Current Literature In Clinical Science
Will Brivaracetam Help My Patient? Only Time Will Tell
Efficacy and Safety of Brivaracetam for Partial-Onset Seizures in 3 Pooled Clinical Studies. Ben-Menachem E, Mameniškienė R, Quarato PP, Klein P, Gamage J, Schiemann J, Johnson ME, Whitesides J, McDonough B, Eckhardt K. Neurology 2016;87:314–323.
OBJECTIVE: To assess the efficacy, safety, and tolerability of adjunctive brivaracetam (BRV), a selective, high-affinity ligand for SV2A, for treatment of partial-onset (focal) seizures (POS) in adults. METHODS: Data were pooled from patients (aged 16–80 years) with POS uncontrolled by 1 to 2 antiepileptic drugs receiving BRV 50, 100, or 200 mg/d or placebo, without titration, in 3 phase III studies of BRV (NCT00490035, NCT00464269, and NCT01261325, ClinicalTrials. gov, funded by UCB Pharma). The studies had an 8-week baseline and a 12-week treatment period. Patients receiving concomitant levetiracetam were excluded from the efficacy pool. RESULTS: In the efficacy population (n = 1,160), reduction over placebo (95% confidence interval) in baseline-adjusted POS frequency/28 days was 19.5% (8.0%–29.6%) for 50 mg/d (p = 0.0015), 24.4% (16.8%–31.2%) for 100 mg/d (p < 0.00001), and 24.0% (15.3%–31.8%) for 200 mg/d (p < 0.00001). The ≥50% responder rate was 34.2% (50 mg/d, p = 0.0015), 39.5% (100 mg/d, p < 0.00001), and 37.8% (200 mg/d, p = 0.00003) vs 20.3% for placebo (p < 0.01). Across the safety population groups (n = 1,262), 90.0% to 93.9% completed the studies. Treatment-emergent adverse events (TEAEs) were reported by 68.0% BRV overall (n = 803) and 62.1% placebo (n = 459). Serious TEAEs were reported by 3.0% (BRV) and 2.8% (placebo); 3 patients receiving BRV and one patient receiving placebo died. TEAEs in ≥5% patients taking BRV (vs placebo) were somnolence (15.2% vs 8.5%), dizziness (11.2% vs 7.2%), headache (9.6% vs 10.2%), and fatigue (8.7% vs 3.7%). CONCLUSIONS: Adjunctive BRV was effective and generally well tolerated in adults with POS. CLASSIFICATION OF EVIDENCE: This analysis provides Class I evidence that adjunctive BRV is effective in reducing POS frequency in adults with epilepsy and uncontrolled seizures.
Commentary Brivaracetam (BRV) is the latest antiepileptic drug to reach the marketplace, and many clinicians are contemplating how they will use it, and in whom. BRV is a close cousin of levetiracetam (LEV), and both drugs are known to bind to the SV2A receptor. BRV binds to the SV2A receptor with an affinity that is 15- to 30-fold greater than LEV, although the interaction with the receptor may not be identical. In some animal models, BRV provides superior efficacy compared with LEV at maximum doses (1). Whether these differences will translate to an advantage over LEV in the clinic is uncertain. Since none of the phase III trials included a LEV comparison arm, the relative efficacy and tolerability of the two compounds remain unknown. Many prescribers will try to inform themselves by reading the available literature. Ben-Menachem and colleagues have made this task somewhat easier by providing a pooled analysis of the three pivotal phase III trials that led to the regulatory approval of BRV. This useful article provides information on the efficacy and tolerability seen in the three studies. The efficacy, at face value, is in line with many recently approved drugs, whereas tolerability appears somewhat better, at least at higher doses,
with overall fewer dropouts because of adverse events (2). When reviewing this data, clinicians will be looking for answers to pragmatic questions that can inform the use of the drug. Several of these are discussed below.
Epilepsy Currents, Vol. 17, No. 1 (January/February) 2017 pp. 35–36 © American Epilepsy Society
What Should Be Targeted as the Initial Maintenance Dose? The data on dose-response are confusing for BRV. In the meta-analysis, the higher doses of 100 and 200 mg did not differ from each other but were more efficacious than 50 mg.
When Initiating BRV, Is Titration Necessary? None of the phase III studies of BRV included titration. All patients in these studies began the dose to which they were randomized (20, 50, 100, or 200 mg) on the very first day. This was well tolerated, as demonstrated by the low number of adverse event–related dropouts (6–7.5%), and there was no rise in dropouts with increasing doses. All these data suggest that no titration will be needed in the clinic either. While this may very well be true, one only has to look at closely related LEV to see that studies and clinical use are not always the same. LEV was titrated in most studies, but in one study, either 2,000 or 4,000 mg was started without titration and appeared to be very well tolerated (in fact, fewer dropouts occurred on either dose than on placebo) (3). Despite this evidence, in practice some patients seem to do better when LEV is slowly titrated. Whether this will also be true for BRV remains to be seen.
35
Will Briviact Help My Patient?
The 50-mg dose has been effective in some studies, but not in others (4). Yet, in a flexible dose study (in which 20% of patients had idiopathic generalized epilepsy, and the rest had focal epilepsy) in which patients were started on 20 mg, but could be increased from 20 to 150 mg/d at the investigator’s discretion, only 72% of subjects were titrated up to 100 or 150 mg. The remainder were maintained on doses of 20 or 50 mg throughout the study (4). The FDA label suggests starting at 50 mg twice a day without titration, and down-titrating or up-titrating based on the effect (5). Again, it remains to be seen whether this strategy is optimal, and whether it will be followed in the clinic.
ued owing to treatment-emergent adverse events. The small sample size prevented a clear answer to whether an overnight switch can be recommended. Conclusion So, what is the bottom line? Essentially, that clinical trials can inform about several important drug characteristics, but at the end of the day, many important details can only be learned once a drug hits the market. At this point, we can hope that BRV provides an important benefit, is easy to use and well tolerated, but only time will tell. by Jacqueline French, MD
Will Patients Who Have Failed LEV for Efficacy or Tolerability Have Better Luck With BRV? Unfortunately, this meta-analysis did not address prior LEV exposure in an efficacy subanalysis (only the number of prior antiepileptic drugs [AEDs] and the presence or absence of inducing AEDs were analyzed, neither of which affected efficacy). Many of the patients who were included in this study had previously been exposed to LEV (slightly less than half in most arms), and Ben-Menachem and colleagues discuss that a prior meta-analysis found “efficacy” in patients with prior LEV exposure. In fact, the prior post hoc analysis, from one phase 3 study, suggested that LEV-naïve patients experienced better efficacy than patients who had been exposed to LEV previously, with a hint that patients who failed LEV because of the side effects did better than those who failed owing to lack of efficacy (6). However, the data on this topic remain slim. How Do I Switch Patients Already Taking LEV Onto BRV? Only two of the three studies in this meta-analysis allowed concomitant LEV exposure, and the number of subjects taking LEV was limited to 20%. The FDA indicates in the label that “BRIVIACT (BRV) provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered” (5). Nonetheless, it may commonly occur that patients receiving LEV have received insufficient benefit or have experienced side effects, and for this reason, their physician wishes to convert to BRV. A small study (29 patients) was performed in which patients who had experienced nonpsychotic behavioral adverse events on LEV, 1 to 3 g/d, were switched overnight to BRV, 100 mg twice a day (7). Most did well, but approximately onefourth required dose adjustments, and two patients discontin-
36
References 1. Klitgaard H, Matagne A, Nicolas JM, Gillard M, Lamberty Y, De Ryck M, Kaminski RM, Leclercq K, Niespodziany I, Wolff C, Wood M, Hannestad J, Kervyn S, Kenda B. Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia 2016;57:538–548. 2. Brigo F, Bragazzi NL, Nardone R, Trinka E. Efficacy and tolerability of brivaracetam compared to lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal epilepsy: Results of an indirect comparison meta-analysis of RCTs. Seizure 2016;42:29–37. 3. Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000;9:80–87. 4. Klein P, Tyrlikova I, Brazdil M, Rektor I. Brivaracetam for the treatment of epilepsy. Expert Opin Pharmacother 2016;17:283–295. 5. Full BriviactTM prescribing information. Center for Drug Evaluation and Research. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2016/205836Orig1s000_205837Orig1s000_205838Orig1s000Lbl.pdf. Accessed October 23, 2016. 6. Klein P, Schiemann J, Sperling MR, Whitesides J, Liang W, Stalvey T, Brandt C, Kwan P. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia 2015;56:1890–1898. 7. Yates SL, Fakhoury T, Liang W, Eckhardt K, Borghs S, D’Souza J. An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epilepsy Behav 2015;52(pt A):165–168.
Will Brivaracetam Help My Patient? Only Time Will Tell
Efficacy and Safety of Brivaracetam for Partial-Onset Seizures in 3 Pooled Clinical Studies. Ben-Menachem E, Mameniškienė R, Quarato PP, Klein P, Gamage J, Schiemann J, Johnson ME, Whitesides J, McDonough B, Eckhardt K. Neurology 2016;87:314–323.
OBJECTIVE: To assess the efficacy, safety, and tolerability of adjunctive brivaracetam (BRV), a selective, high-affinity ligand for SV2A, for treatment of partial-onset (focal) seizures (POS) in adults. METHODS: Data were pooled from patients (aged 16–80 years) with POS uncontrolled by 1 to 2 antiepileptic drugs receiving BRV 50, 100, or 200 mg/d or placebo, without titration, in 3 phase III studies of BRV (NCT00490035, NCT00464269, and NCT01261325, ClinicalTrials. gov, funded by UCB Pharma). The studies had an 8-week baseline and a 12-week treatment period. Patients receiving concomitant levetiracetam were excluded from the efficacy pool. RESULTS: In the efficacy population (n = 1,160), reduction over placebo (95% confidence interval) in baseline-adjusted POS frequency/28 days was 19.5% (8.0%–29.6%) for 50 mg/d (p = 0.0015), 24.4% (16.8%–31.2%) for 100 mg/d (p < 0.00001), and 24.0% (15.3%–31.8%) for 200 mg/d (p < 0.00001). The ≥50% responder rate was 34.2% (50 mg/d, p = 0.0015), 39.5% (100 mg/d, p < 0.00001), and 37.8% (200 mg/d, p = 0.00003) vs 20.3% for placebo (p < 0.01). Across the safety population groups (n = 1,262), 90.0% to 93.9% completed the studies. Treatment-emergent adverse events (TEAEs) were reported by 68.0% BRV overall (n = 803) and 62.1% placebo (n = 459). Serious TEAEs were reported by 3.0% (BRV) and 2.8% (placebo); 3 patients receiving BRV and one patient receiving placebo died. TEAEs in ≥5% patients taking BRV (vs placebo) were somnolence (15.2% vs 8.5%), dizziness (11.2% vs 7.2%), headache (9.6% vs 10.2%), and fatigue (8.7% vs 3.7%). CONCLUSIONS: Adjunctive BRV was effective and generally well tolerated in adults with POS. CLASSIFICATION OF EVIDENCE: This analysis provides Class I evidence that adjunctive BRV is effective in reducing POS frequency in adults with epilepsy and uncontrolled seizures.
Commentary Brivaracetam (BRV) is the latest antiepileptic drug to reach the marketplace, and many clinicians are contemplating how they will use it, and in whom. BRV is a close cousin of levetiracetam (LEV), and both drugs are known to bind to the SV2A receptor. BRV binds to the SV2A receptor with an affinity that is 15- to 30-fold greater than LEV, although the interaction with the receptor may not be identical. In some animal models, BRV provides superior efficacy compared with LEV at maximum doses (1). Whether these differences will translate to an advantage over LEV in the clinic is uncertain. Since none of the phase III trials included a LEV comparison arm, the relative efficacy and tolerability of the two compounds remain unknown. Many prescribers will try to inform themselves by reading the available literature. Ben-Menachem and colleagues have made this task somewhat easier by providing a pooled analysis of the three pivotal phase III trials that led to the regulatory approval of BRV. This useful article provides information on the efficacy and tolerability seen in the three studies. The efficacy, at face value, is in line with many recently approved drugs, whereas tolerability appears somewhat better, at least at higher doses,
with overall fewer dropouts because of adverse events (2). When reviewing this data, clinicians will be looking for answers to pragmatic questions that can inform the use of the drug. Several of these are discussed below.
Epilepsy Currents, Vol. 17, No. 1 (January/February) 2017 pp. 35–36 © American Epilepsy Society
What Should Be Targeted as the Initial Maintenance Dose? The data on dose-response are confusing for BRV. In the meta-analysis, the higher doses of 100 and 200 mg did not differ from each other but were more efficacious than 50 mg.
When Initiating BRV, Is Titration Necessary? None of the phase III studies of BRV included titration. All patients in these studies began the dose to which they were randomized (20, 50, 100, or 200 mg) on the very first day. This was well tolerated, as demonstrated by the low number of adverse event–related dropouts (6–7.5%), and there was no rise in dropouts with increasing doses. All these data suggest that no titration will be needed in the clinic either. While this may very well be true, one only has to look at closely related LEV to see that studies and clinical use are not always the same. LEV was titrated in most studies, but in one study, either 2,000 or 4,000 mg was started without titration and appeared to be very well tolerated (in fact, fewer dropouts occurred on either dose than on placebo) (3). Despite this evidence, in practice some patients seem to do better when LEV is slowly titrated. Whether this will also be true for BRV remains to be seen.
35
Will Briviact Help My Patient?
The 50-mg dose has been effective in some studies, but not in others (4). Yet, in a flexible dose study (in which 20% of patients had idiopathic generalized epilepsy, and the rest had focal epilepsy) in which patients were started on 20 mg, but could be increased from 20 to 150 mg/d at the investigator’s discretion, only 72% of subjects were titrated up to 100 or 150 mg. The remainder were maintained on doses of 20 or 50 mg throughout the study (4). The FDA label suggests starting at 50 mg twice a day without titration, and down-titrating or up-titrating based on the effect (5). Again, it remains to be seen whether this strategy is optimal, and whether it will be followed in the clinic.
ued owing to treatment-emergent adverse events. The small sample size prevented a clear answer to whether an overnight switch can be recommended. Conclusion So, what is the bottom line? Essentially, that clinical trials can inform about several important drug characteristics, but at the end of the day, many important details can only be learned once a drug hits the market. At this point, we can hope that BRV provides an important benefit, is easy to use and well tolerated, but only time will tell. by Jacqueline French, MD
Will Patients Who Have Failed LEV for Efficacy or Tolerability Have Better Luck With BRV? Unfortunately, this meta-analysis did not address prior LEV exposure in an efficacy subanalysis (only the number of prior antiepileptic drugs [AEDs] and the presence or absence of inducing AEDs were analyzed, neither of which affected efficacy). Many of the patients who were included in this study had previously been exposed to LEV (slightly less than half in most arms), and Ben-Menachem and colleagues discuss that a prior meta-analysis found “efficacy” in patients with prior LEV exposure. In fact, the prior post hoc analysis, from one phase 3 study, suggested that LEV-naïve patients experienced better efficacy than patients who had been exposed to LEV previously, with a hint that patients who failed LEV because of the side effects did better than those who failed owing to lack of efficacy (6). However, the data on this topic remain slim. How Do I Switch Patients Already Taking LEV Onto BRV? Only two of the three studies in this meta-analysis allowed concomitant LEV exposure, and the number of subjects taking LEV was limited to 20%. The FDA indicates in the label that “BRIVIACT (BRV) provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered” (5). Nonetheless, it may commonly occur that patients receiving LEV have received insufficient benefit or have experienced side effects, and for this reason, their physician wishes to convert to BRV. A small study (29 patients) was performed in which patients who had experienced nonpsychotic behavioral adverse events on LEV, 1 to 3 g/d, were switched overnight to BRV, 100 mg twice a day (7). Most did well, but approximately onefourth required dose adjustments, and two patients discontin-
36
References 1. Klitgaard H, Matagne A, Nicolas JM, Gillard M, Lamberty Y, De Ryck M, Kaminski RM, Leclercq K, Niespodziany I, Wolff C, Wood M, Hannestad J, Kervyn S, Kenda B. Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia 2016;57:538–548. 2. Brigo F, Bragazzi NL, Nardone R, Trinka E. Efficacy and tolerability of brivaracetam compared to lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal epilepsy: Results of an indirect comparison meta-analysis of RCTs. Seizure 2016;42:29–37. 3. Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000;9:80–87. 4. Klein P, Tyrlikova I, Brazdil M, Rektor I. Brivaracetam for the treatment of epilepsy. Expert Opin Pharmacother 2016;17:283–295. 5. Full BriviactTM prescribing information. Center for Drug Evaluation and Research. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2016/205836Orig1s000_205837Orig1s000_205838Orig1s000Lbl.pdf. Accessed October 23, 2016. 6. Klein P, Schiemann J, Sperling MR, Whitesides J, Liang W, Stalvey T, Brandt C, Kwan P. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia 2015;56:1890–1898. 7. Yates SL, Fakhoury T, Liang W, Eckhardt K, Borghs S, D’Souza J. An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epilepsy Behav 2015;52(pt A):165–168.
