Eslicarbazepine acetate

Real-world data on eslicarbazepine acetate as add-on to antiepileptic monotherapy

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Abstract

Objective

To assess retention, tolerability, and safety, efficacy and effects on quality of life (QoL) of eslicarbazepine acetate (ESL) add-on treatment over 6 months in a real-world adult population with partial-onset seizures.

Methods

This non-interventional, multicenter, prospective study was performed in eight European countries. Adult patients (n = 247) for whom the physician had decided to initiate ESL as add-on to an existing antiepileptic drug (AED) monotherapy were invited to participate. The study comprised three visits: baseline, and after 3 and 6 months. Data on ESL retention, efficacy, tolerability, safety, and QoL were collected.

Results

After 6 months, the retention rate of ESL was 82.2%, and 81.8% of patients reported a reduction of seizure frequency of at least 50%; 39.2% of patients reported seizure freedom at this time. The mean QOLIE-10 score improved from 2.9 (SD ± 0.8) at baseline to 2.1 (SD ± 0.8) after 6 months. 109 adverse events (AEs) were reported in 57 patients (26.0%); the majority were rated as related to ESL by the investigator and led to a discontinuation of ESL in 25 patients (11.4%). Eight patients (3.7%) suffered at least one serious AE. The most frequently reported AEs were dizziness, headache, convulsion, and fatigue.

Conclusions

This study shows that ESL was well tolerated and efficacious as add-on therapy to one baseline AED. The use of ESL in patients less refractory than those included in previous clinical trials led to higher responder and seizure freedom rates. No new safety issues were observed.

Discussion

Eslicarbazepine acetate (ESL), a once-daily anticonvulsant approved for adjunctive therapy of adults with POS has shown a favorable pharmacokinetic profile [6] and good efficacy and tolerability in controlled clinical settings [7-9, 12]. The population evaluated in this non-interventional trial showed a relatively low baseline seizure frequency (median of nine seizures in 3 months, Table 1), most likely attributable to the design of the study as early add-on study, in which only patients with monotherapy at baseline were to be included, and with differences in capturing seizure data (more frequent visits in interventional clinical trials) being another possible source of variation. Together with the possibility for an individualized dosing of ESL and adaptations of adjunct AED regimen, these aspects represent the major differences between this real-life observational study, and the pivotal clinical trials with ESL, where much higher baseline seizure frequencies were observed [7-9, 12].

The most frequent ESL target dose was 800 mg/day. Only a minority of patients required dose adaptations after titration. If required, for the vast majority of these patients, one post-titration dose change was sufficient to achieve satisfactory results. These findings suggest that ESL add-on treatment is easy to handle.

For the majority of patients, no changes of adjunct AED medications, or their dosage, were necessary under ESL add-on therapy, thus suggesting good efficacy and tolerability of the add-on treatment and indicative of a clinically unproblematic interaction profile [6]. Retention rate has been recommended as useful outcome measure for clinical trials with AEDs, as it comprises clinical drug effectiveness (efficacy and tolerability aspects) and patient choice [13]. Accordingly, the high proportion of patients who retained the treatment for 6 months (82.2%) is likely to reflect patients’ and physicians’ satisfaction with ESL add-on treatment, with the vast majority of patients stating their intent to continue with ESL add-on treatment beyond the present study. Correspondingly, reported efficacy was good, with almost 40% of the patients reporting at least 3 months of seizure freedom after 6 months and a responder rate at 6 months of 81.8% (Fig. 1). These figures are much higher than in previous clinical trials with ESL where responder rates between 30 and 40% [7-9, 12] were observed, likely attributable to a less severe seizure situation at baseline and potentially less refractory epilepsies in the patients included in the present study. This assumption is strengthened by observations from longer-term trials with other AEDs, which also suggest that outcome measures like retention may vary in dependency of the severity of epilepsy in the population studied [14].

The median of the QOLIE-10 score showed improvement after 3, and further after 6 months, indicating that ESL add-on treatment led to some improvement in health-related quality of life (Fig. 2). Therefore, it may be concluded that for the majority of the present patients, the addition of ESL to an existing monotherapy did not worsen, but rather stabilizes or even improves QoL. This finding in itself is important, as dissatisfaction with AED treatment and poor tolerability of AED regimens are well-known determinants of poor QoL [2, 3].

Subgroup analyses of ESL add-on treatment retention according to baseline AED medication indicate that ESL can be combined with the most frequently prescribed and currently monotherapy-approved AEDs, as retention rates were higher than 75% for all combinations: carbamazepine (100.0%), levetiracetam (85.5%), valproate (80.0%), and lamotrigine (75.9%). Correspondingly, reported efficacy (responder rate) at 6 months was also high when ESL was combined with the most frequent baseline AEDs: carbamazepine (92.9%), valproate (88.5%), levetiracetam (81.9%), and lamotrigine (69.8%). The apparent differences should be interpreted cautiously, due to the relatively small sample size in some subgroups. The findings of high retention and reported efficacy rates in the carbamazepine subgroup are noteworthy, as they appear to correspond to previous findings, where additional efficacy of ESL was observed also in combination with carbamazepine [12]. Eslicarbazepine and carbamazepine have been shown to display differential kinetics regarding the inactivation of voltage-gated sodium channels [5], which may be linked to differential clinical efficacy. More recently, both in humans and experimental models of epilepsy, it was demonstrated that eslicarbazepine may overcome a cellular resistance mechanism to carbamazepine [15].

In terms of reported efficacy, responder rate was also affected by the degree of failure of previous AED treatments: the highest responder rate at 6 months was seen in patients with one previously discontinued AED regimen (90.9%), followed by patients with two (82.2%) and those with ≥ 3 previous AED regimens (77.4%), corroborating previous findings [16]. In contrast, responder rate in the group of patients without any documentation of previously discontinued AED was lowest at 71.1%. At a first glance, this finding might seem contradictory. However, this group is most likely to be highly heterogeneous in terms of illness severity and treatment refractoriness [17] and could therefore contain a higher proportion of patients in whom early add-on AED therapy was consciously preferred over switching to an alternative monotherapy (e.g. due to knowledge of the underlying pathology or higher seizure density) [18]. Indeed, a post hoc subgroup analysis of the baseline seizure situation revealed the highest mean numbers of simple and complex partial seizures as well as total seizure number in these patients (over 3 months prior to baseline; not shown).

The overall analysis of tolerability was favorable and in line with the known tolerability profile of ESL [10]. Fifty-seven patients (26.0%) suffered from adverse events (AE, n = 109). The majority of the AE were considered adverse drug reactions, that is assessed as related to ESL treatment by the physician (84 AE in 49 patients). Of the 13 serious AE (in eight patients) (Table 2), nine were judged as related to ESL treatment by the physicians. One patient died during the study (cause of death unknown), but the physician did not see a causal relationship to ESL treatment. The most frequently reported events were dizziness (4.6%), headache (3.2%), convulsion (3.2%), and fatigue (2.7%); all other events were reported for less than six patients.

Compared to controlled clinical studies, the limitations of the present research are obvious and predetermined by the non-interventional, single-arm character of the trial, which only allows for descriptive analyses. The relatively low numbers especially for subgroups imposes the necessity for careful interpretation of the obtained results. Nonetheless, studies like the present one are of value for the treating physician as they help obtain a realistic picture of the real-life clinical practice, where patient populations are highly variable in terms of disease severity, adjunct medication, and comorbidities.

Taken together, the present study shows a high retention rate as well as promising reported efficacy of ESL add-on treatment in a real-life clinical setting. The treatment was well tolerated by the majority of patients and did not negatively affect health-related quality of life. Subgroup analyses indicate potentially differential effects of AED combination partners on ESL effectiveness. However, due to small sample size, these subgroup findings should be interpreted cautiously.

Add-on Eslicarbazepine Reduces Partial-Onset Seizures.

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Once-daily adjunctive therapy with eslicarbazepine significantly reduced the frequency of partial-onset seizures in adult patients compared with adding a placebo, and the effect was sustained out to 1 year. In an analysis of pooled data from 3 phase-3 pivotal trials, doses of 800 mg and 1200 mg were well tolerated.

Eslicarbazepine is an oral drug that stabilizes the inactive state of voltage-gated sodium channels and blocks T-type voltage-gated calcium channels.

Patrício Soares-da-Silva, MD, PhD, head of research and development at BIAL in S. Mamede do Coronado, Portugal, the developer of the drug, presented trial results here at the XXI World Congress of Neurology (WCN).

The 3 trials had slight variations in protocols, but in general involved an 8-week observation or single-blind drug period, 2 weeks of drug titration depending on dose, a 12-week double-blind maintenance period, 4 weeks of tapering of the drug or not, and an open-label extension period. Two trials (BIA-2093-301 and 302) tested the drug at 400 mg, 800 mg, or 1200 mg daily or placebo for the maintenance period, with about 100 patients in each group. Trial BIA-2093-303 dropped the 400-mg dose (about 84 patients per group).

The pooled groups were well matched for mean age (about 37 years), sex (half were men), seizure types, duration of epilepsy (22 years), and the number of concomitant antiepileptic drugs (AEDs) they were taking. About 70% of patients in each group were receiving 2 other AEDs besides the trial drug.

Dr. Soares-da-Silva said that eslicarbazepine significantly reduced the seizure frequency in each 4-week period of the 12-week double-blind maintenance phase from 8.17 ± 0.034 with placebo (n = 279) to 6.24 ± 0.034 with 800 mg (n = 262) and to 5.95 ± 0.035 with 1200 mg (n = 253) (both P < .001 vs placebo), the primary endpoint of the trials.

The responder rate, defined as a 50% or greater reduction in seizure frequency over the 12-week period, rose from 21.5% with placebo to 36.3% with 800 mg of eslicarbazepine and 43.5% with 1200 mg.

Positive Results Continue to 1 Year

Of 857 patients completing the double-blind period, 833 entered the open-label extension phase, and 612 (73.5%) completed the full year, with a median daily dose of 800 mg. The maximum allowed dose was 1200 mg.

The drug maintained its efficacy during the open-label extension period and showed a slight rise in both the responder rate and the proportion of patients free of seizures.

Table. Eslicarbazepine Efficacy During 1-year Extension Period*

Time Period

Responder Rate (%)

Proportion of Seizure-Free Patients (%)

Weeks 5 to 16

46.1

6.3

Weeks 17 to 28

47.0

9.4

Weeks 29 to 40

48.2

10.1

Weeks 41 to 52

50.1

13.6

*Median eslicarbazepine dose was 800 mg.

 

Treatment with adjunctive eslicarbazepine was associated with improvements in mood and quality of life, as assessed by QOLIE-31 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Whether patients had mild, moderate, or severe symptoms, all those who improved had improved significantly at the final assessment compared with baseline (all P < .001).

On the basis of the results of the pivotal trials, Dr. Soares-da-Silva said the European Medicines Agency approved eslicarbazepine for use in Europe as adjunctive therapy for adults with partial-onset seizures. It has not been approved in the United States, but he noted it is now undergoing trials in the United States as monotherapy.

Monotherapy Trials

Topline results of 2 phase 3 monotherapy trials of eslicarbazepine were just reported by Sunovion Pharmaceuticals. In both trials the drug met the primary endpoints.

Treatment was well tolerated and demonstrated seizure control rates superior to those among historical controls in adult patients with partial-onset seizures with or without secondary generalization who were not well controlled with current antiepileptic drugs, a statement from Sunovion released September 17 notes.

The agent is under review by the US Food and Drug Administration (FDA) as a once-daily adjunctive therapy for partial-onset seizures in patients aged 18 years or older with epilepsy.

“Pending the outcome of FDA review of the current New Drug Application (NDA) resubmission for eslicarbazepine acetate as an adjunctive treatment, Sunovion plans to submit these data as part of a supplemental NDA in support of a monotherapy indication,” Fred Grossman, DO, senior vice president, clinical development and medical affairs at Sunovion, said in the company’s statement.

The phase 3 studies, dubbed 093-045 and 093-046, were double-blind, historical-controlled, randomized trials with identical designs. Study 093-045 included 193 patients from 67 study centers in North America, and study 093-046 included 172 patients from 41 centers in 5 countries.

The primary endpoint of both studies was the proportion of patients meeting predefined exit criteria, “signifying worsening seizure control,” the statement notes, 16 weeks after titration compared with historical controls.

In both studies, adults with partial-onset seizures that were not well controlled, defined as 4 or more partial-onset seizures in the 8 weeks before screening and no 4-week seizure-free period, with 1 to 2 AEDs, were gradually converted to monotherapy treatment with eslicarbazepine. They were then randomly assigned in a 1:2 ratio to receive 1200 or 1600 mg of eslicarbazepine daily.

Detailed results from the 2 monotherapy studies will be presented at upcoming scientific meetings, the company notes.

Difference Debated?

Asked to comment about what eslicarbazepine may add to the AED armamentarium as adjunctive therapy, session chair Reeta Kälviäinen, MD, from the Kuopio Epilepsy Center, and professor of clinical epileptology at the University of Eastern Finland in Kupio, told Medscape Medical News that it is something of a debate at the moment whether eslicarbazepine differs significantly from oxcarbazepine.

“It’s a metabolite of oxcarbazepine, and we think at the moment that it might have a little bit less adverse effects than oxcarbazepine, less hyponatremia and less idiosynchrous reactions,” she said. “And we hope that therefore it would be better tolerated, perhaps as carbamazepine, as effective as oxcarbazepine, and then you can dose it once daily, which is a benefit.”

She said that she was “a little bit disappointed” that the study did not show which AEDs eslicarbazepine might be best used with but that current studies and clinical practice may reveal the better combinations. But for now, “definitely you shouldn’t add it on top of other sodium channel blockers. That’s not the way to use it,” because of additive adverse effects.

Similarly, if a patient has problems while receiving carbamazepine or oxcarbazepine, switching to eslicarbazepine would be a bad idea. “It’s nearly the same drug, so that’s a dangerous situation. So that’s a contraindication,” Dr. Kälviäinen noted. She said clinicians are now “a little bit mixed up” in choosing among these similar drugs, and clearer studies on the differences among them are needed.

Otto Muzik, PhD, a professor of radiology and pediatrics at Wayne State Medical School in Detroit, Michigan, questioned the value of adding another drug in this same class.

“It’s still not approved in the States, and it appears to me that the FDA does not believe that there is added value,” he mentioned to Medscape Medical News. “So that means that…it’s probably going to do better than a placebo, but if you now say, ‘Give me the best combined therapy of drugs,’ and now we throw in this new drug, is it more efficacious or not, and the jury seems to be still out on that.”

Eslicarbazepine acetate add-on for drug-resistant partial epilepsy.

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The majority of people with epilepsy will have a good prognosis, but up to 30% of patients will continue to have seizures despite several regimens of antiepileptic drugs. In this review we summarized the current evidence regarding eslicarbazepine acetate (ESL) when used as an add-on treatment for drug-resistant partial epilepsy.
OBJECTIVES: To evaluate the efficacy and tolerability of ESL when used as an add-on treatment for people with drug-resistant partial epilepsy. SEARCH
METHODS: We searched the Cochrane Epilepsy Group Specialized Register (3 November 2011), The Cochrane Central Register of Controlled Trials (CENTRAL issue 4 of 4, The Cochrane Library 2011), and MEDLINE (1948 to October week 4, 2011). There were no language restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of ESL and experts in the field for information about any unpublished or ongoing studies.
SELECTION CRITERIA: Randomized placebo controlled double-blind add-on trials of ESL in people with drug-resistant partial epilepsy.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency; seizure freedom; treatment withdrawal; adverse effects; and drug interactions. Primary analyses were by intention to treat. The dose response relationship was evaluated in regression models.
MAIN RESULTS: Four trials (1146 participants) were included; all studies were funded by BIAL. The overall relative risk (RR) with 95% confidence interval (CIs) for 50% or greater reduction in seizure frequency outcome was 1.86 (95% CI 1.46 to 2.36). Dose regression analysis showed evidence that ESL reduced seizure frequency with an increase in efficacy with increasing doses of ESL. ESL was significantly associated with seizure freedom (RR 3.04, 95% CI 1.44 to 6.42). Participants seemed more likely (albeit not significantly) to have ESL withdrawn for adverse effects (RR 2.26, 95% CI 0.98 to 5.21) but not for any reason (RR 1.07, 95% CI 0.73 to 1.57). The following adverse effects were significantly associated with ESL: dizziness (RR 3.09, 99% CI 1.76 to 5.43); nausea (RR 3.06, 99% CI 1.07 to 8.74); and diplopia (RR 3.73, 99% CI 1.19 to 11.64).
AUTHORS’ CONCLUSIONS: Eslicarbazepine acetate reduces seizure frequency when used as an add-on treatment for people with drug-resistant partial epilepsy. The trials included in this review were of short-term duration and focused on adults.

Source:Cochrane Database.