SUMMARYObjective: Brivaracetam (BRV), a selective and high-affinity synaptic vesicle protein 2A ligand, is in development as adjunctive treatment for partial-onset (focal) seizures (POS). This phase 3 study (N01358; NCT01261325) aimed to confirm the efficacy and safety/tolerability of BRV in adults (≥16-80 years) with POS. Methods: This randomized, double-blind, placebo-controlled, multicenter study enrolled patients with uncontrolled POS despite ongoing treatment with 1-2 antiepileptic drugs. Patients exposed to levetiracetam ≤90 days before visit 1 were excluded. Patients entered an 8-week prospective baseline period, followed by a 12-week treatment period when they were randomized 1:1:1 to placebo (PBO), BRV 100 mg/day, or BRV 200 mg/ day, started without up-titration. The co-primary efficacy outcomes were percent reduction over placebo in 28-day adjusted POS frequency, and ≥50% responder rate based on percent reduction in POS frequency from baseline to the treatment period. Results: Seven hundred sixty-eight patients were randomized; 760 were included in the efficacy analysis: 259, 252, and 249 in PBO, BRV 100 mg/day, and BRV 200 mg/day groups, respectively. Percent reduction over PBO in 28-day adjusted seizure frequency (95% confidence interval [CI]) was 22.8% for BRV 100 mg/day (13.3-31.2%; p < 0.001) and 23.2% for BRV 200 mg/day (13.8-31.6%; p < 0.001). The ≥50% responder rate (odds ratio vs. PBO; 95% CI) was 21.6% for PBO, 38.9% for BRV 100 mg/day (2.39; 1.6-3.6; p < 0.001), and 37.8% for BRV 200 mg/day (2.19; 1.5-3.3; p < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 155 (59.4%) of 261 PBO patients versus 340 (67.6%) of 503 BRV-treated patients (safety population). Discontinuation rates due to TEAEs were 3.8%, 8.3%, and 6.8% for PBO, BRV 100 mg/day, and BRV 200 mg/day, respectively. Most frequent TEAEs (PBO versus BRV) were somnolence (7.7% vs. 18.1%), dizziness (5.0% vs. 12.3%), and fatigue (3.8% vs. 9.5%). Significance: Adjunctive BRV 100 and 200 mg/day was efficacious in reducing POS in adults without concomitant levetiracetam use and was well tolerated.

In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS-2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society

Objective:To assess the efficacy, safety, and tolerability of adjunctive brivaracetam (BRV), a selective, high-affinity ligand for SV2A, for treatment of partial-onset (focal) seizures (POS) in adults.Methods:Data were pooled from patients (aged 16–80 years) with POS uncontrolled by 1 to 2 antiepileptic drugs receiving BRV 50, 100, or 200 mg/d or placebo, without titration, in 3 phase III studies of BRV (NCT00490035, NCT00464269, and NCT01261325, ClinicalTrials.gov, funded by UCB Pharma). The studies had an 8-week baseline and a 12-week treatment period. Patients receiving concomitant levetiracetam were excluded from the efficacy pool.Results:In the efficacy population (n = 1,160), reduction over placebo (95% confidence interval) in baseline-adjusted POS frequency/28 days was 19.5% (8.0%–29.6%) for 50 mg/d (p = 0.0015), 24.4% (16.8%–31.2%) for 100 mg/d (p < 0.00001), and 24.0% (15.3%–31.8%) for 200 mg/d (p < 0.00001). The ≥50% responder rate was 34.2% (50 mg/d, p = 0.0015), 39.5% (100 mg/d, p < 0.00001), and 37.8% (200 mg/d, p = 0.00003) vs 20.3% for placebo (p < 0.01). Across the safety population groups (n = 1,262), 90.0% to 93.9% completed the studies. Treatment-emergent adverse events (TEAEs) were reported by 68.0% BRV overall (n = 803) and 62.1% placebo (n = 459). Serious TEAEs were reported by 3.0% (BRV) and 2.8% (placebo); 3 patients receiving BRV and one patient receiving placebo died. TEAEs in ≥5% patients taking BRV (vs placebo) were somnolence (15.2% vs 8.5%), dizziness (11.2% vs 7.2%), headache (9.6% vs 10.2%), and fatigue (8.7% vs 3.7%).Conclusions:Adjunctive BRV was effective and generally well tolerated in adults with POS.Classification of evidence:This analysis provides Class I evidence that adjunctive BRV is effective in reducing POS frequency in adults with epilepsy and uncontrolled seizures.

SUMMARYObjectives: To report pooled safety/tolerability and seizure outcome data from adults with uncontrolled partial-onset (focal) seizures (POS) receiving adjunctive brivaracetam (BRV) during phase IIb/III and long-term follow-up (LTFU) studies. Methods: Seizure outcome data were pooled from phase IIb (NCT00175929 and NCT00175825), III/IIIb (NCT00490035, NCT00464269, NCT00504881, and NCT01261325) and associated LTFU studies (NCT00175916, NCT00150800, and NCT01339559). Safety/tolerability data were pooled from these studies plus NCT01405508, NCT01653262, and NCT01728077 (LTFU). Patients received placebo (during core studies) or BRV 5-200 mg/day. Safety/tolerability and seizure outcomes (BRV modal doses 50-200 mg/day) were assessed until January 17, 2014. Results: Of 2,186 patients (97.3% with POS and 2.7% with other seizure types) who received BRV 50-200 mg/day, 2,051 (93.8%) completed core studies and continued in LTFU studies. Total BRV exposure: 5,339.4 patient-years (≥8.0 years in 41 patients); 6-, 12-, 24-, and 60-month retention: 91.0%, 79.8%, 68.1%, and 54.4%, respectively. Safety/tolerability data pooled from 2,186 patients: ≥1 treatmentemergent adverse event (TEAE) reported by 1,848 (84.5%) patients; 1,184 (54.2%) reported ≥1 TEAE considered treatment-related. Most frequent TEAEs (≥10%): headache (20.9%), dizziness (17.5%), somnolence (15.2%), nasopharyngitis (13.2%), fatigue (11.3%), and convulsion (10.6%). Serious TEAEs (SAEs) and treatmentrelated SAEs: 401 (18.3%) and 95 (4.3%) patients, respectively. Of 28 (1.3%) deaths, four (14.3%) were considered possibly treatment related by the investigator. Pooled seizure outcome data (1,836 patients): median POS frequency/28 days at baseline was 8.9; on treatment, median percentage reduction from baseline in POS/28 days was 48.8%, and ≥50% responder rate was 48.7%. Complete seizure freedom: 4.9%, 4.2%, 3.0%, and 3.3% for ≥6, 12, 24, and 60 months, respectively. Improvements were seen in health-related quality of life (HRQoL) from baseline, assessed by Quality of Life in Epilepsy Inventory-31. Significance: Adjunctive BRV treatment in adults with POS was effective and generally well tolerated when administered long-term (≥8.0 years). Retention was high and HRQoL improvements were observed.

Brivaracetam (BRV; Briviact) is a new antiepileptic drug (AED) approved for adjunctive treatment of focal (partial-onset) seizures in adults. BRV is a selective, high-affinity ligand for synaptic vesicle 2A (SV2A) with 15- to 30-fold higher affinity than levetiracetam, the first AED acting on SV2A. It has high lipid solubility and rapid brain penetration, with engagement of the target molecule, SV2A, within minutes of administration. BRV has potent broad-spectrum antiepileptic activity in animal models. Phase I studies indicated BRV was well tolerated and showed a favorable pharmacokinetic profile over a wide dose range following single (10–1,000 mg) and multiple (200–800 mg/day) oral dosing. Three pivotal Phase III studies have demonstrated promising efficacy and a good safety and tolerability profile across doses of 50–200 mg/day in the adjunctive treatment of refractory focal seizures. Long-term data indicate that the response to BRV is sustained, with good tolerability and retention rate. BRV is highly effective in patients experiencing secondarily generalized tonic–clonic seizures. Safety data to date suggest a favorable psychiatric adverse effect profile in controlled studies, although limited postmarketing data are available. BRV is easy to use, with no titration and little drug–drug interaction. It can be initiated at target dose with no titration. Efficacy is seen on day 1 of oral use in a significant percentage of patients. Intravenous administration in a 2-minute bolus and 15-minute infusion is well tolerated. Here, we review the pharmacology, pharmacokinetics, and clinical data of BRV.