Brivaracetam: How Well Does It Fare as an Anti-Epileptic? A Review
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.314584
Source of Support: None, Conflict of Interest: None
Keywords: Adjuvant, adverse effects, Brivaracetam, focal onset seizures, idiopathic generalized epilepsyKey Message: Brivaracetam, a Levetiracetam derivative, is effective as an adjuvant in refractory focal epilepsies. It has been tried in Generalized onset seizures with reasonable success. It is well tolerated in organ failure patients, has minimal drug-drug interactions, and has shown promising response in people not tolerating Levetiracetam.
Neurological ailments constitute 3% of Disability Adjusted Life Years (DALYs), of which epilepsy accounts for one-quarter of the number, second only to migraine. Practitioners and patients fighting epilepsy are keen on newer molecules for treating epilepsy. Brivaracetam (BRV) is an orally bioavailable anti-epileptic agent in the armamentarium of an epileptologist. Being a derivative of Levetiracetam (LEV), it shares the hitherto known LEV mechanism as well. Although most of the literature so far is on its efficacy in Focal Onset Seizures (FOS), the evidence of BRV in generalized epilepsies, rare epilepsy subtypes like myoclonic epilepsy, absence epilepsy, in individual settings like pregnancy and pediatric age group, status epilepticus, efficacy as monotherapy, the usefulness of therapeutic drug monitoring is scarce. In 2016, BRV was approved as a treatment for FOS in the population older than 16 years. Recently (in May 2018), the oral formulation was approved for the treatment of FOS in the pediatric population (four years and older) as well. The long-term data on its efficacy in FOS, its approved indication, is not adequate. BRV short-term efficacy as a first or second adjuvant is also not known. We aimed to address this question and assess its efficacy as a first or second add-on anti-seizure drug in refractory FOS in this analysis. This review article will also dwell upon this novel drug's pharmacological features, available clinical data to date, and discuss its practical implications.
Brivaracetam [(BRV) (UCB34714)] is a pyrroline derivative and n-propyl analog of LEV. This molecule was identified as a compound with ten-fold more affinity for the ubiquitous synaptic vesicle glycoprotein, SV2A, and 20-fold more potency in comparison with LEV., It was the result of a target-based rational drug discovery program, zeroed in after screening 12,000 compounds for in vitro SVA2 binding affinity.
The in vitro, animal studies, and physiologically based pharmacokinetic modeling have shown that BRV had better penetration into the brain, than LEV, attributable to higher lipophilicity of BRV (0.315 vs. 0.015 ml/min/g brain for Brivaracetam and LEV respectively). This quality is desirable in acute settings, making BRV likely choice over LEV in Status epilepticus. The protein binding for both these drugs is low, that for BRV being 17.5%, and is independent of drug concentrations. Therefore, higher free drug levels are available in circulation.
The additional action of BRV on voltage-gated sodium channels has been purported as a contributory mechanism for greater potency of BRV over LEV, although some reports refute this mechanism as contributing to anti-epileptic properties. In contrast, LEV has an action on both GABA (A) and glycine-mediated responses, on voltage-gated calcium channels and AMPA receptors, which also could contribute to the difference in behavioral side effects of this drug. In addition, the post-binding molecular conformations attained at the SV2A, qualitatively different functional responses after SV2A binding by LEV and BRV, could attribute to their distinct properties. For several such reasons, BRV has been shown to achieve complete suppression of seizures and kindling acquisition - better results than LEV in in-vivo and in-vitro epilepsy models.
Absorption of BRV is not affected by food, and its plasma half-life is 7-8 hours. The peak plasma levels have been found to reach by 1.5 hours in healthy subjects. Metabolism is via several P-450 and non-P-450 mediated mechanisms. The steady state concentration is attained by two days. Elimination is through the kidney entirely. There are around ten metabolites of BRV obtained through hydrolysis, oxidation, and conjugation; the former being a major route and all the metabolites being inactive. This indicates that there is low potential for interference with BRV metabolism through P-450 mediated mechanism. The hepatic clearance accounted for only 20% of total in-vivo clearance. However, hepatic impairment results in the production of increased acid and reduced hydroxylated metabolites, culminating in a 50-60% increase in BRV exposure irrespective of the degree of liver failure. In a nutshell, no dose adjustment is required for renal metabolism. However, a dose reduction by one-third is recommended in hepatic impairment, to adjust for the prolongation of half-life, the maximum dose being 150 mg. BRV clearance rates in the pediatric population are similar to the adult values.
Brivaracetam as an early add-on for Focal Onset Seizures
After reviewing the basic pharmacology and mechanism, we decided to look into the evidence for its use in various situations. We formulated a question for meta-analysis on its use in FOS.
Objectives of the Meta-analysis: The aim of the meta-analysis was a comparison of the efficacy of BRV (at doses from 5 mg to 200 mg) when used as an early add-on drug (first or second adjuvant) with placebo, in adult (>16 years) subjects with refractory FOS.
Methods of the Meta-analysis: Refractory FOS were defined as persistence of two or more seizures for at least a period of three months, despite being on a stable anti-epileptic drug regimen. For the meta-analysis efficacy was defined in terms of the 50% responder rate and seizure freedom while on treatment. The 50% responder rate was defined as more than 50% reduction in seizure frequency from baseline at the end of treatment period. Seizure freedom was described as complete cessation of clinical seizures after initiation of treatment, sustained during the treatment period.
Medline and Cochrane Central databases were searched for the meta-analysis. Each of the two databases was searched independently by two authors. The keywords used for Medline search were “Brivaracetam” AND (Focal Onset Seizures OR Partial Onset seizures OR Focal Seizures OR Partial Seizures OR Drug Refractory Focal Seizures). Search term “Brivaracetam” was used for Cochrane Central Database search. We focused on Randomized parallel group double-blinded studies on BRV for FOS. We excluded observational studies, ongoing trials, post hoc studies. Six randomized controlled trials (RCTs) for addressing the meta-analysis question were critically appraised and selected [Flow Chart 1]. Selection and Information bias were looked for.,,,,, Heterogeneity among the trials was assessed by the Chi-square (χ2) test and the I2 statistics for heterogeneity. When no significant heterogeneity was present (P > 0.05), results were synthesized using a fixed-effect model. If the P value was ≤ 0.05, the heterogeneity was interpreted according to the I2 statistic. A χ2 test for heterogeneity indicated no significant statistical heterogeneity between trials.
All the studies had followed central randomization; thus, selection bias was low. Information about masking subjects was not available in one study by Ryvlin et al. [Table 1]. Selective reporting was observed in four of the studies ([Table in supplementary data]). All studies had followed the Intention to treat population for the data analysis. Assessment of Bias was done using the Cochrane revised Risk of Bias 2 (ROB2) tool (Table in supplementary data).
Data analysis was performed by calculating the risk ratio of patients who received BRV as a first or second adjuvant for attaining >50% responder rate and seizure freedom against a placebo. The STATA 15 (Stata Corp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP) was used for analyses.
Results of Meta-analysis: Intention to treat (ITT) population was 2549, of whom 1938 patients received BRV as a first or second add-on for 7-16 weeks. The overall RR (95% CI) for 50% responders across the trials was 1.88 (1.55–2.29). Similarly, the overall RR (95% CI) was 5.82 (2.15–15.70) for seizure freedom. Participants receiving BRV as first or second add-on anti-seizure drug were significantly more likely to attain >50% response rate and seizure freedom. [Figure 1]. summarizes the findings of the meta-analysis.
Interpretation of the Meta-analysis: Clinical Pivotal randomized control trials so far have studied the efficacy and safety of BRV for focal epilepsy [Table 2]. The primary endpoints of these trials varied in terms of measures of efficacy. Although a few trials had failed to attain significance (discussed below) for the primary endpoint in terms of BRV efficacy as an adjuvant in FOS,,, the meta-analysis shows its efficacy as a first or second adjuvant in FOS, in terms of ≥50% response rate and seizure freedom. This meta-analysis provides a moderate-quality evidence for the use of Brivaracetam as an early adjuvant in refractory FOS in the approved doses.
The clinical trials N01193, N01114, N01252, N01253 had included primary efficacy analysis as the percentage reduction in seizure frequency in BRV groups per week over that in the Placebo group in the treatment period. These groups differed in the doses of BRV used in the study groups (N01193: 5-50 mg/day, N01114:50,150 mg/day, N01252: 20-100 mg/day, N01253: 5-50 mg/day). Multiple factors like patient selection, diagnostic accuracies, and sample size differences could have contributed to the differences in primary efficacy analysis at different doses, although no conclusive dose-related effect was found [Table 2]. Also, for a primary efficacy analysis in terms of percentage reduction in seizure frequency of BRV over Placebo, the analysis depends on any apparent Placebo response. This Placebo response may be more prominent over seven days, as considered in all these trials. It has been mentioned that a seizure frequency standardization over 28 days instead of 7 days may give a better idea of this parameter; by proper characterization of drug treatment effect and possible normalization of the apparent placebo response recorded initially. Study N01358 considered one of their co-primary outcomes as the percentage reduction in seizure frequency over placebo in 28-day period and clearly showed a significant efficacy [Table 2]. Other patient selection differences could have contributed to the differences in primary efficacy outcomes. For example, Study N01193 and N01254 had 49% and 36% respectively, of subjects who had tried and discontinued two or more anti-seizure medications, whereas this number was much higher, being 82.8% in study N01114, and 68.1% in the study N01252, 62.6% in study (study N01253), and >75% in study N01358. Concomitant LEV with BRV has been shown less effective in the subgroup analysis of trials N01252 and N01253, and subjects with concomitant LEV were excluded in N01358 study.
In the subgroup analysis of the Randomized Controlled Trials on BRV so far, the highest response rate for BRV was seen in focal to bilateral tonic-clonic seizures. A post hoc analysis also discussed the efficacy of BRV depending on which AEDs failed to control seizures before initiation of BRV. Studies have suggested that previous treatment failure with LEV, Carbamazepine, Topiramate, or Lamotrigine correlated with reduced efficacy of BRV.
A previous meta-analysis suggested that the dose-dependent effect for seizure reduction saturated at 50 mg per day dosage, with higher doses not conferring an additional benefit. However, for seizure freedom, the highest BRV efficacy was at 100 mg daily dose. Cochrane review also stated this drug to be six times more likely to induce seizure freedom as an adjuvant than a placebo, with moderate quality of evidence. Greater than 50% seizure frequency reduction was the primary outcome of this analysis, and BRV was twice as effective as PBO in achieving it. A pooled analysis of three randomized controlled trials (Biton et al., Klein et al., Ryvlin et al.) showed static or improved Health-related Quality of Life (HRQL) scores with BRV, as compared to the placebo. The quality of life benefit was most extensive in patients who showed a response (>50% seizure reduction) to BRV.
In the present meta-analysis, our main aim was to assess BRV in FOS as an early adjuvant (add-on drug). The dose-specific response has not been addressed here. Data on patients receiving three concomitant anti-epileptic drugs was not sufficient and could not be synthesized. As the randomized controlled trials used in this review were short term (7-16 weeks), the main limitation of this analysis is the lack of information on the long-term outcomes. Moreover, most of these studies included in the present analysis had excluded patients with focal aware non-motor seizures. The effect of Vagus Nerve Stimulation (VNS) was discounted. Only one research included (Kwan et al.) mentions the status of VNS included as stable. The VNS data about other studies is unclear in the journal text (details available in supplementary table: Risk of Bias assessment ROB2 tool). Also, in all these studies included, VNS was not considered as an added anti-epileptic drug.
Summarizing, BRV could be an effective and well tolerated add-on drug for FOS in subjects over 16 years old and has been FDA approved as an adjuvant for treatment of FOS in that age group. Ongoing open-label long-term extension follow-up study results may throw light on the long-term efficacy of BRV as an anti-epileptic.
Brivaracetam usage in other indications
Detailed analysis of other indications of BRV was deemed unyielding owing to a lack of Randomized Controlled Trials on these indications. However, a comprehensive review was done.
Brivaracetam as an adjuvant in generalized epilepsies
Synaptic vesicle glycoprotein (SV2A) has implications in focal and generalized onset epilepsies. It has hence been proposed that drugs acting on SV2A would have broad-spectrum anti-convulsant action. There is a high correlation between anti-convulsant potency, and SV2A binding affinity that has been proven on models like mice audiogenic seizures, corneal kindling and generalized epilepsy in rats.
However, in the clinical trials so far, the subset of generalized epilepsies was negligible. Kwan et al. had included 49 patients (10.2%) with primary generalized epilepsy with two or more seizures per month and demonstrated a seizure reduction from 1.42 to 0.63 seizure days/week which translated to 42.6% seizure reduction; and 44.4% of them had >50% responder rate, which was higher than placebo. However, in this study, demography and epilepsy characteristics were not well balanced. Sterzelczyk et al. reported that this drug was well tolerated in refractory genetic generalized epilepsy, and response rates were similar to that of patients with focal epilepsies. This study had recruited 61 patients with generalized refractory epilepsy, of these, 23 had myoclonic seizures, and 19 had absence seizures, and two patients had absence status epilepticus. Patients with juvenile myoclonic epilepsy showed a response rate as high as 60%, with 40% attaining seizure freedom. For absence seizures, 50% responder rate was 36.8%, and 26.3% out of total 19 patients were seizure-free. Of these three patients had childhood absence epilepsy; these three, along with the other 63. 2% of generalized of BRV; however, much lower doses also achieved a significant epilepsy patients with absence seizures had not responded to BRV. In a retrospective cohort study on 37 patients with Idiopathic generalized epilepsy, 11 patients responded, and six of these attained seizure freedom. Fourteen of them were drug-refractory. BRV did not significantly reduce myoclonus in Unverricht- Lundborg disease (EPM1), but an aggravation of myoclonus was not seen.
In a small study on 18 patients with photosensitive epilepsy, single-dose BRV effectively suppressed the photo paroxysmal EEG responses in 17 of them. The median response was seen as early as after 30 minutes of administration and for as long as 59.5 hours, indicating the prolonged duration of response to BRV.
Overall, BRV though seemingly beneficial in Genetic generalized epilepsies with Generalized tonic-clonic movements and myoclonus, its efficacy needs to be established. Its effect on absence seizures is limited by the fewer numbers, in case reports showing exceptional benefits, in observational studies showing unfavorable response and requires validation in a greater number of subjects.
Brivaracetam in status epilepticus
BRV has higher permeability facilitating faster entry and distribution into the brain (few minutes compared to 1 h for LEV), and speedier occupancy of SV2A receptors following intravenous administration. This is consistent with non-human primate studies and audiogenic mice seizure assay. Rat models of self-sustaining status epilepticus and acute repetitive seizures showed a promising response to intravenous BRV. This response was significant for high doses of BRV; however, much lower doses also achieved a significant response in reducing the spontaneous recurrent seizures, spike frequency, and the total seizure time when combined with diazepam. The faster kinetics, better tolerance, more lipid solubility, intravenous availability, all weigh in favor of BRV as a potential for treatment in status epilepticus. A case series in eight patients with refractory and three patients with super refractory status epilepticus showed a low success rate of 27%. Another case series with seven patients with convulsive and non-convulsive status epilepticus showed immediate seizure cessation in two, and early EEG regression of Status epilepticus in three patients. They noted that response was more in patients with early-stage status epilepticus. The most extensive retrospective observational study on status epilepticus with 43 patients reported about 50% improvement with BRV. Five of these patients had Idiopathic Generalized Epilepsy, three of these with myoclonic component responded, and the other two with absences did not. In the former, a rapid response was seen. An early response was also seen with higher doses of 300 mg (>1.85 mg/kg), and more initial administration of BRV. This dose-related effect and 50% responder rate was seen in another retrospective case series with status epilepticus with 11 patients. However, the clinical evidence is not sufficient for usage of BRV as a first-line Anti-epileptic drug in status epilepticus. Hence its efficacy in Status epilepticus and its subtypes like Focal, Generalized, Myoclonic, and Absence in different stages of Status epilepticus requires further randomized controlled trials for validation.
Brivaracetam as monotherapy in focal seizures
Although approved as monotherapy for FOS, evidence for BRV efficacy for the same is still scarce. Prediction models were used to simulate BRV monotherapy dose from the BRV as add-on agent Randomized controlled trials. BRV was recommended in the same dose for monotherapy, as in the add-on trials. Two conversion to monotherapy randomized controlled trials with historical control data had tried BRV in 50 and 100 mg/day doses as monotherapy while tapering previous one or two anti-epileptic drug in patients with uncontrolled focal seizures. Both these trials were terminated because of a very high discontinuation rate (65.3%) owing to lack of efficacy. FDA, however, no longer requires conversion to monotherapy trials for approving indication for Anti-epileptic drug monotherapy. In September 2017, US FDA approved BRV as monotherapy for focal seizures in subjects older than 16 years.
Brivaracetam as monotherapy in idiopathic generalized epilepsy
Exhaustive data on BRV as monotherapy in Idiopathic Generalized Epilepsy patients are lacking. In a retrospective cohort study on adult patients with Idiopathic Generalized Epilepsy that had assessed 37 subjects on BRV, 32.4% had received BRV as monotherapy (n = 12), of these 11 had responded, and ten were seizure-free. It could be a suitable option in these patients, but data with respective subtypes of Idiopathic generalized epilepsies like the Juvenile Myoclonic Epilepsy or Childhood Absence Epilepsy is lacking.
Brivaracetam in the pediatric population
FDA has recently approved the use of oral BRV for the pediatric population as well, in patients four years and older, as an adjunctive anti-epileptic drug in patients with FOS with or without bilateral tonic-clonic seizures. The approved doses are according to body weight. For children weighing 20-50 kg, the initial dose is 0.5 to 1 mg/kg twice daily, and the maintenance dose is 1-4 mg/kg/day. For patients weighing 11-20 kg, the corresponding dose ranges are 1-2.5 mg/kg/day and 5 mg/kg/day. Studies have shown that BRV, when administered at a dose of 2.0 mg/kg with a maximum of 100 mg twice a day for a bodyweight >50 kg; gave a steady-state plasma concentration similar to that of adults. BRV was assessed in a phase IIa, single-arm trial in infants of a month or more age until children with 16 years of age (total n = 100) suffering from the focal or generalized or undetermined onset seizures. These subjects were on one or more anti-epileptic drug and had one or more seizures in three weeks before the recruitment. The exact degree of drug refractoriness in these children was, however, unknown. 66.7% of these children had mild to moderate treatment-emergent adverse effects, and about 6.1% had serious adverse effects mandating discontinuation. An exploratory efficacy at three weeks for these subjects was 21.3% of all patients having >50% responder rates, and it rose to 29.7% in focal epilepsy patients. This study is further continued as the ongoing long-term follow-up phase III open-label single-arm study recruiting 206 children. A retrospective post-marketing surveillance showed a higher >50% responder rate of 47% in 34 children with focal epilepsy. Adolescents and children with difficult to control genetic generalized epilepsy have also been tested in small numbers (n = 10) in a study, three of whom had shown a response to BRV.
Usage of Brivaracetam in special situations
The role of BRV in Pregnancy, lactation, and its usage in epileptic encephalopathy in patients who received LEV, is discussed here.
Pregnancy and lactation
BRV has not been adequately tested in pregnant women. In animal studies, developmental side effects were seen. In rat studies, BRV was found excreted in milk.
In a multicenter retrospective study, 30-45% of the epileptic encephalopathy patients attained >50% response in seizure reduction, and 9% of these were seizure-free, and the drug was well tolerated. However, if this efficacy translates into an improvement in cognitive and quality of life outcomes is unknown.
Patients who were on Levetiracetam
Most of the randomized controlled studies included subgroups in the form of subjects who were LEV naïve, ones on concomitant LEV, and on prior LEV, though the proportion of patients on concomitant LEV was small in these trials (<20%), and no conclusions could be drawn. However, Ryvlin et al. and Kwan et al. reported that LEV naïve patients and those with prior LEV-exposure had better results than those receiving concomitant LEV., A previous meta-analysis concluded that BRV had greater efficacy in LEV naïve patients, hypothesized as being due to occupancy of SV2A receptors by LEV at the time of BRV administration when concomitantly given. For both LEV as well as BRV, maximal efficacy was seen at middle doses (3 g LEV, 200 mg BRV), doses higher than these not conferring higher efficacy. There is no significant difference between the responder rate between BRV dose of 50 mg/day and LEV dose of 1000 mg/day, according to another meta-analysis. Zahnert et al. reported that patients who were previously tried on LEV and had adverse effects had a meaningful reduction in the adverse effects and no emergence of previous side effects on switching to BRV. An immediate switch from LEV to BRV at 10-15:1 is possible., In a study done in Germany, 43 persons with epilepsy on LEV were switched to BRV without any complications; however, 60% of these subjects were switched back to LEV, due to no change in seizure control. In five of these patients, the seizure frequency and severity worsened after starting BRV; however, switching back to LEV was not associated with any adverse effects either.
Adverse effects of Brivaracetam
Most of the clinical trials' adverse effects were mild to moderate, with few serious ones [Table 3]. A meta-analysis of eight Randomized Controlled Trials concluded that psychiatric adverse effects and the adverse effects needing withdrawal were not significantly associated with BRV treatment. The studies that were included in this meta-analysis had used BRV as an adjuvant anti-epileptic drug. Psychiatric side-effects were the commonest cause of discontinuation in the randomized controlled trials mentioned in this analysis. The withdrawal rates resulting from these psychiatric adverse effects were similar for both BRV and Placebo. Significant adverse effects found were dizziness (as against LEV), fatigue, and back pain. Somnolence and dizziness were the only dose-related side effects. Suicidal ideation was noted only in one study, one in 100 and 200 mg study groups each, equal to that in the placebo group (one patient). The incidence of behavioral adverse effects with BRV in the Randomized controlled trials ranged from 3-12.3% [Table 3]. However, Zahnert et al. reported higher behavioral adverse effects in their case series (22.6%). This discordance from previous Randomized controlled studies could be because of the exclusion of patients with serious psychiatric disorders in previous trials. In contrast to the Randomized controlled trials on BRV, Zahnert et al. had included 45.2% of patients with psychiatric comorbidities.
Tolerability profile of BRV might be better than other newer adjuvants like perampanel and eslicarbazepine when used in the highest effective doses. Doses up to 50 mg per day have been found to have less dysphoria, euphoria, and sedative effects when compared to a drug like alprazolam having clear cut addiction potential. However, higher doses of 200 mg and above had shown comparability with alprazolam in terms of drug liking and feeling high with minimal sedative effects. Overall, it has been placed in schedule V drugs, indicating a lower potential for abuse.
Available strengths and formulations
Across the globe, BRV is available as 10 mg, 25 mg, 50 mg, 75 mg and 100 mg film-coated tablets, 10 mg/ml oral solution and 10 mg/ml solution for bolus injection/infusion. In India, tablets are available at 50 mg and 100 mg strengths. BRV film-coated tablets contain lactose. Hence, it prudent to avoid BRV in rare hereditary conditions, such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
The injectable formulation is available at 50 mg/5 mL and is desirable for rapid administration in status epilepticus. At present, though, injectable BRV is FDA approved for in the treatment of focal epilepsy only, for subjects beyond 16 years, in whom oral administration is not possible. This formulation is not yet available in India.
BRV is an effective early (first or second) adjuvant in short-term control of FOS in individuals >16 years of age and on 1-2 concomitant drugs. Like its predecessor, it is well tolerated in patients with renal and hepatic failure and has minimal drug interactions. BRV has an added advantage of being efficacious in FOS, even in LEV unresponsive subjects, and has a faster onset of action. BRV could be an effective alternative in patients intolerant to LEV. This newer drug also can easily be switched over LEV overnight. However, its long-term effects need further evaluation. Unlike LEV, BRV's efficacy in Idiopathic Generalized Epilepsy is still subject to clinical trials. Also, the efficacy of BRV as monotherapy in FOS, and efficacy in children (though approved by the FDA) is not yet fully established. Efficacy of BRV as monotherapy in FOS, along with the drug tolerance and adverse effect profile, needs better elucidation with more studies.
Dr. Sudhir Kumar, Consultant Neurologist, Apollo Health City, Jubilee Hills- general support for writing the article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]