Oxcarbazepine Extended ReleaseOxcarbazepine Extended ReleaseOXC XROXC XR

Janet K. Johnson, Ph.D.Director, Clinical Research

Supernus Pharmaceuticals, Inc.

ASENT Pipeline Projects Session

March 5, 2010

Development of OXC XRDevelopment of OXC XR

• Supernus Pharmaceuticals, Inc– Small pharmaceutical company with

proprietary drug delivery methodology– Experience with CNS products (ADHD,

epilepsy) as Shire Labs

• OXC as candidate for XR development– Effective doses 600 – 2400mg/d– Increase response rate with increase in dose– Highest doses associated with significant AEs

OXC v Placebo, Barcs Study% Seizure Free% Seizure Free

Med

ian

% s

eizu

re re

ducti

on

0.6%3% 10%

22%

26%*

40%*

50%*

8%

N=173

N=169

N=178

N=174~

Epilepsia, 41(12):1597, 2000* p=0.0001 compared to placebo

~ includes 47 pts at 1800 mg; 73% of patients on 2400mg dropped from the study or decreased to 1800mg

Relationship between a given serum MHD level and the presence/absence of an AE (ROC curve analysis) (n = total number of MHD samples).

Striano et al, Epilepsy Research 2006, 69(2):170-176

Incentives for Development of OXC XRIncentives for Development of OXC XR

• Current Formulation– BID dosing– Association of AEs with peak levels

• Possible Advantages of XR Formulation– QD dosing – may increase compliance– Lower peak – may increase tolerablity

Drug + Polymer Core

Receding Solid Interface

Hydrated Polymer Layer

Solubilized Drug Release Path

Solutrol

Drug + Polymer Core

Receding Solid Interface

Solubilized Drug Release Path

Solutrol

0

20

40

60

80

100

0 2 4 6 8 10 12

Time (hr)

Dru

g D

isso

lve

d (

%)

pH 1.2 pH 6.8

Solutrol vs pH Dependent Dissolution

0

20

40

60

80

100

0 2 4 6 8 10 12

Time (hr)

Dru

g D

isso

lve

d (

%)

Control pH 1.2 Control pH 6.8

OXC solubility

15 mg/mL at pH 1.0 0.22 mg/mL at pH 7.0

OXC XR vs IR at Steady State Healthy Normal Volunteers, 7 days, 1200mg, crossover

0

5

10

15

20

25

312 318 324 330 336 342 348 354 360 366 372 378 384

Timepoint (Hr.)

Me

an

MH

D C

on

ce

ntr

ati

on

s (

µg

/mL

)

OXC-XR

OXC-IR

OXC XR vs IR at Steady State (7 days, 1200mg)

PK studies of OXC XR vs IR

Ratios of LSM and 90% CI*

Pharmacokinetic Metrics

MHD in Plasma OXC XR Fed vs. OXC XR Fasted

AUC0-24 113.5% (109.5 – 117.7%) AUC 112.0% (107.9 – 116.2%) Cmax 162.6% (156.7 – 168.7%)

OXC XR - Food Effect (single 600mg dose)

Ratios of LSM and 90% CI*

Pharmacokinetic Metrics

MHD in Plasma OXC XR vs. OXC-IR

AUC0-24 80.8% (77.5 – 84.3%) Cmax,ss 80.8% (77.0 – 84.9%) Cmin,ss 83.7% (78.8 – 88.9%)

OXC XR vs OXC IR - Steady StateNumber of AEs, Total Nervous & GI Systems

804P103 Number of AEs

0

20

40

60

80

100

120

140

160

180

200

Nervous GI TOTAL

System disorders

Nu

mb

er

of

Eve

nts

OXC-XR

OXC-IR

120

190

24

54

19

53

0

5

10

15

20

NERVOUS

D

izzin

ess

H

eadac

he

H

ypoae

sthes

ia

GASTROIN

TES

C

onstip

atio

n

H

ypoae

sth o

ral

N

ause

a

PSYCH

E

uphoric

mood

RENAL

P

olla

kiuria

System Disorder

Num

ber

of

Subje

cts

OXC-XR

OXC-IR

804P103 - Comparative Steady StateAEs Experienced by >10% of Subjects

OXC XR Phase 3 • Study Design

– 360 adult patients, 90+ sites, 8 countries

– Refractory partial seizures, 1-3 AEDs

– Baseline of ≥ 3 countable seizures/28d

– Seizure classification reviewed by Epilepsy Study Consortium

– QD, 1:1:1, Placebo: 1200mg OXC XR: 2400mg OXC XR

– 8 wk baseline, 4 wk titration, 12 wk treatment, 3 wk taper

– Option for 1 year open-label follow-on study– 1Efficacy = % change seizures/28d, OXC XR vs Placebo

– 2Efficacy = % seizure-free, other efficacy, safety, QOL

804P301 Study Design

6

1800

1200

2400 mg/d

1200 mg/d

Placebo

1800

1200

600 600

MaintenanceTitration ConversionScreening

BASELINE TREATMENT

VISIT

WEEK

1 2 33

1-8 to -1 2 3 4 5 9 13 17 18 19

44 55 66 7

3 weeks12 weeks8 weeks 4 weeks

SEIZURE DIARY

Seizure Identification Form PK Sampling

Development of XR, CR for Epilepsy

• Supernus status– Development of OXC XR for partial epilepsy

• QD formulation, 80% AUC, Cmax vs OXC IR• Lower incidence of AEs in PK study of HNV at 1200mg• Possible greater utility of high dose (2400mg)• Ongoing Phase 3 placebo-controlled study in adults• Ongoing PK study in pediatrics

– Development of Topiramate Controlled Release