Introduction

Almost 30% of epilepsy patients cannot achieve seizure freedom with currently available antiseizure medications (ASMs) which may be attributed to nonadherence to ASMs due to lack of tolerability leading to breakthrough seizures. Real-world studies have shown brivaracetam (BRV) to be effective and tolerable in patients with focal-onset seizures. However, there is limited clinical efficacy data on BRV in the Asian population.

Aim

• To evaluate efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with focal-onset seizures (FOS)
• To explore the effects of previous levetiracetam (LEV) exposure and common concomitant ASMs at study entry on key efficacy and tolerability outcomes

Patient Profile

• 448 Asian patients (aged ≥16–80 years) with a history of FOS with or without secondary generalization (focal to bilateral tonic–clonic seizures) and on 1 or 2 concomitant ASMs

Method

Study Design

• Phase III randomized, double-blind, placebo-controlled, multicenter, parallel-group, therapeutic confirmatory study
• Patients were randomized to placebo, BRV 50 mg/day, or BRV 200 mg/day as adjunctive treatment, and entered a 12-week treatment period

Endpoints

• Primary efficacy endpoint: percent reduction over placebo in 28-day FOS frequency of each BRV dose individually
• Secondary efficacy endpoints:
  • 50% responder rate based on percent reduction in 28-day focal-onset seizure frequency from baseline
  • median percent reduction in 28-day focal-onset seizure frequency from baseline
  • seizure freedom
• Primary safety endpoints:
  • incidences of treatment-emergent adverse events (TEAEs)
  • TEAEs leading to discontinuation
  • serious TEAEs

Results

Efficacy

• Adjunctive BRV significantly achieved percent reduction in 28-day FOS frequency (24.5% with BRV 50 mg/day, p = 0.0005 and 33.4% with 200 mg/day p < 0.0001) over placebo (Figure 1)
• The 50% responder rate was significantly higher in BRV (41.1% with 50 mg/day dose and 49.3% with 200 mg/day dose) versus placebo (19.0% with placebo; p < 0.0001 for both)
• BRV achieved higher median percent reduction in FOS frequency from baseline as compared to placebo (21.3%, 38.9%, 46.7% with placebo, BRV 50 mg and BRV 200 mg/day, respectively)
• Significant seizure freedom was achieved during BRV treatment versus placebo (4.6% with BRV 50 mg/day, p = 0.0146, and 6.8% with BRV 200 mg/day, p = 0.0017 vs. 0 with placebo)
• BRV was clinically effective in achieving the efficacy endpoints versus placebo, irrespective of LEV status
• BRV achieved the primary efficacy endpoint irrespective of the type of most common concomitant ASM used
• The 50% responder rate for focal-onset seizure frequency was greater with BRV versus placebo in patients on concomitant carbamazepine (CBZ), lamotrigine (LTG), or valproate (VPA); response rate was higher in patients on concomitant VPA

Figure 1: Effect of adjunctive BRV on the primary endpoint

Safety 

Table 1: Incidence of TEAEs

Conclusion

• Adjunctive BRV (in 50 mg/day and 200 mg/day doses) was significantly more effective and well-tolerated in adult Asian patients with FOS as compared to placebo
• The safety parameters were similar in patients randomized to placebo or BRV, indicating that BRV treatment can be initiated at therapeutic doses without titration
• BRV was found to be efficacious irrespective of the type of most common concomitant ASM used

Epilepsia Open 2024; 9: 1007-1020