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VIENNA -- Pooled phase III study results on eslicarbazepine acetate, a prodrug for S(+)-liscarbazepine, showed that the drug outperformed placebo as add-on therapy for partial-onset seizures in adults, a researcher said here.
During the double-blind phase of three pivotal studies, mean 12-week seizure counts were 6.24 (95% CI 5.58-6.95) with eslicarbazepine at 800 mg once daily and 5.95 (95% CI 5.30-6.65) at 1,200 mg once daily, compared with 8.17 (95% CI 7.39-9.00) with placebo, with P values <0.0001 for both doses versus placebo, reported Rui Sousa, MD, of ., of Trofa, Portugal, the product's developer.
Action Points
- This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Pooled phase III study results on eslicarbazepine acetate, a prodrug for S(+)-liscarbazepine, showed that the drug outperformed placebo as add-on therapy for partial-onset seizures in adults.
- Note that ratings of depression and patients' self-reported quality of life during the extension phases showed improvements over pretreatment baseline.
Also, pooled results from 1-year open-label extensions of the double-blind controlled trials indicated that responses were maintained in patients choosing to remain in the studies, Sousa said during the first platform session at the
S(+)-liscarbazepine is also the active metabolite of the currently marketed drug oxcarbazepine (Trileptal). Pharmacokinetic studies have suggested that eslicarbazepine acetate is metabolized more slowly, reducing peak levels of the metabolite in circulation, thought to improve its tolerability for some patients.
Eslicarbazepine acetate has been marketed in Europe since 2009 as Zebinix. A U.S. marketing application from U.S. licensee Sunovion is now under review by the FDA, with a decision expected later this year, Sousa said.
The FDA rejected an initial application for the drug in 2010, requesting additional data that Sunovion has since supplied. The drug is currently being tested in bipolar disorder as well.
Sousa presented combined data from the three phase III trials used to support the European approval. All three had similar designs. Patients first had an initial 8-week baseline evaluation during which seizures were counted while patients were on their current treatment regimens. Eslicarbazepine acetate was then added, with patients started on low doses that were increased to preset targets over 2 weeks, followed by 12 weeks of treatment at the target dose, and finally a 4-week tapering. All three trials also had 1-year open-label extensions.
Some of the details differed between trials. For example, the first two to be conducted also included a 400-mg dose that proved to be less effective as 800- and 1,200-mg doses. The exact protocols during the initial titration and final tapering phases also differed. For example, in one of the trials, patients started immediately on the 400- and 800-mg doses without initial titration and there was no tapering.
Mean patient age was about 37, with a mean duration of epilepsy of 22 years (SD 12). About 70% were currently on two or more antiepileptic drugs. Sousa did not present data on the specific drugs patients were taking at enrollment.
Pooled results from the 12-week double-blind phases showed that 21.5% of the 279 patients assigned to placebo showed reductions of at least 50% in seizure frequency -- classifying them as responders -- compared with 36.5% of 262 patients receiving 800 mg/day of the active drug and 43.5% of 253 patients receiving 1,200 mg/day (both P<0.001 versus placebo), Sousa reported.
More than 97% of patients continued into the open-label extensions, Sousa reported, with 73.5% completing 1 year of follow-up. Median daily dose in the extensions was 800 mg.
Responder rates (calculated as reduction from baseline rates) grew slightly from about 45% during weeks five to 16 of the extensions to just over 50% during the final 12 weeks. Rates of seizure freedom rose from 6.3% to 13.6% over the same intervals.
Sousa said that ratings of depression (using the ) and patients' self-reported quality of life during the extension phases also showed improvements over pretreatment baseline. For example, the mean decline in Montgomery-Asberg scores in 12 patients with severe baseline depression was 19 points (SD 5.3, P<0.0001); in 25 patients with moderate depression at baseline, scores dropped by a mean of 10.3 points (SD 6.8, P<0.0001).
, a neurology researcher at Wayne State University in Detroit, commented after the session that, although placebo is commonly used as control in drug trials, it's not helpful for clinicians who already have many drugs to choose from.
"This is always the question -- do we have added value or is this the same thing," he said, noting that other drugs in the same class are currently available. Oxcarbazepine is now a relatively inexpensive generic drug as well.
Muzik said he wished that more head-to-head trials would be conducted with new drugs.
Disclosures
The trial was funded by BIAL-Portela. Sousa was an employee of BIAL-Portela.
Muzik said he had no conflicts of interest.
Primary Source
World Congress of Neurology
Gil-Nagel A, et al "Efficacy of eslicarbazepine acetate as adjunctive therapy of adult patients with partial-onset seizures up to one year of follow-up" WCN 2013; Abstract 1277.