Adjunctive Brivaracetam Effective and Well-tolerated in Patients with Uncontrolled Focal Seizures, Irrespective of Previous Antiseizure Medication Usage

22 Sep, 21

Introduction

Brivaracetam (BRV) is an antiseizure medication (ASM) with selective action on synaptic vesicle protein 2A (SV2A). Various clinical trials have demonstrated adjunctive BRV to be effective and well tolerated in patients with epilepsy (PWE) having seizures uncontrolled by 1 or 2 concomitant ASMs. In fact, one of the trials had demonstrated that BRV reduced the seizure frequency in PWE with prior >2 ASMs as well as amongst those with ≤2 ASMs.

Aim

To compare the efficacy and tolerability of adjunctive BRV in PWE with severely drug-resistant focal seizures vs. those with less drug resistant disease.

Patient Profile

PWE with uncontrolled, well-characterized focal seizures, with or without secondary generalization, despite treatment with 1 or 2 ASMs (age; 16-70 years)
The study subjects had experienced ≥8 focal seizures during the 8-week baseline period. In one of the included trials, patients also had to have had ≥2 focal seizures
during each 4-week interval of the baseline period
All the study subjects were on stable ASM at least one month prior to the trial entry

Methods

Study Design

A pooled analysis (post hoc analysis) of three phase III trials conducted across Europe, North America, South America, Asia, and Australia

Details of the Pooled Analysis

Data were pooled from patients with focal seizures on 1–2 concomitant ASMs who were randomized to BRV 50, 100, 200 mg/day, or placebo in the three trials with a 12-week treatment period.
Outcomes were compared in patients with ≥5 ASMs and 0–4 previous ASMs (stopped before trial drug initiation).

Outcomes

Efficacy Outcomes

50% responder rate (≥50% reduction in focal seizure frequency from baseline)
Median percentage reduction in 28-day adjusted focal seizure frequency from baseline
Seizure freedom (including all seizure types) during the treatment period

Tolerability Outcomes

Incidence of treatment-emergent adverse events (TEAEs)

Results

The efficacy set (ES) comprised of 434 patients with ≥5 previous ASMs (age range; 16–75 years, BRV-treated; n=283, placebo-treated; n=151), and 726 patients with 0–4 previous ASMs (age range; 16–80 years, BRV-treated; n=459, placebo-treated; n=267)
The safety set (SS) comprised of 449 patients with ≥5 previous ASMs (BRV-treated; n=294, placebo-treated; n=155), and 813 patients with 0–4 previous ASMs (BRV-treated; n=509, placebo-treated; n=304)
BRV treatment; overall, and individually for BRV 50, 100 and 200 mg/day was associated with reduction in 28-day adjusted seizure frequency (p=0.001) as compared with placebo, in the ≥5 previous ASMs subgroup (Table 1).
BRV treatment was also associated with significantly better 50% responder rate as compared with placebo in the ≥5 previous ASMs subgroup (Table 1).

Table 1: Impact of BRV vs. placebo treatment on seizure parameters in patients with ≥5 previous ASMs subgroup

Seizure Parameter	BRV 50 mg/day (n=26)		BRV 100 mg/day (n=137)		BRV 200 mg/day (n=120)		BRV 50-200 mg/day (n=283)		Placebo (n=151)
Seizure Parameter	%Reduction	P value	%Reduction	P value	%Reduction	P value	%Reduction	P Value	%Reduction
28-day adjusted seizure frequency	13%	0.38	18.1%	0.006	19.8%	0.004	17%	0.001	-
50% Responder rate	26.9%	0.11	29.9%	0.002	30.0%	0.002	29.7%	0.0003	13.2%

Amongst patients in 0–4 previous ASMs subgroup, all dosage of BRV were associated with significantly greater reduction in 28-day adjusted frequency and with better 50% responder rate as compared with placebo (Table 2).

Table 2: Impact of BRV vs. placebo treatment on seizure parameters in patients with 0-4 previous ASMs subgroup

Seizure Parameter	BRV 50 mg/day (n=135)		BRV 100 mg/day (n=195)		BRV 200 mg/day (n=129)		BRV 50-200 mg/day (n=459)		Placebo (n=267)
Seizure Parameter	%Reduction	P value	%Reduction	P value	%Reduction	P value	%Reduction	P Value	%Reduction
28-day adjusted seizure frequency	21.4%	0.38	28.7%	0.006	27.9%	0.004	25.6%	0.001	-
50% Responder rate	35.6%	0.006	46.2%	<0.0001	45.0%	0.003	42.7%	<0.0001	24.3%

Compared to the subgroup of patients with previous ≥5 ASMs, those with previous 0-4 ASMs had a numerically higher seizure freedom rate for BRV 50, BRV 200 and BRV 50-200 mg/day. Moreover, the seizure freedom rate increased with the dose of BRV in this subgroup of patients.

The incidences of TEAE (73.8% vs. 64.6%) and discontinuation due to TEAEs (10.5% vs. 4.5%) were higher amongst the ≥5 vs. 0–4 previous ASMs subgroups. The incidence of serious TEAEs was rare in both subgroups.

Conclusion

This post hoc analysis demonstrated adjunctive BRV to be effective and generally well tolerated in adults with focal seizures, irrespective of the number of previous ASMs.

Adv Ther. 2021; 38:4082–99.