FormalPara Key Summary Points

Brivaracetam (BRV) has higher affinity and selectivity for synaptic vesicle protein 2A than levetiracetam

BRV enters the brain rapidly and can be used in acute situations

BRV (50–200 mg/day) is an effective and well-tolerated treatment for focal-onset seizures which does not require titration

Long-term safety and tolerability of adjunctive BRV has been established, with efficacy maintained over time (up to 14 years)

It is available in three bioequivalent formulations (tablets, oral solution, and solution for intravenous injection), lacks drug-drug interactions, and is easy to use

Introduction

Epilepsy is one of the most common and disabling neurological disorders, affecting all age groups and approximately 65 million people globally [1]. Although seizure control can be achieved in many patients with a single antiseizure medication (ASM), other patients require multiple ASMs, neuromodulation devices, resective surgery, or dietary therapies [2]. Despite the many epilepsy treatment options, one third of patients continue to have uncontrolled seizures [3], driving the need for development of new ASMs to enhance seizure control, minimize side effects, and improve overall quality of life for individuals affected by epilepsy. Personalized ASM selection has the potential to improve outcomes for patients when matching ASM characteristics to patient profile (e.g., age, gender, comorbidities) [4]. The ideal ASM should offer robust control of seizures while minimizing adverse effects [5]. Rapid onset of action, no or simple titration schedules, and sustained efficacy are important. The medication should exhibit a favorable pharmacokinetic (PK) profile and lack drug-drug interactions (DDIs). The ideal ASM should be well tolerated to promote compliance and long-term use. As research advances, the development of such medications stands to significantly enhance the quality of life for individuals with epilepsy.

Brivaracetam (BRV) was identified in a drug discovery program focused on synaptic vesicle protein 2A (SV2A), the target of levetiracetam (LEV), with superior binding affinity to SV2A compared with LEV [6,7,8]. BRV is indicated for the treatment of focal-onset seizures in patients ≥ 1 month of age in the US [9] and as adjunctive therapy for the treatment of focal-onset seizures with or without secondary generalization in patients ≥ 2 years of age with epilepsy in the European Union [10]. In the current narrative review, we summarize the key characteristics of BRV, the key outcomes of its development program, and the accumulating evidence from daily clinical practice focusing on distinct epilepsy patient populations with high unmet needs (e.g., elderly, pediatrics, patients with comorbidities, and patients with acquired epilepsy). This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

BRV Discovery, Preclinical Data, and PK Profile

BRV Discovery and Preclinical Data

SV2A is a known molecular target for ASM action (Fig. 1) [6, 11]. SV2A modulation by both BRV and LEV results in reduced release of neurotransmitter into the synapse, although it is at present unknown how this translates into the antiseizure activity [8, 11, 12].

Fig. 1
figure 1

Mechanism of action of clinically approved ASMs. Drugs marked with asterisks indicate that these compounds act by multiple mechanisms (not all mechanisms shown here). AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, ASM antiseizure medication, GABA gamma-aminobutyric acid, GABA-T GABA aminotransferase, GAT GABA transporter, KCNQ a family of voltage-gated potassium channels (also known as the Kv7 family), NMDA N-methyl-D-aspartate, SV2A synaptic vesicle protein 2A. Reproduced with small modifications from Fig. 1 of Löscher et al. [69], licensed under CC BY-NC 4.0

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BRV was identified in a large drug discovery effort to develop molecules with greater binding affinity and selectivity to SV2A than LEV (Fig. 2a) [6,7,8]. BRV has approximately 15- to 30-fold higher affinity to SV2A than LEV and its ability to inhibit vesicle release is superior to LEV [7, 13]. Its action is more selective than that of LEV because it does not affect any other targets, unlike LEV, which also acts at the AMPA glutamatergic postsynaptic receptor and at the presynaptic calcium channel (Fig. 2b) [14]. Evidence from radioligand studies suggests that BRV and LEV act at different binding sites or interact with different conformational states of the SV2A protein [12]. BRV is effective in seizure suppression in a wide range of animal models of epilepsy, at doses that do not impact motor or cognitive functions [7]. BRV further differs from LEV by having higher lipophilicity, which results in faster brain penetration [7]. Overall, the available preclinical data support the notion that BRV may be beneficial for patients with uncontrolled seizures as either monotherapy or adjunctive treatment, including in patients who have previously failed other ASMs, including LEV, or experienced significant adverse events.

Fig. 2
figure 2

Overview of drug discovery efforts at UCB based on modulation of the pyrrolidone-acetamide scaffold (a), properties of BRV and LEV (b), and proposed mechanism of action of BRV and LEV (C). AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, BRV brivaracetam, GABA gamma-aminobutyric acid, GAD 65 glutamate decarboxylase 65, HVA high-voltage-activated, IC50 inhibitory half maximal concentration, Ki equilibrium constant, LEV levetiracetam, MES maximal electroshock seizure test, PTZ subcutaneous pentylenetetrazole seizure test, SV2A synaptic vesicle protein 2A. a Reproduced from Fig. 1 of Klitgaard et al. [7], licensed under CC BY-NC-ND 4.0. b Reproduced from Table 31.2 of D’Souza et al. [70], with permission from John Wiley & Sons, Ltd. Panel C: Reproduced with small modifications from Fig. 1 of Feyissa [71], licensed under CC BY-NC 4.0

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PK Profile

BRV is available in three bioequivalent formulations: tablets, oral solution, and a solution for intravenous (IV) injection (administered undiluted as 2-min bolus or diluted as 15-min infusion) [9, 10]; it offers simple 1:1 dose conversion between formulations. It has a favorable PK profile and is rapidly absorbed after single and multiple oral doses, with a median time to maximum concentration of approximately 1 h [15, 16]. BRV exhibits linear and dose-proportional PK across a range of doses which far exceed the therapeutic ones [15,16,17]. It has little protein binding (< 20%), and its distribution volume is slightly lower than the total volume of body water [16, 18]. BRV is primarily metabolized by hydrolysis of the acetamide group to form a carboxylic acid metabolite, followed by hydroxylation by cytochrome P450 (CYP)2C9 to form a hydroxy-acid metabolite, and secondarily by β-oxidation of the propyl side chain, mainly by CYP2C19 (Fig. 3) [8]. The metabolites are inactive, and within 72 h, almost all (> 95%) of the BRV dose is eliminated in the urine; 8.6% of the BRV dose is eliminated unchanged, and the rest is excreted as metabolites [18, 19]. Mean half-life was approximately 9 h, and plasma clearance was 3.4 l/h after a single oral dose of 50 mg BRV in healthy participants [20].

Fig. 3
figure 3

Reproduced from Fig. 1 of Moseley et al. [17], licensed under CC BY-NC-ND 4.0

Overview of BRV metabolism. BRV brivaracetam, CYP cytochrome P450.

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Population PK analysis of data from phase II and III trials in an ethnically diverse patient population showed that most of the inter-individual variability in BRV PK was accounted for by differences in concomitant use of enzyme-inducing ASMs and body weight [19, 21]. These changes were modest, not clinically relevant, and would not require dose adjustments. Characteristics that did not significantly affect the PK profile of BRV were dose, sex, age, race, creatinine clearance, and categories of concomitant ASMs other than inducers [19, 21].

A phase I, placebo (PBO)-controlled, double-blind, randomized, single (2.5–100 mg) and multiple (2.5–50 mg twice daily) rising oral dose study assessed the adverse event profile and PK of BRV in healthy Japanese men (n = 80), as well as the impact on PK of the CYP2C19 genotype [22]. The tolerability, adverse event profile, and PK were comparable with those previously reported in healthy European volunteers [22]. No clinically relevant change in the PK of BRV was seen in participants with impaired CYP2C19 metabolism, indicating that genotype screening or dose adaptations are not required for Asian patients treated with BRV.

A phase I, open-label, repeated-dose study assessed the PK, metabolism, safety, and tolerability of BRV in 16 healthy elderly volunteers (65–78 years of age) [23]. Participants received a single dose of BRV (200 mg) on day 1, followed by 200 mg twice daily for 10 days (twice the maximum recommended dose [9, 10]). Safety and tolerability, adverse event profile, and PK and metabolism were similar to those observed in younger populations. No dose adjustments are therefore needed in the elderly (65–78 years of age), but it should be mentioned that there are no data for patients ≥ 80 years old [23].

In a phase I, open-label, single-dose, parallel-group study, BRV (200 mg) was administered to nine adult patients with severe renal impairment not requiring dialysis and nine matched healthy controls [24]. Severe renal impairment had a modest effect on the PK profile of BRV, resulting in unchanged Cmax and a 21% increase in area under the curve relative to matched healthy controls. No dose adjustment of BRV is needed at any stage of renal dysfunction [24]. However, BRV is not recommended in patients undergoing dialysis because of the lack of available data [9, 10].

In a phase I, open-label, single-dose study, BRV (100 mg) was administered to adult patients with different degrees of hepatic impairment (mild n = 6; moderate n = 7; severe n = 7) and matched healthy controls (n = 6) [25]. BRV exposure was 50–60% higher in patients with hepatic impairment, irrespective of severity. BRV can be administered in patients with hepatic impairment, but dose adjustments are recommended [9, 10, 25].

Currently, no information is available on the impact of pregnancy on BRV plasma PK. As a precaution, BRV should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the fetus [10].

DDIs of BRV have been previously reviewed [17]. BRV does not affect most metabolizing enzymes and drug transporters (e.g., the P-gp-mediated efflux of substrates such as new oral anticoagulants is not expected to be impacted by BRV). No dose adjustment of BRV is needed when used with other ASMs [9, 10]. Few agents affect the PK of BRV significantly. Rifampicin reduces BRV plasma levels by ~ 45% because of its induction of the BRV-metabolizing isoenzyme, CYP2C19 [17]. BRV dose should be adjusted accordingly in rifampicin-treated patients. BRV inhibits the enzyme epoxide hydrolase, which metabolizes the active metabolite of carbamazepine (CBZ), carbamazepine epoxide, to an inactive metabolite. Epoxide levels increase up to 200% with BRV [26]. This has not been associated with clinical symptoms but should be considered in patients treated with both CBZ and BRV in case dose-related CBZ adverse events arise [27]. Caution should also be used when adding or ending treatment with the strong enzyme inducer, St. John’s wort.

Clinical and Real-World Studies

Clinical Trials

The tolerability and efficacy of adjunctive BRV in adult patients with focal-onset seizures was shown in three phase III, double-blind, randomized, PBO-controlled trials (ClinicalTrials.gov: NCT00490035, NCT00464269, NCT01261325) [28,29,30]. A pooled analysis of these three phase III trials supported the efficacy and safety of adjunctive BRV (50–200 mg/day; approved therapeutic dose range for adults) in a large number of patients with focal-onset seizures [31]. The percent reduction over PBO in baseline-adjusted focal-onset seizure frequency per 28 days was 19.5% for patients receiving BRV 50 mg/day (n = 161), 24.4% for patients receiving BRV 100 mg/day (n = 332), and 24.0% for patients receiving BRV 200 mg/day (n = 249). The median percent reduction in focal-onset seizure frequency from baseline was 34.7% for patients receiving BRV 50 mg/day, 37.6% for patients receiving BRV 100 mg/day, and 35.6% for patients receiving BRV 200 mg/day compared with 17.2% for patients receiving PBO (Fig. 4a). In patients receiving BRV 50 mg/day, 100 mg/day, and 200 mg/day, the ≥ 50% responder rates were 34.2%, 39.5%, and 37.8%, respectively, compared with 20.3% for PBO (n = 418) (Fig. 4b), and seizure freedom rates were 2.5%, 5.1%, and 4.0%, respectively, compared with 0.5% for PBO. Treatment-emergent adverse events (TEAEs) were reported by 68.0% of patients on BRV (n = 803) and 62.1% of patients on PBO (n = 459). The most common TEAEs (reported in ≥ 5% of patients on BRV) were somnolence (15.2%; PBO 8.5%), dizziness (11.2%; PBO 7.2%), headache (9.6%; PBO 10.2%), and fatigue (8.7%; PBO 3.7%). The incidences of severe TEAEs (5.6%; PBO 4.1%) and serious TEAEs (3.0%; PBO 2.8%) were similar for BRV and PBO; 6.7% of patients on BRV and 3.9% of patients on PBO discontinued the trials because of TEAEs. Findings from the first two of these trials suggested no additional benefit of BRV in patients taking concomitant LEV [28, 29]. The third trial therefore excluded patients with concomitant LEV while including patients who had previously failed LEV [30]. A post hoc analysis of the pooled phase III trials of patients randomized to BRV 50–200 mg/day or PBO showed higher percent reduction from baseline in focal seizure frequency and higher ≥ 50% responder rates in LEV-naive patients (percent reduction over PBO: 28.7%; ≥ 50% responder rate: 44.3% versus PBO 22.5%) than patients with previous LEV exposure (percent reduction over PBO: 12.8%; ≥ 50% responder rate: 30.0% versus PBO 17.8%) (Fig. 5a) [32]. Patients with concomitant LEV were excluded from this analysis. Thus, BRV was efficacious even in patients who had previously failed LEV. This difference was present regardless of whether LEV discontinuation had occurred because of lack of efficacy or because of side effects, although the response to BRV was generally higher in patients who had discontinued LEV because of adverse events (percent reduction over PBO: BRV 100 mg/day 12.5%, BRV 200 mg/day 23.7%; ≥ 50% responder rate: BRV 100 mg/day 34.6%, BRV 200 mg/day 52.2%, versus PBO 25.0%) rather than lack of efficacy (percent reduction over PBO: BRV 100 mg/day 17.6%, BRV 200 mg/day 14.4%; ≥ 50% responder rate: BRV 100 mg/day 26.7%, BRV 200 mg/day 22.9%, versus PBO 11.5%) (Fig. 5b and c) [30]. Patients with previous LEV exposure had a higher baseline focal seizure frequency and higher number of prior ASMs, indicative of drug resistance and severity of epilepsy, possibly explaining the difference in efficacy [32]. Similar results were seen in patients with and without prior exposure to CBZ, topiramate, and lamotrigine.

Fig. 4
figure 4

Reproduced from Fig.3a and 2B of Ben-Menachem et al. [31], licensed under CC BY-NC-ND 4.0

Median percent reduction in POS frequency from baseline (a) and ≥ 50% responder rates (b). BRV brivaracetam, POS partial-onset seizure (focal-onset seizure).

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Fig. 5
figure 5

Greater than 50% responder rates in patients treated with BRV, with or without previous LEV exposure (a), percent reduction over PBO in 28-day adjusted POS frequency during the treatment period according to reason for previous discontinuation of LEV (b), and ≥ 50% responder rates for POS frequency from baseline to the end of treatment period according to reason for previous discontinuation of LEV (c). p values are derived from a logistic regression model with effects for treatment, study, and log-transformed baseline focal seizure frequency as a continuous covariate. All p values are exploratory. BRV brivaracetam, LEV levetiracetam, PBO placebo, POS partial-onset seizure (focal-onset seizure). Panel A: Reproduced from Fig. 1A of Asadi-Pooya et al. [32], licensed under CC BY-NC-ND 4.0. Panel B and C: Reproduced from Fig. 4C and D of Klein et al. [30], licensed under CC BY-NC-ND 4.0

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In a phase III, double-blind, randomized, flexible-dose, PBO-controlled trial in adult patients with uncontrolled epilepsy (NCT00504881), 49 patients had generalized-onset epilepsy [33]. The most frequently reported seizure types at baseline in these patients were tonic-clonic seizures (BRV 83.3% versus PBO 69.2%), absence seizures (BRV 38.9% versus PBO 53.8%), and myoclonic seizures (BRV 19.4% versus PBO 7.7%). In patients treated with BRV with generalized seizures only, the number of seizure days per week decreased from 1.42 at baseline to 0.63 during the treatment period (PBO: 1.47–1.26). The median percent reduction from baseline in generalized seizure days per week was 42.6% versus 20.7% in BRV- and PBO-treated patients, respectively, and the ≥ 50% responder rate was 44.4% versus 15.4%.

In the three pivotal phase III trials, BRV was initiated at therapeutic dose without up-titration [28,29,30]. The option of starting an ASM at target dose is potentially advantageous for achieving seizure control faster [31]. A post hoc analysis of the pooled phase III trials assessed the time to onset of sustained ≥ 50% responder status in patients randomized to BRV 50–200 mg/day or PBO [34]. Patients were sustained ≥ 50% responders on a particular day if they were ≥ 50% responders (i.e., ≥ 50% reduction in focal seizure frequency from baseline) on both that day and every successive day until the end of the 12-week-long treatment period; 15.5%, 18.1%, and 19.4% of patients taking BRV 50 mg/day (n = 161), 100 mg/day (n = 332), or 200 mg/day (n = 249), respectively, achieved sustained ≥ 50% responder status on day 1 versus 6.7% for PBO. On day 1, ≥ 75% sustained responder rates were 10.8% and 9.3% for BRV 100 mg/day and 200 mg/day versus 3.1% for PBO and ≥ 90% sustained responder rates were 6.9% and 5.3% for BRV 100 mg/day and 200 mg/day versus 1.2% for PBO [35]. Thus, approximately half of patients who achieve sustained 50–90% reduction in seizure frequency with BRV do so on the first day of treatment.

Efficacy, safety, and tolerability of adjunctive BRV (50 mg/day and 200 mg/day) in adult Asian patients with focal-onset seizures were demonstrated in a phase III, randomized, double-blind, PBO-controlled trial (NCT03083665) and were consistent with BRV trials in predominantly non-Asian populations [36]. Percent reduction over PBO in 28-day adjusted focal-onset seizure frequency was 24.5% with BRV 50 mg/day (n = 151) and 33.4% with BRV 200 mg/day (n = 148). Median percent reduction in focal-onset seizure frequency from baseline was 38.9% and 46.7%, respectively, versus 21.3% for PBO. The ≥ 50% responder rates were 41.1% and 49.3%, respectively, versus 19.0% for PBO (n = 147). Seizure freedom rates were 4.6% and 6.8%, respectively, versus 0% for PBO. TEAEs were reported by 58.5% of patients on BRV (n = 299) and 58.4% on PBO (n = 149). The most common TEAEs (≥ 10% of patients on BRV) were somnolence (14.4%; PBO 8.1%) and dizziness (12.7%; PBO 4.0%).

Long-Term Extension Trials

In several open-label extension trials (NCT00150800, NCT00175916, NCT01339559) in more than 2000 patients ≥ 16 years of age with a variety of seizure types, the long-term safety and tolerability of adjunctive BRV was established for up to 14 years [37,38,39]. The safety profile of BRV was consistent with its known safety profile from previous trials.

Efficacy and tolerability of BRV treatment in adults with focal-onset seizures was also confirmed in a pooled analysis of > 2000 patients receiving BRV 50–200 mg/day during the phase IIb and phase III trials and their associated long-term follow-up trials [40]. Total BRV exposure was 5339.4 patient-years; 84.5% of patients reported TEAEs (n = 2186). The most frequent TEAEs (≥ 10% of patients) were headache (20.9%), dizziness (17.5%), somnolence (15.2%), nasopharyngitis (13.2%), fatigue (11.3%), and convulsion (10.6%). The overall median percent reduction in focal-onset seizure frequency per 28 days from baseline was 48.8% (n = 1836) and increased over time in patients continuing with the treatment (77.0% at 58–60 months [n = 540]). The ≥ 50% responder rate was 48.7% (n = 1836) and also increased over time (71.0% at 58–60 months [n = 541]). Seizure freedom rates were 4.9%, 4.2%, 3.0%, and 3.3% for the first 6, 12, 24, and 60 months of treatment with BRV, respectively. Among patients who had ≥ 60 months of BRV treatment (n = 518), 32.4%, 22.4%, 13.7%, and 3.3% of patients were seizure-free for any 6-, 12-, 24-, or 60-month period. Patients had high long-term retention rates: 6-, 12-, 24-, and 60-month retention rates were 91.0%, 79.8%, 68.1%, and 54.4%, respectively. BRV retention rates were high, even with conservative calculation methods [41].

Titration and Fast Brain Penetration

Titration of ASMs to first therapeutic dose is common practice for epilepsy treatment but is frequently linked to increased incidences of seizures, an increased rate of hospitalization, and subsequent increase of health cost utilization as compared to the ASM maintenance phase [42]. In a survey of 461 patients with epilepsy from seven European countries, 51% of participants considered a reduced titration period as an important factor in treatment decision making [43]. BRV is the only ASM discovered since the 1960s that does not require titration and is started at target dose from Day 1—which is possible because of BRV’s favorable tolerability profile—and it is associated with a fast and sustained response from the first day of treatment [9, 10, 34, 35]. It also has a rapid onset of action. Early control of seizures may reduce the risk of complications and potential harm [44].

Preclinical data demonstrated that BRV has rapid brain entry and fast brain SV2A occupancy; BRV has higher permeability and lipophilicity than LEV [45]. Non-human primate and human positron emission tomography studies highlight faster central nervous system entry versus LEV (calculated half-lives 1–10 min for BRV and 7–28 min for LEV) [45,46,47,48].

Electroencephalogram (EEG) response to intermittent photic stimulation occurs in some patients with epilepsy. These patients have reproducible EEG epileptiform discharges triggered by photic stimulation, termed photoparoxysmal response (PPR) [49]. PPR has been used in proof-of-concept phase IIa trials to evaluate ASMs. Both LEV and BRV eliminated the PPR at clinically relevant doses. Patients had a faster EEG PPR response with IV BRV than with LEV, with a shorter median time to PPR elimination (2 min versus 7.5 min) (Fig. 6a) [50]. Most patients had a more rapid EEG response with BRV than with LEV (Fig. 6b).

Fig. 6
figure 6

Adapted from Table 1 and 3 of Reed et al. [50], licensed under CC BY-NC 4.0

Time to PPR elimination in patients with photosensitive epilepsy (a) and proportion of patients with PPR elimination on EEG at designated timepoints (b). Part 1: IV infusion over 15 min (n = 8); part 2: IV infusion over 15 min (n = 8); parts 1 and 2 combined (n = 16). aRange when excluding patient NNN (non-responder in Part 1): 1–5; bPatient OOO completed part 1, but patient PPP participated in part 2. BRV brivaracetam, EEG electroencephalogram, IV intravenous, LEV levetiracetam, PPR photoparoxysmal response.

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The rapid onset of action of BRV was further evaluated in a phase II, open-label, randomized, proof-of-concept trial (NCT03021018) in patients with drug-resistant epilepsy (18–70 years of age) admitted to an epilepsy monitoring unit for seizure characterization or pre-surgical treatment evaluation. After the first seizure, patients were administered IV BRV 100 or 200 mg or lorazepam (LZP; 1–4 mg) and were monitored for 12 h for seizure recurrence. The efficacy of IV BRV in reducing subsequent seizures was similar to IV LZP [51]. Five of 15 patients had a seizure within 12 h of LZP administration versus 3 of 15 patients each treated with BRV 100 mg and 200 mg. Nine of 15 (60%) LZP-treated patients were seizure-free over 12 h versus 12/15 (80%) each of BRV 100 mg- and 200 mg-treated patients. There was a numerically higher use of rescue medication within 12 h for LZP (6/15 [40.0%]) versus BRV 100 mg (1/15 [6.7%]) and versus BRV 200 mg (2/15 [13.3%]). TEAEs were reported by 5/16 (31.3%) of patients treated with LZP, 6/15 (40.0%) treated with BRV 100 mg, and 3/15 (20.0%) treated with BRV 200 mg. The most common TEAEs with LZP were sedation and somnolence, and with BRV were dizziness, headache, and nausea); these TEAEs were as expected for each drug. In patients receiving BRV, the incidences of TEAEs did not appear to be dose dependent. Although patient numbers in this trial were low, the results suggest a possible role of BRV in the acute treatment of increased seizure activity.

A recent scoping review showed that IV BRV was effective and well tolerated in patients with acute seizures in hospital and critical care settings, with low incidences of TEAEs related to behavioral disorders [52]. In addition, several studies suggest that IV BRV reduces seizures and is well tolerated in patients with status epilepticus [52]. In a cohort of 97 patients treated in neurology units, IV BRV was well tolerated for the treatment of seizure clusters, and early administration was associated with a lower risk of evolution into status epilepticus [53].

Real-World Studies

BRV was effective and well tolerated in a large analysis (n = 1644) of patient records from multiple independent non-interventional studies of highly drug-resistant epilepsy patients treated with BRV (EXPERIENCE/EPD332) in routine clinical practice [54]. Patients had failed a median of five prior ASMs and 92.2% of patients had focal-onset seizures. At 12 months, BRV retention was 71.1%, ≥ 50% seizure reduction was achieved in 36.9% of patients, seizure freedom (defined as no seizures recorded within 3 months prior to the timepoint) in 14.9%, and continuous seizure freedom (defined as no seizures recorded since baseline) in 11.7%. TEAEs (since prior visit) were reported in 25.6% (n = 1542), 14.2% (n = 1376), and 9.3% (n = 1232) of patients at 3, 6, and 12 months, respectively, and 18.1%, 15.9%, and 9.6% of patients (n = 540) discontinued because of tolerability at 3, 6, and 12 months, respectively. Most TEAEs reported at 12 months were of mild (44.9%) or moderate (48.7%) severity, and the most frequently reported TEAEs were somnolence, dizziness, irritability, and fatigue.

For the subgroup analyses by seizure type at baseline, there were 861 patients with focal-onset seizures without secondary generalization, 678 patients with focal-onset seizures with secondary generalization, and 162 patients with generalized-onset seizures [54]. At 12 months, BRV retention was 72.1% in patients with focal-onset seizures without secondary generalization, 71.3% in patients with focal-onset seizures with secondary generalization, and 73.1% in patients with generalized-onset seizures. The proportions of patients with ≥ 50% seizure reduction, seizure freedom, and continuous seizure freedom were 40.4%, 12.1%, and 7.5%, respectively, in patients with focal-onset seizures without secondary generalization; 34.0%, 18.1%, and 16.7% in patients with focal-onset seizures with secondary generalization; and 24.0%, 18.8%, and 15.6% in patients with generalized-onset seizures. At 12 months, TEAEs (since prior visit) were reported by 10.0% of patients with focal-onset seizures without secondary generalization, 9.7% of patients with focal-onset seizures with secondary generalization, and 4.0% of patients with generalized-onset seizures.

Subgroup analyses by BRV treatment type included 45 patients on monotherapy and 1599 patients on polytherapy [54]. At 12 months, BRV retention was 77.3% in patients on monotherapy and 71.0% in patients on polytherapy. The proportions of patients with ≥ 50% seizure reduction, seizure freedom, and continuous seizure freedom were 30.8%, 36.0%, and 28.0%, respectively, in patients on monotherapy and 37.0%, 14.5%, and 11.3%, respectively, in patients on polytherapy. The incidence of TEAEs at 12 months was 3.8% with monotherapy versus 9.5% with polytherapy.

Subgroup analyses by ASM switch at baseline included 709 patients who switched from LEV to BRV and 887 patients who switched from other ASMs to BRV [54]. The most common reasons for switching from LEV to BRV (patients with data, n = 583) were lack of effectiveness (39.8%), tolerability unrelated to behavioral adverse events (BAEs) (38.3%), and BAEs (17.7%) (reasons were not mutually exclusive). At 12 months, BRV retention was 72.1% and 69.7% in patients switching from LEV and other ASMs, respectively. The proportions of patients with ≥ 50% seizure reduction, seizure freedom, and continuous seizure freedom were 34.6%, 14.9%, and 11.4%, respectively, in patients switching from LEV and 38.3%, 13.9%, and 10.9% in patients switching from other ASMs. TEAE incidence at 12 months was 9.5% versus 9.1% in patients switching from LEV and other ASMs, respectively. The incidences of BAEs were low in patients switching from LEV (irritability 1.3%; aggression 0.8%; n = 525) and patients switching from other ASMs (irritability 0.5%; aggression 0.3%; n = 662).

A multicenter retrospective study (BRIVAFIRST) in Italy assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients (≥ 16 years of age; n = 1029) with epilepsy in clinical practice [55]. BRV was effective and well tolerated over 1 year. At 12 months, 16.4% of patients were seizure-free and 37.2% had a ≥ 50% reduction in seizure frequency. Overall, 30.1% of patients reported adverse events, most commonly (≥ 2.5% of patients) somnolence (6.6%), nervousness/agitation (5.9%), vertigo (3.6%), fatigue (3.1%), and headache (2.6%).

A 12-month, prospective, real-world, noninterventional study in nine European countries (NCT02687711) also evaluated the effectiveness and tolerability of adjunctive BRV in patients ≥ 16 years of age with focal-onset seizures in daily clinical practice (n = 544) [56]. BRV was effective in patients with predominantly difficult-to-treat focal-onset seizures, with 57.7% remaining on BRV treatment for 12 months after starting BRV. Overall, 41.2% of patients experienced TEAEs. Compared with baseline, there was a lower proportion of patients who reported significantly or mildly impaired cognitive performance (EpiTrack) at 12 months (36.1%, 4.9% [n = 61]; baseline (49.3%, 14.8% [n = 142]), whereas there was a higher proportion of patients with average or excellent cognitive performance at 12 months (52.5%, 6.6%) compared with baseline (33.1%, 2.8%) [56]. From baseline to 12 months (n = 61), 23.0% of patients reported significant improvement (an increase of ≥ 4) in total EpiTrack score; 67.2% remained unchanged (a change of − 2 to 3), and 9.8% reported worsening (a decrease of ≥ 3).

Use in Special Populations

Elderly

The intersection of aging and epilepsy brings forth complex medical issues, including cognitive decline, comorbidities, and polypharmacy [57]. These factors complicate diagnosis and management, requiring a tailored approach that considers the specific needs of elderly individuals. Currently, there are limited data assessing BRV outcomes in the elderly. A post hoc analysis of the pooled phase III trials assessed safety, tolerability, and efficacy of adjunctive BRV (50–200 mg/day) in older patients ≥ 65 years of age (n = 32) [58]. TEAEs were reported by 66.7% of patients on BRV (n = 24) and 87.5% on PBO (n = 8), most commonly (≥ 10% of patients on BRV) headache (12.5%; PBO 25.0%), paresthesia (12.5%; PBO 0%), and somnolence (12.5%; PBO 50.0%). Drug-related TEAEs were reported in 54.2% of patients on BRV (PBO 62.5%), a serious TEAE was reported by one patient on BRV, and one patient on BRV discontinued due to TEAEs. Median percent reduction from baseline in focal-onset seizure frequency per 28 days for patients receiving BRV 50 mg/day (n = 4), 100 mg/day (n = 14), and 200 mg/day (n = 6) was 25.5%, 49.6%, and 74.9%, respectively (PBO 14.0%; n = 7), and ≥ 50% responder rates were 25.0%, 50.0%, and 66.7%, respectively (PBO 14.3%). Three patients on BRV and none on PBO were continuously free of all seizures during the trial.

In the EXPERIENCE study, BRV was similarly effective and well tolerated in the elderly (≥ 65 years of age; n = 147) and younger patients (≥ 16 to < 65 years of age; n = 1497) [59]. Numerically higher effectiveness was seen in the elderly versus the younger subgroup at 12 months: ≥ 50% responder rates of 46.5% versus 36.0%, seizure freedom rates of 26.0% versus 13.8%, and continuous seizure freedom rates of 22.0% versus 10.7%. The incidence of TEAEs (since prior visit) at 12 months was similar in both age groups (7.7% versus 9.5%).

A subgroup analysis of the BRIVAFIRST study assessed the effectiveness and tolerability of adjunctive BRV in older patients (≥ 65 years of age) with epilepsy in clinical practice [60]. BRV was effective and had good tolerability in older patients with uncontrolled focal seizures. At 12 months, 31.5% of older patients (n = 111) versus 14.6% of younger patients (< 65 years of age; n = 918) were seizure-free, and 44.1% of older versus 36.4% of younger patients had a ≥ 50% reduction in seizure frequency. Adverse events were reported by 24.2% of older (n = 95) versus 30.8% of younger patients (n = 782), most commonly (≥ 3% of patients) somnolence, nervousness/agitation, vertigo, and fatigue in both subgroups.

Pregnancy

Only limited data are available on the use of BRV in pregnant women [9, 10]. No data exist on placental transfer in humans, but BRV was shown to cross the placenta in rats. The potential risk for humans is unknown. In animal studies of BRV, a teratogenic potential was not detected.

Pediatrics

In a phase II, open-label trial (NCT00422422), BRV oral solution (0.8–4.0 mg/kg/day) was generally well tolerated and exhibited linear PK in pediatric patients (1 month to < 16 years of age) with epilepsy [61]. In a phase III, open-label extension trial (NCT01364597), the long-term safety, tolerability, and efficacy of adjunctive BRV was established up to 9.5 years in pediatric patients (aged 1 month to < 17 years of age) with epilepsy [62]. TEAEs occurred in 93.4% of patients and were considered drug related by the investigator in 30.7% of patients. The most commonly reported drug-related TEAEs (≥ 3% of patients) were somnolence (4.7%), decreased appetite (4.3%), aggression (3.9%), and fatigue (3.5%). The median decrease in 28-day adjusted focal seizure frequency was 62.9% and 96.9% in patients ≥ 2 years and < 2 years of age, respectively. A ≥ 50% response in all seizures was achieved by 50.9% and 68.2% of patients ≥ 2 years and < 2 years of age, respectively. Kaplan-Meier estimated treatment retention was 72.7%, 64.5%, 57.8%, 53.3%, 50.1%, and 44.8% at 1, 2, 3, 4, 5, and 6 years, respectively. Behavior and cognitive functioning scores were generally stable or slightly improved with BRV [62].

In a subgroup of pediatric patients (< 16 years of age; n = 66) in the EXPERIENCE study, BRV was effective and well tolerated [63]. At 12 months, the ≥ 50% responder rate was 31.3%, 15.2% of patients were seizure-free, and 12.1% of patients were continuously seizure-free. TEAEs (since prior visit) were reported in 4.8% of patients at 12 months.

Psychiatric and Behavioral Comorbid Conditions

The intricate interplay between epilepsy and mental health challenges, such as depression, anxiety, or cognitive impairments, often leads to a complex clinical picture that demands specialized attention [64].

In a phase III, open-label trial (N01395; NCT01653262) in patients receiving LEV who switched to BRV (50–200 mg/day) because of non-psychotic BAEs, 93.1% of patients had clinically meaningful reductions in BAEs, suggesting that patients who experience BAEs with LEV treatment may benefit from a switch to BRV [65]. A systematic review of BAEs (irritability, anger, aggression) in patients with epilepsy reported that switching from LEV to BRV led to improvement in BAEs in 33.3–83.0% of patients [66].

Subgroup analyses of epilepsy patients with psychiatric comorbidities (PC) and cognitive or learning disability (CLD) in the EXPERIENCE study demonstrated that BRV was effective and well tolerated in these patients [67]. These subgroup analyses included 403 patients with and 1232 patients without CLD at baseline. At 12 months, ≥ 50% responder rates were achieved in 35.6% and 37.4% of patients with and without CLD, respectively, seizure freedom was achieved in 7.9% and 17.9% of patients with and without CLD, respectively, and continuous seizure freedom was achieved in 5.7% and 14.2% of patients with and without CLD, respectively. The incidence of TEAEs (since previous visit) at 12 months was similar in patients with (11.3%) and without CLD (8.7%). Interestingly, the percentage of patients reporting cognitive TEAEs was similar between patients who reported CLD or not at baseline (1.1% versus 0.8%), suggesting that BRV does not trigger cognitive TEAEs in patients with this comorbidity. Six hundred five patients had PC at baseline while 1011 patients did not. At 12 months, ≥ 50% responder rates occurred in 38.7% and 36.1% of patients with and without PC, respectively, seizure freedom was achieved in 16.0% and 14.4% of patients with and without PC, respectively, and continuous seizure freedom was achieved in 31.7% and 10.4% of patients with and without PC, respectively. The incidence of TEAEs (since prior visit) at 12 months was similar in patients with (10.0%) and without PC (8.8%). The incidence of psychiatric TEAEs was also similar in patients with and without PC (2.7% versus 2.5%), suggesting that BRV does not exacerbate preexisting PC.

Etiologies of Acquired Epilepsies

Unlike those with idiopathic epilepsy, patients with acquired forms often have to contend with specific underlying issues that complicate treatment strategies.

A subgroup analysis of the BRIVAFIRST study assessed the effectiveness and tolerability of adjunctive BRV in patients with post-stroke epilepsy (PSE) (n = 75) [68]. Patients had a median age of 57 years. At 12 months, 34.7% of patients with PSE were seizure-free and 42.7% of patients had a ≥ 50% reduction in seizure frequency. Adverse events were reported by 20.3% of patients, and all events were mild (84.6%) or moderate (15.4%).

Additional subgroup analyses from the EXPERIENCE study demonstrated that BRV was well tolerated and effective in patients with different etiologies: PSE, brain-tumor related epilepsy (BTRE), and traumatic brain injury-related epilepsy (TBIE) [67]. These subgroup analyses included 51 patients with PSE at baseline and 1397 patients without PSE at baseline. At 12 months, ≥ 50% responder rates were 41.7% and 36.7% in patients with and without PSE, respectively, seizure freedom was achieved in 35.3% and 15.2% of patients with and without PSE, respectively, and continuous seizure freedom was achieved in 29.4% and 12.1% of patients with and without PSE, respectively. The incidence of TEAEs (since prior visit) at 12 months were 16.7% in patients with and 7.9% in patients without PSE. The analysis included 68 patients with and 1380 patients without BTRE at baseline. At 12 months, ≥ 50% responder rates were 34.1% and 37.0% in patients with and without BTRE, respectively, seizure freedom was achieved in 18.2% and 15.8% of patients with and without BTRE, respectively, and continuous seizure freedom was achieved in 11.4% and 12.9% of patients with and without BTRE, respectively. The incidence of TEAEs (since prior visit) at 12 months were 12.5% in patients with and 8.0% in patients without BTRE. At baseline, 49 patients had TBIE while 1399 did not. At 12 months, ≥ 50% responder rates were 50.0% and 36.4% in patients with and without TBIE, respectively, seizure freedom was achieved in 17.2% and 15.9% of patients with and without TBIE, respectively, and continuous seizure freedom was achieved in 13.8% and 12.8% of patients with and without TBIE, respectively. The incidences of TEAEs (since prior visit) at 12 months were 3.0% in patients with and 8.4% in patients without TBIE.

Limitations

The primary focus of this review was to present available data about BRV. Studies were identified for inclusion by searching PubMed, supplemented with Google searches and searches of congress abstracts until February 2024 using “brivaracetam” and various other keywords. Because this is a narrative review, the selection of articles was not standardized and did not include exclusion criteria. Therefore, as with other narrative reviews, there is a potential for selection bias.

Conclusion

BRV was developed in an effort to identify new SV2A ligands with higher selectivity and affinity than LEV. BRV’s efficacy, safety profile, favorable PK, lack of DDIs, and ease of use (i.e., lack of titration, availability in three bioequivalent formulations) make it useful in the management of epilepsy. BRV is effective in focal-onset seizures, both as monotherapy and adjunctive therapy. Its favorable tolerability contributes to its appeal in diverse patient populations in which tolerability, adherence, and lack of DDIs are major concerns (e.g., the elderly, pediatric population, patients with psychiatric of cognitive comorbidities, or patients with acquired symptomatic epilepsy). Its rapid blood-brain barrier penetration and fast therapeutic outcome combined with its availability in an IV formulation and bolus administration are advantageous in acute conditions requiring fast seizure resolution. Recently published evidence from daily clinical practice highlight that BRV can offer treatment solutions addressing previously unmet patient needs.