An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for

Partial-Onset Seizures

Mark Versavel MD, PhD, MBA

Vice President, Clinical Research and Medical Affairs, CNS

05 March, 2010

Page 2

STEDESA™ (Eslicarbazepine Acetate) Regulatory Status

• Sepracor in-licensed rights for the United States and Canada from BIAL

• Sepracor is seeking approval for the use of eslicarbazepine acetate as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy.

• The proposed tradename for eslicarbazepine acetate is STEDESA™.

• STEDESA is currently an unapproved product in the U.S.

• The NDA for STEDESA was submitted to FDA on March 31st, 2009 and accepted for standard review, but still pending approval.

Page 3

Firing Sequence of Voltage-gated Sodium Channels (VGSC)

Active(channel open)

Inactive(channel closed)

Resting/normal(channel recovering)

• ESL, CBZ and OXC competitively inhibit the VGSC by binding with the receptor in its inactive state, prolonging the period between successive firings

• ESL has a much higher affinity for the inactive state of VGSC compared with its resting state1

• The activity of ESL is therefore concentrated on rapidly-firing channels, rather than those which are not actively firing1

1.Bonifacio MJ, et al. Epilepsia 2001;42(5):600-608

Page 4

Eslicarbazepine Acetate — Metabolic Profile

• Eslicarbazepine is the predominant metabolite in both plasma and urine1

• Glucuronidation is the main metabolic pathway2

• Eslicarbazepine and its glucuronide correspond to 92% of the total drug material excreted in urine2

• The main metabolic pathway of ESL generates no epoxide metabolites, which are associated with toxic effects3

ESL, Eslicarbazepine Acetate

Eslicarbazepine

First-pass Hydrolysis

Eslicarbazepine-GLU

UGT

URINEGLU

2/3

1/3

N

O NH2

O

H3CO

N

O NH2

HO

N

O NH2

HO

1. Maia J, et al. Int J Clin Pharmacol Therapeut 2008 ;46(3):119-1302. Almeida L, et al. Eur J Clin Pharmacol 2008;64:267-2733. Bialer M, et al. Epilepsy Res 2007;73(1):1-52

Page 5

Higher Brain/Plasma Exposure Ratio of Eslicarbazepine1

Lower brain exposure of R-licarbazepine is due to its susceptability to be back transported by P-glycoprotein (a verapamil-sensitive process)

Brain exposure of Eslicarbazepine is twice that of R-licarbazepine1

Brain to Plasma ratio

Vehicle Probenecid Verapamil0.15

0.30

0.45EslicarbazepineR-licarbazepine

**

Bra

in t

o p

lasm

a ra

tio

1.Almeida L, Bialer M, Soares-da-Silva P. Eslicarbazepine Acetate pp 485 - 498The Treatment of Epilepsy, 3rd edition, Ed. Shorvon S, Perucca E, Engel J 2009 Blackwell Publishing,

* p < 0.05

*

Page 6

Responder* Rate – Intention to treat population (ITT)1

60

50

40

30

20

10

0

P = 0.008

P = 0.12

% o

f R

esp

on

der

s

ESLQD (n = 50)

ESL BID (n = 46)

Placebo(n = 47)

Phase II, 12 Week, Double-blind, Adjunctive Fixed Dose Escalation Study (400-1200 mg daily doses)1

1.Elger C, et al. Epilepsia 2007;48(3):497-504

*subjects with a 50% reduction from baseline in seizure frequency

Page 7

Integrated Results from Phase III Studies (Primary Endpoint)1,2

• ANCOVA analysis for seizure frequency per 4 weeks over the 12-week maintenance period (ITT)1,2

ANCOVA LS Mean [95%CI] P valuevs. Placebo

Placebo 8.2 [7.4, 9.0] -

400 mg 7.4 [6.6, 8.3] 0.1122

800 mg 6.2 [5.6, 7.0] <0.0001

1200 mg 6.0 [5.3, 6.7] <0.0001 Placebo 400 mg 800 mg 1200 mg

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

LS

me

an a

nd

95

%C

Io

f se

izu

re f

req

ue

nc

y p

er

4 w

ee

ks

ANCOVA model: based on log-transformed seizure frequencies. ANCOVA model was based on log-transformed seizure frequencies with baseline seizure frequency as covariate. Estimates from the model were back transformed using the exponential function. Dunnett’s multiple comparison procedure was used for the comparison of the active treatment means to the placebo mean.

1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-4292.Data on file. BIAL-ESL Phase III - Integrated Clinical Report

Page 8

Integrated Results from Phase III Studies (Secondary Endpoint)1,2

• Responder rate: percentage of patients with 50% reduction in seizure frequency over the 12-week maintenance period1,2

Responder rate Placebo 400 mg 800 mg 1200 mg

ITT 21.5% 22.9% 36.3% 43.5%

PP 20.2% 24.4% 36.1% 46.6%

ITT PP

0

5

10

15

20

25

30

35

40

45

50Placebo400 mg800 mg1200 mg

Res

po

nd

er r

ate

(%)

ITT P value

400 mg 0.3668

800 mg 0.0001

1200 mg <0.0001

PP P value

400 mg 0.1530

800 mg 0.0002

1200 mg <0.0001

1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-4292.Data on file. BIAL-ESL Phase III - Integrated Clinical Report

Page 9

Treatment-emergent adverse events (%)

Placebo

(N=289)

400 mg

(N=196)

800 mg

(N=284)

1200 mg

(N=280)

Dizziness 7.3 13.3 21.1 28.9

Somnolence 9.3 10.7 13.0 15.0

Headache 8.7 8.7 10.2 13.6

Diplopia 1.7 5.1 8.1 8.6

Abnormal coordination 2.1 3.1 5.3 6.1

Blurred vision 1.0 4.1 3.9 3.9

Vertigo 0.3 2.0 1.8 3.9

Depression 0.3 3.1 0.7 1.8Convulsion 2.1 1.5 1.1 0.7

Incidence rate of CNS-related TEAEs affecting >2% of patients in any group1,2

1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-4292.Data on file. BIAL-ESL Phase III - Integrated Clinical Report

Page 10

1-year Open-Label Extension

BIA-2093-3011 BIA-2093-3022 BIA-2093-3033

Number of patients enrolled (Total 833)

314 325 194

Patients who completed 1 year (Total 612)

239 223 150

Completion rate (73.5%) 76.1% 68.6% 78.5%

Median dose of ESL 800 mg 800 mg 800 mg

High Completion Rates for Phase III 1-Year Open-Label Extension1- 3

1. Halász P, et al. Epilepsia. 2008;49(suppl.7):435-4362. Gabbai AA ,et al. Epilepsia. 2008;49(suppl.7):432-4333. Lopes-Lima J, et al. Epilepsia. 2008;49(suppl.7):441-442

Page 11

Eslicarbazepine Acetate in Partial-Onset Epilepsy – Summary of Results1

• Long apparent half life of 13-20h

• Studied as adjunctive therapy in a population of 1,049 refractory partial-onset epilepsy patients

•Enrolled by 125 sites distributed by 23 countries

• 800 mg and 1200 mg once-daily reduced partial-onset seizures

•Maintained reduction in seizure frequency during a 1-year open-label treatment period

•Consistent results between different studies, subpopulations

• Tolerability and safety profile

• Few discontinuations due to adverse events

• Low incidence of serious dermatologic reactions and hyponatremia

•Changes in serum lipids, ECG parameters, body weight similar to placebo

1.Data on file

Page 12

Eslicarbazepine acetate – ongoing and planned studies

• Adjunctive treatment•Safety and efficacy trial including US sites (started)•Safety and efficacy in elderly (BIAL, ex-US)

• Monotherapy•Conversion to Monotherapy: program started April 2009•Monotherapy in newly diagnosed subjects: planned (BIAL, ex-US)

• Conversion study•Switch from carbamazepine or phenytoin to eslicarbazepine acetate (planned)

• Pediatric•PK study completed, ex-US efficacy study ongoing (BIAL)•Further PK and US efficacy study planned

• Other trials•Neuropathic pain•Bipolar disorder

Page 13

St Valentine, Patron Saint of the ‘‘Falling Sickness” (Epilepsy)

ceiling fresco, Unterleiterbach, Germany, 1740: child with possible infantile spasm and demonGerhard Kluger, Verena Kudernatsch Epilepsy & Behavior 14 (2009) 219–225