Safety, tolerability and effectiveness of transition to eslicarbazepine acetate from carbamazepine or oxcarbazepine in clinical practice

Journal Pre-proof Safety, tolerability and effectiveness of transition to eslicarbazepine acetate from carbamazepine or oxcarbazepine in clinical practice Rodrigo Rocamora, Jukka Peltola, Giovanni Assenza, Rob McMurray, Vicente Villanueva

PII:

S1059-1311(19)30781-2

DOI:

https://doi.org/10.1016/j.seizure.2019.12.022

Reference:

YSEIZ 3627

To appear in:

Seizure: European Journal of Epilepsy

Received Date:

15 November 2019

Revised Date:

19 December 2019

Accepted Date:

21 December 2019

Please cite this article as: Rocamora R, Peltola J, Assenza G, McMurray R, Villanueva V, Safety, tolerability and effectiveness of transition to eslicarbazepine acetate from carbamazepine or oxcarbazepine in clinical practice, Seizure: European Journal of Epilepsy (2019), doi: https://doi.org/10.1016/j.seizure.2019.12.022

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Safety, tolerability and effectiveness of transition to eslicarbazepine acetate from carbamazepine

or

oxcarbazepine

in

clinical

practice

Rodrigo Rocamoraa,*, Jukka Peltolab, Giovanni Assenzac, Rob McMurrayd, Vicente Villanuevae aEpilepsy

Monitoring Unit, Department of Neurology, Hospital del Mar, Barcelona, Spain,

[email protected]; b

Department of Neurology, Tampere University and Tampere University Hospital, Tampere,

Finland, [email protected]; dEisai

Europe Ltd, Hatfield, Hertfordshire, UK, [email protected];

eHospital

*

Campus Bio-Medico di Roma, Rome, Italy, [email protected];

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cUniversità

Universitario y Politécnico La Fe, Valencia, Spain, [email protected]

Corresponding author

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Rodrigo Rocamora, MD, PhD, Epilepsy Monitoring Unit,

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Department of Neurology, Hospital del Mar, Passeig Marítim, 25–29,

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Barcelona, 08003, Spain

Highlights

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E-mail: [email protected]

Euro-Esli is the largest eslicarbazepine acetate (ESL) clinical practice study

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Some patients transitioned from carbamazepine (CBZ) and oxcarbazepine (OXC) to

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

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ESL 

At 12 months, ≥25% of patients who transitioned from CBZ and OXC were seizure free



ESL was generally well tolerated in patients who transitioned from CBZ and OXC

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ESL may be effective in patients for whom CBZ and OXC are ineffective/intolerable

ABSTRACT

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Purpose: To assess the efficacy, safety and tolerability of eslicarbazepine acetate (ESL) in patients transitioning from carbamazepine or oxcarbazepine to ESL in clinical practice, by analysing data from the Euro-Esli study. Methods: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness assessments included responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit), assessed after 3, 6 and 12 months of ESL treatment, and at the last visit. Safety and tolerability were assessed throughout follow-up by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Data were analysed for cohorts of patients who transitioned from carbamazepine and oxcarbazepine to ESL either due to lack of efficacy or poor tolerability.

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Results: Euro-Esli included 2058 patients, of whom 233 (11.3%) transitioned from carbamazepine to ESL and 134 (6.5%) transitioned from oxcarbazepine to ESL. After 12 months of ESL treatment, responder and seizure freedom rates for patients transitioning from carbamazepine due to lack of efficacy (n=163) were 70.0% and 30.9%, respectively. Corresponding values for patients transitioning from oxcarbazepine due to lack of efficacy

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(n=90) were 57.1% and 25.0%, respectively. Among patients who transitioned from carbamazepine and oxcarbazepine to ESL due to poor tolerability (n=64 and n=61,

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respectively), 26.6% and 39.5% experienced AEs, and 8.3% and 6.8% discontinued ESL due to AEs, respectively.

Conclusion: ESL was efficacious and generally well tolerated in patients transitioning from

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carbamazepine or oxcarbazepine in clinical practice due to inadequate seizure control or intolerable AEs with these agents.

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KEY WORDS: Carbamazepine; Clinical practice; Epilepsy; Eslicarbazepine acetate; EuroEsli; Oxcarbazepine

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Abbreviations

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AE, adverse event; AED, antiepileptic drug; CBZ, carbamazepine; CYP3A4, cytochrome P450 3A4; ESL, eslicarbazepine acetate; OXC, oxcarbazepine; SD, standard deviation

INTRODUCTION

Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug (AED) that is approved for the treatment of focal-onset seizures as monotherapy or adjunctive therapy [1, 2]. The efficacy and safety/tolerability of ESL as adjunctive therapy for focal-onset seizures in adults have been established in a series of randomised, double-blind, placebo-controlled, Phase III trials [3–6] and long-term extension studies [7–9]. The efficacy and safety/tolerability of ESL

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in the monotherapy setting have been established in a randomised, double-blind, activecontrolled, Phase III trial, conducted in patients with newly diagnosed focal epilepsy [10], and in two randomised, Phase III, withdrawal to monotherapy trials, conducted in patients with uncontrolled focal epilepsy [11, 12].

ESL is a member of the dibenzazepine family of AEDs, which also includes carbamazepine (CBZ) and oxcarbazepine (OXC), but differs from these agents in terms of pharmacokinetics, pharmacodynamics and metabolism [13, 14]. ESL also differs from CBZ and OXC in terms of its mechanism of action [15, 16]. These differences may have an impact on the relative effectiveness and tolerability of these AEDs [17], as indicated by evidence from clinical trials,

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which have shown, for example, that ESL is associated with fewer neurological adverse events (AEs) than immediate-release OXC [18], and that ESL may be effective in patients who have previously not achieved adequate seizure control with CBZ [19].

Clinical trials are essential in the development and approval of new medications but they do

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not necessarily reflect effectiveness and tolerability in real life, because they select relatively homogeneous patient populations and typically use rigid dosing and titration schedules,

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whereas patients encountered in clinical practice have diverse clinical characteristics that require an individualised approach to treatment [20, 21]. There is consequently a need for real-world studies to complement evidence from clinical trials by elucidating the

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effectiveness of an agent when used under everyday clinical practice conditions. The EuroEsli study was an exploratory pooled analysis of data from 14 clinical practice studies conducted across Europe to evaluate the effectiveness and tolerability of ESL in the real-

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world setting [22]. Euro-Esli is the largest ESL clinical practice study to date, including data from more than 2000 patients treated with ESL in everyday practice. The pooling of such a large body of data has enabled subgroup analyses to be conducted, thereby allowing

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specific aspects of the use of ESL in epilepsy management to be evaluated.

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Studies have demonstrated that patients for whom a particular AED is unsuccessful, either due lack of efficacy (i.e. failure to achieve adequate seizure control) or poor tolerability, may subsequently achieve treatment success if they are transitioned to an alternative AED treatment [23, 24]. Therefore, in order to further clarify differences in effectiveness, safety and tolerability between ESL, CBZ and OXC when used in clinical practice, we conducted subgroup analyses of data from Euro-Esli specifically for patients who transitioned from CBZ or OXC to ESL, either due to lack of efficacy or poor tolerability.

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METHODS Study design The Euro-Esli study was an exploratory, pooled analysis of data from European clinical practice studies (both prospective and retrospective) that evaluated the effectiveness, safety and tolerability of ESL as an adjunctive treatment for focal-onset seizures, and the methodology and primary results have been published previously [22]. The effectiveness of ESL was assessed after 3, 6 and 12 months of treatment and at the last visit. Safety and tolerability were assessed for the duration of ESL treatment.

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The current analysis focussed on subsets of patients from the Euro-Esli study who were transitioned from CBZ or OXC to ESL. The transition from CBZ or OXC to ESL could either be abrupt (i.e., ESL was initiated at the same time that CBZ or OXC treatment was withdrawn) or gradual (i.e., ESL was initiated and taken concomitantly with CBZ or OXC for

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a variable time until CBZ or OXC was withdrawn).

Study population

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Details of the specific inclusion/exclusion criteria used in the individual studies have been published or presented previously [22, 25–37]. As these were real-world studies, there were generally few inclusion/exclusion criteria, in order to be more representative of the variety of

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patients encountered in clinical practice. The current analysis included all patients who were transitioned to ESL following treatment with either CBZ or OXC. Patients were excluded if their records contained insufficient data for analysis. Duplicate data from patients who were

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included in more than one study were also excluded.

Study assessments

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Assessments of effectiveness comprised responder rate; seizure freedom rate; the percentage of patients whose seizure frequency remained unchanged and whose seizure

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frequency worsened, relative to baseline; and the rate of discontinuation of ESL due to lack of effectiveness. Response was defined as ≥50% seizure frequency reduction from baseline (prior to ESL initiation) and seizure freedom was defined as no seizures since at least the prior visit (either 3 or 6 months, depending on the timepoint at which seizure freedom was assessed).

Safety was assessed by evaluating the incidence of AEs. Tolerability was assessed by evaluating the rate of discontinuation of ESL due to AEs.

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Statistical analyses Details of the statistical methodology employed in Euro-Esli have been published previously [22]. The safety population was defined as all patients who initiated ESL treatment, and the efficacy population was defined as all patients who initiated ESL treatment with at least one efficacy assessment. Safety, tolerability and effectiveness data were not available for all patients at every timepoint. Missing data were not imputed, except in cross-sectional studies, in which the last visit data were captured and included in the established cut-off points (3, 6 or 12 months). When the observation time point of a study did not match the established cutoff points, the following allocations were made: observations performed between 1.5 and

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<4.5 months were allocated to the 3-month visit; those performed between 4.5 and <9 months were allocated to the 6-month visit; and those performed between 9 and 15 months were allocated to the 12-month visit. A ‘final’ variable was also created, in which the last observation of each patient was included, independently of the moment when it occurred. The total number of patients with data available for each variable was used as denominator

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for analysis. A descriptive analysis of quantitative variables was performed. Qualitative

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variables were described as means of absolute frequencies and percentages [22].

RESULTS

A total of 2058 patients from 14 European clinical practice studies were included in the Euro-

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Esli study [22]. Of these 2058 patients, 233 (11.3%) patients were transitioned from CBZ to ESL, and 134 (6.5%) were transitioned from OXC to ESL.

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Demographic and baseline characteristics

Demographic and baseline characteristics of patients who transitioned to ESL from CBZ and OXC were generally similar (Table 1). However, mean baseline seizure frequency was

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higher in patients who transitioned from OXC versus CBZ for total focal-onset seizures (22.6 vs. 11.0 seizures/month) and focal aware seizures (45.5 vs. 13.9 seizures/month). Although

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the numbers of previous and concomitant AEDs were generally similar between groups, three patients who transitioned from OXC to ESL received monotherapy at baseline, whereas all patients who transitioned from CBZ received concomitant AEDs at baseline. The majority of patients in both groups (approximately two-thirds) were treated with one or two concomitant AEDs at baseline.

ESL treatment Most patients were transitioned from CBZ or OXC to ESL due to lack of efficacy of previous AEDs (61.8% and 48.5% of patients, respectively), adverse reactions to previous AEDs 5

(19.3% and 26.9%, respectively), or a combination of these reasons (8.2% and 18.7%, respectively) (Table 2).

Although the timing of the transition from CBZ or OXC to ESL was not known, data were available regarding the dose of CBZ or OXC at the time of the transition, together with the final dosage of ESL. In patients who transitioned from CBZ to ESL, the mean dose of CBZ was 757.3 mg/day (median dose, 800 mg/day; n=158) and the final mean dose of ESL in these patients was 1026.7 mg/day (median dose, 1200 mg/day; n=232). In patients who transitioned from OXC to ESL, the mean dose of OXC was 1043.6 mg/day (median dose, 1200 mg/day; n=94) and the final mean dose of ESL in these patients was 1100.8 mg/day

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(median dose, 1200 mg/day; n=133).

In patients who transitioned from CBZ to ESL due to lack of efficacy, the mean dose of CBZ at the time of transition was 801.4 mg/day (median dose, 800 mg/day: n=107) and the final mean dose of ESL was 1072.4 mg/day (median dose, 1200 mg/day; n=163). In those who

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transitioned from CBZ to ESL due to poor tolerability, the mean dose of CBZ at the time of transition was 710.6 mg/day (median dose, 600 mg/day: n=52) and the final mean dose of

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ESL was 891.3 mg/day (median dose, 800 mg/day; n=64). In patients who transitioned from OXC to ESL due to lack of efficacy, the mean dose of OXC at the time of transition was 1000.9 mg/day (median dose, 1200 mg/day: n=52) and the final mean dose of ESL was

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1162.2 mg/day (median dose, 1200 mg/day; n=90). In those who transitioned from OXC to ESL due to poor tolerability, the mean dose of OXC at the time of transition was 998.4 mg/day (median dose, 1200 mg/day: n=32) and the final mean dose of ESL was 1042.6

Effectiveness

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mg/day (median dose, 1200 mg/day; n=61).

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Responder and seizure freedom rates

In patients who transitioned from CBZ to ESL due to lack of efficacy (n=163), responder

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rates were 70.0% at 12 months and 59.4% at the last visit, and the corresponding seizure freedom rates were 30.9% and 25.6%, respectively (Figure 1a). In patients who transitioned from OXC to ESL due to lack of efficacy (n=90), responder rates were 57.1% at 12 months and 56.5% at the last visit. In addition, seizure freedom rates were 25.0% and 23.5% at 12 months and the last visit, respectively (Figure 1b).

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Figure 1. Responder and seizure freedom rates at 3 months, 6 months, 12 months and

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the last visit for (a) patients who transitioned from CBZ to ESL due to lack of efficacy and (b) patients transitioned from OXC to ESL due to lack of efficacy. Response was defined as ≥50% seizure frequency reduction from baseline. Seizure freedom was defined as no seizures since at least the prior visit. CBZ, carbamazepine; ESL, eslicarbazepine acetate; OXC, oxcarbazepine

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Percentage of patients with unchanged or worsened seizure frequency Among patients who transitioned from CBZ to ESL due to lack of efficacy, the percentages of patients with unchanged or worsened seizure frequency were 10.5% and 5.7%, respectively, at 12 months, and 12.9% for both assessments at the last visit (Figure 2a). In these patients, mean (median) ESL doses at 12 months and the last visit were 1000 (1000) and 1053.1 (1200) mg/day, respectively. Among patients who transitioned from OXC to ESL due to lack of efficacy, the percentages of patients with unchanged or worsened seizure frequency were 18.9% and 11.3%, respectively, at 12 months, and 20.7% and 11.0%, respectively, at the last visit (Figure 2b), and the mean (median) ESL doses at 12 months and the last visit were 1120 (1200) and 1157.4 (1200) mg/day, respectively, in these

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patients. The proportions of patients with unchanged seizure frequency following transition to ESL due to lack of efficacy were not significantly different for those who transitioned from CBZ versus OXC (10.5% vs. 18.9% at 12 months, p=0.142; 12.9% vs. 20.7% at last visit, p=0.114). Similarly, the proportions of patients with worsened seizure frequency following transition to ESL due to lack of efficacy were not significantly different for those who

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transitioned from CBZ versus OXC (5.7% vs. 11.3% at 12 months, p=0.209; 12.9% vs.

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11.0% at last visit, p=0.667).

Among patients who transitioned from CBZ and OXC to ESL due to poor tolerability (n=64 and n=61, respectively), the proportions of patients with worsened seizure frequency at 12

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months and the last visit were 7.1% and 11.1%, respectively, for patients who transitioned

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from CBZ and 6.9% and 6.6%, respectively, for those who transitioned from OXC.

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Figure 2. Percentage of patients with unchanged or worsened seizure frequency,

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relative to baseline, at 3 months, 6 months, 12 months and the last visit for (a) patients who transitioned from CBZ to ESL due to lack of efficacy and (b) patients who transitioned from OXC to ESL due to lack of efficacy. CBZ, carbamazepine; ESL, eslicarbazepine acetate; OXC, oxcarbazepine

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Withdrawals due to lack of effectiveness In patients who transitioned from CBZ to ESL due to poor seizure control with previous AEDs, ESL was subsequently withdrawn due to lack of efficacy in 11.6% (18/155) of patients. Similarly, ESL was withdrawn due to lack of efficacy in 10.5% (9/86) of patients who had transitioned from OXC to ESL due to poor seizure control with previous AEDs.

Safety and tolerability The number of patients who transitioned from CBZ and OXC to ESL due to poor tolerability was 64 and 61, respectively. Among those of these patients who had data recorded, 26.6% (17/64) of those who transitioned from CBZ to ESL and 39.5% (15/38) of those who

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transitioned from OXC to ESL reported AEs (Table 3; Figure 3). AEs reported by ≥5% patients in either group comprised dizziness (7.8% in patients transitioning from CBZ; 15.8% in patients transitioning from OXC) and instability/ataxia (1.6% in patients transitioning from CBZ; 7.9% in patients transitioning from OXC). The incidence of psychiatric AEs was similar between groups (6.3% in patients transitioning from CBZ; 7.9% in patients transitioning from

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OXC), but the incidence of cognitive AEs was lower in those transitioning from CBZ (1.6%) than in those who transitioned from OXC (7.9%). One patient in each group experienced

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hyponatraemia; sodium levels were 127 mEq/L in the patient transitioning from CBZ and 121 mEq/L in the patient transitioning from OXC. Among patients who had data recorded, AEs led to discontinuation in 8.3% (5/60) of patients who transitioned from CBZ to ESL due to

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poor tolerability and 6.6% (4/61) of patients who transitioned from OXC to ESL due to poor tolerability. In patients transitioning from CBZ, no individual AE led to discontinuation of more than one patient. In patients transitioning from OXC, AEs leading to discontinuation of more

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than one patient comprised dizziness (n=2; 3.3%) and instability/ataxia (n=2; 3.3%).

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Figure 3. Incidence of AEs and AEs leading to discontinuation in patients who

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transitioned to ESL from CBZ and OXC due to tolerability problems (adverse reactions). AE, adverse event; CBZ, carbamazepine; ESL, eslicarbazepine acetate; OXC,

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oxcarbazepine

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DISCUSSION

These subanalyses of data from the Euro-Esli study demonstrate that ESL was efficacious and generally well tolerated in patients transitioning from CBZ or OXC in clinical practice.

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Twelve months after initiating ESL treatment, the responder rates in patients who had transitioned from CBZ and OXC to ESL due to lack of efficacy were 70.0% and 57.1%, respectively, and the seizure freedom rates were 30.9% and 25.0%, respectively. In the

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overall Euro-Esli population, the 12-month responder and seizure freedom rates were 75.6% and 41.3%, respectively [22]. Although the responder and seizure freedom rates observed in

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patients who transitioned from CBZ or OXC to ESL due to lack of efficacy were lower than those observed in the overall population, it is encouraging that substantial proportions of those who transitioned from CBZ or OXC due to lack of efficacy responded to ESL treatment and achieved seizure freedom, indicating that these subgroups of patients were not necessarily more refractory to treatment than the overall population, but, rather, required a change in AED in order to achieve a response.

Reasons for transitioning to ESL differed somewhat between patients who transitioned from CBZ and those who transitioned from OXC, the proportion of patients transitioning due to 11

lack of efficacy being higher in those who transitioned from CBZ and the proportion of patients transitioning due to tolerability problems (adverse reactions) being higher in those who transitioned from OXC. It is also notable that three patients who transitioned from OXC to ESL received monotherapy at baseline, whereas all patients who transitioned from CBZ to ESL were treated with concomitant AEDs at baseline. These findings may reflect published guidance recommending that patients can be transitioned directly overnight from OXC to ESL, whereas the transition from CBZ to ESL should be cross-tapered gradually over a period of 1–3 weeks, to mitigate the risk of seizure deterioration and minimise the potential influence of CBZ enzyme induction on ESL plasma levels [38, 39]. Published guidance also recommends that dose ratios of 1:1.3 for CBZ:ESL and 1:1 for OXC:ESL should be

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employed when transitioning patients from these agents [38, 39]. It is therefore encouraging that the ratios of mean final doses for CBZ:ESL (757.3 mg/day:1026.7 mg/day, corresponding to 1:1.36) and OXC:ESL (1043.6 mg/day:1100.8 mg/day, corresponding to 1:05) employed in this clinical practice setting were broadly in line with these recommendations. In patients transitioning from CBZ to ESL, the mean CBZ dose at the time

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of transition was lower in those who transitioned due to poor tolerability than in those who transitioned due to lack of efficacy (710.6 vs. 801.4 mg/day); similarly, the final mean dose of

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ESL was lower in those transitioning due to poor tolerability versus lack of efficacy (891.3 vs. 1072.4 mg/day). In patients transitioning from OXC to ESL, the mean OXC dose at the time of transition was similar in those who transitioned due to poor tolerability versus lack of

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efficacy (998.4 vs. 1000.9 mg/day), and the final mean dose of ESL was slightly lower in those who transitioned due to poor tolerability versus lack of efficacy (1042.6 vs. 1162.2

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mg/day).

There are pharmacodynamic differences between CBZ and ESL, since CBZ is thought to alter the fast inactivation of voltage-gated sodium channels, while ESL is thought to act

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primarily by enhancing the slow inactivation of these channels [15]. Although OXC and ESL share the same main active metabolite, eslicarbazepine (S-licarbazepine) [40, 41], there are

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also pharmacodynamic differences between these agents, since the pharmacodynamic effect of OXC is elicited via its monohydroxy derivative, which includes a substantial proportion of R-licarbazepine in addition to eslicarbazepine, whereas the pharmacodynamic effect of ESL is accounted for almost exclusively by eslicarbazepine [17, 42]. The apparent affinity of eslicarbazepine for voltage-gated sodium channels in the resting and inactivated states is substantially lower than that of CBZ and R-licarbazepine, which may mean that eslicarbazepine has enhanced selectivity for inhibiting rapidly firing active ‘epileptic’ neurons [16, 17]. These pharmacodynamic differences may in part account for the significant add-on effects observed when ESL was used in combination with CBZ in experimental models of 12

carbamazepine-resistant epilepsy [43, 44]. Furthermore, in clinical trials, ESL has demonstrated efficacy in patients who have previously not achieved adequate seizure control with CBZ [19, 45]. These findings are consistent with data from cross-sectional studies demonstrating that some patients with persistent focal-onset seizures benefit from adjunctive therapy with newer AEDs, enabling them to improve seizure control or achieve seizure freedom [46]. Such data indicate that subtle differences in the pharmacodynamics of AEDs may potentially have an important impact on treatment response. The heterogeneity of treatment patterns in patients included in Euro-Esli illustrates the complexity of potential combinations of AED therapy available in clinical practice. Further research is required to determine whether specific AED combinations can potentially be tailored for particular

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seizure types/clinical profiles [46]. The International League Against Epilepsy defines drug-resistant epilepsy as the ‘failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom’ [47]. In the overall

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Euro-Esli, 74.0% of patients (1403/1897) had been treated with at least two previous AEDs before being treated with ESL [22]. In the current analysis, patients transitioning to ESL from

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both CBZ and OXC had been treated with a median of two previous AEDs and it is therefore likely that, as in the overall Euro-Esli population, the majority would be considered to have drug-resistant epilepsy. Given that a substantial proportion of these patients achieved

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seizure freedom after transitioning to ESL, this lends further support to the idea that subtle differences in pharmacodynamics can result in treatment response in previously ‘refractory’

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patients.

In the overall Euro-Esli population, the percentage of patients with worsened seizure frequency, relative to baseline, remained relatively stable throughout follow-up, ranging from

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approximately 8% to 11% [22]. During follow-up, 7.8% of patients discontinued ESL due to lack or efficacy, and a further 3.2% of patients discontinued ESL due to a combination of

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lack of efficacy and AEs [22]. In the current study, the percentage of those patients who transitioned from CBZ to ESL due to lack of efficacy who experienced worsening seizure frequency decreased over time (19.8%, 9.7% and 5.7% after 3, 6 months and 12 months, respectively). Overall, ESL treatment was discontinued due to lack of efficacy in 11.6% of patients who transitioned from CBZ to ESL due to poor seizure control with previous AEDs. The percentage of those patients who transitioned from OXC to ESL due to lack of efficacy who experienced worsening seizure frequency remained relatively stable during follow-up (8.1%, 11.7% and 11.3% after 3, 6 and 12 months, respectively), and ESL treatment was discontinued due to lack of efficacy in 10.5% of patients who transitioned from OXC to ESL 13

due to poor seizure control with previous AEDs. The higher rate of seizure worsening observed after 3 months (the earliest assessment point) in patients transitioning from CBZ to ESL, compared with those who transitioned from OXC to ESL, may reflect the fact that it is generally less straightforward to transition patients from CBZ to ESL than from OXC to ESL [38, 39], primarily because CBZ is a potent inducer of cytochrome P450 3A4 (CYP3A4) and other enzyme systems in the liver, and may therefore reduce plasma concentrations of AEDs and other comedications that are mainly metabolised by CYP3A4 [48]. It is therefore possible that some patients who transitioned from CBZ to ESL initially experienced seizure worsening due to the effects of CBZ withdrawal on the plasma concentrations of concomitant AEDs and/or while dosing adjustments to concomitant AEDs were made. Given the

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aforementioned pharmacodynamic differences between CBZ and ESL, it is also possible that some patients who previously responded to CBZ may not have responded as well to ESL (while others responded better after transitioning from CBZ to ESL). Conversely, the lower rate of seizure worsening observed after 3 months in patients transitioning from OXC, in comparison to those transitioning from CBZ, may reflect the fact that OXC and ESL share

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the same active metabolite, making the transition from OXC to ESL more straightforward

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than the transition from CBZ to ESL.

Among patients who transitioned from CBZ or OXC to ESL due to poor tolerability, the proportions of those who experienced AEs (26.6% and 39.5% for patients who transitioned

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from CBZ and OXC, respectively) were similar to the proportion of patients who experienced AEs in the overall Euro-Esli population (34.0% [22]). However, the proportions of patients who discontinued ESL due to AEs (8.3% and 6.6%, respectively) were somewhat lower than

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in the overall population (13.6% [22]). The AEs reported by patients transitioning from CBZ and ESL were consistent with the known safety profile of ESL [1]. The only AEs reported by ≥5% of patients in either group were dizziness and instability/ataxia, which were both

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reported by a higher proportion of patients transitioning from OXC versus CBZ (15.8% vs. 7.8% for dizziness; 7.9% vs. 1.6% for instability/ataxia). Similarly, a higher proportion of

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patients transitioning from OXC versus CBZ experienced cognitive AEs (7.9% vs. 1.6%). Only one patient in each group experienced hyponatraemia. The incidence of AEs leading to discontinuation was low in both groups and the only AEs leading to discontinuation of more than one patient were dizziness and instability/ataxia, which each led to discontinuation of two patients transitioning from OXC.

The tolerability profile of ESL differs from that of OXC, due to differences in metabolism and pharmacokinetics [13]. Experiments conducted in healthy volunteers have demonstrated that ESL metabolism avoids the early peaks in R-licarbazepine and OXC concentrations 14

observed in plasma and cerebrospinal fluid following immediate-release OXC administration, which may be associated with OXC-related adverse AEs, including headache and dizziness [17, 42]. Consistent with this, clinical trials have shown that ESL is associated with fewer neurological AEs than immediate-release OXC [18]. The results of the current study support the evidence from clinical trials, since ESL was well tolerated by the majority of patients who previously experienced intolerable AEs with OXC (as well as those who previously experienced intolerable AEs with CBZ). The tolerability profile of ESL also differs from that of CBZ since, unlike ESL, CBZ is metabolised to carbamazepine-10,11-epoxide, which is thought to play a role in causing CBZ-associated AEs, including drowsiness, dizziness and diplopia [17, 49–51]. Moreover, as a potent enzyme inducer, CBZ may lead to tolerability

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problems due to interaction with concomitant AEDs and other comedications [17, 52, 53]. Over the longer term, CBZ may additionally play a role in the development of somatic comorbidities, such as vascular disease, sexual dysfunction and osteoporosis, due to its effects on enzymes involved in endogenous metabolic pathways

[17, 52, 53].

Eslicarbazepine is a less potent enzyme inducer than CBZ, being a weak inducer of

-p

CYP3A4 and uridine 5'-diphospho-glucuronosyl transferases [1].

re

A limitation of this study was that information was not collected regarding whether patients treated with OXC received the immediate-release or extended-release formulation of the drug. However, it is likely that the majority of patients treated with OXC received the

lP

immediate-release formulation, since the extended-release formulation is not widely available in Europe and is currently not approved by the European Medicines Agency. Since extended-release OXC (which is approved in the USA [54]) has been reported to have a

na

more favourable tolerability profile than the immediate-release formulation [55], the findings from the current study are not relevant when considering transitioning patients from extended-release OXC to ESL; further research into such transitioning is required. As with

ur

other studies assessing the effects of transitioning patients from one agent to another, the current study was also limited because the study population was preselected for patients

Jo

who experienced lack of efficacy or poor tolerability with the previous agent (in this case, CBZ and OXC), which would have introduced negative bias favouring the subsequent agent (in this case, ESL). Therefore, the findings cannot be extrapolated to infer more favourable efficacy and/or tolerability with ESL, in comparison with CBZ and OXC, in patients who were not preselected in this way. A prospective, controlled study would be required in order to assess the effects of transitioning non-preselected patients from CBZ or OXC to ESL. This study was further limited in being a subanalysis of the Euro-Esli study, which was itself a retrospective pooled analysis [22]. Nevertheless, given the size of the Euro-Esli population, the numbers of patients included in the current study were large enough to allow meaningful 15

analysis to be conducted. The findings of the study add to a growing body of evidence (from clinical trials and clinical practice studies) demonstrating that ESL differs from other dibenzazepine AEDs [17] and supporting expert guidance recommending that there may be clinical situations in which it is appropriate to consider transitioning patients from CBZ or OXC to ESL [38, 39].

CONCLUSION This study demonstrated that ESL was efficacious and generally well tolerated in patients transitioning from CBZ or OXC in clinical practice, suggesting that it may be a useful treatment option for patients who either do not achieve adequate control or experience

ro of

intolerable AEs with these agents. It may also be a useful treatment for patients who are poorly compliant with two- or three-times daily dosing, since AED compliance has been shown to be significantly greater with once-daily dosing compared with multiple daily dosing regimens [56]. These findings illustrate the importance of adapting AED treatment to the

-p

individual patient’s needs, in terms of effectiveness, tolerability and patient preference.

This study was funded by Eisai Ltd.

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FUNDING SOURCE

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DECLARATION OF CONFLICTS OF INTEREST

RR is a consultant for Eisai, Bial, UCB, GlaxoSmithKline and Shire, and receives grant and research support from Bial, Eisai, and UCB.

na

JP has participated in clinical trials for Eisai, UCB, and Bial; received research grants from Eisai, Medtronic, UCB, and Cyberonics; received speaker honoraria from Cyberonics, Eisai, Medtronic, Orion Pharma, and UCB; received support for travel to congresses from

ur

Cyberonics, Eisai, Medtronic, and UCB; and participated in advisory boards for Cyberonics, Eisai, Medtronic, UCB, and Pfizer.

Jo

GA has no conflicts of interest. RM is a current employee of Eisai Europe Ltd. VV has participated in advisory boards and pharmaceutical industry-sponsored symposia for Eisai, UCB Pharma, Bial, Pfizer, GSK, Esteve, Novartis and GW Pharma.

ACKNOWLEDGEMENTS

16

Editorial assistance was provided by John Scopes of mXm Medical Communications and

Jo

ur

na

lP

re

-p

ro of

funded by Eisai Ltd.

17

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23

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ro of

-p

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TABLES Table 1. Demographic and baseline characteristics in patients who transitioned to ESL from CBZ and OXC Transitioned

from Transitioned

from

CBZ

ESL OXC

ESL

to

N=233

N=134

N

233

134

Male

131 (56.2)

65 (48.5)

Female

102 (43.8)

69 (51.5)

to

Demographic characteristics

Age, years 233

Mean (SD)

44.1 (14.7)

Median (range)

44.0 (18–86)

Epilepsy-related characteristics Age at onset of epilepsy, years

134

42.6 (15.5)

39.0 (19–87)

-p

N

ro of

Sex, n (%)

188

Mean (SD)

23.2 (16.1)

25.0 (19.0)

Median (range)

20.0 (0–67)

20.0 (0–82)

N

lP

Duration of epilepsy, years

re

N

93

188

93

20.5 (14.4)

18.2 (14.1)

18.0 (0–67)

15.0 (0–56)

180

112

Structural-metabolic

124 (68.9)

80 (71.4)

Unknown

53 (29.4)

32 (28.6)

Genetic

3 (1.7)

0

N

201

95

Mean (SD)

11.0 (26.2)

22.6 (77.4)

Median (range)

3.1 (0.2–210.0)

4.0 (0.1–600.0)

46

16

Median (range) Aetiology, n (%)

Jo

ur

N

na

Mean (SD)

Monthly seizure frequency Total focal-onset seizures

Focal aware seizures Na

25

Mean (SD)

13.9 (35.1)

45.5 (148.2)

Median (range)

2.7 (0.3–210.0)

3.0 (1.0–600.0)

Na

92

33

Mean (SD)

6.1 (14.3)

10.0 (16.9)

Median (range)

2.7 (0.3–122.3)

3.5 (0.3–90.0)

Na

43

11

Mean (SD)

1.0 (1.2)

1.6 (2.0)

Median (range)

0.6 (0.2–6.0)

0.7 (0.3–6.0)

Focal impaired awareness seizures

Focal to bilateral tonic–clonic seizures

N

205

Mean (SD)

1.9 (2.2)

Median (range)

1.0 (0–10)

114

2.0 (2.2)

Mean (SD)

2.2 (1.0)

Median (range)

2.0 (1–6)

Number of concomitant AEDs, n (%)

re

226

1.0 (0–11)

134

-p

Number of concomitant AEDs N

ro of

Number of previous AEDsb

2.1 (1.1) 2.0 (0–5)

226

134

0

0

3 (2.2)

65 (28.8)

45 (33.6)

82 (36.3)

46 (34.3)

54 (23.9)

23 (17.2)

25 (11.1)

17 (12.7)

lP

N

1 2

na

3 ≥4 aNumber

of patients with seizures whose number of seizures is known;

bExcluding

ur

concomitant AEDs. AED, antiepileptic drug; CBZ, carbamazepine; ESL, eslicarbazepine

Jo

acetate; OXC, oxcarbazepine; SD, standard deviation

26

Table 2. Reason for transitioning to ESL from CBZ and OXC Reason

Transitioned

from Transitioned

from

CBZ

ESL OXC

ESL

to

N=233

N=134

Lack of effectiveness, n (%)

144 (61.8)

65 (48.5)

Adverse reaction, n (%)

45 (19.3)

36 (26.9)

Both, n (%)

19 (8.2)

25 (18.7)

Other, n (%)

18 (7.7)

7 (5.2)

Unknown, n (%)

7 (3.0)

1 (0.7)

to

Jo

ur

na

lP

re

-p

ro of

CBZ, carbamazepine; ESL, eslicarbazepine acetate; OXC, oxcarbazepine.

27

Table 3. Summary of AEs in patients transitioning to ESL from CBZ and OXC due to poor tolerability (adverse reactions) Transitioned

from Transitioned

from

CBZ

ESL OXC

ESL

to

N=64

N=61

17 (26.6)

15 (39.5)a

Dizziness

5 (7.8)

6 (15.8)a

Somnolence

3 (4.7)

0

Tremor

3 (4.7)

1 (2.6)a

Instability/ataxia

1 (1.6)

3 (7.9)a

Irritability

2 (3.1)

Weight increased

2 (3.1)

Patients with AEs, n (%)

to

4 (6.3)

Patients with cognitive AEsc, n (%)

1 (1.6)

Patients with hyponatraemia, n (%)

1 (1.6)

Patients

with

AEs

leading

to 5 (8.3)d

3 (7.9)a 3 (7.9)a 1 (2.6)a 4 (6.6)

Dizziness

1 (1.7)d

2 (3.3)

Tremor

lP

AEs leading to discontinuation, n (%)

1 (2.6)a

re

discontinuation, n (%)

1 (2.6)a

-p

Patients with psychiatric AEs, n (%)

ro of

Most frequently reportedb AEs, n (%)

1 (1.7)d

0

1 (1.7)d

2 (3.3)

1 (1.7)d

0

1 (1.7)d

0

1 (1.7)d

0

1 (1.7)d

0

Diplopia/blurred vision

1 (1.7)d

0

Nausea

0

1 (1.6)

0

1 (1.6)

Instability/ataxia

Psychosis Oedema

ur

Weight increased

Jo

Pruritus/burning

aN=38

na

Irritability

(data not known for 23 patients); b>1 patient in either group; cCognitive AEs were

defined as ‘disturbance in attention/concentration’, ‘memory problems’, ‘confusion’, ‘cognitive disturbance’, ‘sedation’, ‘encephalopathy’ and ‘bradypsychia’; dN=60 (data not known for four patients). AE, adverse event; CBZ, carbamazepine; ESL, eslicarbazepine acetate; OXC, oxcarbazepine

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