CNS Drugs DOI 10.1007/s40263-016-0376-x

ADIS DRUG EVALUATION

Brivaracetam: A Review in Partial-Onset (Focal) Seizures in Patients with Epilepsy Sheridan M. Hoy1

Ó Springer International Publishing Switzerland 2016

Abstract Brivaracetam (BriviactÒ; BRIVLERATM) is a high affinity synaptic vesicle protein 2A (SV2A) ligand available orally (as a tablet or solution) or intravenously (as a bolus or infusion) in various countries worldwide, including the USA, Canada and those of the EU. It is approved as adjunctive therapy for the treatment of partial-onset seizures (POS) in adults (aged C18 years) [USA, EU and Canada] and adolescents (aged 16 to\18 years) [USA and EU] with epilepsy. In multinational, phase III studies in adults and adolescents (aged C16 years), oral brivaracetam as adjunctive therapy to other antiepileptic drugs (AEDs) was generally associated with significant median percent reductions over placebo in seizure frequency and significant improvements in the proportion of patients achieving a C50 % reduction in seizure frequency compared with placebo. These benefits appeared to be sustained during up to 96 months’ therapy in follow-up studies. Whether administered orally or intravenously, adjunctive brivaracetam was generally well tolerated in clinical studies, with the majority of treatment-emergent adverse events (TEAEs) being mild or moderate in intensity. In the absence of

The manuscript was reviewed by: F. M. C. Besag, ELFT Family Consultation Clinic, Bedford, UK; K. Haas, Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN, USA; P. Kwan, Department of Medicine, University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria, Australia; M. Mula, Atkinson Morley Regional Neuroscience Centre, St George’s University Hospitals NHS Foundation Trust and Institute of Medical and Biomedical Science, St George’s University of London, London, UK; M. Toledo, Vall d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain. & Sheridan M. Hoy [email protected] 1

Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand

head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of brivaracetam versus newer AEDs are not yet possible. In the meantime, brivaracetam extends the options currently available for the treatment of POS in patients aged C16 years with epilepsy.

Brivaracetam: clinical considerations in partialonset (focal) seizures in patients with epilepsy Has a 15–30-fold higher binding affinity for SV2A than levetiracetam Available as oral (tablet or solution) or intravenous (bolus or infusion) formulations As adjunctive therapy to other AEDs, reduces POS frequency compared with placebo, with benefits maintained during up to 96 months’ therapy in follow-up studies Generally well tolerated, with somnolence, dizziness, fatigue and headache the most frequently reported TEAEs

1 Introduction Achieving partial-onset seizure (POS; also known as focal seizure) control whilst avoiding unnecessary adverse events from antiepileptic drug (AED) therapy remains a major challenge in epilepsy management [1]. Moreover, treatment-resistant epilepsy is present in approximately one-third of patients despite increasing AED availability [2]. Among currently available AEDs is the pyrrolidone

S. M. Hoy

derivative levetiracetam [3]. Although the primary mechanism of action of levetiracetam involves binding to synaptic vesicle protein 2A (SV2A), which is widely distributed in the brain, its affinity for SV2A is modest (dissociation constant 780 nmol/L [4]) and additional mechanisms of action are involved [3, 5, 6]. Following the discovery that a substitution on the 4-position of the pyrrolidone ring of levetiracetam could enhance the binding affinity of levetiracetam analogues, brivaracetam (BriviactÒ; BRIVLERATM) was identified (through an extensive drug discovery programme aimed at optimizing pharmacodynamic activity at SV2A) as a suitable candidate for further development [5–7]. This narrative review discusses the therapeutic efficacy and tolerability of brivaracetam as an adjunct to other AEDs for the treatment of POS in adults and adolescents (aged C16 years) with epilepsy, and summarizes the pharmacological properties of brivaracetam.

2 Pharmacodynamic Properties of Brivaracetam The exact mechanism of action by which brivaracetam exerts its antiepileptic effects remains to be fully elucidated [8]. However, it displays a high and selective affinity for SV2A (a transmembrane protein present on synaptic vesicles in endocrine cells and neurons that has been shown to modulate neurotransmitter exocytosis) [8–10]. Specifically, in an vitro study, the binding affinity of brivaracetam for SV2A was 15–30-fold higher than that of levetiracetam in rat and human cerebral cortex, and in Chinese Hamster Ovary cells expressing recombinant human SV2A [11]. Ex vivo binding experiments in mice found a strong correlation between the SV2A occupancy and seizure protection potency of brivaracetam. Intraperitoneal brivaracetam was also shown to reach maximal SV2A occupancy and maximal (clonic and tonic) seizure protection within 5–15 min. At a concentration of 10 lmol/L (i.e. [100-fold above the affinity of brivaracetam for SV2A), brivaracetam did not bind, activate or inhibit 55 other receptors, channels and enzymes [11]. Brivaracetam has reduced epileptiform responses in rat hippocampal slices and displayed antiepileptic activity in a variety of innate or induced rodent seizure models, including mouse maximal electroshock and maximal pentylenetetrazol dose seizure models, rat amygdala- and hippocampal-kindled seizure models, mouse corneal-kindled seizure models, rat genetic absence epilepsy models and audiogenic mouse models [7]. Moreover, in an audiogenic mouse model, brivaracetam penetrated the brain more quickly than levetiracetam, which correlated with its faster onset of action against seizures [12]. Physiologically based pharmacokinetic modelling of the audiogenic mouse data in humans predicted that the blood–brain barrier permeability for intravenous brivaracetam was higher than that for

intravenous levetiracetam (0.315 and 0.015 mL/min/g), suggesting that brivaracetam may distribute to the brain within a few minutes (compared with &1 h for levetiracetam). These data were supported by a primate positron emission tomography study, which showed faster SV2A occupancy with brivaracetam than levetiracetam [12]. The plasma brivaracetam concentration corresponding to 50 % of the maximum effect (on daily seizure frequency) was estimated to be 0.57 mg/L, according to a population pharmacokinetic/pharmacodynamic model of data from three placebo-controlled phase III studies [13]. This concentration is slightly above the median exposure achieved following the administration of brivaracetam 50 mg/day dosages [9]. Maximum seizure frequency reduction appears to be achieved with a brivaracetam dosage of 150–200 mg/day [13]. The coadministration of a single 200 mg dose of brivaracetam and a continuous infusion of ethanol 0.6 g/L was associated with additional deterioration in alcoholassociated psychomotor and cognitive impairment compared with ethanol alone in healthy volunteers [14]. Therefore, the intake of brivaracetam with alcohol is not recommended in the EU [9]. Brivaracetam (75 or 400 mg twice daily for 6.5 days) had no clinically relevant effect on the corrected QT interval in healthy volunteers [8, 15].

3 Pharmacokinetic Properties of Brivaracetam Bioequivalence (corrected for dose) between the brivaracetam 10, 75 and 100 mg tablets and the brivaracetam 50 mg tablet was established in a randomized, nonblind, crossover, phase I study in healthy volunteers [16]. Intravenous brivaracetam 100 mg (administered as a bolus over 2 min) provided bioequivalent exposure to oral brivaracetam 50 and 100 mg (administered as tablets); however, the 90 % confidence intervals for the maximum concentration (Cmax) ratio (1.19–1.39 and 1.12–1.31) were outside the range for bioequivalence of 0.80–1.25 [16]. This difference in Cmax between the two formulations was not considered clinically relevant [17]. Brivaracetam exhibited linear and dose-proportional area under the concentration–time curve (AUC) and Cmax values over a 10–600 mg dose range following single oral doses in healthy volunteers [18]. Following the administration of a single oral 100 mg dose, brivaracetam was rapidly and completely absorbed, with a median time to Cmax (tmax) of 1 h and an absolute bioavailability of &100 % [17]. Food decreased the rate, but not the extent, of absorption of brivaracetam following a single 150 mg dose by delaying gastric emptying, suggesting that brivaracetam can be administered with or without food [18] (Sect. 6). Brivaracetam is B20 % bound to plasma proteins and is rapidly and evenly distributed in most tissues [8, 9]. It is

Brivaracetam: A Review

metabolized primarily via hydrolysis of the amide moiety (mediated by hepatic and extra-hepatic amidase) to form the (pharmacologically inactive) carboxylic metabolite and secondarily by hydroxylation on the propyl side chain [mediated primarily by cytochrome P450 (CYP)2C19] to form the (pharmacologically inactive) hydroxy metabolite. A third (pharmacologically inactive) metabolite is formed from both metabolites [8, 9]. Brivaracetam is predominantly eliminated via metabolism and renal excretion [8, 9, 19]. Over 95 % of a dose of brivaracetam is excreted in the urine within 72 h, with 34 % of the dose excreted as the carboxylic acid metabolite and \10 % excreted unchanged. Faecal excretion accounts for \1 % of the dose [8, 9, 19]. The terminal plasma elimination half-life of brivaracetam is &9 h [8, 9]. 3.1 Special Patient Populations and Potential Drug Interactions Exposure to brivaracetam (administered as a single 100 mg dose) was increased by 50–60 % in patients with hepatic impairment, regardless of severity, compared with healthy volunteers [20], with dosage adjustments recommended in these patients [8, 9]. The use of brivaracetam is not recommended in patients with end-stage renal disease undergoing haemodialysis (owing to a lack of data) [8, 9]. Hydroxy metabolite production was reduced 2- and 10-fold and blood brivaracetam levels were increased by 22 and 42 % in individuals with one or both mutated alleles for CYP2C19, respectively [8, 9]. Thus, the US prescribing information states that brivaracetam dose reduction may be required in CYP2C19 poor metabolizers and patients receiving CYP2C19 inhibitors [8]. Local prescribing information should be consulted regarding the use of brivaracetam in specific patient populations. Brivaracetam appears to have a low potential for clinically relevant drug–drug interactions, including interactions with various AEDs (e.g. carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate) [8, 9], drugs that undergo CYP2C19 and CYP3A-mediated biotransformation (e.g. midazolam) [9, 21], oral ethinylestradiol/levonorgestrel [22] and ethanol [14]. However, the potential for a clinically relevant pharmacodynamic interaction between brivaracetam and ethanol should be noted (Sect. 2). Brivaracetam is a reversible inhibitor of epoxide hydrolase; inhibiting epoxide hydrolase results in an increased concentration of carbamazepine epoxide (an active metabolite of carbamazepine) [8, 9]. The US prescribing information [8] states that carbamazepine dose reduction should be considered if tolerability issues arise following the concurrent use of carbamazepine and brivaracetam (as exposure to the active metabolite of carbamazepine may be increased with coadministration [23]). It also states that phenytoin levels should

be monitored when brivaracetam is added or withdrawn from phenytoin therapy [8] [as a 20 % increase in the plasma phenytoin concentration was seen with a supratherapeutic dosage of brivaracetam (400 mg/day) [8, 9]]. The coadministration of a single oral dose of brivaracetam 150 mg with rifampicin (rifampin) 600 mg/day for 5 days reduced brivaracetam AUC values by 45 % in healthy volunteers [24]. Therefore, the dose of brivaracetam should be adjusted when rifampin is added or withdrawn from brivaracetam therapy [9] or when brivaracetam is coadministered with rifampin [8]. In vitro studies indicate that brivaracetam does not inhibit various transporters, or various CYP isoenzymes with the exception of CYP2C19 [8, 9]. CYP2C19 was weakly inhibited (by brivaracetam) in vitro, but is not expected to be significantly inhibited in humans [8]. Local prescribing information should be consulted regarding the coadministration of brivaracetam with these and other AEDs, and other drugs.

4 Therapeutic Efficacy of Brivaracetam The potential for oral brivaracetam to be used as adjuvant therapy to other AEDs for the treatment of POS in adults and adolescents (aged C16 years) with uncontrolled epilepsy was established in two randomized, double-blind, placebocontrolled, dose-ranging, phase IIb studies [25, 26]. This section includes the findings of three randomized, doubleblind, placebo-controlled, multinational, phase III studies assessing the therapeutic efficacy of fixed dosages of adjunctive oral brivaracetam in the treatment of POS in this patient population (N01252 [27], N01253 [28] and N01358 [29]) (Sect. 4.1.1). Efficacy data from another randomized, double-blind, placebo-controlled, multinational phase III study (N01254 [30]), which was primarily designed to evaluate the safety and tolerability of flexible dosages of adjunctive oral brivaracetam and included patients with generalized epilepsy, are also briefly reviewed (Sect. 4.1.2), as are preliminary data (derived from the EU assessment report [17]) from nonblind, follow-up studies assessing the longer-term efficacy of adjunctive brivaracetam (Sect. 4.2). Discussion focuses on the recommended brivaracetam dosages of 50–200 mg/day (Sect. 6). 4.1 Shorter-Term Efficacy The fixed-dosage studies enrolled patients with well-characterized partial epilepsy or an identified epileptic syndrome, and a history of POS with or without secondary generalization who had C2 POS per month in the 3 months prior to screening and C8 POS during the 8-week baseline period [17, 27–29]. In N01252 and N01253, the number of patients receiving concomitant levetiracetam was limited to 20 % of

S. M. Hoy

the total study population [17, 27, 28]. In N01358, patients receiving concomitant levetiracetam, or those who had received levetiracetam in the 90 days prior to screening were excluded [29]. The flexible-dose study recruited patients with partial or generalized epilepsy, with the number of patients with generalized epilepsy limited to 20 % of the total number of randomized patients; these patients are not discussed further. Those enrolled had C2 POS per month with or without secondary generalization or C2 days with primary generalized seizures per month in the 3 months prior to screening, and C4 POS or generalized seizure (any type) days during the 4-week baseline period [30]. Across the four studies, patients were required to be receiving stable dosage regimens of at least one, but no more than two [17, 27–29] or three [30] concomitant AEDs. Key exclusion criteria included nonmotor simple partial seizures as the only seizure type and a history or presence of status epilepticus (within the 12 months prior to screening or during baseline), seizures occurring only in clusters, or pseudoseizures [17, 27–30]. Analyses were conducted in the intent-to-treat (ITT) population [27, 29] or modified ITT population [28, 30]. 4.1.1 Fixed-Dosage Studies Following an 8-week baseline period, the assignment of patients to randomized treatment arms [brivaracetam (administered twice daily in equal doses) or placebo] was stratified by concomitant levetiracetam therapy [27, 28], previous levetiracetam therapy (yes vs. no) [29], country [29], geographic region [27] and number of previous AEDs (B2 vs. [2) [29]. Patients received brivaracetam 5 mg/day [28], 20 mg/day [27, 28], 50 mg/day [27, 28], 100 mg/day [27, 29] or 200 mg/day [29], or placebo, for 12 weeks (with one down-titration permitted for patients receiving brivaracetam or placebo [27, 28]). Down-titration occurred in B4.5 % of patients receiving the recommended dosages of brivaracetam, or placebo [27, 28]. Following completion of the treatment period, patients in each study could undertake a downtitration period (1 [28], 2 [27] or 4 [29] weeks) or enter a long-term, nonblind, follow-up study (N01125, N01199 or N01379) (Sect. 4.2). Baseline characteristics were generally similar across the treatment groups of each study [27–29]. According to a pooled analysis [31] of these studies (Sect. 4.1.3), baseline median POS frequency per 28 days was 8.9 in the brivaracetam 50 and 100 mg/day groups, 9.3 in the brivaracetam 200 mg/day group and 9.6 in the placebo group, with carbamazepine, lamotrigine and valproic acid the most common concomitant AEDs. In N01252 [27] and N01253 [28], the primary efficacy endpoint was the percent reduction over placebo in weekly POS frequency from baseline to the end of the treatment

period. In N01358 [29], the co-primary efficacy endpoints were the percent reduction over placebo in 28-day adjusted POS frequency from baseline to the end of the treatment period and the C50 % responder rate (i.e. the proportion of patients achieving a C50 % reduction in POS frequency over the course of treatment). In both N01252 [27] and N01253 [28], the dosages of brivaracetam were compared with placebo according to a prespecified hierarchical testing procedure (i.e. commencing with brivaracetam 50 mg/day followed by 100 mg/day then 20 mg/day [27] or commencing with brivaracetam 50 mg/day followed by 20 mg/day then 5 mg/day [28]). In N01252 [27] and N01253 [28], the primary efficacy endpoint had to be met for the 50 mg/day dosage for the study to be declared positive. In N01358 [29], statistical significance was assessed using the Hochberg multiple comparison procedure. Adjunctive therapy with brivaracetam was efficacious in reducing POS frequency during short-term (12 weeks) treatment, although findings varied depending on the dosage [27–29]. At the lowest recommended dosage (50 mg/day), brivaracetam was associated with a significant median percent reduction over placebo in weekly POS frequency (primary endpoint) in one [28] of the two studies (N01252 [27] and N01253 [28]) that evaluated this dosage (Table 1), with a sensitivity analysis supporting the findings of the primary analysis (p = 0.003) [28]. A benefit in this endpoint was also seen at the higher recommended dosage of 100 mg/day in N01252 (Table 1), although the p value reported is unadjusted for multiplicity as the preceding dosage (50 mg/day) in the hierarchy did not reach statistical significance [17, 27]. The median percent reductions over placebo in POS frequency per 28 days were significant for the brivaracetam 100 and 200 mg/day dosages in N01358 (in which this endpoint was assessed as a co-primary endpoint) [29]. According to post hoc analyses (produced for POS frequency standardized to a 28-day duration), this endpoint was significant at the 50 mg/day dosage in one [28], but not the other [27], study that evaluated this dosage (Table 1); the p value reported for the 100 mg/day dosage comparison in N01252 [27] was unadjusted for multiplicity (Table 1). The C50 % responder rates ranged from 27.3 to 38.9 % with adjunctive brivaracetam therapy and 16.7–21.6 % with placebo and were significant versus placebo for all brivaracetam dosages assessed, including those evaluated in N01358 (in which the C50 % responder rate was assessed as a co-primary endpoint) [29], apart from the 50 mg/day dosage in N01252 [27] (Table 1). Median percent reductions from baseline in weekly POS frequency were significantly greater following therapy with brivaracetam 50 mg/day than placebo in one (30.5 vs. 17.8 %; p = 0.003) [28], but not the other (26.8 vs. 17.0 %) [27], study that evaluated this dosage, and following therapy with brivaracetam 100 mg/day (32.5 vs. 17.0 %; p = 0.004) [27]. Median weekly POS frequency

Brivaracetam: A Review Table 1 Efficacy of oral brivaracetam as an adjunct to other antiepileptic drugs for the treatment of partial-onset seizures in adults and adolescents (aged C16 years) with uncontrolled epilepsy. Results from three fixed-dosage, multinational, phase III studies Study

N01252 [27]

N01253 [28]

Treatmenta (mg/day)

Per week

Per 28 days

6.5d

9.2e

C50 % responder ratec (% of pts)

Seizure freedom (% of pts)

27.3

0

BRV 100

100

11.7

20.5**e,f

36.0 

4

PL BRV 50

100 101

12.8*d

22.0**e

20.0 32.7  

0 4

16.7

0

BRV 50

PL N01358 [29]

Median reductionb over PL in POS frequency (%)

No. of pts

BRV 100 BRV 200 PL

99

*d,f

96 252 249

22.8

***d

23.2

***d

259

38.9

   d

5.2  

37.8

   d

4.0 

21.6

d

0.8

BRV brivaracetam, PL placebo, POS partial-onset seizure, pts patients * p \ 0.05, ** p B 0.010, *** p \ 0.001; a

 

p \ 0.05,

  

p \ 0.01,

   

p \ 0.001 vs. PL

Only recommended dosages are tabulated

b

From baseline to the end of the treatment period

c

Proportion of patients achieving a C50 % reduction in POS frequency from baseline to the end of the treatment period

d

(Co-)primary efficacy endpoint Post hoc analysis

e f

p value provided for descriptive purposes only

was 1.49 [27] and 1.7 [28] in brivaracetam 50 mg/day recipients, 1.26 in brivaracetam 100 mg/day recipients [27] and 1.75 [27] and 2.2 [28] in placebo recipients. Significantly (p \ 0.001) greater median percent reductions from baseline in POS frequency per 28 days were seen with brivaracetam 100 and 200 mg/day versus placebo in N01358 (37.2 and 35.6 vs. 17.6 %) [29]. According to prespecified and post hoc analyses, numerical benefits with brivaracetam 50–200 mg/day therapy over placebo on median percent reductions from baseline in weekly [27, 28] or 28-day [29] POS frequency and/or C50 % responder rates were generally seen across the following subgroups: simple POS, complex POS or secondary generalized POS [27–29]; patients who were levetiracetamnaı¨ve or who had previously received levetiracetam [27, 28]. Moreover, in prespecified subgroups from N01358, beneficial effects with brivaracetam 100 and 200 mg/day therapy on the median percent reduction over placebo in 28-day POS frequency and the C50 % responder rate were demonstrated regardless of the number of prior AEDs or exposure to levetiracetam [29]. Specifically, brivaracetam 100 and 200 mg/day was associated with a significant (p \ 0.05; post hoc statistical analysis) median percent reduction over placebo in 28-day POS frequency, both in patients who were levetiracetam-naı¨ve [n = 347 (46 %)] and those who had previously received levetiracetam [n = 413 (54 %)]. Significant (p \ 0.05) between-group differences in the C50 % responder rate favouring brivaracetam 100 and 200 mg/day over placebo were also seen in these patient subgroups. However, in this study, median percent reductions over

placebo in 28-day POS frequency and C50 % responder rates following brivaracetam 100 and 200 mg/day therapy were numerically lower in patients who had previously received levetiracetam (compared with those who were levetiracetam-naı¨ve) [29]. This may be due to the higher number of prior AEDs and higher baseline seizure frequency in this population [9]. Indeed, according to a post hoc analysis (available as an abstract [32]) of N01358 [29], lower prior AED count and lower historical seizure frequency were significant predictors of treatment response in patients receiving brivaracetam, a finding that is not unique among AEDs. For the most part, in N01252 [27] and N01253 [28], numerically lower treatment effects were seen in brivaracetam recipients receiving concomitant levetiracetam compared with those who were levetiracetam naı¨ve or who had previously received levetiracetam, although only 19 % of patients in each study were receiving concomitant levetiracetam [27, 28]. The proportions of patients achieving seizure freedom are reported in Table 1. In N01358 [29], seizure freedom rates were significantly higher in the brivaracetam 100 and 200 mg/day groups than in the placebo group. 4.1.2 Flexible-Dosage Study Following a 4-week baseline period, the assignment of patients to randomized treatment arms [brivaracetam (administered twice daily in equal doses) or placebo] was stratified by concomitant levetiracetam therapy, epilepsy type (partial or generalized) and geographic region [30].

S. M. Hoy

Brivaracetam was initiated at 20 mg/day, with the dosage increased in a stepwise manner to 50, 100 or 150 mg/day at 2-week intervals over 8 weeks based on efficacy and tolerability (with one down-titration permitted for patients receiving brivaracetam [20 mg/day or matching placebo), and then maintained for a further 8 weeks. Following completion of the treatment period, patients could undertake a down-titration period (1–3 weeks) or enter a long-term, nonblind, follow-up study (N01125 or N01199) [Sect. 4.2]. Baseline characteristics were generally similar across the treatment groups [30]. In patients with POS, baseline median POS frequency per week was 2.21 and 2.29 in the brivaracetam and placebo groups, with carbamazepine and valproic acid the most common concomitant AEDs [30]. The percent reductions in baseline-adjusted weekly POS frequency over placebo during the 16-week treatment and the 8-week maintenance periods were not statistically significant; however, statistical significance (p = 0.011) was demonstrated for this endpoint during the dose-finding period [30]. These findings were consistent with those seen for median percent reduction from baseline in weekly POS frequency. The C50 % responder rate was significantly higher in the brivaracetam group (n = 323) than the placebo group (n = 108) during the treatment (30.3 vs. 16.7 %; p = 0.006) and dose-finding (28.5 vs. 13.9 %; p = 0.003) periods, but not the maintenance period (34.1 vs. 24.1 %). Seizure freedom was seen in 1.5 and 0 % of patients receiving brivaracetam or placebo during the treatment period, with a statistically significant betweengroup difference seen during the maintenance period (p = 0.003). The median time to the first, fifth and tenth POS was 4, 18 and 38 days, respectively, in the brivaracetam group and 3, 14 and 36 days in the placebo group. Of note, percent reductions in baseline-adjusted weekly POS frequency over placebo were numerically higher in brivaracetam recipients who were not receiving concomitant levetiracetam compared with those who were [30]. 4.1.3 Pooled and Meta-Analyses Results from two meta-analyses [33, 34] of the two phase IIb studies [25, 26], two of the fixed-dosage phase III studies [27, 28] and the flexible-dosage phase III study [30] and from one pooled analysis [31] of the three fixed-dosage phase III studies [27–29] were consistent with those of the individual studies. For instance, in one meta-analysis (n = 1639), the proportion of C50 % responders [relative risk (RR) 1.80; 95 % CI 1.43–2.26; p \ 0.00001] and seizure freedom rates [RR 4.11; 95 % CI 1.39–12.21; p = 0.01] were significantly higher with brivaracetam than placebo regardless of the dosage of brivaracetam (5–150 mg/day) [33]. No heterogeneity among the studies was seen [33]. In the pooled

analysis (n = 1160; patients who received concomitant levetiracetam were excluded), the percent reductions over placebo in baseline-adjusted 28-day POS frequency were significant (p B 0.001) for brivaracetam 50 mg/day (n = 161), 100 mg/day (n = 332) and 200 mg/day (n = 249) [19.5, 24.4 and 24.0 %, respectively] [31]. Median percent reductions from baseline in 28-day POS frequency were significantly (p \ 0.001) greater following therapy with brivaracetam 50 mg/day, 100 mg/day and 200 mg/day than placebo (n = 418) [34.7, 37.6 and 35.6 vs. 17.2 %]. At baseline, the median 28-day POS frequency ranged from 8.9–9.6. The proportions of C50 % responders were significantly (p \ 0.005) higher with brivaracetam 50 mg/day, 100 mg/day and 200 mg/day than with placebo (34.2, 39.5 and 37.8 vs. 20.3 %). Seizure freedom rates were significantly (p B 0.001) higher in the brivaracetam 100 and 200 mg/day groups, but not the brivaracetam 50 mg/day group, than in the placebo group (5.1, 4.0 and 2.5 vs. 0.5 %) [31]. A prespecified subgroup analysis of these pooled data found that the benefits (as assessed by median percent reduction from baseline in 28-day POS frequency) achieved with adjunctive brivaracetam 50–200 mg/day were not affected by the coadministration of inducing or non-inducing AEDs [31]. However, as expected (given that, in general, seizures in patients with more prior AEDs are difficult to treat regardless of the AED), an inverse correlation between the number of prior AEDs and the median percent reduction from baseline in 28-day POS frequency was seen [31]. A post hoc subgroup analysis of pooled data (n = 1160; patients who received concomitant levetiracetam were excluded) [available as an abstract [35]] from the three fixed-dosage studies [27–29] found that C50 % responder rates for patients who were levetiracetam-naı¨ve (n = 629) were numerically higher than for those who had previously received levetiracetam (n = 531) following therapy with brivaracetam 50 mg/day (37.2 and 27.1 %), brivaracetam 100 mg/day (48.3 and 29.7 %) and brivaracetam 200 mg/day (45.2 and 31.3 %). The C50 % responder rates in the respective levetiracetam exposure subgroups following the administration of placebo were 22.5 and 17.8 %. Of note, patients who had previously received levetiracetam had higher baseline median weekly POS frequency (compared with those who were levetiracetamnaı¨ve). Moreover, more patients who had previously received levetiracetam than those who were levetiracetamnaı¨ve had received C5 prior AEDs (67.0 vs. 12.4 %). Following brivaracetam therapy, numerically higher C50 % responder rates were also seen in patients who had not previously received carbamazepine, lamotrigine or topiramate compared with those who had [35]. In another subgroup analysis of pooled data (n = 409; available as an abstract [36]) from the three fixed-dosage

Brivaracetam: A Review

studies [27–29], median percent reductions from baseline in secondary generalized (Type IC) POS frequency per 28 days were 66.6, 61.2 and 82.1 % following adjunctive therapy with brivaracetam 50 mg/day (n = 62), 100 mg/day (n = 100) and 200 mg/day (n = 75), respectively, versus 33.3 % with placebo (n = 115) [9, 36]. In the respective groups, C50 % responder rates for secondary generalized POS were 61.3, 55.0, 64.0 and 33.0 %, and secondary generalized POS freedom rates were 22.6, 31.0, 36.0 and 14.8 % [36]. Although data are limited, according to the EU summary of product characteristics, the efficacy of adjunctive brivaracetam was generally similar between patients aged 65–80 years (n = 38) and those aged \65 years [9]. In terms of health-related quality of life (HR-QOL), the mean change from baseline to last observation in the Quality of Life in Epilepsy–Patient-Weighted (QOLIE-31P) total score did not significantly differ between brivaracetam 50 mg/day (n = 179), 100 mg/day (n = 324) and 200 mg/day (n = 235) recipients and placebo (n = 422) recipients in a pooled analysis (available as an abstract [37]) of the three fixed-dosage studies [27–29]. A meaningful (not defined) improvement in the QOLIE-31-P score was achieved by 43.6, 41.7, 36.6 and 38.6 % of patients, respectively. A significant (p = 0.044) difference favouring brivaracetam 100 mg/day over placebo was seen in the seizure worry subscale score [37]. 4.2 Longer-Term Efficacy Following completion of the two phase IIb studies [25, 26], the three fixed-dosage phase III studies [27–29], the flexible-dosage phase III study [30], and a further phase III study [38] (discussed in Sect. 5.2), patients could enter one of three long-term, follow-up studies (N01125, N01199 and N01379 [n = 853, 668 and 627] [17]). During the follow-up studies, patients received a flexible dose of adjunctive brivaracetam up to a maximum of 200 mg/day; the starting dosage of brivaracetam was the same as that received at the end of the initial study (N01125, N01199 and N01379) or 150 mg/day (N01379) [17, 38]. At a clinical cut-off date of 17 January 2014, the duration of exposure was up to 96 months (N01125), up to 90 months (N01199) and up to 30 months (N01379) [17]. The antiepileptic efficacy of adjunctive brivaracetam 50–200 mg/day appeared to be sustained during longer-term therapy [17]. At the clinical cut-off date, the median percent reduction from baseline in POS frequency per 28 days was 41.5 % in N01125, 54.6 % in N01199 and 52.2 % in N01379. In the respective studies, the proportions of C50 % responders were 42.9, 53.9 and 51.2 % [17]. These data were confirmed in a pooled analysis (n = 1836; patients with generalized epilepsy were excluded) [39] of the two phase IIb studies [25, 26], the

three fixed-dosage phase III studies [27–29], the flexibledosage phase III study [30], and three follow-up studies (N01125, N01199 and N01379). Overall, the median percent reduction from baseline in POS frequency per 28 days was 48.8 % and the C50 % responder rate was 48.7 %. For the patients exposed to brivaracetam for 58–60 months, the median percent reduction from baseline in POS frequency per 28 days was 77.0 % (n = 540) and the C50 % responder rate was 71.0 % (n = 541). At baseline, the median POS frequency per 28 days was 8.9. Seizure freedom was seen in 4.9, 4.2, 3.0 and 3.3 % of patients exposed to brivaracetam during the first 6, 12, 24 and 60 months of treatment, respectively, and in 16.9, 10.4, 5.5 and 1.4 % of patients exposed to brivaracetam for any 6-, 12-, 24- and 60-month period, respectively. It is worth noting that almost half of the patients in the efficacy population who entered the follow-up studies discontinued therapy owing to a lack of efficacy [39], potentially resulting in a selection bias (as patients who remained in the study responded better than those who discontinued therapy) [9]. At each timepoint up to month 60, clinically meaningful improvements in the QOLIE-31-P total score (defined as a change from baseline of[5.19 points) and the seven QOLIE-31-P subscale scores (defined as a change from baseline of [3.95–7.42 points) were seen in over 30 % of patients [39]. For the most part, these improvements were greatest in the QOLIE-31-P seizure worry and daily activities/social functioning subscale scores [39].

5 Tolerability of Brivaracetam 5.1 Oral Administration Within the recommended dosage range of 50–200 mg/day, adjunctive brivaracetam was generally well tolerated in adults and adolescents (aged C16 years) with POS participating in the fixed-dosage studies [27–29] discussed in Sect. 4.1.1, with the majority of treatment-emergent adverse events (TEAEs) being mild or moderate in intensity [31]. In a pooled analysis of these studies [31], TEAEs occurred in 71.0 % of 200 brivaracetam 50 mg/day recipients, 66.9 % of 353 brivaracetam 100 mg/day recipients, 67.2 % of 250 brivaracetam 200 mg/day recipients and 62.1 % of 459 placebo recipients, with 47.0, 39.9, 43.6 and 30.3 % of patients, respectively, experiencing treatmentrelated adverse events (TRAEs). The most frequently reported TEAEs were somnolence, dizziness, fatigue and headache, with an apparent relationship seen between the dose of brivaracetam and the incidences of somnolence and fatigue (Fig. 1) [31]. Of note, the risk of somnolence, fatigue and dizziness is greatest early in treatment [8]. A meta-analysis [33] (discussed in Sect. 4.1.3) revealed no

S. M. Hoy

statistically significant association between the use of brivaracetam (5–150 mg/day) and most TEAE endpoints, with the exception of somnolence (RR 1.63; 95 % CI 1.08–2.45; p = 0.02) and fatigue (RR 2.05; 95 % CI 1.19–3.53; p = 0.009). In the pooled analysis [31], serious TEAEs occurred in \4 % of patients in each of the brivaracetam 50, 100 and 200 mg/day groups and in \3 % of patients in the placebo group, with \1 % in each group considered related to treatment. Two patients receiving brivaracetam (dosage not reported) and three patients receiving placebo reported suicidal ideation; there were no reports of suicide attempts or completed suicides. Overall, 5.0, 7.6 and 6.8 % of patients in the brivaracetam 50, 100 and 200 mg/day groups and 3.9 % of patients in the placebo group discontinued treatment. Four deaths were reported: one placebo recipient, one brivaracetam 50 mg/day recipient and two brivaracetam 200 mg/day recipients. All three deaths in the brivaracetam group met the Ryvlin et al. criteria [40] for sudden unexplained death in epilepsy (SUDEP) [31]. Psychiatric disorders are common in adults with epilepsy [41]. Such events have a multifactorial aetiology (comprising patient-related, epilepsy-related and AED-related factors), making it often difficult to determine causality [42]. Like levetiracetam and various other AEDs [43], brivaracetam is associated with psychiatric adverse reactions [8]. In a pooled analysis (data derived from the US prescribing information [8]) of the fixed-dosage studies [27–29], psychiatric adverse reactions were seen in approximately 13 % of 803 brivaracetam (C50 mg/day) recipients and 8 % of 459 placebo recipients, with 1.7 and 1.3 % of patients discontinuing therapy with brivaracetam or placebo because of psychiatric reactions. Psychiatric adverse reactions seen in these and long-term follow-up studies included nonPL (n = 459) Insomnia

BRV 50 mg/day (n = 200) BRV 100 mg/day (n = 353)

Irritability BRV 200 mg/day (n = 250) Headache

Fatigue

Dizziness

Somnolence 0

5

10 Incidence (% of patients)

15

20

Fig. 1 Treatment-emergent adverse events occuring in C5 % of patients in any of the adjunctive brivaracetam groups and with a higher incidence than with adjunctive placebo in a pooled analysis [31] of the fixed-dosage studies [27–29]. BRV brivaracetam, PL placebo

psychotic symptoms such as anxiety, depression and irritability, and psychotic symptoms such as psychotic disorder, acute psychosis, hallucination and paranoia. Therapy with brivaracetam had a minimal effect on bodyweight, with changes (i.e. increases and decreases) in bodyweight seen in \2 % of brivaracetam 50–200 mg/day recipients and in \1 % of placebo recipients, according to another pooled analysis (data derived from the EU assessment report [17]). The experience with adjunctive brivaracetam in the flexible-dosage study [30] was consistent with that seen in the fixed-dosage studies [27–29]. Most TEAEs were mild to moderate in intensity, with C1 TEAE reported in 66.0 % of 359 brivaracetam recipients and 65.3 % of 121 placebo recipients over the 16-week treatment period. Overall, 6.1 and 5.0 % of patients in the respective groups discontinued therapy because of TEAEs. It is worth noting that the incidences of TEAEs and discontinuations due to TEAEs were numerically higher in both the brivaracetam and placebo groups during the dose-finding period (TEAEs: 56.0 and 55.4 %; discontinuations: 4.5 and 3.3 %) compared with the maintenance period (TEAEs: 36.8 and 40.9 %; discontinuations: 0.3 and 0 %). The most frequently reported TEAEs (occurring in [8 % of brivaracetam recipients and with a higher incidence in the brivaracetam group than the placebo group) were somnolence (11.1 vs. 4.1 %) and dizziness (8.6 vs. 5.8 %). Psychiatric adverse events were reported in 12.3 and 11.6 % of patients in the brivaracetam and placebo groups, with the incidences of depression (1.9 and 1.7 %), irritability (1.9 and 0 %) and aggression (1.4 and 0.8 %) numerically higher in patients receiving brivaracetam than in those receiving placebo. Serious adverse events occurred in 5.3 and 7.4 % of patients receiving brivaracetam and placebo, respectively; one death occurred (in a patient receiving brivaracetam 50 mg/day during the maintenance period) and was considered unlikely to be related to the study medication [30]. The experience with adjunctive brivaracetam seen in patients with secondary generalized POS was consistent with that seen in all patients with POS, according to a subgroup analysis [36] of pooled data from the three fixed-dosage studies [27–29]. Moreover, the tolerability profile of elderly (aged C65 years) patients (n = 130) participating in the adjunctive brivaracetam phase II/III development programme appears to be similar to that seen in younger patients (aged \65 years) [9]. Longer-term (B8.5 years) adjunctive brivaracetam 50–200 mg/day was generally well tolerated, according to a pooled analysis (n = 2186) [39] of the two phase IIb studies [25, 26], the three fixed-dosage phase III studies [27–29], the flexible-dosage phase III study [30], two phase III (N01258) [38] and phase IIIb (N01395) [44] studies, and four long-term, follow-up studies (N01125, N01199,

Brivaracetam: A Review

N01372 and N01379). The tolerability profile with longerterm adjunctive brivaracetam therapy was generally similar to that seen in the shorter-term, placebo-controlled studies [9]. In the pooled analysis, TEAEs were reported in 84.5 % of patients, with 54.2 % experiencing TRAEs. Of note, there was no evidence to suggest that the incidence of TEAEs or TRAEs increased with higher modal doses of brivaracetam. Headache (20.9 % of patients), dizziness (17.5 %), somnolence (15.2 %), nasopharyngitis (13.2 %), fatigue (11.3 %) and convulsion (10.6 %) were the most frequently (C10 % of patients) reported TEAEs. The most frequently reported ([2.0 % of patients) psychiatric/ behavioural TEAEs were depression (7.1 % of patients), insomnia (6.2 %), irritability (5.2 %) and anxiety (4.9 %). Of note, there was no evidence to suggest that the incidence of psychiatric/behavioural TEAEs increased with dose. Serious TEAEs occurred in 18.3 % of patients, with convulsion the most frequently reported (2.6 %), and 4.3 % had serious TRAEs. TEAEs leading to treatment discontinuation occurred in 12.1 % of brivaracetam 50–200 mg/day recipients, with convulsion (1.4 % of patients), pregnancy (0.9 %), somnolence (0.7 %), depression (0.6 %), dizziness (0.6 %), fatigue (0.5 %), suicidal ideation (0.5 %) and suicide attempt (0.5 %) the TEAEs most frequently (C0.5 % of patients) resulting in the discontinuation of brivaracetam. Death occurred in 28 (1.3 %) patients, with 4 considered possibly related to the study medication. Two were classified as SUDEP events and one as potentially a SUDEP event [39]. 5.2 Intravenous Administration When used de novo or as a replacement for oral brivaracetam, intravenous brivaracetam 200 mg/day (administered as a 15-min infusion or a 2-min bolus) was generally well tolerated, with no new safety concerns identified, in 105 adults and adolescents (aged C16 years) with partial or generalized epilepsy participating in a randomized, nonblind, multinational, phase III study (N01258) [38]. Patients (uncontrolled on B2 concomitant AEDs) underwent a double-blind run-in period for 7 days (during which they received oral brivaracetam 100 mg twice daily or placebo) and then received brivaracetam 100 mg twice daily (administered as an infusion or a bolus) for a total of nine doses. Patients who completed the study were switched to a longerterm, follow-up study (N01379) or down-titrated [38]. During the 11.5-day treatment period, TEAEs were reported in 76.2 % of patients, with 63.8 % experiencing a TRAE [38]. Somnolence and dizziness were the most frequently reported TEAEs (29.5 and 14.3 %) and TRAEs (28.6 and 12.4 %). Severe TEAEs (vertigo, nausea) were reported in one patient and were considered to be related to the study medication. Two patients discontinued therapy

because of TEAEs. There were no serious TEAEs reported, and no patients died. During the 4.5-day evaluation period, 65.4 and 71.2 % of patients who received brivaracetam as an infusion (n = 52) or a bolus (n = 52) and 70.6 and 66.0 % of patients in whom intravenous brivaracetam was used de novo (n = 51) or as a replacement for oral brivaracetam (n = 53) had TEAEs. Somnolence (occurring in 25.0, 19.2, 21.6 and 22.6 % of patients, respectively) was the most frequently reported TEAE. The incidence of injection-related TEAEs in the respective groups was 11.5, 9.6, 7.8 and 13.2 % [38].

6 Dosage and Administration of Brivaracetam Brivaracetam is available in various countries worldwide, including the USA [8], Canada [45] and those of the EU [9]. Prescribing information and/or indications may differ between individual countries and local prescribing information should be consulted for detailed information regarding contraindications, discontinuation, missed doses, potential drug interactions, use in special patient populations and warnings and precautions. Brivaracetam is approved as adjunctive therapy in the treatment of POS (with or without secondary generalization [9]) in adults (aged C18 years) [USA, EU and Canada] and adolescents (aged 16 to\18 years) [USA and EU] with epilepsy [8, 9, 45]. It can be administered orally (as a tablet or solution) or, in patients in whom oral administration is temporarily not feasible, intravenously (as a bolus or over 15 min [9], or over 2–15 min [8]). There is no clinical experience with the intravenous administration of brivaracetam for [4 days [8, 9]. Oral brivaracetam can be administered with or without food [8]. The recommended starting dosage of adjunctive brivaracetam is 50 mg/day [9] or 100 mg/day [8, 9] (administered in two equally divided doses), with the dose adjusted based on efficacy and tolerability to a minimum dosage of 50 mg/day and a maximum dosage of 200 mg/day. The total daily dose and frequency of administration should be maintained when switching between oral and intravenous brivaracetam [8, 9]. The dose of brivaracetam should be increased by up to 100 % when brivaracetam is coadministered with rifampin [8].

7 Place of Brivaracetam in the Management of Partial-Onset Seizures in Patients with Epilepsy AEDs are the mainstay of treatment for patients with epilepsy, with the goal of antiepileptic therapy being the achievement of seizure freedom with minimal adverse

S. M. Hoy

events [46]. When selecting an AED, treatment should be individualized, taking into account the following factors: mechanism of action, spectrum of activity against different seizure types and epilepsy syndromes, administration parameters (e.g. frequency, route), onset of efficacy and magnitude of clinical response, and the drug interaction and tolerability profile [2, 46, 47]. Patient characteristics (e.g. age, sex and comorbidities) may also influence treatment decisions [2, 47]. Over the last two decades, numerous AEDs have been developed and approved for the treatment of patients with POS; however, no individual AED is ideal for all patients and approximately one-third of patients have treatmentresistant epilepsy [1, 2, 47]. More recently, brivaracetam, a high affinity SV2A ligand, was approved as adjunctive therapy in the treatment of POS in various countries worldwide, including the USA, Canada and those of the EU (Sect. 6). Owing to its more recent development and approval, brivaracetam was not considered in the most recent (2004) American Academy of Neurology and American Epilepsy Society guidelines for the then new AEDs (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and zonisamide) [48, 49] nor in the more recent (2012) National Institute for Health and Clinical Excellence (NICE) guidelines [46] for the treatment of epilepsy. The NICE guidelines recommend adjunctive therapy with carbamazepine, clobazam, gabapentin, lamotrigine, oxcarbazepine, sodium valproate, topiramate or levetiracetam [46]. Other AEDs that may be considered in those patients in whom initial adjunctive therapy is ineffective or not tolerated include eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin, zonisamide [46]. Brivaracetam has a favourable pharmacokinetic profile, in terms of its availability as both oral and intravenous formulations, its linear and dose-proportional pharmacokinetics, rapid and complete absorption that is unaffected by food, minimal protein binding and low potential for clinically relevant drug–drug interactions (including with various AEDs that are commonly used as adjunctive therapy for POS) (Sect. 3). As adjunctive therapy to other AEDs in patients with POS, fixed-dosage brivaracetam 100 and 200 mg/day and, in general, 50 mg/day, was associated with significant median percent reductions over placebo in POS frequency and significant improvements in C50 % response rates compared with placebo in three short-term (12 weeks) studies (Sect. 4.1.1). Moreover, in follow-up studies, the efficacy of adjunctive brivaracetam 50–200 mg/day appeared to be sustained during treatment for up to

60 months (based on fully published data) and up to 96 months (based on preliminary data) [Sect. 4.2]. Adjunctive brivaracetam provided effective seizure control irrespective of POS subtype (Sect. 4.1.1) or whether the concomitant AED regimen included inducing or non-inducing AEDs (Sect. 4.1.3), and in patients who were levetiracetam-naı¨ve and those who had previously received levetiracetam (Sects. 4.1.1 and 4.1.3), according to individual and pooled data from the three fixed-dosage studies. In the two fixed-dosage studies in which patients received concomitant levetiracetam (19 % of the total patient population of each study), numerically lower treatment effects were generally seen in brivaracetam recipients receiving concomitant levetiracetam than in those who were levetiracetam naı¨ve or who had previously received levetiracetam (Sect. 4.1.1). In fact, following the completion of these studies, a meta-analysis was performed, with the results concluding that the use of concomitant levetiracetam may have influenced overall therapeutic response [17]. The EMA [9] and the US FDA [8] have concluded that brivaracetam provides no additional therapeutic benefit when coadministered with levetiracetam, which may reflect competition at the SV2A binding site. However, the patients enrolled in these studies (N01252 and N01253) had uncontrolled epilepsy despite receiving concomitant levetiracetam therapy, suggesting that this subgroup of patients may have had seizures that did not respond well to AEDs acting at the SV2A binding site. It is worth noting that brivaracetam had a 15–30-fold higher binding affinity for SV2A than levetiracetam in vitro, reached both maximal SV2A occupancy and maximal seizure protection within 5–15 min ex vivo (with a strong correlation demonstrated between SV2A occupancy and seizure protection potency), and had higher predicted blood–brain barrier permeability than levetiracetam, potentially permitting its use in emergency situations that require a fast onset of action (Sect. 2). Whether administered orally or intravenously (bolus or infusion), adjunctive brivaracetam 50–200 mg/day was generally well tolerated by the patients participating in the fixed-dosage phase III and follow-up studies (oral administration; Sect. 5.1) and in a phase III study (intravenous administration; Sect. 5.2). Moreover, in terms of tolerability, the experience with brivaracetam in the flexible-dosage study was consistent with that seen in the fixed-dosage studies (Sect. 5.1). TEAEs were generally mild or moderate in intensity in the fixed-dosage studies, with somnolence, dizziness, fatigue and headache the most frequently reported. Of note, an apparent relationship was seen between the brivaracetam dose and the incidences of somnolence and

Brivaracetam: A Review

fatigue. Therapy with brivaracetam had a minimal effect on bodyweight (Sect. 5.1). The tolerability profile of intravenous brivaracetam appeared to be similar to that of oral brivaracetam, although, in addition, intravenous brivaracetam was associated with injection-related TEAEs (Sect. 5.2). Like levetiracetam and various other AEDs, brivaracetam is associated with psychiatric adverse reactions (Sect. 5.1). Although data from a small, noncomparative, multicentre, phase IIIb study (N01395) [44] suggested that adults and adolescents (aged C16 years) with POS or primary generalized epilepsy in whom behavioural adverse events were reported with adjunctive levetiracetam therapy may benefit from switching to brivaracetam, such data are subject to confounding factors. Further data from well-designed studies would be of interest. In conclusion, as adjunctive therapy to other AEDs, brivaracetam provided effective seizure control and was generally well tolerated when used for the treatment of POS in adults and adolescents (aged C16 years) with uncontrolled epilepsy. In the absence of head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of brivaracetam versus newer AEDs are not yet possible. In the meantime, current evidence suggests brivaracetam extends the options currently available for the management of POS in patients aged C16 years with epilepsy. Data selection sources: Relevant medical literature (including published and unpublished data) on brivaracetam was identified by searching databases including MEDLINE (from 1946), PubMed (from 1946) and EMBASE (from 1996) [searches last updated 25 July 2016], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Brivaracetam, BRIVIACT, UCB34714. Study selection: Studies in patients with partial-onset seizures who received brivaracetam. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Acknowledgments During the peer review process, the manufacturer of brivaracetam was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit. Compliance with Ethical Standards Funding The preparation of this review was not supported by any external funding. Conflicts of interest Sheridan Hoy is a salaried employee of Adis/ Springer, is responsible for the article content and declares no relevant conflicts of interest.

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