BIAL

Bial Announces Zebinix® (eslicarbazepine acetate) Meets Primary Endpoint in Phase 3 Monotherapy Study for Patients With Newly Diagnosed Partial-Onset Seizures

Porto, Portugal (ots/PRNewswire) - PRESS RELEASE FOR EU MEDIA ONLY

Bial - Portela & Cª., S.A. (Bial) is pleased to announce positive results for a pivotal phase 3 non-inferiority study comparing the efficacy and safety of eslicarbazepine acetate (ESL) to controlled release carbamazepine (CBZ-CR) as monotherapy in newly diagnosed adult patients with partial-onset seizures (POS).

"The study met its primary endpoint, which was the proportion of seizure-free patients for six consecutive months under monotherapy treatment. This is an important addition to the well-known value of ESL as adjunctive therapy. The complete study results will shortly be disclosed at major neurology and epilepsy conferences and published in specialized journals in the field," said Professor Patrício Soares-da-Silva, Director of Research & Development Department at Bial.

"The efficacy of ESL was clearly demonstrated in a high proportion of patients that remained seizure-free for six consecutive months, which was non-inferior to the seizure-free rate observed in patients treated with CBZ-CR, positioning ESL as a first-line treatment for newly diagnosed patients with focal epilepsies.", said Professor Eugen Trinka, principal study coordinator and ?Chairman of the Department of Neurology, Paracelsus Medical University, CDK, Salzburg, Austria.

"This study reflects our commitment to the development of new treatment options for people living with focal epilepsies", said António Portela, CEO of Bial Group.

This pivotal phase 3 study was a randomised, double-blind, parallel-group, active-controlled and non-inferiority study, investigating the efficacy and safety of once-daily ESL (800 to 1600 mg/daily) as monotherapy treatment for newly diagnosed adults with partial-onset seizures in comparison with twice-daily CBZ-CR (400 to 1200 mg/daily).

Based on these results, Bial intends to submit in the second quarter of 2016 a variation file to the European Medicines Agency (EMA), to expand the marketing authorization of eslicarbazepine acetate (ESL) as monotherapy in adults with partial-onset seizures.

ESL is currently approved by the European Medicines Agency (tradename Zebinix®). Eslicarbazepine acetate is indicated as adjunctive therapy in adults with partial onset seizures, with or without secondary generalisation (1). ESL is also approved by the US Food and Drug Administration (tradename Aptiom®) for the treatment of POS as monotherapy or adjunctive therapy (1, 2).

Notes to Editors

About epilepsy, partial-onset seizures and their treatment

Epilepsy is a chronic neurological disease characterized 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 generalized to involve the whole body. Patients may also experience abnormal sensations, altered behaviour or altered consciousness. Epilepsies are disorders with many possible causes. Often the cause of epilepsy remains unknown even after intense investigations. However, anything that disturbs the normal pattern of neuron 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 (or focal) 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 sustained seizure control with current anti-epileptic drugs (3).

About eslicarbazepine acetate (Zebinix® / Aptiom®)

Eslicarbazepine acetate is a once-daily anticonvulsant, extensively and rapidly converted to eslicarbazepine after oral administration (4). Eslicarbazepine reduces voltage-gated sodium channels availability through enhancement of slow inactivation and blocks T-type voltage-gated calcium channels (1, 5).

Eslicarbazepine acetate is currently marketed in Europe by BIAL-Portela & Cª, S.A and by BIAL´s licensee, Eisai Europe Limited, a European subsidiary of Eisai Co., Ltd. under the trade name Zebinix®. In the United States and Canada eslicarbazepine acetate (tradename Aptiom®) is marketed by Sunovion Pharmaceuticals Inc., under an exclusive license from BIAL. Eslicarbazepine acetate is approved by the US Food and Drug Administration (tradename Aptiom®) for the treatment of POS as monotherapy or adjunctive therapy (2). The approval of Aptiom as monotherapy for partial-onset seizures was supported by data from two pivotal Phase 3 clinical trials (Studies 093-045 and 093-046). Both trials met the pre-specified primary endpoint agreed upon with the FDA.

Clinical data

The EU approved file for the use of eslicarbazepine acetate as adjunctive treatment is based on efficacy and safety data from an initial proof-of concept phase II study (6) and four subsequent phase III randomized, placebo controlled studies in more than 1700 patients with refractory partial-onset seizures (7-10). These patients had a history of at least four partial-onset seizures per month despite treatment with up to three concomitant anti-epileptic drugs (7-10).

Efficacy

Over the 12-week maintenance period, eslicarbazepine acetate 800mg and 1200mg once-daily used adjunctively significantly reduced seizure frequency, and was significantly more effective than placebo (7-10). Long-term safety and maintenance of therapeutic effect was demonstrated in one-year open-label extensions of these studies (11, 12).

Tolerability

In the Phase III clinical trials adverse events mainly occurred during the first 6 weeks of treatment and the majority of patients experienced adverse events of mild to moderate intensity (7-10). After 6 weeks of treatment, there were no observed differences in the incidence of side effects between patients treated with eslicarbazepine acetate and the placebo group. Treatment-emergent adverse events affecting >10% of patients in the pivotal studies were dizziness and somnolence (1, 7-10).

Quality of life and depressive symptoms

The effect of eslicarbazepine acetate on quality of life was assessed using the Quality of Life in 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 and improvements in individual elements of the QOLIE-31 scale including seizure worry, emotional wellbeing, energy/fatigue, medication effects and social function (11, 12). Improvement in depressive symptoms was also measured using the Montgomery-Asberg Depression Rating Scale (MADRS). During long-term, open-label therapy, eslicarbazepine acetate demonstrated a statistically significant improvement from baseline in the overall MADRS score and individual items of the MADRS scale including pessimistic thoughts, concentration difficulties, apparent sadness and inner tension (11, 12).

About BIAL Group

BIAL is a research based, privately owned, international pharmaceutical group with products available in more than 50 countries.

Strongly committed to therapeutic innovation, BIAL´s research and development (R&D) is focused on the central nervous system, cardiovascular system and allergic immunotherapy, and currently has several innovative programs under development, which it expects to bring to the market within the next years. The R&D projects of the company are also focused on the ongoing clinical development program of eslicarbazepine acetate, which is already commercialised in the United States and in several European markets. This program comprises studies designed to evaluate new therapeutic indications, such as adjuvant treatment in children and monotherapy.

Additionally Bial has completed the clinical development of opicapone, a compound to treat patients living with Parkinson's disease. This new drug is currently under evaluation by EMA.

For additional information on BIAL, please visit the company's web site at: http://www.bial.com

References:

 1. European Medicines Agency. Zebinix® (eslicarbazepine acetate): EU
    summary of product characteristics. Available from:http://www.ema
    .europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information
    /human/000988/WC500047225.pdf (accessed 2 December 2015)
 2. Sunovion Pharmaceuticals Inc. Aptiom® (eslicarbazepine acetate) 
    tablets, for oral use: US prescribing information. Available 
    from:http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022
    416s001lbl.pdf (accessed 2 December 2015).
 3. Brodie MJ, Barry SJ, Bamagous GA et al. Patterns of treatment 
    response in newly diagnosed epilepsy. Neurology. 
    2012;15;78(20):1548-54.
 4. Bialer M, Soares-da-Silva P. Pharmacokinetics and drug 
    interactions of eslicarbazepine acetate. Epilepsia 
    2012;53(6):935-46.
 5. Soares-da-Silva P, Pires N, Bonifácio MJ, et al. Eslicarbazepine 
    acetate for the treatment of focal epilepsy: an update on its 
    proposed mechanisms of action. Pharmacol Res Perspect 2015; 3: 
    e00124.
 6. Elger C, Bialer M, Cramer J et al. Eslicarbazepine acetate: a 
    double-blind, add-on placebo-controlled exploratory trial in 
    adult patients with partial-onset seizures. Epilepsia. 
    2007;48(3):497-504.
 7. Elger C, Halász P, Maia J et al. Efficacy and safety of 
    eslicarbazepine acetate as adjunctive treatment in adults with 
    refractory partial-onset seizures: A randomized, double-blind, 
    placebo-controlled, parallel-group phase III study. Epilepsia. 
    2009;50(3):454-463.
 8. Ben-Menachem E, Gabbai A, Hufnagel A et al. Eslicarbazepine 
    acetate as adjunctive therapy in adult patients with partial 
    epilepsy. Epilepsy Research. 2010;89:278-285.
 9. Lopes-Lima J, Gil-Nagel A, Maia J et al. Efficacy and safety of 
    800 and 1200 mg eslicarbazepine acetate as adjunctive treatment 
    in adults with refractory partial-onset seizures. Acta 
    Neurologica Scandinavica. 2009;120:281-287.
10. Sperling MR, Abou-Khalil B, Harvey J, et al. Eslicarbazepine 
    acetate as adjunctive therapy in patients with uncontrolled 
    partial-onset seizures: Results of a phase III, double-blind, 
    randomized, placebo-controlled trial. Epilepsia. 2015;56:244-253.
11. Halász P, Elger C, Guekht A et al. Long-term efficacy and safety 
    of eslicarbazepine acetate: Results of a 1-year open-label 
    extension study in partial-onset seizures in adults with 
    epilepsy. Epilepsia. 2010;51(10):1963-1969.
12. Hufnagel A, Ben-Menachem E, Gabbai AA et al. Long-term safety and
    efficacy of eslicarbazepine acetate as adjunctive therapy in the 
    treatment of partial-onset seizures in adults with epilepsy: 
    results of a 1-year open-label extension study. Epilepsy 
    Research. 2013;103(2-3):262-9. 

Contact:

Susana Vasconcelos Communication Manager susana.vasconcelos@bial.com
Rui Sousa International Medical Affairs Manager rui.sousa@bial.com
Bial - Portela & Cª
S.A. + 351 22 986 6100 À Av. da Siderurgia Nacional 4745-457 Coronado
(S. Romão e S. Mamede) PORTUGAL

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