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Beyond Seizure Control in the Treatment of Epilepsy With New Anti-Epileptic Drug, Zebinix(TM)

Tuesday, December 9, 2008 General News J E 4
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PORTO, Portugal, December 8

- Data Highlight The Efficacy, Safety and Significant Improvement inQuality of Life and Depressive Symptoms With Zebinix(TM) (EslicarbazepineAcetate)

Positive data from three phase III studies presented today at theAmerican Epilepsy Society (AES) Congress, Seattle, USA, show thatZebinix(TM)(1) (eslicarbazepine acetate), a novel once-daily anti-epilepticagent, significantly reduced the frequency of partial seizures and has thepotential to significantly improve quality of life and depressive symptoms inpatients with partial refractory epilepsy, in combination with otheranti-epileptic agents.(2),(3),(4)

Zebinix(TM) is one of the proposed EU trade names for eslicarbazepineacetate.

Zebinix(TM) 800mg and 1200mg once-daily significantly reduced thefrequency of partial seizures by over one third during the 12 weekmaintenance period of the studies.(5),(6),(7),(8) In addition, new datapresented for the first time at AES demonstrates that the reduction inseizure frequency was sustained over a one-year open-label treatment period.This sustained reduction over one year has now been demonstrated in all threephase III studies for Zebinix(TM).(9),(10),(11)

"The impact of epilepsy on quality of life and the development ofdepression cannot be underestimated. We must go beyond seizure control andensure this is taken into consideration when assessing new treatments forepilepsy," said Joyce Cramer, research scientist at Yale University School ofMedicine, USA and President of The Epilepsy Therapy Project. "During clinicalstudies, Zebinix(TM) has demonstrated that in addition to effective seizurecontrol and good tolerability, it also provides significant improvement inquality of life and a reduction in depressive symptoms in long-termfollow-up. Zebinix(TM) has the potential to become an important treatmentoption for patients with epilepsy who are not achieving seizure control withtheir existing medications."

Epilepsy is one of the most common neurological diseases affecting almostone in 100 people.(12) Treatment of partial seizures, the most common type ofepilepsy, presents a constant challenge with over half of patients notachieving adequate seizure control with current anti-epileptic drugs.(13)

Zebinix(TM), a new anti-epileptic drug that selectively inhibits therapid firing of nerve cells that causes seizures, has been developed toaddress the need for a new anti-epileptic agent that offers a reduction inseizure frequency combined with a favourable tolerability profile.Zebinix(TM) is currently under review by the European Medicines Agency (EMEA)for the treatment of partial-onset seizures with or without secondarygeneralisation in combination with other anti-epileptic drugs. A U.S. NewDrug Application (NDA) is currently being prepared with an anticipatedsubmission to the U.S. Food and Drug Administration in early 2009.

About the trials

The three phase III, multi-centre, randomised, placebo controlled trialsinvolved an aggregate of more than 1,000 patients from 23 countries. Patientshad a history of at least four partial seizures per month despite treatmentwith up to three concomitant anti-epileptic drugs.(8)

During the trials, patients were randomised to various dosages ofeslicarbazepine acetate or placebo and after a 2-week titration period, wereassessed over a 12 week maintenance period, with continued follow-up over aone year open-label period.(2)-(11)

Efficacy

Over the 12 week maintenance period, Zebinix(TM) 800mg and 1200mgonce-daily reduced seizure frequency by over one third, and was significantlymore effective than placebo. This significant decrease in seizure frequencywas sustained over the one-year open label treatment period and wasconsistent regardless of baseline therapy.(2)-(11) Similar positive findingswere observed in the responder rate ((greater than or equal to)50% decreasein seizure frequency) for Zebinix(TM) 800mg and 1200mg once-daily that rangedbetween 32% and 43% across all three phase III trials.(5)-(7)

Tolerability

The safety profile of Zebinix(TM) was favourable. The majority oftreatment related adverse events were mild or moderate in intensity. After 6weeks, the incidence of new CNS side effects was low in patients treated withZebinix(TM).(2)-(11) These results parallel findings from earlier Phase 2.(16)

Quality of life and depressive symptoms

The effect of Zebinix(TM) on quality of life was assessed using theQuality of Life Epilepsy Inventory-31 (QOLIE-31) scale. There was astatistically and clinically significant improvement from baseline duringlong-term open-label therapy, including a mean relative improvement inoverall quality of life (p<0.001 - p<0.01 across the three studies) andimprovements in individual elements of the QOLIE-31 scale including seizureworry, emotional wellbeing, energy/fatigue, medication effects and socialfunction.(2)-(4)

Improvement in depressive symptoms was also measured using the MontgomeryAsberg Depression Rating Scale (MADRS). During long-term, open-label therapy,Zebinix(TM) demonstrated a statistically significant improvement frombaseline in the overall MADRS score (p<0.0001) and individual domains of theMADRS scale including pessimistic thoughts, concentration difficulties,apparent sadness and inner tension.(2)-(4)

Notes to Editors

About partial seizures and their treatment

Epilepsy is one of the most common neurological diseases, affectingalmost 1 in 100 people.(12) Treatment of partial seizures, the most commontype of epilepsy, presents a constant challenge - up to two-thirds ofpatients with partial seizures do not achieve seizure control with currentanti-epileptic drugs.(13)-(14)

Furthermore, adverse events, such as lightheadedness (dizziness),somnolence, and cognitive slowing, are highly prevalent with existinganti-epileptic agents and may affect as many as 97% of patients.(15) Hence,there is a need for new anti-epileptic agents that offer effective reductionin seizure frequency combined with a favourable safety profile.

Epilepsy is characterised by abnormal firing of impulses from nerve cellsin the brain. In partial-onset epilepsy, these bursts of electrical activityare initially focused in specific areas of the brain, but may become moregeneralised; the symptoms vary according to the affected areas. Nerveimpulses are triggered via voltage-gated sodium channels in the nerve cellmembrane.

About Zebinix(TM)

Zebinix(TM) is a novel voltage-gated sodium channel blocker that has beendesigned to reduce the frequency of partial-onset seizures when used incombination with other anti-epileptic drugs.

This treatment has the potential to offer a new therapeutic option forpatients who continue to suffer partial seizures despite receiving otheranti-epileptic agents, with the potential for additional benefits in terms ofimprovements in quality of life and depressive symptoms.2-11 BIAL submitted amarketing authorization application to the EMEA in March 2008. BIAL licensedthe rights to commercialise eslicarbazepine acetate for the U.S. and Canadianmarkets to Sepracor Inc., a U.S., research-based pharmaceutical company thatis currently preparing an NDA for submission to the U.S. Food and DrugAdministration.

About BIAL

Founded in 1924, BIAL is an international pharmaceuticals group withproducts available in nearly 30 countries over four continents. BIAL group isthe largest Portuguese pharmaceutical company and is based in S. Mamede doCoronado, Portugal.

BIAL is strongly committed to therapeutic innovation on research anddevelopment every year. This commitment has been recognised in the group'srecent integration into the EFPIA (European Federation of PharmaceuticalIndustries and Associations), which is dedicated to encouraging research andthe development of new therapeutic options.

Key research areas for BIAL are the central nervous system, thecardiovascular system and allergology. BIAL's dedication to research isfurther demonstrated by the research grants and awards offered by the BIALFoundation.

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

References

(1). Zebinix(TM) is one of the proposed EU trade names foreslicarbazepine acetate

(2). Cramer J, Elger C, Halasz P et al. An Evaluation of Quality of Lifeand Depressive Symptoms During Long-Term Treatment with EslicarbazepineAcetate: BIA-2093-301 Study.QOL 301. Poster presented at the AmericanEpilepsy Society (AES) Congress, 5-9 December 2009, Seattle, WA, USA.

(3). Soares-da-Silva P, Martins-da-Silva A, Gabbai AA et al. AnEvaluation of Quality of Life and Depressive Symptoms During Long-TermTreatment with Eslicarbazepine Acetate: BIA-2093-302 Study. Poster presentedat the American Epilepsy Society (AES) Congress, 5-9 December 2009, Seattle,WA, USA.

(4). Pereira H, Lopes-Lima J, Gil-Nagel A et al. An Evaluation of Qualityof Life and Depressive Symptoms During Long-Term Treatment withEslicarbazepine Acetate: BIA-2093-303 Study. Poster presented at the AmericanEpilepsy Society (AES) Congress, 5-9 December 2009, Seattle, WA, USA.

(5). Czapinski P, Halasz P, Elger C et al. An Evaluation of Efficacy andSafety of Eslicarbazepine Acetate (ESL) as Add-on Treatment in Adults withRefractory Partial-Onset Seizures: BIA-2093-301 Study. Poster presented atthe American Epilepsy Society (AES) Congress, 5-9 December 2009, Seattle, WA,USA.

(6). Ben-Menachem E, Gabbai AA, Hufnagel A et al. An Evaluation ofEfficacy and Safety of Eslicarbazepine Acetate (ESL) as Add-on Treatment inAdults with Refractory Partial-Onset Seizures: BIA-2093-302 Study. Posterpresented at the American Epilepsy Society (AES) Congress, 5-9 December 2009,Seattle, WA, USA.

(7). Gil-Nagel A, Lopes-Lima J, Maia J et al. An Evaluation of Efficacyand Safety of Eslicarbazepine Acetate (ESL) as Add-on Treatment in Adultswith Refractory Partial-Onset Seizures: BIA-2093-303 Study. Poster presentedat the American Epilepsy Society (AES) Congress, 5-9 December 2009, Seattle,WA, USA.

(8). Elger C, French J, Halasz P et al. An Evaluation of Efficacy andSafety of Eslicarbazepine Acetate as Add-On Treatment in Patients withPartial-Onset Seizures: Pooled Analysis of Three Double Blind Phase IIIClinical Studies. Oral presentation at the American Epilepsy Society (AES)Congress, 5-9 December 2009, Seattle, WA, USA.

(9). Halasz P, Elger C, Guekht A et al. Long-Term Treatment of PartialEpilepsy with Eslicarbazepine Acetate (ESL): Results of a One-Year Open-LabelExtension to Study BIA-2093-301. Poster presented at the American EpilepsySociety (AES) Congress, 5-9 December 2009, Seattle, WA, USA.

(10). Gabbai AA, Ben-Menachem E, Maia J et al. Long-Term Treatment ofPartial Epilepsy with Eslicarbazepine Acetate (ESL): Results of a One-YearOpen-Label Extension to Study BIA-2093-302. Poster presented at the AmericanEpilepsy Society (AES) Congress, 5-9 December 2009, Seattle, WA, USA.

(11). Lopes-Lima J, Gil-Nagel A, Maia J et al. Long-Term Treatment ofPartial Epilepsy with Eslicarbazepine Acetate (ESL): Results of a One-YearOpen-Label Extension to Study BIA-2093-303. Poster presented at the AmericanEpilepsy Society (AES) Congress, 5-9 December 2009, Seattle, WA,

(12). WHO Atlas: Epilepsy Care in the World. WHO 2005

(13). Mattson, RH, Cramer, JA, et al. Comparison of carbamazepine,phenobarbital, phenytoin and primidone in partial and secondarily generalizedtonic clonic seizures. New England Journal of Medicine 313:145-151, 1985.

(14). Mattson, RH, Cramer, JA, et al, VA Cooperative Study Group. Acomparison of valproate with carbamazepine for the treatment of partialseizures and secondarily generalized tonic-clonic seizures in adults. NewEngland Journal of Medicine, 327:765-771, 1992.

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

(16). Elger, C; Bialer, M; Cramer, JA; et al. Eslicarbazepine acetate: Adouble-blind, add-on, placebo-controlled exploratory trial in adult patientswith partial-onset seizures. Epilepsia 2007; 48: 497-504.Media contacts For more information please contact: BIAL (head office) Francisco Osorio Tel.: +351-22-986-6100 Mobile: +351-96-346-9968 francisco.osorio@bial.com Paul Gittins Red Health Tel.: +44-207-025-6571 Mobile: +44-7958-533-462 paul.gittins@redconsultancy.com

SOURCE BIAL
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