Presentation on theme: "An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial-Onset Seizures Mark Versavel MD, PhD, MBA Vice President, Clinical Research."— Presentation transcript:
An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial-Onset Seizures Mark Versavel MD, PhD, MBA Vice President, Clinical Research and Medical Affairs, CNS 05 March, 2010
Page 2 STEDESA™ (Eslicarbazepine Acetate) Regulatory Status Sepracor in-licensed rights for the United States and Canada from BIAL Sepracor is seeking approval for the use of eslicarbazepine acetate as adjunctive therapy in the treatment of partial- onset seizures in adults with epilepsy. The proposed tradename for eslicarbazepine acetate is STEDESA™. STEDESA is currently an unapproved product in the U.S. The NDA for STEDESA was submitted to FDA on March 31 st, 2009 and accepted for standard review, but still pending approval.
Page 3 Firing Sequence of Voltage-gated Sodium Channels (VGSC) Active (channel open) Inactive (channel closed) Resting/normal (channel recovering) ESL, CBZ and OXC competitively inhibit the VGSC by binding with the receptor in its inactive state, prolonging the period between successive firings ESL has a much higher affinity for the inactive state of VGSC compared with its resting state 1 The activity of ESL is therefore concentrated on rapidly- firing channels, rather than those which are not actively firing 1 1.Bonifacio MJ, et al. Epilepsia 2001;42(5):600-608
Page 4 Eslicarbazepine Acetate — Metabolic Profile Eslicarbazepine is the predominant metabolite in both plasma and urine 1 Glucuronidation is the main metabolic pathway 2 Eslicarbazepine and its glucuronide correspond to 92% of the total drug material excreted in urine 2 The main metabolic pathway of ESL generates no epoxide metabolites, which are associated with toxic effects 3 1. Maia J, et al. Int J Clin Pharmacol Therapeut 2008 ;46(3):119-130 2. Almeida L, et al. Eur J Clin Pharmacol 2008;64:267-273 3. Bialer M, et al. Epilepsy Res 2007;73(1):1-52
Page 5 Higher Brain/Plasma Exposure Ratio of Eslicarbazepine 1 Lower brain exposure of R-licarbazepine is due to its susceptability to be back transported by P-glycoprotein (a verapamil-sensitive process) Brain exposure of Eslicarbazepine is twice that of R-licarbazepine 1 Brain to Plasma ratio VehicleProbenecidVerapamil 0.15 0.30 0.45 Eslicarbazepine R-licarbazepine ** Brain to plasma ratio 1.Almeida L, Bialer M, Soares-da-Silva P. Eslicarbazepine Acetate pp 485 - 498 The Treatment of Epilepsy, 3rd edition, Ed. Shorvon S, Perucca E, Engel J 2009 Blackwell Publishing, * p < 0.05 *
Page 6 Responder* Rate – Intention to treat population (ITT) 1 60 50 40 30 20 10 0 P = 0.008 P = 0.12 % of Responders ESL QD (n = 50) ESL BID (n = 46) Placebo (n = 47) Phase II, 12 Week, Double-blind, Adjunctive Fixed Dose Escalation Study (400-1200 mg daily doses) 1 1.Elger C, et al. Epilepsia 2007;48(3):497-504 *subjects with a 50% reduction from baseline in seizure frequency
Page 7 Integrated Results from Phase III Studies (Primary Endpoint) 1,2 ANCOVA analysis for seizure frequency per 4 weeks over the 12-week maintenance period (ITT) 1,2 ANCOVALS Mean [95%CI]P value vs. Placebo Placebo8.2 [7.4, 9.0]- 400 mg7.4 [6.6, 8.3]0.1122 800 mg6.2 [5.6, 7.0]<0.0001 1200 mg6.0 [5.3, 6.7]<0.0001 ANCOVA model: based on log-transformed seizure frequencies. ANCOVA model was based on log- transformed seizure frequencies with baseline seizure frequency as covariate. Estimates from the model were back transformed using the exponential function. Dunnett’s multiple comparison procedure was used for the comparison of the active treatment means to the placebo mean. 1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-429 2.Data on file. BIAL-ESL Phase III - Integrated Clinical Report
Page 8 Integrated Results from Phase III Studies (Secondary Endpoint) 1,2 Responder rate: percentage of patients with 50% reduction in seizure frequency over the 12-week maintenance period 1,2 Responder ratePlacebo400 mg800 mg1200 mg ITT21.5%22.9%36.3%43.5% PP20.2%24.4%36.1%46.6% ITTP value 400 mg0.3668 800 mg0.0001 1200 mg<0.0001 PPP value 400 mg0.1530 800 mg0.0002 1200 mg<0.0001 1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-429 2.Data on file. BIAL-ESL Phase III - Integrated Clinical Report
Page 9 Treatment-emergent adverse events (%) Placebo (N=289) 400 mg (N=196) 800 mg (N=284) 1200 mg (N=280) Dizziness7.3 13.321.128.9 Somnolence9.3 10.713.015.0 Headache8.7 10.213.6 Diplopia220.127.116.11.6 Abnormal coordination18.104.22.168.1 Blurred vision1.04.13.9 Vertigo0.32.01.83.9 Depression0.33.10.71.8 Convulsion22.214.171.124.7 Incidence rate of CNS-related TEAEs affecting >2% of patients in any group 1,2 1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-429 2.Data on file. BIAL-ESL Phase III - Integrated Clinical Report
Page 10 1-year Open-Label Extension BIA-2093-301 1 BIA-2093-302 2 BIA-2093-303 3 Number of patients enrolled (Total 833) 314325194 Patients who completed 1 year (Total 612) 239223150 Completion rate (73.5%)76.1%68.6%78.5% Median dose of ESL800 mg High Completion Rates for Phase III 1-Year Open-Label Extension 1- 3 1.Halász P, et al. Epilepsia. 2008;49(suppl.7):435-436 2.Gabbai AA,et al. Epilepsia. 2008;49(suppl.7):432-433 3.Lopes-Lima J, et al. Epilepsia. 2008;49(suppl.7):441-442
Page 11 Eslicarbazepine Acetate in Partial-Onset Epilepsy – Summary of Results 1 Long apparent half life of 13-20h Studied as adjunctive therapy in a population of 1,049 refractory partial-onset epilepsy patients Enrolled by 125 sites distributed by 23 countries 800 mg and 1200 mg once-daily reduced partial-onset seizures Maintained reduction in seizure frequency during a 1-year open-label treatment period Consistent results between different studies, subpopulations Tolerability and safety profile Few discontinuations due to adverse events Low incidence of serious dermatologic reactions and hyponatremia Changes in serum lipids, ECG parameters, body weight similar to placebo 1.Data on file
Page 12 Eslicarbazepine acetate – ongoing and planned studies Adjunctive treatment Safety and efficacy trial including US sites (started) Safety and efficacy in elderly (BIAL, ex-US) Monotherapy Conversion to Monotherapy: program started April 2009 Monotherapy in newly diagnosed subjects: planned (BIAL, ex-US) Conversion study Switch from carbamazepine or phenytoin to eslicarbazepine acetate (planned) Pediatric PK study completed, ex-US efficacy study ongoing (BIAL) Further PK and US efficacy study planned Other trials Neuropathic pain Bipolar disorder
Page 13 St Valentine, Patron Saint of the ‘‘Falling Sickness” (Epilepsy) ceiling fresco, Unterleiterbach, Germany, 1740: child with possible infantile spasm and demon Gerhard Kluger, Verena Kudernatsch Epilepsy & Behavior 14 (2009) 219–225
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