Abstract
Brivaracetam (BRV) in both the USA and EU was developed as a novel molecule for the adjunctive treatment of partial-onset (focal) seizures in patients ≥16 years of age and as of September 2017 was approved for use as monotherapy in the USA uniquely as an antiseizure medication that may be prescribed without a dose finding uptitration. This article reviews BRV's pharmacology, efficacy, safety and adverse event profiles, along with the relevant and noted regulatory hurdles in the USA and the EU. Available postmarketing data will also be summarized. Approximately 3000 patients were studied over about 9 years in the clinical trial program illustrating that BRV has efficacy at 50–200 mg/day with an acceptable adverse event profile.
Historical notes
Brivaracetam (BRV) is a novel molecule that was discovered and developed by UCB Pharmaceuticals of Brussels, Belgium (www.ucb.com), a global biopharmaceutical company [Citation1–15]. BRV was approved by the EMA and US FDA in January 2016 and February 2016, respectively, initially as an adjunctive agent for the treatment of partial-onset seizures (POS) in patients ≥16 years of age and BRV launched in the USA in May 2016 for that indication [Citation4–8]. Approximately 18 months later by September 2017, BRV was approved by the FDA as monotherapy treatment for POS that may uniquely be prescribed without a dose-finding uptitration [Citation4–8].
This article overviews the historical development of BRV [Citation1–15]. BRV's potential place in the current clinical market, which contains a persistent epidemiology of intractable epilepsy despite the existence of numerous products already available, will be discussed [Citation16–22]. The article summarizes the major neurochemistry and pharmacology of BRV highlighting the relevant preclinical data [Citation23–47]. This work identifies the significance of the clinical trial data and program and overviews the relevant issues surrounding regulatory affairs [Citation43–49]. Safety and tolerability and a review of adverse events or treatment-emergent adverse events (AEs and TEAEs) of BRV are discussed [Citation48–57]. Articles published peri- and postlaunch of BRV are identified highlighting recent developments [Citation58–83].
This article reviews MEDLINE-indexed journals cross-referenced with information available in the public domain regarding the 31 USA and 18 European clinical trials from the FDA and EMA [Citation5,Citation6]. The clinical trial program included approximately 3000 patients along with subsets including intractable patients, patients with and without secondarily generalized seizures, and patients that have had prior exposure to levetiracetam (LEV), a similar molecule already prescribed in the world marketplace [Citation1,Citation2,Citation4–8,Citation48–56], see and Discussion section.
The patients in the clinical trials to date have an approximate aggregate 9-year experience of BRV exposure [Citation4–8,Citation48–56]. Clinical trial experience has been complex and initially primary end points were not met in some of the Phase II and early Phase III trials likely due to analyses of less than 50 mg/day dosing, which subsequently has been shown in that range to not have significant responder rates for treating POS in statistical analysis [Citation48–56]. This article summarizes how the evolution and the compendium of all of the Phase III trials identify clinical efficacy for BRV in the 50–200 mg/day dose range and will outline the analysis of the AEs and TEAEs in the pivotal Phase IIb and Phase III trials to identify that those experienced in ≥5% of patients are generally mild and consist of somnolence, dizziness, fatigue, influenza like syndromes, insomnia, nasopharyngitis and other symptoms [Citation4–8,Citation48–56]. A discussion about treatment-emergent nonpsychotic behavioral events is also included and how this issue may be different than another medication LEV in the same class that has already been released to world markets [Citation48–56].
A New Drug Application in the USA and a Marketing Authorization Application in the EU were submitted to those respective agencies and remained under consideration for approval until recently [Citation4–8]. The Phase IIB and Phase III clinical trial dataset and investigations along with preliminary results began and became available by approximately 2007.
By January 2015, BRV progressed to the final review analyses by both the FDA and EMA for potential approval as an adjunctive treatment for focal (POS) in adult patients with epilepsy 16 years or older [Citation4–8]. In November 2015, BRV received positive comments from the EMA and Committee for Human Medicinal Products (CHMP in the EU) and launched in the UK in January 2016. BRV was approved under the trade name ‘Briviact’ in February 2016 in the USA [Citation4–8]. In September 2017, BRV was approved by the FDA for use in monotherapy for POS and may be initiated at a therapeutic dose without uptitration [Citation4–8].
Table 1. Molecular summary for brivaracetam.
Table 2. Receptors and antiseizure medications.
Presently, multiple ongoing studies as part of the clinical trials in the US and EU of BRV are still in effect, including multiple open-label studies to assess the long-term safety and efficacy of BRV [Citation4–8]. The reader is referred to the Discussion section and and that highlight the trials that form the previous and ongoing BRV research and development program.
Table 3. Overview of the extensive clinical research trial program for the development of brivaracetam.
Table 4. Clinical trial highlights – for detailed list of all clinical trials.
Significance & place in the worldwide antiseizure medication market
The first antiseizure medication was first noted around the late 1850s, with the discovery and development of bromide salts/triple bromide therapy [Citation1–3,Citation9]. After bromides became available, in the early part of the 1900s, phenobarbital and phenytoin and multiple new antiseizure/epileptic drugs (AEDs) were developed and introduced in the USA and worldwide markets over the next few decades. Although many medications may have been discovered by chance, others were developed utilizing synthetic organic chemistry or methodologies known as rational (or targeted) drug discovery [Citation3]. In this endeavor, various manufactured compounds are tested and modified within a strategy program or paradigm of investigation, using predictive animal research or biochemical models [Citation2]. Conversely, BRV ensued by studying compounds that optimized the pharmacodynamic activity atSV2A – the molecular target [Citation1,Citation2,Citation9–15].
BRV is related structurally and mechanistically to the action of LEV (brand name, Keppra) – ((S)-α-ethyl-2-oxopyrrolidine acetamide) [Citation1–3,Citation9–15]. BRV is a pyrrolidone that is structurally related to LEV and piracetam and the three compounds bind to the same molecular although with different affinities – BRV having the highest affinity of these [Citation1–3,Citation9–15]. BRV binds at an approximately 90 kDa neuron-specific protein that is widely distributed in the brain and highly enriched in synaptic vesicles. The protein was identified as SV2A that is believed to be involved with neurotransmitter release. There is a high correlation between the binding affinities of a series of LEV analogs and their potencies for protection against audiogenic seizures, confirming that SV2A is the molecular target for anticonvulsant activity [Citation1–3,Citation9–12]. While SV2A appears to be involved in synaptic transmission by preparing vesicles for fusion, its functional role in synaptic transmission is not completely understood at present [Citation1–3,Citation9–12]. BRV binds to the SV2A protein with approximately ten- to 30-fold higher than LEV and in animals – achieves bioavailability in the brain faster than LEV due to a higher CNS/brain permeability as compared with LEV in rodents [Citation13–15]. LEV and BRV might be localized in the luminal side of recycling synaptic vesicles during endocytosis [Citation58]. Although the above is known mechanistically about BRV, a review indicates that many of the molecular and pharmacologic mechanisms of previously approved medications may not have been known until many years after the launch and marketing of the product and that the exact mechanism of action may not actually be required by regulatory authorities [Citation3–15].
Possibly due to the enhanced binding to SV2A, BRV seems to have additional effectiveness in suppressing epileptiform activity in various animal models, in particularly the rodent model, which has been most studied, when compared with LEV [Citation11–13,Citation22,Citation23,Citation25,Citation28–31]. In general, LEV and BRV may reduce excitatory neurotransmitter release and enhance synaptic depression during seizures [Citation1–3,Citation11,Citation15,Citation53]. Although clinical trial data to date may not be totally clear on the head-to-head comparison of BRV versus LEV, it is speculated that BRV might have additional clinical therapeutic efficacy, and potentially a different, broader or enhanced clinical spectrum of action compared with LEV [Citation1–3,Citation14,Citation15,Citation26].
Despite numerous medications and treatments available, the prevalence of epilepsy is approximately 65 million worldwide, with about two million patients in the USA. [Citation16–18]. The incidence of seizures is estimated at one in 26 (the highest in children and in older adults) according to the 2012 report from the Institute of Medicine [Citation18]. As noted in the literature, LEV treatment became associated with nonpsychotic behavioral events, so motivation for finding a molecule, selective for the novel SV2A mechanism with fewer behavioral events seemed an impetus in BRV's development [Citation4–8,Citation19]. A recent open-label study in a small cohort of patients published in the premarketing phase by Yates et al. (which has been reconfirmed in the postmarketing phase/see below for review) indicated that a group of patients might benefit by switching to BRV if they had behavioral side effects on LEV [Citation19].
There is vast literature on the definition and syndromes of epilepsy including what medications might be used and what agents might be used for rational polytherapy and the fact that seizures persist despite medications available along with surgical therapies [Citation14,Citation20–47]. As the clinical trials on surgery emerged in the literature over the last approximately 15 years, a fairly extensive clinical evaluation of BRV also emerged in the literature [Citation23–47]. It was, therefore, speculated that BRV might reduce seizures in a vast number of such refractory epilepsy patients worldwide, or be useful to those with limiting side effects, since such patients were included within the selection of the BRV clinical trial program discussed below [Citation1–15,Citation48–54], and published and pooled data are becoming available identifying the fact that BRV has efficacy in refractory POS at least in a single Phase IIb [Citation43,Citation59,Citation61,Citation62]. The impact of BRV is thought to be therefore potentially significant when considering the epidemiology of both the prevalence and incidence of chronic epilepsy and persistence of refractory seizures. Although there are about 30 such medications available presently for treatment of seizure disorders at this point in time, there are still patients with uncontrolled seizures and side effects, and with the approval and launch of BRV, the full postmarketing significance and clinical experience in treating epilepsy therefore remains to be fully determined, although some recent publications now exist in the literature [Citation2,Citation16–18,Citation20–22,Citation55–57,Citation59–69].
In the 1960s, several cyclic gamma-aminobutyric (GABA) analogs were made using 2-oxopyrrolidine or GABA moieties with anticipation that such molecules would be GABA agonists that generally cause inhibition of seizures [Citation9,Citation22–24]. Such GABAergic derivative molecules were thought to result in various types of tranquilizers in general and they are also sedative-type compounds [Citation2,Citation9,Citation23,Citation24]. This drug development process resulted in piracetam. As the literature indicates, BRV, based on its development, therefore might be considered a ‘third-generation offspring’ of a lineage of molecules designed to have neuroactive properties, starting with piracetam [Citation9,Citation23,Citation25]. Piracetam was first manufactured in 1964 by Corneliu Giurgea and team who thought the drug might boost mental functioning even in healthy individuals – and it was termed nootropic – a term that was to denote to a senior or former generation of neurologists that such a medication would be a cognitive enhancing agent to describe its properties, and ultimately was launched under the trade name of Nootropil [Citation22–25]. Piracetam was used by Janz in treatment of juvenile myoclonic epilepsy, and this use for this indication by a well-respected clinician after its approval probably gave the moiety some significant clinical credibility [Citation24]. In the USA, piracetam is, however, not approved by the FDA for any medical use and is not permitted to be sold as a dietary supplement. In the UK and Europe, piracetam is prescribed predominantly for myoclonus but also in other conditions as off label use, although large-scale meta reviews (such as those by Cochrane initiative) did not support multiple other indications also postulated such as in dementia or cognitive diagnoses [Citation27].
The antiepileptic properties of LEV were first identified in the 1990s, through screening in audiogenic seizure susceptible mice (1.2). LEV was shown to exhibit saturable and stereospecific binding to a brain-specific-binding site, it did not share with any antiepileptic medication and later studies revealed SV2A to be the molecular correlate to this binding site protein [Citation1–12,Citation22–26]. For a more detailed overview on what receptors/ion channels/proteins that various available antiepileptic medications interact with, please see and references.
Review of the basic science and general literature identifies that BRV may have additional features or ramifications compared with LEV [Citation1,Citation2,Citation11–14,Citation19,Citation23,Citation28–35]. For example, BRV in preclinical phase may be superior in rat models of posthypoxic myoclonus and in status epilepticus, although BRV is not currently approved for these indications [Citation27,Citation28]. Like other molecules that treat seizures, its mechanism of action inhibits spreading depression in neocortical preparations, and some mechanisms impacted by BRV were speculated to be involved in pain management, although no significant efficacy in the treatment of postherpetic neuralgia has been shown [Citation2,Citation20,Citation27–30]. BRV inhibited epileptiform features in rat hippocampal sections particularly in the CA3 area induced by a high potassium/low calcium perfusion or with addition of bicuculline to baseline perfusion [Citation23,Citation25,Citation26,Citation28]. This illustrates a preclinical higher efficacy and potency compared with LEV and uniquely seems to reduce the occurrence of spontaneous epileptiform burst-type discharges within the bicuculline methiodide spikes model, as spikes are inhibited by BRV even at low doses (∼0.1 μmol/l) [Citation1,Citation2,Citation4,Citation11,Citation12,Citation23,Citation25–28,Citation45,Citation47,Citation49]. Studies have also shown that BRV (unlike LEV) also seems to inhibit seizures induced by maximal electroshock and pentylenetetrazole and shows evidence of protection in self-sustaining status epilepticus in preclinical investigations [Citation1,Citation2,Citation4,Citation11,Citation12,Citation23,Citation29,Citation44,Citation45,Citation47]. In corneal-kindled mice, BRV could protect better than LEV against secondarily generalized motor seizures, and pretreatment enhanced those effects [Citation2,Citation28–31]. In hippocampal-kindled rats, similar effects were noted, and in fully amygdala-kindled rats (50 Hz, 1 s, 500 μA monophasic square wave pulses, once a day, 5 days/week), BRV suppressed seizures and after-discharges nearly completely [Citation2]. In audiogenic seizure-susceptible mice, animals had fewer clonic convulsions induced by auditory stimuli with BRV compared with LEV [Citation2]. Although the current drug approval process sought the indication for POS at this time as noted above, basic research indicates that BRV suppressed significantly spontaneous spike and wave discharges in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), which serves a model for absence seizures [Citation2]. BRV attenuates generalized photo paroxysmal EEG responses and reverses the inhibitory effects of negative modulators on gamma-aminobutyric acid (GABA) receptors in rat models of status epilepticus [Citation2,Citation29,Citation31,Citation44,Citation45].
Clinical pharmacology of BRV
BRV {[2S]-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide}is a 2-pyrrolidone derivative [Citation1,Citation2,Citation9,Citation10,Citation25]. The discovery and binding site has already been mentioned above [Citation1,Citation2,Citation9,Citation25]. BRV has a molecular weight of 212.15 g/mol [Citation1,Citation2,Citation4,Citation7,Citation8]. The compound is water soluble – having a volume of distribution close to that of total body water at 0.5 l/kg [Citation2]. BRV is rapidly bioavailable and nearly completely absorbed after oral administration with linear pharmacokinetics from about 10–600 mg [Citation1,Citation2]. BRV has an elimination half-life of approximately 6–11 h, a geometric mean elimination half-life of 9 h, with similar pharmacokinetics and bioavailability in both oral and intravenous (iv.) forms [Citation2,Citation32–37]. BRV is eliminated mainly by metabolism and less than 10% by urinary excretion [Citation32–37]. The plasma clearance of BRV and its metabolites is 0.7–1.3 ml/min per kg and the higher clearances are observed in patients that have been studied and comedicated with enzyme inducing AEDs [Citation2,Citation4–8,Citation32–37]. Following repeated administration, at doses of 800 mg/day, there is an increase in metabolic clearance after 2 weeks, this increase in metabolic clearance is not seen in lower doses ≤400 mg/day [Citation2,Citation32–37]. The blood protein binding is less than approximately 20%. Studies on food interaction show no significant effects [Citation2,Citation31–37]. More than 95% of an experimental radioactive dose is recovered in the urine within 72 h after administration [Citation2,Citation31–43]. There are no known active metabolites involving the major metabolic products; a combination of two pathways involving mainly hydrolysis of the acetamide group at the butyramide side chain and through ω-1 hydroxylation of the propyl side chain, mediated by CYP2C19 [Citation35,Citation36]. A recent study indicated that BRV did not significantly impair metabolizing enzymes or transporters, and is unlikely to cause clinically significant drug–drug interactions [Citation43]. BRV pharmacokinetics seems to not be affected by coadministered drugs in general, however, the literature notes some effects with coadministered phenytoin and carbamazepine (CBZ) [Citation37,Citation63,Citation64]. Specifically, in a study by Stockis and Rolan, a Phase I interaction study between BRV and CBZ in 14 healthy subjects showed BRV did not significantly alter CBZ exposure, although it increased the CBZ-epoxide exposure by approximately 2.6-fold and hydrolysis in vitro of the CBZ epoxide was inhibited by BRV, and enzyme induction by CBZ led to only modest reduction in BRV exposure [Citation63,Citation64]. Metabolic reaction phenotyping suggested that BRV disposition potentially is only modestly affected by genetic polymorphism such as in a paper reviewing the influence of the CYP2C19 genotype in Japanese patients [Citation38].
Gender does not seem to alter pharmacokinetics, although bodyweight, use of other enzyme, inducing agents/antiepileptic medications, can cause variability on pharmacokinetics [Citation2,Citation32–37]. Special populations may experience specific pharmacokinetics with BRV such as with the elderly, in populations with impaired renal function, and hepatic impairment and exposures to other medications [Citation32–37,Citation63,Citation64]. In general, it was postulated that these effects do not seem clinically significant enough to effect any significant dose adjustment [Citation32–43]. Impaired hepatic function may result in greater exposure to the medication with elevations in the main alpha metabolite and decrease in the hydroxy metabolite [Citation32–39]. This would make it prudent for clinicians to consider a 50-mg starting dose and a maximal daily dose to 150 mg/day in groups with hepatic impairment [Citation32–39]. Exposure to BRV in patients with liver disease may be increased up to about 60% and the half-life may increase to about 17 h in severe liver impairment [Citation2,Citation32–37,Citation39].
BRV's pharmacokinetics that are generally linear over the therapeutic dose range may be altered by enzyme inducers mainly by reducing plasma BRV concentrations up to about 30% and the half-life may be reduced to about 5 h [Citation2,Citation32–37]. These effects may be mediated by induction of the BRV metabolism with phenytoin, phenobarbital or CBZ (as noted above), although in Phase II data the coadministration of enzyme-inducing AEDs did not significantly change the percentage of responders or worsen seizure frequency, and as already noted – according to the approved product insert labels, no dose adjustments are needed [Citation2,Citation32–37]. It is known that plasma levels may be reduced about 55% with rifampicin, so in this case, clinicians may consider administering an increased dose of BRV [Citation2,Citation40]. According to UCB data, it seems from pharmacokinetic data that came from some of the clinical trials, BRV up to 200 mg/day did not cause any appreciable changes in plasma concentration of concomitantly administered (seizure medications or oral contraceptives, but only few articles exist and therefore an exhaustive statement on these matters is not clear, see below [Citation2,Citation37,Citation41–43]. At high doses of BRV, there may have been up to approximately 15% reduction in peak serum levels of ethinylestradiol and levonorgestrel in one study but no changes in other hormones indicative of ovulation [Citation2,Citation37,Citation41,Citation43]. Exactly what dose or dose titration yields clinical effects in patients is not known, although the clinical trial data indicate that the therapeutic effects may begin at around 50 mg/day [Citation48–53]. At this time, it is noted that BRV interacts with other AEDs as noted by several abstracts and pooled analyses of Phase II/III clinical trial data, along with results from an open-label study without uptitration, including a post hoc analysis evaluating what might predict treatment response [Citation7,Citation38,Citation48–53,Citation59,Citation60,Citation62]. Articles indicate that BRV confers no added efficacy or benefit with concomitant LEV [Citation14].
No pharmacokinetic data or effects on pregnant women's exposure are noted, nor are there such data available regarding exposure and or effects in infants who are breastfeeding. BRV is categorized as class C in pregnancy in the USA [Citation4,Citation65,Citation66]. An iv. formulation was studied within the clinical trial program () [Citation4,Citation7,Citation8,Citation34,Citation46].
Clinical efficacy of BRV: review of the clinical trial experience
Although a significant amount of preclinical mechanistic and pharmacokinetic data exist as already noted above, the proposed efficacy of BRV for its therapeutic indication – as with any medication in the USA and EU – is defined mainly through the pivotal Phase IIB and Phase III clinical trials [Citation48–53]. Postmarketing real-world analysis is reviewed below, and discussion from the pooled Phase III dataset will be included in this and subsequent sections. As previously noted, a total of 31 USA- and 18 EU-registered clinical trials exist at present, as previously noted with more than 3000 patients in all, some patients have been in these trials for about 9 years [Citation4–8,Citation46–54]. The complete set of clinical trial designations and significance and correspondence to UCB protocol designation and clinical trial numbers at the FDA and EU EMA and resultant peer review or other publications and significance are summarized in and from information currently available in the public domain. These tables aim to cross-reference clinical trial numbers in the EU and USA, UCB protocols, publications and other data in an organized compendium.
This section of the manuscript will discuss the relevant summary of the Phase IIb and pivotal Phase III studies highlighting the clinical efficacy of BRV in the clinical development program. This section will discuss the initial disappointment from Phase II and early Phase III trials in the trial experience and the resolution that followed. But after this initial disappointment, ultimately the entire compendium of BRV's Phase III clinical trial program that resulted over this time period from approximately 2007 until present is what ultimately led to the approval of BRV.
For all of the clinical trials, the primary end point for the European regulatory authorities is the 50% responder rate for POS frequency compared with placebo, over the treatment period standardized to the 28-day duration [Citation5]. The primary end point for the FDA is the percent reduction compared with placebo for POS frequency, over the treatment period standardized to the 28-day duration [Citation6]. During the clinical trial periods prior to approval, both a Phase II and a Phase III trial had issues of not meeting their primary end points, see below for discussion causing administrative hurdles at the FDA and EMA that assisted in development of the later clinical trials [Citation47–49]. In retrospect, it seemed that these trials likely failed to reach the proposed end points mainly because of the hierarchical statistical design that included detailed analysis of dosing BRV less than 50 mg/day, which further analysis over multiple studies identifies that these doses are simply not efficacious when using BRV for seizure control, see below for details [Citation47–49].
The pivotal studies performed in the Phase III program ultimately consisted of studies designated as UCB protocols N01252, N01253, N01254, and N01358 ( ) [Citation48–53]. These protocols corresponded to clinical trials in the EU and USA and ultimately led to various peer-reviewed publications, see below and the corresponding designations in & . These studies reviewed the safety and efficacy and tolerability of adjunctive BRV from 20 to 200 mg/day (see ) [Citation48–53]. Patients in these four study protocols included patients with or without POS that secondarily generalized and there were also refractory patients with POS included in subgroups containing more than 1 but up to and beyond three AEDs in some cases.
The most recent study performed prior to approval in the EU and USA is the N01358 study. published by Klein et al. in the latter portion of 2015 [Citation53]. This study aimed to confirm the safety and efficacy and safety and tolerability in POS from ages 16 to 80 years. This is one of the largest Phase III studies to date and excluded patients on LEV. BRV was added without a dose finding uptitration at a starting dose. 768 patients were studied with BRV dosing up to 200 mg/day. French et al. published results of an exploratory dose-finding study that reflected a promising overview of efficacy and tolerability data, but in retrospect after this trial it seemed that the doses up to 50 mg/day were likely subtherapeutic, and in subsequent studies (see below) higher doses met efficacy end points in the collective compendium in the later Phase III study program [Citation48,Citation49,Citation54].
An additional study as noted by Van Paesschen et al. – a Phase IIB dose-finding study was performed that investigated doses from 50 to 150 mg/day in a total of 157 patients, with approximately 50 patients per treatment arm (1:1:1 to placebo, BRV 50 or 150 mg/day) [Citation49]. These exploratory dose-finding studies indicated that BRV at 50 mg/day might be a starting dose and extended the range of administration to 200 mg/day, although in the Van Paesschen et al.'s study, no difference was seen between the 50 and 150 mg daily doses of BRV [Citation48,Citation49]. Additionally as already alluded to, study N01252 which was considered a pivotal study, did not meet statistical significant for the 50 mg dose (its primary efficacy end point) based on a predefined sequential testing strategy, as noted by Ryvlin et al. [Citation4–8,Citation50]. The primary efficacy analysis (percent reduction over placebo in baseline-adjusted focal seizure frequency per week) based on the 50 mg/day dose was not statistically significant. However, the primary efficacy end point for the BRV 100 mg/day arm did achieve statistical significance (p = 0.037). Secondary efficacy analyses provided supportive evidence for the efficacy of 100 mg/day [Citation50].
The subsequent pivotal study (N01253) examined doses of 5, 20 and 50 mg/day and confirmed that the 50 mg/day dose shows statistically significant efficacy as outlined by Biton et al. [Citation4–8,Citation51,Citation48–52]. In a Phase III, double-blind, randomized, placebo-controlled, flexible-dose trial, Kwan et al. reported that individualized tailored doses (20–150 mg/day) were well tolerated in adults with uncontrolled epilepsy, and that the results provide support for further evaluation of efficacy in reducing focal and generalized seizures [Citation52]. It seems that a pooled analysis of three fixed dose, Phase III studies showed statistically significant median percentage reduction in both weekly focal seizure frequency from baseline and in general, with BRV there is a ≥50% responder rate for BRV compared with placebo starting at 50 mg/day ( and ) [Citation46–53]. Results from the N01358 study indicate that the percent reduction over placebo also occurred with statistical significance within the design protocol of patients receiving doses of BRV up to 200 mg/day [Citation53]. Although the clinical trial program met end points for the control for epilepsy, studies of BRV in patients with Unverricht–Lundborg disease with progressive myoclonic epilepsy did not provide statistically significant clinical benefit in reaching the primary end point of reducing the severity of action myoclonus (as measured by the Unified Myoclonus Rating Scale), however, this may have been due to the high variability in disease severity as well as the lower doses that were used (2.5–50 mg/day) [Citation4–8,Citation61]. Additionally these were done earlier than the Phase III studies for BRV at a period in time, when it was not proven that such low doses of BRV might not have appreciable efficacy in POS, but in the subsequent publication in 2016, BRV up to 150 mg/day was studied and was deemed well tolerated, but primary end point of statistically significant control of myoclonus was not demonstrated [Citation61]. It was speculated that rare subpopulations of various epilepsy populations might require yet to be defined methods of study for demonstrating optimal indication [Citation61].
Additionally, two international conversion to monotherapy BRV studies (N01276 and N01306) were conducted but were halted as a review by an independent data monitoring committee determined that predefined exit criteria for stopping the studies were met, but no unexpected safety concerns were noted [Citation2,Citation4–8,Citation14]. In retrospect from review of the clinical trial program, the disappointing failure of the early clinical trials for BRV for meeting end points in the Phase II/III program was likely because of including doses less than 50 mg/day in the overall analyses and not due to the study design of these types of clinical trials, and the reader is referred to the trials that settled this issue and literature reviewing the general study design for AED trials [Citation49–54].
Safety & tolerability: results & AEs from Phase III studies
The most frequent TEAEs, in general, seem consistent across the large Phase III study program and were somnolence, dizziness and fatigue, as noted in Klein et al. [Citation53]. This article by Klein et al. is one of the largest Phase III trials completed on BRV just prior to and at the perilaunch period of BRV [Citation53]. However, additional studies have appeared later and postmarketing such as those from Ben-Manachem et al., Kalvianen et al., Lattanzi et al., Toledo et al. and Asadi-Pooya et al. [Citation59,Citation61,Citation62,Citation75,Citation76]. This section will review the preapproval dataset, please see the regarding TEAEs/SAEs that will also review the known complete pooled dataset at time of this article's publication that also includes data from the ongoing clinical trials and the above.
Klein et al. indicate that TEAEs occurred in 155 (59.4%) of 261 PBO patients and in 340 (67.6%) of 503 BRV-treated patients in that article [Citation53]. Klein et al. note that the discontinuation rates due to TEAEs were 3.8, 8.3 and 6.8% for PBO, BRV (100 mg/day) and BRV (200 mg/day), respectively [Citation48]. Most frequent TEAEs (PBO vs BRV) were somnolence (7.7 vs 18.1%), dizziness (5.0 vs 12.3%) and fatigue (3.8 vs 9.5%) [Citation53]. Study discontinuation rates for any reason were 11 and 10% for BRV at 100 and 200 mg/day versus 7% for placebo were previous statements released from the UCB website from data on file as part of this trial [Citation53]. Headache in placebo and BRV groups’ percentage was similar at approximately 8%. BRV group contained 503 patients, placebo group contained 261 patients [Citation53].
Additionally, 88% of patients in the N01358 trial elected to go into the open-label phase and receive BRV. In subgroup analysis, it was also noted that seizure reduction occurred in those that had previously discontinued off LEV as well as patients that were not previously exposed to LEV [Citation53]. This efficacy in patients with prior LEV or other AED exposure was confirmed in another post hoc analysis [Citation78]. TEAEs, in general, were more common in the BRV-treated patients compared with placebo, with the majority of such being mild or moderate, see and figures below [Citation48]. Psychiatric TEAEs were noted also to be mild or infrequent, and included anxiety (1.1% placebo; 2.2% BRV overall), insomnia (1.1% placebo; 2.0% BRV overall) and depression (0.4% placebo; 0.8% BRV overall) [Citation53]. The overall incidence of psychiatric TEAEs was similar for both BRV dosages in that study (10.3% 100 mg/day and 11.2% 200 mg/day) versus placebo (7.7%) [Citation53]. The incidence of suicidal ideation was low and equal for placebo, two deaths occurred during that study; one was attributed to sudden unexplained death in epilepsy patients (SUDEP), and the other was by unknown mechanism, but both thought not due to BRV [Citation53].
In general, it seems that pooled data from the studies by French et al., Van Paesschen et al., Ryvlin et al., Biton et al. and Kwan et al.'s studies – the noted AEs or TEAEs (sometimes reported either way in the studies but representing the same designation) profile seems consistent throughout the Phase II and III trials [Citation48–52]. AEs include nausea, vomiting, fatigue, anorexia, dizziness, headache, somnolence, insomnia, nasopharyngitis [Citation48–52]. They were typically mild to moderate in severity, generally similar to that of the Klein et al.'s study cited above [Citation48–53]. Please see for more exact breakdown of these items. Nonpsychotic behavioral adverse events (BAEs) with LEV and BRV are of particular concern because previous studies have shown about a 13% of patients treated with LEV reported a behavioral symptom compared with about 6% that with a placebo [Citation48–53]. Articles also identify that it has been suggested that patients taking LEV clinically experience behavioral events above that which is reported in the clinical trials, which may impact long-term tolerability [Citation19,Citation55,Citation56]. The emergence of side effects or behavioral effects including suicide seemed to be a reason for discontinuing LEV [Citation19,Citation53,Citation55,Citation56]. About 54% of patients continued LEV as adjunctive therapy for POS after 2 years, whereas 46% had discontinued, and BAEs contributed to about 40% of the cases who had discontinued therapy [Citation56].
Table 5. Adverse events from selected Phase II and III clinical trial data for brivaracetam.
Yates et al.'s recent review of NCT01653262 Phase IIIb study noted that of the 29 patients enrolled, 26 (89.7%) completed the study and at the conclusion of the treatment period, 27/29 (93.1%) patients switched to BRV had clinically meaningful reductions in BAEs [Citation19]. Yates et al. studied evaluated BAEs in patients receiving LEV, who switched to BRV [Citation19]. Patients ≥16 years of age receiving 2–3 AEDs including LEV at 1–3 g/day, and experiencing BAEs within 16 weeks of LEV initiation enrolled in this Phase IIIb open-label study with a less than 1-week screening period, and an immediate switch from LEV to BRV at 200 mg/day without a titration and a 12-week treatment period and had Quality of Life in Epilepsy Inventory – Form 31 (QOLIE-31-P) scales performed [Citation19]. Of the 29 patients enrolled, 26 (90%) completed the study and at the end of the treating period, 27/29 (93%) switched to BRV and had meaningful reductions in the BAEs [Citation19]. Physician reports of BAEs also reported reductions in BAEs in 93% of patients. 23/29 patients reported TEAEs with one patient having reported a suicidal ideation and a suicidal attempt [Citation19]. Two patients discontinued BRV during the study. Of the two patients that discontinued BRV, one discontinued due to perceived lack of efficacy and the other reported a suicidal ideation and attempt [Citation19]. Nonbehavioral TEAEs were reported in 23/29 patients (79%) included headache – 5/29 patients (17.2%), fatigue – three patients (10.3%) and back pain – three patients (10.3%). Additional TEAEs that were reported included depression, dizziness, insomnia, nasopharyngitis and tremor, each of these in two patients at 7% [Citation19].
In the Biton et al.'s study of 2014, a noted reason for discontinuing BRV was behavioral abnormalities and according to Pack, it seems that comparing nonpsychotic BEAs such as irritability and aggression, the numbers/percentages reported may be less than that of LEV, but since no head-to-head comparison has been done at the time of the Pack's article publication, the recommendation at that time was noted that any such claim should be viewed circumspectly [Citation14,Citation51]. In the Ryvlin et al., Kwan et al., French et al. and Van Paesschen et al.'s studies, prior LEV exposure may be associated with an attenuated effect of BRV [Citation48–50,Citation52,Citation78]. reviews comparative study designs, cohorts of subcategories of patients and corresponding AEs or TEAEs in further detail.
Preclinical studies mentioned that the maximal nonlethal oral dose is above 1000 mg/kg with no effects to about 500 mg/kg in animal studies [Citation1,Citation2,Citation4–8]. For additional discussion and more comprehensive review of AEs/TEAEs, please see . A review of comparative neurocognitive effects of BRV and LEV and lorazepam is noted in the literature [Citation57].
Postmarketing surveillance & recent newer developments peri- to postlaunch of BRV
The postmarketing phase began after the approval and launch of BRV and the reader is referred to publications that document that process and articles reviewing the preclinical properties of BRV and BRV development are now available [Citation65–83]. Review of the EU and US clinical trial rosters shows that there are multiple clinical trials that are currently continuing into the postmarketing phase () [Citation4–8]. There have been pre- and postmarketing abstract presentations at the American Academy of Neurology in 2016 and 2017 and at the American Epilepsy Society meetings in 2015 and 2016 noting newer developments and observations [Citation68,Citation69]. For example, data delineating the enhanced brain permeability for BRV as compared with LEV were noted in these meetings, and some of these abstracts and or related concepts more recently are now published [Citation68,Citation69,Citation73,Citation74]. In 2017, at the American Academy of Neurology, Moseley et al. also reviewed the drug–drug interactions of BRV in the peri- to postmarketing phase and identified the efficacy of adjunctive BRV in patients with secondarily generalized tonic–clonic seizures at baseline using pooled results from long-term follow-up studies, and this is now published [Citation75]. Evaluation of abuse potential of BRV in healthy recreational CNS-depressant users is being explored and defined [Citation66–69]. Pooled analysis of the three pivotal clinical studies are now available [Citation59,Citation60,Citation62]. Newer data identified during the perilaunch period regarding pharmacokinetics BRV when taken with other medications are noted in the recent literature [Citation63,Citation64,Citation67]. Steinig et al. published a postmarketing trial in Germany and Milovanocic et al. provide an overview at time of launch of BRV [Citation70,Citation71]. Steinig et al.'s study noted that 262 patients were treated with BRV from 1 day to 12 months with a median retention time of 6.1 months and identify that the retention rate at 3 months was 79.4 and 75.8% at 6 months [Citation70]. 14.9% were seizure free at 3 and 6 months, 15.3% were seizure free in the Steinig et al.'s study [Citation71]. TEAEs were observed in 37.8% with the most common being somnolence, dizziness and BAEs. BAEs that presented under previous LEV treatment improved upon switch to BRV in 57.1% (20/35 patients) and LEV-induced somnolence improved in 70.8% (17/24 patients) [Citation70]. Patients with BAEs on LEV were, in general, seemed more likely to develop BAE(s) on BRV, odds ratio: 3.48, 95% CI: 1.53–7.95 [Citation70].
More recently, Russo et al. opined that the increased permeability of BRV compared with LEV may be useful in emergency treatment for seizures, although there is currently no approved indication for this [Citation67]. Subsequently, the postmarketing literature notes a potential role of BRV in both uncontrolled POS and in status epilepticus [Citation67,Citation79–82]. Specifically recent postmarketing studies note efficacy in refractory uncontrolled POS and in status epilepticus and possibly super-refractory status epilepticus [Citation79–82]. Experimental models in animal models may indicate enhanced CNS drug entry time of 3 min for BRV compared with 23 min for LEV, which represents a factor of about seven-fold increase in entry speed into the brain [Citation74]. Further publications of postmarketing meta-analyses such as by Brigo et al. and Zhu et al. involving comparing BRV to multiple products and adjunctive medications available for POS are also noted in the recent literature [Citation81,Citation82].
In general, at this point in time, physicians are pondering as in the 2017 French commentary and replies and as in this current paper – how exactly BRV will impact their epilepsy patients based on the preclinical experience, the clinical trial program and the recent abstracts, presentations and publications of the postmarketing literature [Citation83,Citation84].
Conclusion
BRV underwent an initial complex research and development followed by a complex series of Phase III investigations starting around 2007 that ultimately led to approval by the EMA and the subsequent launch in the UK. Subsequently, BRV was approved for use by the FDA in February 2016. The FDA approved BRV for treatment of POS in monotherapy in patients ≥16 years old in September 2017 as a unique antiseizure medication without a dose-finding uptitration.
This article speculates that BRV has the potential to make a significant impact on the treatment of epilepsy from the review of the current clinical trial program and the initial and early approximately 18-month postmarketing experience. The clinical trial program included a representative cohort of some of the most difficult to manage patients in clinical practice including those with secondarily generalized seizures, and in refractory patients that were on adjunctive 1–3 or more additional agents for POS. Data to date seem to indicate an acceptable side-effect profile and while the full extent of BAEs are not known with agents that interface with the SV2A mechanism, recent publications of small cohorts of patients who had previously experienced BAEs on LEV suggest that patients might benefit by switching from LEV to BRV. Initial Phase IIb trials and one of the pivotal Phase III trials were disappointing as they did not meet statistical significance for the primary end point, which prompted discussions with and guidance from the FDA and EU, which led to a redesign on the Phase III program that was ultimately successful. Additional studies were performed that showed statistically significant efficacy for the respective primary end points. The initial disappointing performance of BRV in the clinical trials was likely due to studying total daily doses less than 50 mg and not due to the study design of the clinical trial program itself. After studies were designed with dosing from 50 to 200 mg/day, the Phase III program met statistical end points.
Exactly how BRV will have an impact in treating epilepsy within a marketplace with multiple options, remains to be fully determined. Postmarketing analyses continue that will potentially clarify BRV's role in treating epilepsy. As of the time of the publication of this article effective doses in clinical trials as noted above have been studied from the range of 50–200 mg/day. BRV as compared with LEV has an enhanced mechanism of action at the molecular target. BRV exhibits more rapid brain permeability presumably due to a different chemical structure compared with LEV, and preliminarily there is a different and potentially more favorable potential BEA profile compared with LEV, the full extent may ultimately be delineated in the evolving postmarketing literature. There may also be additional efficacy in patients previously not gaining efficacy with LEV or other currently available medications in a market place that contains a significant epidemiology patients with refractory epilepsy despite the already numerous treatment and products available. The preclinical and animal models outline a potentially enhanced and different antiepileptic effect profile for BRV mechanistically as compared with LEV. In general to date, the clinical trial program along with select pooled and postmarketing datasets indicate an overall acceptable side-effect profile. Oral tablets, an iv. formulation and an oral solution were all investigated within the clinical trial program. As this review suggests, it is anticipated therefore that BRV represents a potentially successful option in treating epilepsy.
Overview of brivaracetam
Brivaracetam (BRV) developed and marketed by UCB Pharma, ‘3rd Generation molecule’ from piracetam (‘first generation’; 1960s) which the development program yielded levetiracetam (LEV; ‘second generation; c. 1992) and now BRV (‘third generation’).
Multiple clinical trials: approximately 3000 patients in 31 USA and 18 EU trials with including refractory epilepsy patients (those patients included were on one to three or more antiepileptic drugs, and some patients experienced secondarily generalized seizures, and others on LEV vs being LEV naive) some having an approximate 9-year experience in the trials.
Tablet, oral solution and intravenous forms exist.
Mechanism of action
BRV is a novel SV2A ligand, chemically related to LEV. BRV binds SV2A with ten- to 30-fold higher affinity compared with LEV specificity for SV2A about 30-times more compared with LEV.
BRV inhibits epileptiform discharges and in the available animal models and may offer neural protection in epilepsy compared with LEV.
Unlike LEV, BRV has activity protecting cells from becoming epileptogenic or attenuates epileptiform discharges in maximal electroshock models, corneal kindled mice and hippocampal kindled animals in preclinical models.
In audiogenic seizure susceptible mice, BRV prevents more convulsive motor seizures compared with LEV.
BRV suppresses epileptiform discharges more completely in Generalized Auditory Epilepsy Rats of Strasbourg models.
BRV and LEV when taken together seem to not have any added benefit.
Safety & tolerability
Current data indicate: somnolence, dizziness, fatigue and headache (which seems, however, in some of the Phase III trials to occur at similar rate as placebo-treated patients) are the most common adverse effects. Nausea and anorexia have also been noted, see Discussion and for details.
Discontinuation of BRV in clinical trials for any reason: 11% (compared with 7% in the placebo group).
Treatment emergent side effects for any issue in the recent clinical trial (NCT01261325) and pooled data: 100 and 200 mg/day groups were 68 and 67%, respectively, and around 59% in placebo control group.
BRV may represent a potential option for patients who have previously failed LEV.
Company review
In addition to the peer-review process, with the author's consent, the manufacturer of the product discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made by the author at their discretion and based on scientific or editorial merit only. The author maintained full control over the manuscript, including content, wording and conclusions.
Financial & competing interests disclosure
The author was principal investigator (PI) on a number of Clinical Trials, including with UCB, had been consultant speaker previously but not after 2009. The authors have 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 apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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