Add-on Eslicarbazepine Reduces Partial-Onset Seizures

Daniel M. Keller, PhD

October 28, 2013

VIENNA, Austria — 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."

Dr. Soares-da-Silva is an employee of BIAL. Dr. Kälviäinen and Dr. Muzik have disclosed no relevant financial relationships.

XXI World Congress of Neurology (WCN). Free Papers Session 1. Presented September 2013.

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