Oxcarbazepine Extended Release OXC XR Janet K. Johnson, Ph.D. Director, Clinical Research Supernus Pharmaceuticals, Inc. ASENT Pipeline Projects Session March 5, 2010

Development 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

% Seizure Free OXC v Placebo, Barcs Study % Seizure Free Median % seizure reduction 0.6% 3% 10% 22% 26%* 40%* 50%* 8% N=173 N=169 N=178 N=174~ Epilepsia, 41(12):1597, 2000 * p= 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):

Incentives 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 

Solutrol  vs pH Dependent Dissolution OXC solubility 15 mg/mL at pH mg/mL at pH 7.0

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

OXC XR vs IR at Steady State (7 days, 1200mg) PK studies of OXC XR vs IR OXC XR - Food Effect (single 600mg dose)

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

804P103 - Comparative Steady State AEs 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 –1  Efficacy = % change seizures/28d, OXC XR vs Placebo –2  Efficacy = % seizure-free, other efficacy, safety, QOL

804P301 Study Design mg/d 1200 mg/d Placebo Maintenance Titration Conversion Screening BASELINETREATMENT VISIT WEEK to weeks 12 weeks 8 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, C max 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