Data Demonstrates Long-Term Reduction In Seizure Frequency With Novel Once Daily Anti-Epileptic Zebinix(R)

S. MAMEDE DO CORONADO, Portugal, June 29 /PRNewswire/ -- Data presented today, in Budapest, demonstrated that add-on treatment with the novel, once-daily anti-epileptic Zebinix(R)* (eslicarbazepine acetate; ESL) resulted in a marked and sustained decrease in seizure frequency over the long-term(1).

Results from the one-year extension of a pivotal Eslicarbazepine Acetate phase III study were presented at the International Congress for Epilepsy in Budapest, Hungary. Patients not controlled with existing anti-epileptic drugs who were given eslicarbazepine acetate as an add-on treatment experienced a mean reduction in seizure frequency of more than 61% (95%CI: -68.2%, -55.5%)1. Nearly 65% of patients were classified as responders, meaning that they had achieved at least a 50% reduction in seizure frequency with Zebinix(R) treatment(1).

"These data continue to demonstrate the efficacy and safety of Zebinix(R) in the treatment of partial onset seizures", said Joyce Cramer, research scientist at Yale University School of Medicine, USA and President of The Epilepsy Therapy Project. "Epilepsy is a devastating condition that can be very difficult to manage and the availability of eslicarbazepine acetate adds an important new choice of therapy for patients who are in vital need of better seizure control."

Epilepsy is one of the most common neurological diseases, affecting approximately one in 100 people6. Treatment of partial-onset seizures, the most common type of epilepsy, remains a constant challenge and up to 40% of patients with partial seizures do not achieve seizure control with current anti-epileptics(2).

Additional studies presented at the IEC further reinforce the efficacy and safety of eslicarbazepine acetate in the treatment of partial-onset seizures, with or without secondary generalisation(3,4).

Pooled data from more than 1,000 patients enrolled in the three pivotal phase III studies demonstrated that add-on therapy with once-daily Zebinix(R) (800mg and 1200mg) was effective in reducing partial-onset seizures in patients not controlled with one of the most commonly used anti-epileptics, carbamazepine (CBZ), (p<0.01 and p<0.0001 respectively)(3).

Across the clinical studies conducted, eslicarbazepine acetate has demonstrated a favourable safety profile(5). This has been further reinforced by a pooled analysis indicating that most adverse events begin within the first weeks of treatment but after six weeks, no relevant difference was found between eslicarbazepine acetate and placebo(4).

Zebinix(R), researched and developed by BIAL, received marketing authorisation from the European Commission in April 2009, as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalisation. Under the terms of a deal with BIAL, announced in February this year, Eisai Europe Ltd received a sole license to market, promote and distribute ESL within Europe**. Eisai and BIAL plan to launch Zebinix(R) across Europe during 2009 and into 2010, providing a novel and effective treatment to patients with partial-onset seizures who are not adequately controlled with their existing medications. The rights to commercialise the product in the U.S. and Canadian markets were licensed to Sepracor Inc., in late 2007 (the proposed name for eslicarbazepine acetate in the U.S. and Canada is STEDESA(TM)). In June 2009, Sepracor announced that the U.S. Food and Drug Administration (FDA) accepted for filing its New Drug Application (NDA) for STEDESA(TM) as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy, and the NDA is currently under formal review.

Notes to Editors

* Zebinix(R) is the EU trade name for eslicarbazepine acetate.

** European Territories

Austria, Belgium, Bulgaria, Czech Republic, Belarus, Bosnia, Croatia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Monaco, Netherlands, Norway, Poland, Romania, Russia, Serbia, Slovakia, Slovenia, Spain (co-promotion with BIAL from launch) Sweden, Switzerland, Turkey, Ukraine and United Kingdom.

About epilepsy, partial-onset seizures and their treatment

Epilepsy is one of the most common neurological diseases, affecting approximately 1 in 100 people(6).

Epilepsy is a chronic neurological disease characterised by abnormal discharges of neuronal activity causing seizures. Clinically, these manifest as convulsions or jerking of muscles. Depending on the seizure type, seizures may be limited to one part of the body, or may be generalised to involve the whole body. Patients may also experience abnormal sensations, altered behaviour or altered consciousness. Epilepsy is a disorder with many possible causes. Often the cause of epilepsy is unknown. However, anything that disturbs the normal pattern of neurone activity - from illness to brain damage to abnormal brain development, can lead to seizures.

Epilepsy is characterised by abnormal firing of impulses from nerve cells in the brain. In partial-onset seizures, these bursts of electrical activity are initially focused in specific areas of the brain, but may become more generalised; the symptoms vary according to the affected areas. Nerve impulses are triggered via voltage-gated sodium channels in the nerve cell membrane.

Treatment of partial-onset seizures, the most common type of epilepsy, presents a constant challenge - up to 40% of patients with partial-onset seizures do not achieve seizure control with current anti-epileptic drugs(2).

Furthermore, adverse events, such as lightheadedness (dizziness), somnolence (sleepiness), and cognitive slowing, are highly prevalent with existing anti-epileptic agents and may affect as many as 97% of patients(7). Hence, there is a need for new anti-epileptic agents that offer effective reduction in seizure frequency combined with a favourable safety profile.

About Eslicarbazepine Acetate

Eslicarbazepine acetate (ESL) is a novel once-daily voltage-gated sodium channel blocker designed to selectively inhibit the rapid firing of nerve cells that causes seizures. It specifically targets the inactivated state of the ion channel, preventing its return to the active state, and thereby reduces repetitive neuronal firing. The efficacy of ESL has been demonstrated in three randomised, placebo controlled studies in 1049 patients with refractory partial onset seizures. ESL also significantly improved patient's health related quality of life (HRQoL) as measured by the QOLIE-31 score during a one year open label extension of the above 3 studies. ESL is given orally once-daily. ESL can be used as an add-on to carbamazepine (one of the most commonly utilized therapies for partial onset seizures) or with other anti-epileptics.

Clinical data

The EU approval was based on data from phase II and three phase III, double-blind, randomised, placebo-controlled, multi-centre trials involving 1,192 patients from 23 countries. Patients had a history of at least four partial seizures per month despite treatment with up to three concomitant anti-epileptic drugs.

During the trials, patients were randomised to various dosages of ESL or placebo and after a 2-week titration period, were assessed over a 12 week maintenance period, with continued follow-up over a one year open-label period.

Efficacy

Over the 12 week maintenance period, ESL 800mg and 1200mg once-daily reduced seizure frequency by over one third, and was significantly more effective than placebo. This significant decrease in seizure frequency was sustained over the one-year open label treatment period and was consistent regardless of baseline therapy.

Tolerability

The safety profile of ESL was favourable. The majority of treatment related adverse events were mild or moderate in intensity. After 6 weeks of treatment, there were no observed differences in the incidence of side effects between patients treated with ESL and the placebo group.

Quality of life and depressive symptoms

The effect of ESL on quality of life was assessed using the Quality of Life Epilepsy Inventory-31 (QOLIE-31) scale. There was a statistically and clinically significant improvement from baseline during long-term open-label therapy, including a mean relative improvement in overall quality of life (p<0.001 - p<0.01 across the three studies) and improvements in individual elements of the QOLIE-31 scale including seizure worry, emotional wellbeing, energy/fatigue, medication effects and social function(8).

Improvement in depressive symptoms was also measured using the Montgomery Asberg Depression Rating Scale (MADRS). During long-term, open-label therapy, ESL demonstrated a statistically significant improvement from baseline in the overall MADRS score (p<0.0001) and individual domains of the MADRS scale including pessimistic thoughts, concentration difficulties, apparent sadness and inner tension(8).

These data were presented at the 28th International Epilepsy Congress held in Budapest, 28 June 2009 - 2 July 2009, the 8th European Congress on Epileptology held in Berlin last September 2008 and at the Annual Meeting of the American Epilepsy Society (AES) in December 2008, Seattle, WA, USA.

About BIAL

Founded in 1924, BIAL is an international pharmaceutical group with products available in over 30 countries throughout four continents. BIAL is the largest Portuguese pharmaceutical company and is based in S. Mamede do Coronado, Portugal.

It is the partner of choice for many companies, having a strong presence in the Iberian peninsula as well as in over 10 countries in Latin America and in around 20 French or Portuguese speaking African countries.

BIAL is strongly committed to therapeutic innovation investing approximately 20% of its turnover in research and development every year. Key research areas for BIAL are the central nervous system, the cardiovascular system and allergology. BIAL currently has several other innovative programs under development, which the company expects to bring to the market within the next years, thereby strengthening its position throughout Europe.

Further information about BIAL can be found at http://www.bial.com

References:

1. Elger C, Halász P, Moreira J et al. Long-term add-on treatment of partial epilepsy with eslicarbazepine acetate. Abstract presented at the 28th International Epilepsy Congress, Budapest, Hungary, 28 June 2009 - 2 July 2009.

2. Brodie MJ. Management strategies for refractory localization-related seizures. Epilepsia 2001; 42(Suppl 3):27-30.

3. Halász P, Elger C, Ben-Menachem E et al. Efficacy and safety of eslicarbazepine acetate as add-on treatment to carbamazepine in patients with partial-onset seizures. Abstract presented at the 28th International Epilepsy Congress, Budapest, Hungary, 28 June 2009 - 2 July 2009.

4. Gama H, Elger C, Halász P et al. Time of occurence of adverse events in relation to start of treatment with eslicarbazepine acetate as add-on treatment in patients with partial-onset seizures. Abstract presented at the 28th International Epilepsy Congress, Budapest, Hungary, 28 June 2009 - 2 July 2009.

5. Elger C, French J, Halasz P. et al. Evaluation of Eslicarbazepine Acetate as Add-On Treatment in Patients with Partial-Onset Seizures: Pooled Analysis of Three Double-Blind Phase III Clinical Studies. Poster presented at the American Epilepsy Society (AES) Congress, 5-9 December 2008, Seattle, WA, USA (Epilepsia, 49(Suppl. 7), 1-498, 2008).

6. WHO Atlas: Epilepsy Care in the World. WHO 2005

7. Mei PA, Montenegro MA, Guerreiro MM, Guerreiro CA. Pharmacovigilance in epileptic patients using antiepileptic drugs. Arq Neuropsiquiatr 2006 Jun;64(2A): 198-201. Epub 2006 Jun 9

8. Cramer J, Elger C, Halász P et al. An Evaluation of Quality of Life and Depressive Symptoms During Long-Term Treatment with Eslicarbazepine Acetate: BIA-2093-301 Study.QOL 301. Poster presented at the American Epilepsy Society (AES) Congress, 5-9 December 2009, Seattle, WA, USA (Epilepsia, 49(Suppl. 7), 1-498, 2008).

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