oxcarbazepine extended release oxc xr janet k. johnson, ph.d. director, clinical research supernus...
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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
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