New STEDESA Clinical Data Presented at American Epilepsy Society Annual Meeting in Boston

Among the new data presented were evaluations of hyponatremia, cardiac repolarization, metabolic parameters and rash in a pooled analysis of three Phase III studies of STEDESA

Sepracor Inc. today announced that clinical study data for STEDESA^™ (eslicarbazepine acetate; ESL) were presented during a scientific poster session at the 2009 annual meeting of the American Epilepsy Society (AES) in Boston. Seven posters were presented on Dec. 5, 2009 and included data regarding safety and efficacy evaluations of STEDESA. These data were derived from the pooled results of three, placebo-controlled Phase III studies of STEDESA in which adult patients who had a history of at least four partial-onset seizures per month despite treatment with one to three concomitant antiepileptic drugs (AEDs) were randomized to 400 mg, 800 mg or 1200 mg of ESL or placebo.

An Investigation of the Effects of Eslicarbazepine Acetate (STEDESA) on Hyponatremia: A Pooled Analysis of Three Double-Blind Phase III Clinical Studies

Hyponatremia occurs when there is insufficient sodium in extracellular body fluids, which can have a negative impact on blood pressure and muscle and nerve function. This analysis was conducted to determine the risk of hyponatremia in patients with partial-onset seizures who were administered ESL as adjunctive therapy.

In this analysis, reports of hyponatremic treatment-emergent adverse events (TEAEs) were low for patients administered ESL plus an AED (0.9% versus 0% for patients administered placebo plus an AED). When analyzed by subgroup, the incidence of hyponatremic TEAEs was more pronounced for patients administered ESL plus carbamazepine (CBZ), lamotrigine (LTG) or CBZ and LTG: 1.4%, 2.5%, 6.1%, respectively, versus 0% for all corresponding placebo groups. In patients not administered CBZ or LTG, the rate of TEAEs ranged from 0.3% to 0.6% with ESL versus 0% for the placebo groups.

Decreases in sodium levels that were greater than 10 mEq/L (milliequivalents of sodium per liter) were observed in a dose-response manner in those administered ESL plus an AED, with 0% incidence for those taking placebo plus an AED; 0.5% for ESL 400 mg; 2.5% for ESL 800 mg; and 3.7% for ESL 1200 mg. Sodium levels reverted to baseline when treatment was discontinued.

The normal range for blood sodium is 135 to 145 mEq/L, according to the National Institutes of Health Medline Plus.¹ In this analysis, more patients administered ESL (four; 0.5%) had at least one serum sodium value of less than 125 mEq/L during the treatment period compared to zero (0%) in the placebo group. All of these four patients were receiving concomitant CBZ, one of whom was also being treated with LTG. Among patients administered ESL plus CBZ, there was a trend toward a higher incidence of low sodium levels:

• Less than 135 mEq/L – 18.3% (n=77) versus 9.6% (n=17) for placebo plus CBZ
• Less than 125 mEq/L – 1.0% (n=4) versus 0% (n=0) for placebo plus CBZ.

For those patients who received ESL but not with concomitant CBZ, the incidence was:

• Less than 135 mEq/L – 7.4% (n=24) versus 3.7% (n=4) for placebo
• Less than 125 mEq/L – 0% (n=0) versus 0% (n=0) for placebo.

An Investigation of the Effect of Eslicarbazepine Acetate (STEDESA) on Cardiac Repolarization: A Pooled Analysis of Over-Read Electrocardiograms from Three Double-Blind Phase III Clinical Studies

An evaluation of the effect of ESL on cardiac parameters when administered concomitantly with other AEDs in patients with partial-onset seizures, as measured by electrocardiogram (ECG), was performed. During Part I of the studies, 12-lead ECGs were performed on all patients at screening, at study baseline and at Week 14. Of the 5,532 ECGs performed, 4,541 (82%) were successfully over-read by a cardiologist at a central vendor. The ECGs were analyzed for ventricular heart rate, QT interval, PR interval, QRS duration, RR interval and QTc interval.

In this analysis, differences in each ECG parameter from baseline to Week 14 were found to be small and similar across all treatment groups, and these differences were considered not clinically relevant. The placebo and ESL groups had similar incidences of post-dose ECG abnormalities. Potentially clinically significant abnormalities were similar between the placebo and ESL groups and did not exceed 1% for any treatment group.²

An Evaluation of the Effect of Eslicarbazepine Acetate (STEDESA) on Metabolic Parameters: A Pooled Analysis of Three Double-Blind Phase III Clinical Studies

Increases in cholesterol, including both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides, are associated with many AEDs. This evaluation was made to determine ESL's effect on these same lipid levels.

In this evaluation, potentially clinically significant values were defined as: greater than 300 mg/dL (milligrams per deciliter) for total cholesterol; greater than 160 mg/dL for LDL cholesterol; less than 30 mg/dL for HDL; and greater than 2.5 x ULN (upper limit of normal reference range) for triglycerides. The evaluation revealed no clinically relevant differences between the placebo and ESL groups for any of the measures.

Incidence of Rash in the Pooled Population of Three Placebo-Controlled Phase III Clinical Trials with Eslicarbazepine Acetate (STEDESA)

Rash is a known adverse event associated with many AEDs. This analysis of the Phase III program results evaluated the incidence of rash and pruritis with the use of ESL.

Of the 22 patients who reported pruritis and/or rash during the double-blind treatment phase, four (1.3%) were in the placebo group. Of the remaining 18 (2.6%) who reported rash and/or pruritis while treated with ESL, 11 were considered by the investigator to be possibly, probably or definitely related to the medication with the highest incidence of 7 patients, or 2.5%, in the ESL 1200 mg group. Overall, there were six discontinuations due to rash or pruritis: 1 (0.3%) placebo, 1 (0.5%) ESL 400 mg, 0 (0%) ESL 800 mg, and 4 (1.4%) ESL 1200 mg. While most rash or pruritis events were mild or moderate in severity, during the double-blind treatment period, one patient in the ESL 400 mg group reported severe pruritis, and one subject in the ESL 1200 mg group reported severe rash, leading to study discontinuation in both cases.

An Investigation of the Effect of Eslicarbazepine Acetate (STEDESA) on the Pharmacokinetics of Carbamazepine: A Pooled Analysis of Three Placebo-Controlled Phase III Clinical Studies

The effect that ESL may have on the pharmacokinetics of CBZ, an AED chemically related to ESL, was conducted by evaluating blood samples taken pre-dose and at 12 weeks in the Phase III studies of ESL. Of the 1,049 patients in the Phase III program, plasma concentrations were available for 414 of whom who had been receiving CBZ prior to the start of the studies. Using geometric mean ratios (GMR) and 95% confidence intervals (CIs) of the GMR, trough values of CBZ at the end of treatment were compared to pre-dose levels and calculated against a range of 0.80 – 1.25.

All 95% CIs of the GMR were found to be within the bioequivalence standard ratio range of 0.80 to 1.25. The lowest GMR was 0.87 for the CBZ plus ESL 1200 mg group, and the highest was 1.05 in the CBZ plus placebo group.

An Investigation of the Therapeutic Effect of Eslicarbazepine Acetate (STEDESA) Combined with Carbamazepine: Pooled Analysis of Three Placebo-Controlled Phase III Clinical Studies

A subgroup analysis evaluating ESL's safety and efficacy when used concomitantly with CBZ was performed. In the studies, 611 patients received concomitant treatment with CBZ. Efficacy was determined based on seizure frequency (relative and standardized) and responder rate (defined as a decrease in seizure frequency greater than or equal to 50% compared to baseline).

For patients administered ESL plus any concomitant AED, responder rates were statistically significant (p<0.0001) between the treatment groups. Patients who received ESL 800 mg or ESL 1200 mg had the highest responder rates (36.3% and 43.5%, respectively; 21.5% for placebo). The responder rate for patients treated specifically with ESL plus concomitant CBZ was also statistically significant (p<0.0001) between the treatment groups. Patients who received ESL 800 mg or ESL 1200 mg with CBZ had the highest responder rates (33.8% and 46.7%, respectively; 18.9% for placebo). Results were similar for analyses of reduction in seizure frequency.

In both the placebo and total ESL groups, subjects with concomitant CBZ generally had higher incidence of common TEAEs than subjects without concomitant CBZ.

In patients receiving ESL with concomitant CBZ, the incidence of diplopia, dizziness and nausea occurred at more than twice the frequency than in those who received ESL with an AED other than CBZ. For patients given placebo, nausea and vomiting occurred at more than twice the frequency in those receiving concomitant CBZ than in those receiving just placebo.

An Evaluation of Depressive Symptoms Following Treatment with Eslicarbazepine Acetate (STEDESA): A Pooled Analysis in the Open-Label Extensions of Three Phase III Studies in Subjects with Partial-Onset Seizures

Because the incidence of depression is high among patients with epilepsy, an evaluation of depressive symptoms was conducted. The three Phase III studies of ESL each had a one-year, open-label extension in which patients' depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS) at baseline and then upon discontinuation.

The majority of patients who participated in the open-label extensions were categorized as either mild (246, 29.7%) or symptom-free (539, 65.11%) according to their MADRS scores. Only 13 (1.6%) patients categorized as severe and 30 (3.6%) patients categorized as moderate participated in the extensions. In both the intent-to-treat (N=828) and per-protocol (N=457) populations, each total MADRS score by severity category, except symptom-free, showed a significant (p<0.0001 for each category) decrease from baseline in symptom score. The greatest decreases in symptom scores were in the patients classified in the severe category at baseline with a mean decrease of 18.8 in the intent-to-treat population and a mean decrease of 19.0 in the per-protocol population.

Additional posters for STEDESA will be presented as part of a Scientific Exhibit on Monday,Dec. 7, 2009, which will be held from 8:00 am to 5:00 pm EST at the Sheraton Boston Hotel in Ballroom C.These posters will include:

• Investigation of the Influence of Eslicarbazepine Acetate on the Plasma Concentrations of Concomitant Antiepileptic Drugs in Patients With Partial-Onset Epilepsy
• Pharmacokinetics of Eslicarbazepine Acetate in Subjects With Renal Impairment
• Effect of Eslicarbazepine Acetate on the Steady-State Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects
• A Double-Blind, Add-On, Placebo-Controlled, Exploratory Trial of Eslicarbazepine Acetate in Patients With Partial-Onset Seizures
• An Evaluation of the Efficacy and Safety of Eslicarbazepine Acetate (ESL) as Add-On Treatment in Adults With Refractory Partial-Onset Seizures: Study BIA-2093-301
• Long-Term Treatment of Partial-Onset Seizures With Eslicarbazepine Acetate (ESL): Results of a One-Year Open-Label Extension to Study BIA-2093-301
• Assessment of Quality-of-Life and Depressive Symptoms During Long-Term Treatment With Eslicarbazepine Acetate: Study BIA-2093-301
• Evaluation of Efficacy and Safety of Eslicarbazepine Acetate (ESL) as Add-On Treatment in Adults With Refractory Partial-Onset Seizures: Study BIA-2093-302
• Long-Term Treatment of Partial-Onset Epilepsy With Eslicarbazepine Acetate (ESL): Results of a One-Year Open-Label Extension of Study BIA-2093-302
• Assessment of Quality-of-Life and Depressive Symptoms During Long-Term Treatment With Eslicarbazepine Acetate: Study BIA-2093-302
• Evaluation of the Efficacy and Safety of Eslicarbazepine Acetate as Add-On Treatment in Patients With Partial-Onset Seizures: Pooled Analysis of Three Double-Blind Phase III Clinical Studies
• Efficacy and Safety of Eslicarbazepine Acetate (BIA 2-093) as Adjunctive Therapy for Refractory Partial Seizures in a Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Clinical Trial
• Sepracor Study 093-045 Design Overview: Double-Blind, Randomized, Historical Control Study of Safety and Efficacy of Eslicarbazepine Acetate Monotherapy in Subjects With Partial Epilepsy Not Well Controlled by Current AEDs

The studies on which these analyses and posters are based were conducted by BIAL-Portela & C^a, S.A. (BIAL) with editorial support for the posters provided by Sepracor.

About partial-onset seizures and their treatment

Epilepsy is one of the most common neurological diseases that, according to the Epilepsy Foundation, afflicts more than 3 million people in the United States.³ Treatment of partial-onset seizures, the most common type of epilepsy, presents a constant challenge – up to 58% of patients with partial-onset seizures do not achieve seizure control with current antiepileptic drugs.⁴ Patient compliance with antiepileptic agents represents a significant area of unmet need, with poorly compliant patients more likely to have breakthrough seizures⁵ and have higher mortality risk⁶. Additionally, patients with epilepsy often suffer from other concomitant diseases, further complicating the management of these patients.⁷ Finally, certain adverse events are highly prevalent with antiepileptic agents and may affect as many as 97% of patients.⁸

Epilepsy is characterized 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 generalized, with symptoms varying according to the affected areas. Nerve impulses are triggered via voltage-gated sodium channels in the nerve cell membrane.

About STEDESA

STEDESA, a new chemical entity, is a novel voltage-gated sodium channel blocker. STEDESA has been studied in three Phase III, multi-center, randomized, placebo-controlled trials, which involved more than 1,000 patients from 23 countries. Patients involved in the trials had a history of at least four partial-onset seizures per month despite treatment with one to three concomitant antiepileptic drugs. During the trials, patients were randomized to eslicarbazepine acetate or placebo, and after a two-week titration period, were assessed over a 12-week maintenance period with continued follow-up over a one-year, open-label period.

BIAL-Portela & C^a, S.A. (BIAL), a privately held Portuguese pharmaceutical company, was responsible for the research and development of eslicarbazepine acetate. Sepracor acquired the rights to commercialize eslicarbazepine acetate in the U.S. and Canadian markets from BIAL in late 2007.

Sepracor is seeking U.S. Food and Drug Administration (FDA) approval of STEDESA for adjunctive therapy with once-daily doses of 800 mg and 1200 mg in the treatment of partial-onset seizures in adults with epilepsy.

About Sepracor

Sepracor Inc., an indirect, wholly owned subsidiary of Dainippon Sumitomo Pharma Co., Ltd., is a research-based pharmaceutical company dedicated to treating and preventing human disease by discovering, developing and commercializing innovative pharmaceutical products that are directed toward serving large and growing markets and unmet medical needs. Sepracor's drug development program, corporate development, and licensing efforts have yielded a portfolio of pharmaceutical products and candidates with a focus on respiratory and central nervous system disorders. Currently marketed products include LUNESTA^® brand eszopiclone, XOPENEX^® brand levalbuterol HCl Inhalation Solution, XOPENEX HFA^® brand levalbuterol tartrate Inhalation Aerosol, BROVANA^® brand arformoterol tartrate Inhalation Solution, OMNARIS^® brand ciclesonide Nasal Spray and ALVESCO^® brand ciclesonideHFA Inhalation Aerosol. Sepracor's corporate headquarters are located in Marlborough, Massachusetts.

¹ MedlinePlus website http://www.nlm.nih.gov/medlineplus/ency/article/003481.htm, accessed Dec. 3, 2009

² Almeida L, et al. A randomized, double-blind, placebo- and moxifloxacin-controlled, 4 period crossover trial to evaluate the effect of eslicarbazepine acetate on cardiac repolarization in healthy subjects. Poster presented at the European Congress on Epileptology. September 21-25, 2008; Berlin, Germany. Epilepsia. 2008;50 (Suppl 4): 104 (abstract T210).

³ The Epilepsy Foundation of America^® website http://www.epilepsyfoundation.org/about/statistics.cfm, accessed Dec. 1, 2009

⁴ Brodie MJ. Management strategies for refractory localization-related seizures. Epilepsia 2001;42(Suppl 3):27-30

⁵ Cramer JA, Glassman M, Rienzi V. The relationship between poor medication compliance and seizures. Epilepsy Behav. 2002;3:338-342

⁶ Faught E, Duh, M, Weiner J, Guerin A, Cunnington M. Nonadherence to antiepileptic drugs and increased mortality, Findings from the RANSOM Study. Neurology 2008; 71: 1572-1578

⁷ Gidal BE, French JA, Grossman P, Le Teuff G. Assessment of potential drug interactions in patients with epilepsy: Impact of age and sex. Neurology 2009; 72: 419-431

⁸ 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

LUNESTA, XOPENEX, XOPENEX HFA and BROVANA are registered trademarks of Sepracor Inc. STEDESA is a trademark of BIAL-Portela & C^a, S.A. OMNARIS and ALVESCO are registered trademarks of Nycomed GmbH.

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visit Sepracor's web site at www.sepracor.com.

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Sepracor Inc.
Jonaé R. Barnes, 508-481-6700
Sr. Vice President, Investor Relations and
Corporate Communications