Director Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA Bethesda, Maryland
Rationale: To evaluate the long-term retention, reasons for discontinuation, efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal seizures by number of lifetime antiepileptic drugs (AEDs). Methods: Post hoc analysis of randomized, double-blind, placebo-controlled (N01358; NCT01261325) and open-label extension (OLE; N01379; NCT01339559) trials of adjunctive brivaracetam in patients (≥16 years) with focal seizures randomized to BRV (100/200mg/day) or placebo (PBO) in the double-blind trial. Outcomes were assessed from first day of BRV treatment by number of lifetime AEDs (stopped before BRV initiation + ongoing at BRV initiation). Results: Seven hundred forty patients received BRV in the double-blind or OLE trial (safety population; median modal dose: 200mg/day [n=737]; median treatment duration: 973.5 days). The proportions of patients with 1-2 (n=102), 3-4 (n=154), 5-6 (n=156) and ≥7 (n=328) lifetime AEDs who completed the OLE trial were 52.9%, 45.5%, 52.6% and 39.9%, respectively. The main reason for BRV discontinuation in patients with 1-4 lifetime AEDs was consent withdrawn; in those with ≥5 lifetime AEDs, the main reason was lack of efficacy. Kaplan-Meier estimated retention on BRV was 83.2%, 71.3%, 72.4% and 65.9% at 12 months and 63.0%, 56.0%, 59.3% and 44.1% at 36 months in patients with 1-2, 3-4, 5-6 and ≥7 lifetime AEDs, respectively (Fig 1A). The estimated proportion of patients discontinuing BRV due to lack of efficacy (Fig 1B) or treatment-emergent adverse events (TEAEs; Fig 1C) increased with the number of lifetime AEDs. During the entire treatment period (efficacy population), median percent reductions from baseline in focal seizure frequency/28 days in patients with 1-2 (n=102), 3-4 (n=153), 5-6 (n=156) and ≥7 (n=327) lifetime AEDs were 76.3%, 56.7%, 50.9%, and 39.6%; 50% responder rates were 66.7%, 56.9%, 51.9% and 39.8%; and 75% responder rates were 51.0%, 34.0%, 26.3%, and 19.6%. Continuous seizure-freedom for ≥1 year at any time during BRV treatment was 35.3%, 15.7%, 12.2%, and 6.1%. In patients completing at least 48, 96 or 144 weeks, median percent reduction in focal seizure frequency (Fig 2A-C) and 50% and 75% responder rates were sustained over time in all lifetime AED subgroups. Incidences of TEAEs (safety population) were 86.3%, 84.4%, 90.4% and 90.5% in patients with 1-2, 3-4, 5-6 and ≥7 lifetime AEDs, respectively. Discontinuations due to TEAEs occurred in 7.8%, 10.4%, 14.1% and 20.1% of patients. Conclusions: Adults with focal seizures exposed to fewer AEDs before adjunctive BRV initiation had numerically higher one- and three-year retention rates and were less likely to discontinue long-term BRV treatment due to lack of efficacy or TEAEs. Long-term efficacy was highest in patients with one to two lifetime AEDs and decreased by number of lifetime AEDs, though patients exposed to ≥7 AEDs could also benefit from long-term BRV treatment. Efficacy of adjunctive BRV was sustained over time independent of number of lifetime AEDs. Funding: Please list any funding that was received in support of this abstract.: UCB Pharma-sponsored.