Drug Profile
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Brivaracetam for the treatment of epilepsy in adults Expert Rev. Neurother. 14(4), 361–365 (2014)
Marco Mula Department of Neurology, Epilepsy Group, St George’s Hospital, Blackshaw Road, London SW17 0QT, UK Tel.: +44 208 725 4322 Fax: +44 208 725 4591 [email protected]
Brivaracetam (BRV) is a new antiepileptic drug structurally related to levetiracetam but with a 15 to 30-fold increased affinity for the same molecular target, namely the SV2A ligand. BRV is currently under Phase III development as adjunctive treatment for partial onset seizures but data from some Phase III suggest also potential efficacy for primary generalized seizures. Although two studies are negative for the primary efficacy endpoint, global results seem to suggest a wide spectrum of efficacy for both partial onset and primary generalized seizures and a favourable safety and pharmacokinetic profile. This article is aimed at providing a comprehensive overview of current evidence about BRV in the treatment of epilepsy taking into account emerging concerns regarding clinical trials in epilepsy. KEYWORDS: antiepileptic drugs • brivaracetam • epilepsy
Epilepsy is a common neurological disorder characterized by recurrent spontaneous seizures. Close to 50 million people worldwide suffer from epilepsy with an overall health burden accounting for 0.5% of the global burden of diseases [1] and total annual costs of approximately e15.5 billion in Europe [2] and US $9.5 billion in the USA [3]. Over 40 types of epilepsies have been described, and they are grouped into two main categories: partial-onset (also defined focal or localization related) [4] and generalized-onset epilepsies, the former accounting for about 60% of all adult epilepsy cases [5]. About twothirds of all epilepsy syndromes is fully controlled by current therapies. However, despite the introduction of several new antiepileptic drugs (AEDs), around a third of patients show resistance to treatment. It is, therefore, evident that further research is needed and new compounds are warranted. Brivaracetam (BRV) is a new AED currently under Phase III development. It is the evolution of levetiracetam (LEV), which is structurally related to the nootropic drug piracetam. This review article is aimed at providing a comprehensive overview of current evidence about BRV in the treatment of epilepsy. References were identified by searches of Medline/ PubMed using the key words ‘brivaracetam’ informahealthcare.com
10.1586/14737175.2014.896200
and ‘epilepsy’. Abstracts or other not peerreviewed material (i.e., book chapters) have been excluded. Mechanism of action
BRV is a highly selective and reversible SV2A ligand with a 15- to 30-fold higher affinity than LEV in rat and human brain [6,7]. At therapeutically relevant doses, BRV occupies 80–90% of SV2A within 5–15 min, representing maximal protection against seizures in animal models [6]. The high anticonvulsant activity of BRV compared with LEV, observed in several animal models of epilepsy [7], seems not simply explained by the high affinity to SV2A but probably resides in the way BRV modulates SV2A function. In this regard, it is important to point that the exact role of SV2A in synaptic transmission is not completely clear. However, a strong functional correlation has been established between SV2A binding and the anticonvulsant potency for both focal and generalized seizures [8]. In addition, BRV displays inhibitory activity at neuronal voltage-dependent sodium channels [9]. How much such effect contributes to the anticonvulsant potency of BRV is not fully elucidated yet. At any rate, the sodium channel modulation represents a distinct activity of BRV compared with LEV [10] and might explain why BRV, and not LEV, is also active
2014 Informa UK Ltd
ISSN 1473-7175
361
Drug Profile
Mula
Table 1. Efficacy results for Phases II and III studies of brivaracetam in focal epilepsies (median percentage reduction from baseline in partial-onset seizures frequency per week during the treatment period). Dose
Phase IIb NO1193 (%)
NO1114 (%)
NO1252 (%)
NO1253 (%)
NO1254‡ (%)
Placebo
21.7
16.3
17.0
17.8
18.9
5 mg
29.9
–
–
20.0
–
20 mg
42.6
–
30.0
22.5
–
50 mg Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 02/10/15 For personal use only.
Phase III
†
53.1
34.9
26.8 †
†
30.5
–
100 mg
–
–
32.5
–
–
150 mg
–
28.3
–
–
26.9
†
Statistically significant. ‡ Flexible-dose study (brivaracetam 20–150 mg).
on the maximal electroshock-induced model [7]. It appears evident that further studies are needed to fully understand the neurobiology of BRV. Direct or indirect activity with other neurotransmitter systems such as dopamine and GABA can be hypothesized [11–13], but proper studies are needed. Pharmacokinetic profile
BRV has nearly complete bioavailability after oral administration [14]. Single-dose studies under fasting conditions show a tmax of about 1 h and a dose proportional Cmax for a dose range between 10 and 1400 mg [15]. However, area under the curve deviates from dose linearity above 600 mg, and high fat meals seem to slightly delay tmax to 3 h and to slightly decrease Cmax of about 28% [15]. BRV is less than 20% protein bound with a volume of distribution of 0.6 l/kg [16]. BRV has a half-life of about 8 h [15,16] and is primarily metabolized via hydrolysis of the acetamide group and CYP2C19-mediated hydroxylation [17], but all metabolites are not pharmacologically active [14]. CYP2C19 mutations affect slightly the BRV metabolism with a 30% decreased clearance which does not seem to be clinically relevant [18]. Patients with severe renal impairment without dialysis require no major adjustments in dosage [19]. However, subjects with severe hepatic failure (Child Plugh class C) present a 50–60% increase in plasma concentrations compared with healthy controls [20]. Data from add-on trials show no significant effect of BRV on plasma concentrations of concomitant AEDs such as lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid or zonisamide [17]. However, in the case of carbamazepine (CBZ), concentrations of the 10,11-epoxide metabolite seem to be increased for BRV doses ‡50 mg/day, suggesting that monitoring for potential CBZ-associated adverse effects is indicated when BRV is added on to a high-dose stabilized CBZ regimen [17,18]. Preliminary data suggest no significant interactions with oral contraceptives [21]. Efficacy
A number of Phases II and III studies for BRV in patients with focal epilepsies have been published (TABLE 1). Two Phase IIb studies investigated the efficacy of BRV across different dosages [22,23]. In study NO1193, patients aged 362
16–65 years with focal epilepsy experiencing ‡4 partial-onset seizures (POS) during 4-week baseline despite 1–2 concomitant AEDs, are randomized (1:1:1:1) to placebo (PBO), BRV 5, 20 or 50 mg/day, administered two-times a day without uptitration during a 7-week treatment period [22]. The primary efficacy endpoint (seizure frequency per week during the treatment period relative to placebo) is statistically significant only for BRV 50 mg/day, but the secondary efficacy endpoint (‡50% responder rate and median percentage reduction from baseline in POS frequency per week) provides supportive evidence for the 20 mg/day [22]. Study N01114 assesses efficacy of BRV at dosages of 50 and 150 mg/day, showing no statistically significant difference compared with PBO for the primary efficacy endpoint [23]. To further evaluate BRV as an adjunctive therapy for patients with focal epilepsy, three Phase III studies have been completed, two of which use a fixed-dose design and include patients with focal epilepsy only [24,25], while the third study adopts a flexible dose design and also enrolls patients with generalized seizures [26]. In study NO1252, the efficacy of BRV (20 mg, 50 mg and 100 mg/day) is investigated against PBO in patients aged 16–70 years with uncontrolled POS with/ without secondary generalization, despite treatment with one to two concomitant AEDs at a stable and optimal dosage [24]. The primary efficacy endpoint (percentage reduction over PBO in baseline-adjusted focal seizure frequency per week over the 12-week treatment period) is statistically significant only for BRV 100 mg/day [24]. In study NO1253, patients aged 16–70 years are randomized (1:1:1:1) to PBO or BRV 5 mg, 20 mg or 50 mg/day without uptitration [25]. The primary efficacy endpoint (percentage reduction over PBO in baselineadjusted POS frequency per week during the 12-week treatment period) is statistically significant only for BRV 50 mg. Finally, study NO1254 adopts a flexible dose design in adults (16–70 years) with uncontrolled epilepsy; however, up to 20% are patients with generalized epilepsies [26]. After a prospective 4-week baseline, patients are randomized (3:1) to BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period followed by another 8-week stable dose maintenance period. During the Expert Rev. Neurother. 14(4), (2014)
BRV for the treatment of epilepsy in adults
16-week treatment period, median percentage reduction from baseline in POS frequency per week is not statistically significant, while 50% responder rate is 30.3% for BRV and 16.7% for PBO (p = 0.006). In addition, results of this study support a potential efficacy of adjunctive BRV in adults with generalized epilepsy [26].
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Safety
In general terms, all studies report no difference in the treatment-emergent adverse events (TEAEs) for patients treated with BRV compared with PBO. TEAEs are reported as mild to moderate in severity and mainly characterized by headache, fatigue, nasopharyngitis, nausea, somnolence and dizziness. Phase IIb studies report 2.6% for BRV (5–50 mg) [22] raising up to 67.3% for BRV 150 mg [23]. The two Phase III fixeddose studies show a proportion of patients on BRV reporting at least one TEAE ranging between 56.6 and 79.0%, with a high proportion of completers (84.5–94.0%) and a low discontinuation rate (4.0–8.2%) [24,25]. These data are similar to those reported by the Phase III flexible-dose trial, where patients reporting at least one TEAE are in the region of 66.0% for BRV against 65.3% of PBO subjects [26]. The most commonly reported TEAEs leading to discontinuation are psychiatric adverse events (PAEs). Phase III studies report a detailed account of PAEs represented mainly by aggression, anxiety, irritability, depression and insomnia [24,25]. PAEs seem to occur in a low proportion of patients (3.0, 4.0 and 3.0% for BRV 20 mg, 50 mg and 100 mg/day) [24] and are described as occurring not more frequently than with PBO: insomnia (BRV 4.0% vs PBO 2.0%), depression (BRV 3.7% vs PBO 1.0%), irritability (BRV 3.7% vs PBO 2.0%), anxiety (BRV 1.7% vs PBO 1.0%), agitation (BRV 1.0% vs PBO 0%) and depressed mood (BRV 1.0% vs PBO 0%) [25]. Finally, one study investigated the potential impact of BRV on qT interval, demonstrating no significant effects on cardiac repolarization [27]. Discussion
Available data seem to suggest that BRV is an effective AED with a favorable safety and pharmacokinetic profile. Currently, the therapeutic window seems to be between 50 mg and 150 mg daily, and the spectrum of efficacy is not only on POS but also on primary generalized ones. This is further supported by a single-blind, placebo-controlled trial showing a specific suppressing effect on the generalized paroxysmal EEG response in patients with photosensitive epilepsy [28]. On the other hand, it is important to point out that a number of issues need to be further elucidated. In fact, it has to be noted that two trials failed to show any difference with PBO for the primary endpoint [23,26]. The issue of contradictory results from clinical trials of AEDs reached great attention during recent years, representing a widely distributed phenomenon. In fact, after 30 years of clinical trials, it is becoming evident that a number of concerns need to be taken into account and, currently, new problems are emerging that may affect the informahealthcare.com
Drug Profile
potency of clinical trials [29]. It is beyond the aim of this paper to discuss such issue that has been examined elsewhere [29]; nevertheless, it is also for this reason that BRV is still under Phase III development with further ongoing trials to evaluate the long-term efficacy and tolerability. At the moment, four trials are running: N01358 is a randomized, double-blind, placebo-controlled, fixed-dose study in adults with POS inadequately controlled with one or two concomitant AEDs to evaluate the efficacy and safety of BRV 100 mg and 200 mg/day. NO1125 is an open-label, multicenter, flexible-dose (up to a maximum dose of 150 mg/day) long-term follow-up study. NO1258 is a multicenter, open-label, adjunctive therapy randomized study of BRV 200 mg/day administered intravenously as an infusion or bolus in adults with POS or generalized seizures. Finally, NO1263 is a multicenter, open-label study to evaluate the steady-state pharmacokinetics, safety and preliminary efficacy of adjunctive BRV in children with any type of epilepsy aged from at least 1 month to 16 years. BRV dose is adjusted by body weight to achieve similar exposure to adults at doses of 50–200 mg/day. Results of these studies will be crucial not only for regulatory purposes, but mostly to have a clear profile of BRV in terms of efficacy, safety and range of applications. Regulatory studies for AEDs basically require a statistically significant seizure reduction in add-on therapy, against PBO, using a double-blind, randomized, controlled design. There are slight regulatory differences between the USA and Europe in quantifying such reduction, namely median reduction in seizure frequency for the former and ‡50% reduction in seizure frequency for the latter. However, a recent document of the International League Against Epilepsy proposed that sustained seizure freedom represents the only efficacy outcome measure consistently associated with improved quality of life [30]. Using this measure, a systematic review and meta-analysis of placebocontrolled studies of AEDs demonstrated that the overall pooled risk difference in favor of new AEDs compared with placebo was only 6% (95% CI: 4–8%) with a number needed to treat of 16 [31]. What the position of BRV is in the future pharmacological armamentarium for epilepsy, it will be clarified by noninferiority trials and ad hoc studies. Obviously, an AED with a wide spectrum of efficacy against focal and generalized seizures, with a low potential for interactions and multiple formulations such as the intravenous, has all characteristics to be successful. A systematic review of 15 randomized controlled trials of newer AEDs suggests that BRV might be more effective than all other newer AEDs, namely eslicarbazepine, retigabine, carisbamate, lacosamide and perampanel [32]. Another relevant issue is related to PAEs. Published data from Phase III trials report no significant differences between BRV and PBO. However, it has to be acknowledged that regulatory trials do not represent the best source of information for PAEs [33,34]. In fact, clinical trials often require fixed-drug doses and specific titration schedules, neither of which is used in clinical practice. Moreover, patients with psychiatric disorders are often excluded, eliminating an important variable. Finally, 363
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Drug Profile
Mula
patients are followed up for short time periods, and evaluations are conducted too soon to detect the occurrence of effects that might appear later. For all these reasons, ‘real life’ data from Phase IV studies will be probably informative. This is even more relevant considering the high prevalence of TEAEs with PBO (around 60%), which definitely reduces the strength of available safety information on BRV. This point is strictly related to the previously mentioned concerns about data from current clinical trials in epilepsy [29]. If some data on PAEs are available but not definite, then data on cognition are more than limited. In general terms, similarities with LEV would suggest a favorable cognitive profile, but ad hoc studies are lacking. At present, there is only a single randomized, double-blind, placebo-controlled, four-way, crossover study comparing cognitive effects of the acute dosing of BRV 10 mg, LEV 500 mg, lorazepam 2 mg and PBO in healthy subjects [35]. The authors report no difference among BRV 10 mg, LEV 500 mg and PBO. However, the dose of BRV is definitely low, limiting the usefulness of these findings. Expert commentary
BRV is currently under Phase III development for the adjunctive therapy of POS. Nevertheless, the mechanism of action and preliminary data suggest a wide spectrum of efficacy
with an interesting potential in primary generalized seizures. Phases II and III studies show a favorable safety and pharmacokinetic profile. However, such preliminary results need to be confirmed by future studies; in particular, data from on-going Phase III trials will be of relevance. Five-year view
A number of issues need to be clarified in future studies, namely the therapeutic window (especially the maximum dose), efficacy and safety in children and the possibility of overnight conversion from LEV. In addition, data in primary generalized seizures will have a great impact. Finally, all data regarding the efficacy of the intravenous formulation in recurrent seizures and status epilepticus will be of great value. Financial & competing interests disclosure
M Mula has received, in the past, travel grants or consultancy fees from Pfizer and UCB Pharma. When the paper was written, the author’ s affiliation was the following: Division of Neurology, Trinity Hospital, Borgomanero, Italy. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript other than those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Brivaracetam is a new antiepileptic drug structurally related to levetiracetam but with a 15- to 30-fold increased affinity for the same molecular target, namely the SV2A ligand. • Brivaracetam is currently under Phase III development as adjunctive treatment for partial-onset seizures, but data from Phase IIb and some Phase III studies are already available. • Available results seem to suggest a favorable safety and pharmacokinetic profile and a therapeutic window between 50 and 150 mg daily. • The mechanism of action and preliminary efficacy results from Phase III trials suggest a wide spectrum of efficacy with a potential in primary generalized seizures.
Classification and Terminology. Epilepsia 2001;42(6):796-803
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Zona C, Pieri M, Carunchio I, et al. Brivaracetam (ucb 34714) inhibits Na(+) current in rat cortical neurons in culture. Epilepsy Res 2010;88(1):46-54
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Rolan P, Sargentini-Maier ML, Pigeolet E, Stockis A. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men. Br J Clin Pharmacol 2008;66(1):71-5
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Sargentini-Maier ML, Sokalski A, Boulanger P, et al. Brivaracetam disposition in renal impairment. J Clin Pharmacol 2012;52(12):1927-33 Stockis A, Sargentini-Maier ML, Horsmans Y. Brivaracetam disposition in mild to severe hepatic impairment. J Clin Pharmacol 2013;53(6):633-41
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Stockis A, Rolan P. Effect of brivaracetam (400 mg/day) on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive in healthy women. J Clin Pharmacol 2013;53(12):1313-21 French JA, Costantini C, Brodsky A, Von Rosenstiel P. Adjunctive brivaracetam for refractory partial-onset seizures: a randomized, controlled trial. Neurology 2010;75(6):519-25 Van Paesschen W, Hirsch E, Johnson M, et al. Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial-onset seizures: a phase IIb, randomized, controlled trial. Epilepsia 2013; 54(1):89-97 Ryvlin P, Werhahn KJ, Blaszczyk B, et al. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double-blind, randomized, placebo-controlled trial. Epilepsia 2014; 55(1):47-5 Biton V, Berkovic SF, Abou-Khalil B, et al. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia 2014; 55(1):57-66 Kwan P, Trinka E, Van Paesschen W, et al. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia 2014;55(1):38-46 Rosillon D, Astruc B, Hulhoven R, et al. Effect of brivaracetam on cardiac repolarisation – a thorough QT study. Curr Med Res Opin 2008;24(8):2327-37 Kasteleijn-Nolst Trenite DG, Genton P, Parain D, et al. Evaluation of brivaracetam,
Drug Profile
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Gao L, Xia L, Zhao FL, Li SC. Clinical efficacy and safety of the newer antiepileptic drugs as adjunctive treatment in adults with refractory partial-onset epilepsy: a meta-analysis of randomized placebo-controlled trials. Epilepsy Res 2013; 103(1):31-44
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Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf 2007;30(7):555-67
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365
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Brivaracetam for the treatment of epilepsy in adults Expert Rev. Neurother. 14(4), 361–365 (2014)
Marco Mula Department of Neurology, Epilepsy Group, St George’s Hospital, Blackshaw Road, London SW17 0QT, UK Tel.: +44 208 725 4322 Fax: +44 208 725 4591 [email protected]
Brivaracetam (BRV) is a new antiepileptic drug structurally related to levetiracetam but with a 15 to 30-fold increased affinity for the same molecular target, namely the SV2A ligand. BRV is currently under Phase III development as adjunctive treatment for partial onset seizures but data from some Phase III suggest also potential efficacy for primary generalized seizures. Although two studies are negative for the primary efficacy endpoint, global results seem to suggest a wide spectrum of efficacy for both partial onset and primary generalized seizures and a favourable safety and pharmacokinetic profile. This article is aimed at providing a comprehensive overview of current evidence about BRV in the treatment of epilepsy taking into account emerging concerns regarding clinical trials in epilepsy. KEYWORDS: antiepileptic drugs • brivaracetam • epilepsy
Epilepsy is a common neurological disorder characterized by recurrent spontaneous seizures. Close to 50 million people worldwide suffer from epilepsy with an overall health burden accounting for 0.5% of the global burden of diseases [1] and total annual costs of approximately e15.5 billion in Europe [2] and US $9.5 billion in the USA [3]. Over 40 types of epilepsies have been described, and they are grouped into two main categories: partial-onset (also defined focal or localization related) [4] and generalized-onset epilepsies, the former accounting for about 60% of all adult epilepsy cases [5]. About twothirds of all epilepsy syndromes is fully controlled by current therapies. However, despite the introduction of several new antiepileptic drugs (AEDs), around a third of patients show resistance to treatment. It is, therefore, evident that further research is needed and new compounds are warranted. Brivaracetam (BRV) is a new AED currently under Phase III development. It is the evolution of levetiracetam (LEV), which is structurally related to the nootropic drug piracetam. This review article is aimed at providing a comprehensive overview of current evidence about BRV in the treatment of epilepsy. References were identified by searches of Medline/ PubMed using the key words ‘brivaracetam’ informahealthcare.com
10.1586/14737175.2014.896200
and ‘epilepsy’. Abstracts or other not peerreviewed material (i.e., book chapters) have been excluded. Mechanism of action
BRV is a highly selective and reversible SV2A ligand with a 15- to 30-fold higher affinity than LEV in rat and human brain [6,7]. At therapeutically relevant doses, BRV occupies 80–90% of SV2A within 5–15 min, representing maximal protection against seizures in animal models [6]. The high anticonvulsant activity of BRV compared with LEV, observed in several animal models of epilepsy [7], seems not simply explained by the high affinity to SV2A but probably resides in the way BRV modulates SV2A function. In this regard, it is important to point that the exact role of SV2A in synaptic transmission is not completely clear. However, a strong functional correlation has been established between SV2A binding and the anticonvulsant potency for both focal and generalized seizures [8]. In addition, BRV displays inhibitory activity at neuronal voltage-dependent sodium channels [9]. How much such effect contributes to the anticonvulsant potency of BRV is not fully elucidated yet. At any rate, the sodium channel modulation represents a distinct activity of BRV compared with LEV [10] and might explain why BRV, and not LEV, is also active
2014 Informa UK Ltd
ISSN 1473-7175
361
Drug Profile
Mula
Table 1. Efficacy results for Phases II and III studies of brivaracetam in focal epilepsies (median percentage reduction from baseline in partial-onset seizures frequency per week during the treatment period). Dose
Phase IIb NO1193 (%)
NO1114 (%)
NO1252 (%)
NO1253 (%)
NO1254‡ (%)
Placebo
21.7
16.3
17.0
17.8
18.9
5 mg
29.9
–
–
20.0
–
20 mg
42.6
–
30.0
22.5
–
50 mg Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 02/10/15 For personal use only.
Phase III
†
53.1
34.9
26.8 †
†
30.5
–
100 mg
–
–
32.5
–
–
150 mg
–
28.3
–
–
26.9
†
Statistically significant. ‡ Flexible-dose study (brivaracetam 20–150 mg).
on the maximal electroshock-induced model [7]. It appears evident that further studies are needed to fully understand the neurobiology of BRV. Direct or indirect activity with other neurotransmitter systems such as dopamine and GABA can be hypothesized [11–13], but proper studies are needed. Pharmacokinetic profile
BRV has nearly complete bioavailability after oral administration [14]. Single-dose studies under fasting conditions show a tmax of about 1 h and a dose proportional Cmax for a dose range between 10 and 1400 mg [15]. However, area under the curve deviates from dose linearity above 600 mg, and high fat meals seem to slightly delay tmax to 3 h and to slightly decrease Cmax of about 28% [15]. BRV is less than 20% protein bound with a volume of distribution of 0.6 l/kg [16]. BRV has a half-life of about 8 h [15,16] and is primarily metabolized via hydrolysis of the acetamide group and CYP2C19-mediated hydroxylation [17], but all metabolites are not pharmacologically active [14]. CYP2C19 mutations affect slightly the BRV metabolism with a 30% decreased clearance which does not seem to be clinically relevant [18]. Patients with severe renal impairment without dialysis require no major adjustments in dosage [19]. However, subjects with severe hepatic failure (Child Plugh class C) present a 50–60% increase in plasma concentrations compared with healthy controls [20]. Data from add-on trials show no significant effect of BRV on plasma concentrations of concomitant AEDs such as lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid or zonisamide [17]. However, in the case of carbamazepine (CBZ), concentrations of the 10,11-epoxide metabolite seem to be increased for BRV doses ‡50 mg/day, suggesting that monitoring for potential CBZ-associated adverse effects is indicated when BRV is added on to a high-dose stabilized CBZ regimen [17,18]. Preliminary data suggest no significant interactions with oral contraceptives [21]. Efficacy
A number of Phases II and III studies for BRV in patients with focal epilepsies have been published (TABLE 1). Two Phase IIb studies investigated the efficacy of BRV across different dosages [22,23]. In study NO1193, patients aged 362
16–65 years with focal epilepsy experiencing ‡4 partial-onset seizures (POS) during 4-week baseline despite 1–2 concomitant AEDs, are randomized (1:1:1:1) to placebo (PBO), BRV 5, 20 or 50 mg/day, administered two-times a day without uptitration during a 7-week treatment period [22]. The primary efficacy endpoint (seizure frequency per week during the treatment period relative to placebo) is statistically significant only for BRV 50 mg/day, but the secondary efficacy endpoint (‡50% responder rate and median percentage reduction from baseline in POS frequency per week) provides supportive evidence for the 20 mg/day [22]. Study N01114 assesses efficacy of BRV at dosages of 50 and 150 mg/day, showing no statistically significant difference compared with PBO for the primary efficacy endpoint [23]. To further evaluate BRV as an adjunctive therapy for patients with focal epilepsy, three Phase III studies have been completed, two of which use a fixed-dose design and include patients with focal epilepsy only [24,25], while the third study adopts a flexible dose design and also enrolls patients with generalized seizures [26]. In study NO1252, the efficacy of BRV (20 mg, 50 mg and 100 mg/day) is investigated against PBO in patients aged 16–70 years with uncontrolled POS with/ without secondary generalization, despite treatment with one to two concomitant AEDs at a stable and optimal dosage [24]. The primary efficacy endpoint (percentage reduction over PBO in baseline-adjusted focal seizure frequency per week over the 12-week treatment period) is statistically significant only for BRV 100 mg/day [24]. In study NO1253, patients aged 16–70 years are randomized (1:1:1:1) to PBO or BRV 5 mg, 20 mg or 50 mg/day without uptitration [25]. The primary efficacy endpoint (percentage reduction over PBO in baselineadjusted POS frequency per week during the 12-week treatment period) is statistically significant only for BRV 50 mg. Finally, study NO1254 adopts a flexible dose design in adults (16–70 years) with uncontrolled epilepsy; however, up to 20% are patients with generalized epilepsies [26]. After a prospective 4-week baseline, patients are randomized (3:1) to BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period followed by another 8-week stable dose maintenance period. During the Expert Rev. Neurother. 14(4), (2014)
BRV for the treatment of epilepsy in adults
16-week treatment period, median percentage reduction from baseline in POS frequency per week is not statistically significant, while 50% responder rate is 30.3% for BRV and 16.7% for PBO (p = 0.006). In addition, results of this study support a potential efficacy of adjunctive BRV in adults with generalized epilepsy [26].
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Safety
In general terms, all studies report no difference in the treatment-emergent adverse events (TEAEs) for patients treated with BRV compared with PBO. TEAEs are reported as mild to moderate in severity and mainly characterized by headache, fatigue, nasopharyngitis, nausea, somnolence and dizziness. Phase IIb studies report 2.6% for BRV (5–50 mg) [22] raising up to 67.3% for BRV 150 mg [23]. The two Phase III fixeddose studies show a proportion of patients on BRV reporting at least one TEAE ranging between 56.6 and 79.0%, with a high proportion of completers (84.5–94.0%) and a low discontinuation rate (4.0–8.2%) [24,25]. These data are similar to those reported by the Phase III flexible-dose trial, where patients reporting at least one TEAE are in the region of 66.0% for BRV against 65.3% of PBO subjects [26]. The most commonly reported TEAEs leading to discontinuation are psychiatric adverse events (PAEs). Phase III studies report a detailed account of PAEs represented mainly by aggression, anxiety, irritability, depression and insomnia [24,25]. PAEs seem to occur in a low proportion of patients (3.0, 4.0 and 3.0% for BRV 20 mg, 50 mg and 100 mg/day) [24] and are described as occurring not more frequently than with PBO: insomnia (BRV 4.0% vs PBO 2.0%), depression (BRV 3.7% vs PBO 1.0%), irritability (BRV 3.7% vs PBO 2.0%), anxiety (BRV 1.7% vs PBO 1.0%), agitation (BRV 1.0% vs PBO 0%) and depressed mood (BRV 1.0% vs PBO 0%) [25]. Finally, one study investigated the potential impact of BRV on qT interval, demonstrating no significant effects on cardiac repolarization [27]. Discussion
Available data seem to suggest that BRV is an effective AED with a favorable safety and pharmacokinetic profile. Currently, the therapeutic window seems to be between 50 mg and 150 mg daily, and the spectrum of efficacy is not only on POS but also on primary generalized ones. This is further supported by a single-blind, placebo-controlled trial showing a specific suppressing effect on the generalized paroxysmal EEG response in patients with photosensitive epilepsy [28]. On the other hand, it is important to point out that a number of issues need to be further elucidated. In fact, it has to be noted that two trials failed to show any difference with PBO for the primary endpoint [23,26]. The issue of contradictory results from clinical trials of AEDs reached great attention during recent years, representing a widely distributed phenomenon. In fact, after 30 years of clinical trials, it is becoming evident that a number of concerns need to be taken into account and, currently, new problems are emerging that may affect the informahealthcare.com
Drug Profile
potency of clinical trials [29]. It is beyond the aim of this paper to discuss such issue that has been examined elsewhere [29]; nevertheless, it is also for this reason that BRV is still under Phase III development with further ongoing trials to evaluate the long-term efficacy and tolerability. At the moment, four trials are running: N01358 is a randomized, double-blind, placebo-controlled, fixed-dose study in adults with POS inadequately controlled with one or two concomitant AEDs to evaluate the efficacy and safety of BRV 100 mg and 200 mg/day. NO1125 is an open-label, multicenter, flexible-dose (up to a maximum dose of 150 mg/day) long-term follow-up study. NO1258 is a multicenter, open-label, adjunctive therapy randomized study of BRV 200 mg/day administered intravenously as an infusion or bolus in adults with POS or generalized seizures. Finally, NO1263 is a multicenter, open-label study to evaluate the steady-state pharmacokinetics, safety and preliminary efficacy of adjunctive BRV in children with any type of epilepsy aged from at least 1 month to 16 years. BRV dose is adjusted by body weight to achieve similar exposure to adults at doses of 50–200 mg/day. Results of these studies will be crucial not only for regulatory purposes, but mostly to have a clear profile of BRV in terms of efficacy, safety and range of applications. Regulatory studies for AEDs basically require a statistically significant seizure reduction in add-on therapy, against PBO, using a double-blind, randomized, controlled design. There are slight regulatory differences between the USA and Europe in quantifying such reduction, namely median reduction in seizure frequency for the former and ‡50% reduction in seizure frequency for the latter. However, a recent document of the International League Against Epilepsy proposed that sustained seizure freedom represents the only efficacy outcome measure consistently associated with improved quality of life [30]. Using this measure, a systematic review and meta-analysis of placebocontrolled studies of AEDs demonstrated that the overall pooled risk difference in favor of new AEDs compared with placebo was only 6% (95% CI: 4–8%) with a number needed to treat of 16 [31]. What the position of BRV is in the future pharmacological armamentarium for epilepsy, it will be clarified by noninferiority trials and ad hoc studies. Obviously, an AED with a wide spectrum of efficacy against focal and generalized seizures, with a low potential for interactions and multiple formulations such as the intravenous, has all characteristics to be successful. A systematic review of 15 randomized controlled trials of newer AEDs suggests that BRV might be more effective than all other newer AEDs, namely eslicarbazepine, retigabine, carisbamate, lacosamide and perampanel [32]. Another relevant issue is related to PAEs. Published data from Phase III trials report no significant differences between BRV and PBO. However, it has to be acknowledged that regulatory trials do not represent the best source of information for PAEs [33,34]. In fact, clinical trials often require fixed-drug doses and specific titration schedules, neither of which is used in clinical practice. Moreover, patients with psychiatric disorders are often excluded, eliminating an important variable. Finally, 363
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Drug Profile
Mula
patients are followed up for short time periods, and evaluations are conducted too soon to detect the occurrence of effects that might appear later. For all these reasons, ‘real life’ data from Phase IV studies will be probably informative. This is even more relevant considering the high prevalence of TEAEs with PBO (around 60%), which definitely reduces the strength of available safety information on BRV. This point is strictly related to the previously mentioned concerns about data from current clinical trials in epilepsy [29]. If some data on PAEs are available but not definite, then data on cognition are more than limited. In general terms, similarities with LEV would suggest a favorable cognitive profile, but ad hoc studies are lacking. At present, there is only a single randomized, double-blind, placebo-controlled, four-way, crossover study comparing cognitive effects of the acute dosing of BRV 10 mg, LEV 500 mg, lorazepam 2 mg and PBO in healthy subjects [35]. The authors report no difference among BRV 10 mg, LEV 500 mg and PBO. However, the dose of BRV is definitely low, limiting the usefulness of these findings. Expert commentary
BRV is currently under Phase III development for the adjunctive therapy of POS. Nevertheless, the mechanism of action and preliminary data suggest a wide spectrum of efficacy
with an interesting potential in primary generalized seizures. Phases II and III studies show a favorable safety and pharmacokinetic profile. However, such preliminary results need to be confirmed by future studies; in particular, data from on-going Phase III trials will be of relevance. Five-year view
A number of issues need to be clarified in future studies, namely the therapeutic window (especially the maximum dose), efficacy and safety in children and the possibility of overnight conversion from LEV. In addition, data in primary generalized seizures will have a great impact. Finally, all data regarding the efficacy of the intravenous formulation in recurrent seizures and status epilepticus will be of great value. Financial & competing interests disclosure
M Mula has received, in the past, travel grants or consultancy fees from Pfizer and UCB Pharma. When the paper was written, the author’ s affiliation was the following: Division of Neurology, Trinity Hospital, Borgomanero, Italy. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript other than those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Brivaracetam is a new antiepileptic drug structurally related to levetiracetam but with a 15- to 30-fold increased affinity for the same molecular target, namely the SV2A ligand. • Brivaracetam is currently under Phase III development as adjunctive treatment for partial-onset seizures, but data from Phase IIb and some Phase III studies are already available. • Available results seem to suggest a favorable safety and pharmacokinetic profile and a therapeutic window between 50 and 150 mg daily. • The mechanism of action and preliminary efficacy results from Phase III trials suggest a wide spectrum of efficacy with a potential in primary generalized seizures.
Classification and Terminology. Epilepsia 2001;42(6):796-803
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