjunctive treatment of focal (partial-onset) seizures in adults, at a dose range of 50–200 mg/day taken in two equal doses, with a recommended starting dose of 100 mg/day. Two Phase III, randomized, double-blind, multicenter, historical-controlled, conversion-to-monotherapy studies (N01276, NCT00698581; N01306, NCT00699283) were conducted to evaluate the efficacy, safety, and tolerability of conversion to BRV 50 mg/day monotherapy in adults with uncontrolled focal seizures. Patients aged 16–75 years, with 2–40 focal seizures per 4 weeks during an 8-week baseline, and on stable doses of 1–2 AEDs were enrolled. Patients were randomized to BRV 50 or 100 mg/day (3:1) in two equal doses without titration. The treatment period comprised 1-week BRV add-on, 8-week baseline AED tapering, and 8-week BRV monotherapy periods. Primary efficacy endpoint was Kaplan-Meier estimate of the cumulative exit rate due to pre-defined exit criteria at Day 112 (50 mg/day, efficacy population). The upper 95% confidence interval (CI) was compared with the historical control threshold (0.722). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs; intent-to-treat population). After randomization of 150 patients (N01276: 88; N01306: 62), both studies were terminated due to the confounding effects of a higher-than-expected discontinuation rate. For BRV 50 mg/day, ≥1 exit criterion was met by 26/67 (38.8%) patients (study N01276) and 18/45 (40.0%) patients (study N01306). In both studies, the cumulative exit rate was lower than the historical control threshold (N01276: 0.487, 95% CI 0.347, 0.626; N01306: 0.474, 95% CI 0.310, 0.638). However, with maximum 10% censoring due to early withdrawal (sensitivity analysis), cumulative exit rates were above historical control (N01276: 0.652, 95% CI 0.532, 0.772; N01306: 0.704, 95% CI 0.563, 0.844). Overall incidence of TEAEs was 110/150, 73.3% (treatment period); 78/147, 53.1% (baseline AED tapering period); 41/84, 48.8% (BRV monotherapy period). In conclusion, BRV 50 mg/day monotherapy demonstrated an exit rate lower than historical control. Results should be interpreted with caution as, following termination of both studies, patient numbers were too low to evaluate the efficacy of BRV monotherapy. These are the first published safety and tolerability data for BRV monotherapy. Monotherapy was well tolerated, with a relatively low incidence of TEAEs, though this should be interpreted with the caveat that the majority of common TEAEs were likely to have occurred earlier in the course of treatment with BRV. No new safety concerns were identified, supporting the favorable safety profile of BRV observed in adjunctive studies.

To evaluate long-term safety and tolerability of adjunctive brivaracetam (BRV) in children with epilepsy.This was an interim analysis (cut-off March 15, 2017) of pooled data from two open-label, single-arm, multicentre trials. N01263 (NCT00422422) was a 3-week trial of BRV 0.8-4 mg/kg/day in patients (1 month-16 years) with epilepsy. Patients who completed this trial could continue into a long-term follow-up trial (N01266, NCT01364597) which also directly enrolled patients (4-17 years) with focal seizures. After dose-escalation, patients received BRV 1-5 mg/kg/day (maximum 200 mg/day) during long-term evaluation. Data are reported for patients aged 4 to16 years with focal seizures.The safety set comprised 149 patients: 34 from the initial trial (26 entered long-term trial) and 115 directly enrolled into the long-term trial. At the cut-off, 90 patients were receiving BRV (total exposure: 299.4 patient-years). Treatment-emergent adverse events (TEAEs) were reported by 140/149 (94.0%) patients, most commonly (≥20%) nasopharyngitis (24.8%), pharyngitis (22.1%), convulsion (21.5%), and pyrexia (20.1%). TEAEs considered drug-related by the investigator were reported by 56/149 (37.6%) patients, most commonly somnolence (6.0%). Two patients died; neither death was considered related to BRV. Mean changes from baseline in child behaviour rating scales were small; most patients remained in their baseline category.In this pooled analysis of two open-label trials including long-term data, adjunctive BRV was generally well tolerated in children aged 4 to16 years with focal seizures. These findings supported approval of BRV as a new therapy option for children aged ≥4 years with focal seizures.

Objective The objective of this analysis was to provide a comprehensive analysis of safety data for adjunctive brivaracetam (BRV), an antiepileptic drug (AED) of the racetam class, for treatment of focal seizures in patients with epilepsy. Methods Data were pooled from two phase II, placebo-controlled, double-blind, dose-ranging trials (N01114 [ ClinicalTrials.gov : NCT00175929 ], N01193 [ NCT00175825 ]) and three phase III, placebo-controlled, double-blind, 12-week trials (N01252 [ NCT00490035 ], N01253 [ NCT00464269 ], and N01358 [ NCT01261325 ]) in patients aged ≥ 16 years with focal seizures, as well as a phase III, placebo-controlled, double-blind, 16-week trial in patients aged ≥ 16 years with focal or generalized epilepsy (N01254 [ NCT00504881 ]). Data are presented for the approved therapeutic dose range of 50–200 mg/day. Data for BRV administered intravenously (25–150 mg doses) were pooled separately from one phase III trial (N01258 NCT01405508 ]) and two clinical pharmacology trials (N01256 [Part B] [UCB Pharma, data on file]; EP0007 [ NCT01796899 ]). Adverse events (AEs) of interest were summarized in relevant categories. Results The safety pool comprised 1957 patients: 1271 receiving adjunctive BRV and 686 receiving placebo. Overall, the incidence of treatment-emergent adverse events (TEAEs) was 66.9% with BRV versus 62.8% with placebo. The most frequently reported TEAEs with BRV (≥ 5% of patients) versus placebo were somnolence (13.3% vs. 7.9%), headache (10.5% vs. 11.5%), dizziness (10.0% vs. 7.0%), and fatigue (8.2% vs. 4.2%). Incidence of psychiatric disorder-related TEAEs was 11.3% with BRV versus 8.2% with placebo. Behavioral disorder-related TEAE incidence was low (4.0% with BRV vs. 2.5% with placebo). Irritability was reported in 2.7% of BRV-treated patients vs. 1.5% of patients receiving placebo; anger, aggression, and agitation were each reported by ≤ 1% of patients receiving BRV. Treatment-emergent adverse events potentially associated with psychosis were psychotic disorder (three patients on BRV vs. two patients on placebo), auditory hallucination, illusion, visual hallucination (one patient each on BRV), epileptic psychosis, and hallucination (one patient each on placebo). No additional safety concerns were identified in patients with intravenous (IV) BRV administration (n = 104). Conclusions These safety data for adjunctive BRV support its acceptable safety and tolerability profile.