An Overview of the Development of Eslicarbazepine Acetate (ESL) as

Adjunctive Therapy for Partial Seizures

A Novel Experimental Sodium Channel Blocker

Mark Versavel, MD, PhD, MBA

Sepracor Inc.

Mechanism of Action of Eslicarbazepine Acetate Blockade of voltage-gated sodium channels (VGSC). Interacts with site 2 of the inactivated state of the channel, with

affinity similar to that of carbamazepine.

1 2 3 4 5 61 2 3 4 5 6 1 2 3 4 5 61 2 3 4 5 6

I II III IV

NC

IInside

Outside

Pore

S6

Eslicarbazepine acetate

ESL

Eslicarbazepine

Hydrolase

Eslicarbazepine-GLU

UGT

URINEGLU

2/3

1/3

N

O NH 2

O

H3CO

N

O NH2

HO

N

O NH2

HO

Eslicarbazepine acetate is

hydrolyzed to eslicarbazepine

Eslicarbazepine is the predominant

metabolite in

both plasma and urine

Glucuronidation is the main

metabolic pathway

Eslicarbazepine and its glucuronide

correspond to 92% of the total drug

material excreted in urine

Eslicarbazepine Acetate: A Simple Metabolic Profile

Pharmacokinetics of Eslicarbazepine Acetate

Binding to plasma proteins is <40%

t½ is 13-20 h in epileptic adult patients

Prolonged t½ in renal impaired subjects that requires dose reduction

Steady state of plasma concentrations is attained after 4 to 5 days of once daily dosing

Linear and dose-proportional PK

PK not affected by gender, age, or food

No significant interactions with other AEDs– May increase concentrations of phenytoin

May reduce the effect of oral contraceptives

Responder Rate (ITT)

60

50

40

30

20

10

0

P = 0.008

P = 0.12

% o

f R

esp

on

der

s

Eslicarbazepine acetate QD (n = 50)

Eslicarbazepine acetate BID (n = 46)

Placebo (n = 47)

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

ESL QD ESL BID Placebo

Integrated Analysis of 3 Phase III, 26 Week, Adjunctive Fixed Dose Studies: Primary Efficacy AnalysisANCOVA analysis for seizure frequency per 4 weeks over the 12-week maintenance period (ITT)

ANCOVA LS Mean [95%CI] P value

Placebo(n=279)

8.2 [7.4, 9.0] -

400 mg(n=192)

7.4 [6.6, 8.3] 0.1122

800 mg(n=262)

6.2 [5.6, 7.0] <0.0001

1200 mg(n=253)

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

Integrated Analysis of 3 Phase III Studies: Safety Results

Most common AEs: dizziness, somnolence, headache, nausea, vomiting, diplopia, and abnormal coordination

Low incidence of hyponatremia

Small decrease of T4, no decreased thyroid function

Not associated with changes in total cholesterol, low density lipoprotein (LDL) levels, and glucose

No systematic effect on body weight

No clinically meaningful effect on ECG parameters

• Novel blocker of voltage-gated sodium channels• Pharmacokinetics and Pharmacodynamics

• Eslicarbazepine acetate is hydrolyzed to eslicarbazepine, which is excreted renally

• Prolonged t½ in renal impaired subjects that requires dose reduction

• Efficacy• 800 mg and 1200 mg once-daily reduced partial-onset seizures • Maintained reduction in seizure frequency during a 1-year

treatment period • Safety and Tolerability

• Most common AEs: dizziness, somnolence, headache, nausea, vomiting, diplopia, and abnormal coordination

Eslicarbazepine Acetate As Adjunctive Therapy:

Summary

Status of Eslicarbazepine Acetate Studies

Phase III completed ex-US (adjunctive therapy)

Plans for additional epilepsy trials

• Monotherapy

• Pediatric

Other ongoing trials

• Neuropathic pain: Phase II

The safety and efficacy of eslicarbazepine acetate for the adjunctive treatment of epilepsy or any other use have not yet been evaluated by the FDA.