Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study Academic research paper on "Clinical medicine"

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Title: Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc

Authors: Ali A. Asadi-Pooya, Michael R. Sperling, Steve Chung, Pavel Klein, Anyzeila Diaz, Sami Elmoufti, Jimmy Schiemann, John Whitesides

PII: DOI:

Reference:

S0920-1211(16)30278-9

http://dx.doi.Org/doi:10.1016/j.eplepsyres.2017.02.007 EPIRES 5687

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Epilepsy Research

Received date: Revised date: Accepted date:

2-11-2016

15-12-2016

23-2-2017

Please cite this article as: Asadi-Pooya, Ali A., Sperling, Michael R., Chung, Steve, Klein, Pavel, Diaz, Anyzeila, Elmoufti, Sami, Schiemann, Jimmy, Whitesides, John, Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study.Epilepsy Research http://dx.doi.org/10.1016Zj.eplepsyres.2017.02.007

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Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: a post-hoc study

Ali A. Asadi-Pooya a,*3 Michael R. Sperling a, Steve Chung b, Pavel Klein c, Anyzeila Diaz d, Sami Elmoufti e, Jimmy Schiemann John Whitesides e

a Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA b Banner University Medical Center, Phoenix, AZ, USA cMid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA d UCB Pharma, Smyrna, GA, USA e UCB Pharma, Raleigh, NC, USA

t Employee of UCB Pharma at the time when the studies and analysis were conducted

* Corresponding author: Ali A. Asadi-Pooya, MD, Department of Neurology, Thomas Jefferson University, 901 Walnut Street, Suite 435, Philadelphia, PA19107, USA. Tel.: +1 215 955 1222; Fax: +1 215 955 3745; E-mail: aliasadipooya@yahoo.com (A.A. Asadi-Pooya).

Highlights

• Post-hoc analysis in patients who failed common AEDs (LEV, CBZ, TPM, LTG)

• Previous treatment failure with some other AEDs can predict reduced response to BRV

• Previous treatment failure with LEV does not preclude BRV use in epilepsy patients

• A similar pattern was seen for treatment failure with CBZ, TPM, or LTG

ABSTRACT

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new

antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with

epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in

patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to

the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies

(NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs

who received placebo or BRV 50-200 mg/day without titration over a 12-week treatment period.

Patients taking concomitant LEV at enrollment were excluded from this analysis. Patients were

categorized by their status of prior exposure to levetiracetam (LEV), carbamazepine (CBZ),

topiramate (TPM), or lamotrigine (LTG), to investigate any consistent trend toward reduced

response in AED-exposed subgroups compared to AED-nai've subgroups, regardless of the

mechanism of action. Study completion rates, percent reduction from baseline in focal seizure

frequency over placebo, >50% responder rates, and tolerability were evaluated for each subgroup.

A total of 1160 patients were investigated. Study completion rates were similar in the AED-exposed subgroups and AED-naive subgroups. In subgroups with (531 patients) or without (629 patients) prior LEV exposure, >50% responder rates for each dose of BRV compared with placebo were generally higher among the LEV-naive subgroups than the previously LEV-exposed subgroups. LEV-exposed subgroups receiving BRV doses >50 mg/day showed greater >50% responder rates than those receiving placebo. Similar results were observed for CBZ, TPM, and LTG. Previous treatment failure with commonly prescribed AEDs (LEV, CBZ, TPM, or LTG) is associated with a reduced response to BRV irrespective of the mechanism of action. Hence, this post-hoc analysis indicates that previous treatment failure with LEV does not preclude the use of BRV in patients with epilepsy.

Keywords:

Antiepileptic drug

Brivaracetam

Efficacy

Tolerability

Failure

1. Introduction

Brivaracetam (BRV) is a new antiepileptic drug (AED) derived from a targeted drug discovery program (Klitgaard et al., 2016). BRV is a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A) (Gillard et al., 2011). Its binding affinity with SV2A is higher than that of levetiracetam (LEV), another SV2A ligand (Gillard et al., 2011). The tolerability and efficacy of adjunctive BRV in patients with drug-resistant focal (partial-onset) seizures with or without secondary generalization have been investigated and demonstrated in three pivotal Phase III studies (Biton et al., 2014; Klein et al., 2015a; Rheims and Ryvlin, 2014). One recent meta-analysis (Ma et al., 2015) identified five randomized, controlled trials of BRV in the treatment of drug-resistant focal epilepsies and included a total of 1639 patients. This meta-analysis demonstrated a statistically significant improvement in seizure control compared with placebo, and favorable tolerability of therapeutic doses of BRV (50-200 mg/day) as an adjunctive treatment for drug-resistant focal epilepsy.

Approximately one-third of individuals with epilepsy have inadequate seizure control despite the use of appropriate AEDs (Kwan and Brodie, 2000b). In addition, treatment in patients with epilepsy is often complicated by the unpredictability of the efficacy of any given AED. This uncertainty of response, particularly in patients with drug-resistant seizures, may obfuscate the use of any newly developed AED (Kwan et al., 2010). This is particularly important if the newly developed AED has similarities to an already existing AED. For example, it is helpful to know whether failure of a currently available AED, such as LEV, precludes the prescription of a newly developed AED (i.e. BRV) that also targets one of the same molecular sites of action. It is noteworthy that BRV differs significantly from LEV by its selective, high affinity, and differential

interaction with SV2A, as well as a higher lipophilicity, correlating with a more rapid brain penetration in preclinical studies (Klitgaard et al., 2016). BRV also differs from LEV by neither inhibiting the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (Margineanu and Klitgaard, 2002; Rigo et al., 2004) nor the high voltage-activated calcium channels at therapeutically relevant concentrations (Klitgaard et al., 2016; Niespodziany et al., 2015; Pisani et al., 2004). In a post-hoc analysis of study N01358, efficacy with adjunctive BRV was demonstrated in subgroups with prior LEV exposure and also in LEV-nai've patients, but the response appeared to be greater in the LEV-nai've population (Klein et al., 2015a). The aim of the current post-hoc analysis was to explore the efficacy of adjunctive BRV in patients with or without prior LEV exposure in a larger patient population pooled from three Phase III studies, and to determine whether any observed trend towards reduced efficacy in LEV-exposed patients compared with LEV-nai've patients was related to mechanism of action. Some other commonly prescribed AEDs [carbamazepine (CBZ), lamotrigine (LTG), and topiramate (TPM)] were also investigated to see whether prior exposure to these drugs was related to BRV efficacy. Tolerability data were evaluated for each subgroup. These data may be helpful in the decision-making process when considering the use of BRV for patients who have previously failed other AEDs.

2. Methods

This is a post-hoc analysis of data pooled from three Phase III studies (N01252, NCT00490035; N01253, NCT00464269; N01358, NCT01261325) (Biton et al., 2014; Klein et al., 2015a; Rheims and Ryvlin, 2014). All patients included in this analysis were randomized to BRV 50, 100, and 200 mg per day or placebo. Patients who were on concomitant LEV at the time of enrollment were excluded from this analysis. Patients were categorized by their status of prior

exposure to LEV, CBZ, TPM, or LTG. We defined AED-naive as "never having been exposed to that particular AED" and AED-exposed as "having been exposed to that particular AED" (during the past 5 years for studies N01252 and N01253, and during the patient's lifetime before study entry for study N01358). For AED-exposed patients, that specific AED had to have been discontinued at least 90 days prior to enrollment in the Phase III study. Demographic and baseline epilepsy characteristics, and the number (%) of patients who completed the study, were summarized for each subgroup.

The efficacy population comprised all randomized patients who received at least one dose of study drug and had at least one post-baseline seizure diary entry. Percent reduction from baseline in focal seizure frequency over placebo, and >50% responder rates, were evaluated for each subgroup of patients. A further subgroup analysis was conducted for >50% responder rate based on the number of prior AEDs (<2, 3-5, and >6). This subgroup analysis was conducted on a modified efficacy population that included patients taking concomitant LEV. In this analysis, a prior AED was defined as any AED that was taken previously and/or concomitantly at study entry.

Treatment group comparisons (BRV >50 mg/day vs. placebo) for >50% responder rates were based on a logistic regression model with >50% responder rate as the outcome, and with effects for treatment, study, and log-transformed baseline focal seizure frequency as a continuous covariate. The logistic regression model was used to examine the relationship between the >50% responder rate and a set of predictor variables. The model used a logit transformation of the outcome, which is the log of the odds or the ratio of the probability of the outcome (yes for >50% response) to the probability of no outcome (no for >50% response). All statistical analyses were exploratory.

Details of the study population, efficacy assessments, safety and tolerability assessments, and ethical issues are explained in the previous Phase III studies (Biton et al., 2014; Klein et al., 2015a; Rheims and Ryvlin, 2014).

3. Results

A total of 1160 patients were included in this analysis. Overall, 531 patients had previously been exposed to LEV and 629 were LEV-nai've. Demographic and baseline epilepsy characteristics are shown in Table 1. Demographic characteristics were similar between the AED-exposed and AED-nai've subgroups. However, the proportion of patients who had previously failed at least 5 AEDs was higher among previously LEV-, CBZ-, TPM-, and LTG-exposed subgroups (61-69%) than among subgroups who had never taken those particular AEDs (13-17%).

Numbers of patients enrolled, study completion (retention) rates, and percent reduction from baseline in focal seizure frequency over placebo for each subgroup of patients are shown in Tables 2-5, and >50% responder rates for each subgroup of patients are shown in Figure 1.

Retention rates, which are predominantly a reflection of tolerability, were similar in the AED-exposed and AED-nai've subgroups. The 12-week retention rates during the study period were >84% in all subgroups (all doses and all drugs) (Tables 2-5).

Percent reduction from baseline in focal seizure frequency over placebo was numerically greater in BRV-treated, LEV-nai've subgroups than in BRV-treated, LEV-exposed subgroups (Table 2). A similar pattern was seen for subgroups with and without prior exposure to CBZ, TPM, and LTG (Tables 3-5).

The >50% responder rates for BRV compared with placebo were higher among the LEV-nai've subgroups than the LEV-exposed subgroups (Figure 1A). However, LEV-exposed subgroups receiving BRV doses >50 mg/day showed higher >50% responder rates than corresponding placebo subgroups. Similar results were observed in subgroups with or without prior CBZ, TPM, and LTG exposure, although the differences between the corresponding AED-exposed and AED-nai've subgroups for BRV versus placebo were less marked for CBZ and LTG (Figures 1B, 1C, and 1D).

Responder rates for subgroups of patients with <2, 3-5, and >6 prior AED exposures are shown in Table 6. When the number of prior AEDs was 3-5, the LEV-nai've subgroup showed a greater response with BRV, compared with placebo, than the LEV-exposed subgroup. A similar trend was observed with other AEDs (i.e. CBZ, TPM, and LTG). In subgroups with <2 prior AEDs, the number of patients was too small for statistical analysis. No clear pattern was seen in subgroups with >6 prior AED exposures.

4. Discussion

BRV is a new AED that has demonstrated efficacy as an adjunctive treatment for adults with focal epilepsies and has been shown to be well tolerated (Biton et al., 2014; Klein et al., 2015a; Kwan et al., 2014; Rheims and Ryvlin, 2014). A previous post-hoc analysis indicated that adjunctive BRV was effective both in subgroups of patients with prior exposure to LEV and in those who were LEV-naive, although the effect appeared to be greater in the LEV-naive population (Klein et al., 2015a). In the current post-hoc analysis, we investigated whether prior exposure to -and failure of - specific, commonly used AEDs (i.e. LEV, CBZ, TPM, or LTG) is a marker for

lack of response to BRV in patients with drug-resistant focal epilepsy, a hypothesis that was not confirmed by the results.

AED treatment in patients with epilepsy is often complicated by many factors, including the unpredictability of efficacy (Kwan et al., 2010). It has been observed that, if the first appropriately chosen AED is not efficacious in controlling seizures, the outcome with respect to seizure control is less favorable with the next prescribed AED (Kwan and Brodie, 2000a). In a cohort of 478 patients who received newly administered AED treatments in a single epilepsy clinic (Schiller and Najjar, 2008), the response to newly administered AEDs was highly dependent on the past treatment history. Seizure freedom rates decreased from 61.8% for the first AED to 41.7%, 16.6%, and 0% after 1, 2-5, and 6-7 prior AED failures, respectively. In the current study, we observed that BRV, compared with placebo, is more efficacious in AED-nai've subgroups than in those who have previously been exposed to any of the particular AEDs tested (i.e. LEV, CBZ, TPM, and LTG). In other words, exposure to prior AEDs can predict a reduced response to BRV. It is likely that mechanism of action does not play a major role in this phenomenon, as we observed similar trends with prior exposure to AEDs with different mechanisms of action. We also did not see a consistent pattern of response in subgroups of patients who had previously been exposed to >6 AEDs. Because patients with >6 prior AED failures are highly unlikely to respond to the next AED, this may be a sufficient reason to exclude this subgroup from the design of future AED trials.

There are various factors that may contribute to the reduced efficacy observed in different patient populations. Genetic variations may explain some of the inter-individual variability in response to AEDs among patients (Franco and Perucca, 2015; Shaheen et al., 2014). The number of previously tried and failed AEDs, which is indicative of drug resistance and severity of epilepsy,

may also explain reduced drug responses observed among patients with refractory epilepsy (Klein et al., 2015b; Schiller and Najjar, 2008; Voll et al., 2015). Another plausible mechanism of drug resistance is the overexpression of multidrug efflux transporters, such as P-glycoprotein (P-gp), which would result in lower interstitial levels of AEDs surrounding the epileptogenic tissue (Loscher, 2005; Schmidt and Loscher, 2005; Sisodiya et al., 2002). Animal and human studies support the multidrug transporter hypothesis of multidrug-resistant epilepsy (Asadi-Pooya et al., 2013; Lazarowski and Czornyj, 2011).

Despite the observed reduced efficacy of BRV in AED-exposed subgroups compared to AED-nai've subgroups, BRV was more efficacious when compared with placebo in the AED-exposed subgroups. This observation was consistent for all the investigated prior AEDs. Therefore, BRV was efficacious for the treatment of focal epilepsies even in patients who had been previously exposed to and failed other commonly prescribed AEDs. This is an important finding and offers promise for patients with multidrug-resistant epileptic seizures.

With respect to BRV tolerability, we observed that retention rates were reasonably high (84.8-93.8%) in all dose groups. In several previous studies, including the original studies for the current analysis, BRV has demonstrated a good safety and tolerability profile (Biton et al., 2014; Klein et al., 2015a; Rheims and Ryvlin, 2014). In a small, open-label, prospective, exploratory study of 29 patients with epilepsy switching from LEV to BRV (Yates et al., 2015), non-psychotic behavioral adverse events were evaluated. At the end of the treatment period, 93.1% of patients that switched to BRV had clinically meaningful reductions in behavioral adverse events. Mean change from baseline to Week 12 in Patient-Weighted Quality of Life in Epilepsy Inventory-Form-31 (QOLIE-31-P) total score was 12.1, indicating improved health-related quality of life. These

data suggest that BRV may have a better profile with respect to behavioral adverse events compared with LEV (Yates et al., 2015).

As this was a post-hoc study, the results of our analysis should be viewed as exploratory and require confirmation by prospective studies. Furthermore, all p-values in this study should be considered in the context of an exploratory analysis. In addition, the numbers of patients in some of the subgroups were too small for valid statistical analysis.

In conclusion, while prior exposure to commonly prescribed AEDs (LEV, CBZ, TPM, and LTG) is associated with a reduced response to BRV, this effect is seen irrespective of the mechanism of action. This is consistent with the previous studies cited above, showing that the likelihood of response to any AED decreases as the number of prior AEDs increases. This post-hoc analysis therefore indicates that previous treatment failure with LEV does not preclude the use of BRV.

Funding

UCB Pharma was responsible for the design and conduct of the original Phase III studies, and the collection, management, and analysis of the data. The post-hoc analysis reported here was sponsored by UCB Pharma. The authors developed the first and second drafts of the manuscript and approved the content of the final version. Editorial support was provided by Jennifer Stewart, MSc (QXV Communications, an Ashfield Business, Macclesfield, UK), which was funded by UCB Pharma.

Disclosures

Ali A. Asadi-Pooya has acted as a consultant for Cerebral Therapeutics, LLC, and UCB Pharma. Michael R. Sperling has received research grants awarded to Thomas Jefferson University from Eisai, UCB Pharma, Sunovion, SK Life Sciences, Marinus, Lundbeck, Medtronics, Accorda, Upsher-Smith, Brain Sentinel, Glaxo, Pfizer, and Neurelis, and has acted as a consultant for Medtronics through Thomas Jefferson University. Steve Chung has acted as a speaker or consultant for Lundbeck, UCB Pharma, Sunovion, Upsher-Smith, and Eisai, and has received research funding from Lundbeck, UCB Pharma, Upsher-Smith, and SK Life Science. Pavel Klein has served on speakers' bureau for UCB Pharma, Sunovion, and Eisai, has participated in advisory boards for UCB Pharma, Sunovion, and Lundbeck, and has received research support from Lundbeck and Eisai. Anyzeila Diaz, Sami Elmoufti, and John Whitesides are employees of UCB Pharma. Jimmy Schiemann was an employee of UCB Pharma at the time when the studies and analysis were conducted and is now employed by Teva Pharmaceuticals.

Acknowledgments

The authors wish to thank the patients, their caregivers, and the investigators and their teams who contributed to the original studies. The authors acknowledge Cedric Laloyaux, Strategic Publication Lead Neurology, UCB Pharma, for critical review of the manuscript and coordination of manuscript development.

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Figure legends

Figure 1 >50% responder rates in patients treated with brivaracetam, with or without prior levetiracetam (A), carbamazepine (B), topiramate (C) or lamotrigine (D) exposure (efficacy population).

^-values (BRV vs. placebo) are derived from a logistic regression model with effects for treatment, study, and log-transformed baseline focal seizure frequency as a continuous covariate. All ^-values are exploratory. The efficacy population comprised randomized patients who received at least one dose of study drug and had at least one post-baseline seizure diary entry; patients taking concomitant LEV were excluded.

BRV, brivaracetam; CBZ, carbamazepine; LEV, levetiracetam; LTG, lamotrigine; TPM, topiramate.

Table 1 Demographic and baseline epilepsy characteristics, by prior exposure to levetiracetam, carbamazepine, topiramate, or lamotrigine (efficacy population).

Levetiracetam Carbamazepine Topiramate Lamotrigine

Exposed Naive Exposed Naive Exposed Naive Exposed Naive

(n = 578) (n = 743) (n = 424) (n = 339) (n = 428) (n = 696) (n = 349) (n = 639)

Age, mean (SD), years 39.8 (13.3) 36.9 (12.6) 39.6 (13.5) 37.4 (14.2) 38.5 (12.8) 38.3 (13.4) 39.7 (13.2) 38.0 (13.1)

Female, n (%) 318 (55.0) 341 (45.9) 229 (54.0) 165 (48.7) 232 (54.2) 306 (44.0) 188 (53.9) 282 (44.1)

No. of prior AEDs, n (%)

0-1 29 (5.0) 304 (40.9) 24 (5.7) 136 (40.1) 11 (2.6) 280 (40.2) 5 (1.4) 263 (41.2)

2-4 176 (30.4) 343 (46.2) 140 (33.0) 145 (42.8) 123 (28.7) 310 (44.5) 107 (30.7) 280 (43.8)

>5 373 (64.5) 96 (12.9) 260 (61.3) 58 (17.1) 294 (68.7) 106 (15.2) 237 (67.9) 96 (15.0)

Baseline focal seizure frequency/ 11.0 7.9a 9.6 8.3 9.7 8.5b 11.3 8.0c

28 days, median (Q1, Q3) (6.4, 26.8) (5.0, 15.9) (5.8, 24.2) (5.5, 19.2) (5.8, 24.5) (5.3, 18.8) (6.1, 25.8) (5.1, 16.9)

The efficacy population comprised randomized patients who received at least one dose of study drug and had at least one post-baseline seizure diary entry; patients taking concomitant LEV were excluded.

an = 742, bn = 695, cn = 638; patients without baseline seizure frequency were excluded. AED, antiepileptic drug; Q1, first quartile; Q3, third quartile; SD, standard deviation.

Placebo

BRV BRV BRV BRV

50 mg/day 100 mg/day 200 mg/day >50 mg/day

LEV- Number of patients

exposed

Number of patients who completed the study (%)

184 (96.3) 43 (89.6)

Percent reduction from baseline in focal seizure -frequency over placebo

141 (89.2) 119 (88.8) 303 (89.1)

LEV- Number of patients 227 113 174 115 402

naïve Number of patients who completed the study (%)

212 (93.4) 104 (92.0) 158 (90.8) 106 (92.2) 368 (91.5)

Percent reduction from

baseline in focal seizure - 26.1 30.0 27.3 28.7

frequency over placebo

The efficacy population comprised randomized patients who received at least one dose of study drug and had at least one post-baseline seizure diary entry; patients taking concomitant LEV were excluded.

BRV BRV BRV BRV

Placebo 50 mg/day 100 mg/day 200 mg/day >50 mg/day

CBZ- Number of patients 143 34 113 98 245

exposed Number of patients who

137 (95.8) 31 (91.2) 100 (88.5) 88 (89.8) 219 (89.4)

completed the study (%)

Percent reduction from

baseline in focal seizure - 5.4 23.1 19.2 15.0

frequency over placebo

CBZ- Number of patients 103 46 89 58 193

Number of patients who

96 (93.2) 39 (84.8) 81 (91.0) 51 (87.9) 171 (88.6)

completed the study (%)

Percent reduction from

baseline in focal seizure - 23.3 30.3 17.7 26.4

frequency over placebo

The efficacy population comprised randomized patients who received at least one dose of study drug and had at least one postbaseline seizure diary entry; patients taking concomitant LEV were excluded.

BRV BRV BRV BRV

Placebo 50 mg/day 100 mg/day 200 mg/day >50 mg/day

TPM- Number of patients 123 38 115 104 257

exposed Number of patients completed the study (%) Percent reduction from 120 (97.6) 35 (92.1) 99 (86.1) 90 (86.5) 224 (87.2)

baseline in focal seizure - 13.1 17.9 18.2 13.1

frequency over placebo

TPM- Number of patients 212 113 170 117 400

naive Number of patients completed the study (%)

197 (92.9) 104 (92.0) 158 (92.9) 108 (92.3) 370 (92.5)

Percent reduction from

baseline in focal seizure - 24.4 29.6 31.3 28.6

frequency over placebo

The efficacy population comprised randomized patients who received at least one dose of study drug and had at least one postbaseline seizure diary entry; patients taking concomitant LEV were excluded.

Placebo

BRV BRV BRV BRV

50 mg/day 100 mg/day 200 mg/day >50 mg/day

LTG- Number of patients

exposed

Number of patients who completed the study (%)

102 (97.1) 24 (SS.9)

S3 (85.б)

74 (90.2)

Percent reduction from baseline in focal seizure -frequency over placebo

1S1 (S7.9)

LTG- Number of patients 202 9б 149 10б 351

naïve Number of patients who completed the study (%)

190 (94.1) 90 (93.S) 139 (93.3) 9б (90.б) 325 (92.б)

Percent reduction from

baseline in focal seizure - 2S.0 30.б 2S.5 29.1

frequency over placebo

The efficacy population comprised randomized patients who received at least one dose of study drug and had at least one postbaseline seizure diary entry; patients taking concomitant LEV were excluded.

Number of prior AEDs

<2 3-5 >6

Placebo BRV >50 mg/day Placebo BRV >50 mg/day Placebo BRV >50 mg/day

Number of patients 15 14 61 105 115 221

LEV-exposed >50% responder rate, n (%) 3 (20.0) 7 (50.0) p=0.128 15 (24.6) 37 (35.2) p=0.224 16 (13.9) 58 (26.2) p=0.010

Number of patients 94 180 106 178 27 44

LEV-naïve >50% responder rate, n (%) 23 (24.5) 84 (46.7) 23 (21.7) 75 (42.1) 5 (18.5) 19 (43.2)

p<0.001 p<0.001 p=0.088

Number of patients 12 20 56 94 82 153

CBZ-exposed >50% responder rate, n (%) 4 (33.3) 13 (65.0) p=0.034 16 (28.6) 39 (41.5) p=0.099 10 (12.2) 46 (30.1) p=0.007

Number of patients 54 89 52 90 18 40

CBZ-naïve >50% responder rate, n (%) 14 (25.9) 41 (46.1) 8 (15.4) 32 (35.6) 3 (16.7) 11 (27.5)

p=0.030 p=0.011 p=0.291

Number of patients 5 11 44 82 82 182

TPM-exposed >50% responder rate, n (%) 4 (80.0) 4 (36.4) p=0.150 13 (29.5) 31 (37.8) p=0.652 12 (14.6) 51 (28.0) p=0.025

Number of patients 92 180 108 197 40 62

TPM-naïve >50% responder rate, n (%) 19 (20.7) 79 (43.9) 23 (21.3) 74 (37.6) 6 (15.0) 18 (29.0)

p<0.001 p=0.003 p=0.058

Number of patients 10 12 33 53 71 157

LTG-exposed >50% responder rate, n (%) 0 (0) 6 (50.0) 5 (15.2) 20 (37.7) p=0.054 13 (18.3) 46 (29.3) p=0.109

Number of patients 84 160 109 162 29 56

LTG-naïve >50% responder rate, n (%) 20 (23.8) 73 (45.6) 22 (20.2) 61 (37.7) 3 (10.3) 17 (30.4)

p=0.001 p=0.003 p=0.045

All ^-values are exploratory. The modified efficacy population comprised randomized patients who received at least one dose of study drug and had at least one post-baseline seizure diary entry; patients taking concomitant LEV were included.

AED, antiepileptic drug; BRV, brivaracetam; CBZ, carbamazepine; LEV, levetiracetam; LTG, lamotrigine; TPM, topiramate.