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(Abst. 2.227), 2019

Time Course of 75%–100% Efficacy Response of Adjunctive Brivaracetam in Adults with Focal (Partial-Onset) Seizures and Secondarily Generalized Seizures: A Pooled Post-Hoc Analysis
Authors: Cedric Laloyaux, UCB Pharma, Brussels, Belgium; Sami Elmoufti, UCB Pharma, Raleigh NC, USA; Teresa Gasalla, UCB Pharma, Raleigh NC, USA; Melinda Martin, UCB Pharma, Smyrna, GA, USA; Pavel Klein, Mid-Atlantic Epilepsy Center, Bethesda, MD, USA
Content: Rationale: A recent post hoc analysis of pooled data from 3 fixed-dose, randomized, controlled trials of adjunctive brivaracetam (BRV) for the treatment of epilepsy reported the sustained 50% responder status for BRV was higher than placebo (PBO) starting from treatment Day 1 and was maintained over the 12-week Treatment Period (Klein P, et al. Epilepsia 2017;58:e21-e25). This post hoc analysis of the same data set explored the time to higher levels of sustained response in the overall population, as well as in the subpopulation of patients with secondarily generalized seizures (SGS). Methods: Data from patients (≥16 years) with focal seizures were pooled from 3 Phase III clinical trials (N01252 [NCT00490035], N01253 [NCT00464269], N01358 [NCT01261325]); patients with SGS during the baseline period were analyzed as a subgroup. Time points included treatment Days 1 to 84. Efficacy outcomes were time to sustained ≥75%, ≥90%, and 100% response based on Kaplan-Meier estimates of seizure frequency/28 days. Sustained response was defined as seizure frequency reduction by the specified percentage that was maintained without interruption from the day it was first achieved until study end. Incidence of treatment-emergent adverse events (TEAEs) were assessed weekly and have been previously reported for the overall population; here we report incidence of TEAEs for the SGS subpopulation. Results: The efficacy population consisted of 1160 patients, including 352 (30.3%) patients with SGS. Overall, BRV 100 and 200 mg/day groups had a higher estimated probability of achieving sustained ≥75%, ≥90%, and 100% response in focal seizure reduction vs PBO from treatment Day 1 (Fig. 1A-C). The probability of sustained 75% response from Day 1 was 10.8% and 9.3% for BRV 100 and 200 mg/day, respectively, vs 3.1% for PBO; sustained 90% response from Day 1 was 6.9% and 5.3% for BRV 100 and 200 mg/day vs 1.2% for PBO. The BRV 50 mg/day group achieved higher sustained 75% and 90% response vs PBO later in treatment. Sustained 100% response from Day 1 was 2.5%, 5.1%, and 4.0% for BRV 50, 100, and 200 mg/day vs 0.5% for PBO (Fig. 1A-C). The probability of achieving sustained 75% SGS reduction on Day 1 was 35.0%, 41.3%, and 15.7% for patients taking BRV 100, 200 mg/day, and PBO; sustained 90% SGS reduction on Day 1 was 34.0%, 37.3% and 14.8% for BRV 100, 200mg/day and PBO; sustained 100% SGS reduction was 32.0%, 36.0%, and 14.8% for BRV 100, 200 mg/day, and PBO (Fig. 2). For overall and SGS populations, estimates of sustained ≥75%, ≥90%, and 100% response showed the BRV response rate was predominately attained at Day 1. In the SGS safety population (N=381), overall TEAE incidence was similar between BRV (65.0% 50-200 mg/day) and PBO (59.1%). TEAEs peaked during Week 1 (33.9% BRV 50–200 mg/day), decreasing thereafter. Conclusions: Sustained ≥75%, ≥90%, and 100% response in focal seizures (overall population) and SGS (SGS subpopulation) were observed in a higher number of patients treated with BRV 100 and 200 mg/day than PBO from treatment Day 1. This analysis extends prior findings of BRV efficacy in reducing seizure frequency from the first day of treatment. These findings may be particularly informative for the treatment of patients with SGS, who are at high risk of falls, injury, and mortality. Funding: UCB Pharma-sponsored
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