An Overview of the Development of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial SeizuresA Novel Experimental Sodium Channel Blocker Mark Versavel, MD, PhD, MBA Sepracor Inc.
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. Mechanism of Action of Eslicarbazepine Acetate I II III IV S6 Outside 1 2 3 4 5 6 1 2 3 4 5 1 2 3 4 5 6 1 2 3 4 5 6 6 Inside I N C Pore Eslicarbazepine acetate
Eslicarbazepine Acetate: A Simple Metabolic Profile • 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 ESL H C 3 O O Hydrolase N O N H 2 Eslicarbazepine H O N O N H 2 UGT 2/3 Eslicarbazepine-GLU H O GLU URINE N O N H 2 1/3
Pharmacokinetics of Eslicarbazepine Acetate • Binding to plasma proteins is <40% • t½is 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
QD Versus BID: Phase II, 12Week, Double-blind, Adjunctive Fixed Dose Escalation Study (400-1200 mg daily doses) Responder Rate (ITT) Eslicarbazepine acetate QD (n = 50) 60 Eslicarbazepine acetate BID (n = 46) P =0.008 Placebo (n = 47) 50 P = 0.12 40 % of Responders 30 20 10 0 ESL QD Placebo ESL BID
Integrated Analysis of 3 Phase III, 26 Week, Adjunctive Fixed Dose Studies: Primary Efficacy Analysis ANCOVA analysis for seizure frequency per 4 weeks over the 12-week maintenance period (ITT)
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
Eslicarbazepine Acetate As Adjunctive Therapy: Summary • 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
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.