An overview of eslicarbazepine acetate esl as adjunctive therapy for partial onset seizures
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An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial-Onset Seizures PowerPoint PPT Presentation


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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. STEDESA ™ (Eslicarbazepine Acetate) Regulatory Status.

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An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial-Onset Seizures

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An overview of eslicarbazepine acetate esl as adjunctive therapy for partial onset seizures

An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy forPartial-Onset Seizures

Mark Versavel MD, PhD, MBA

Vice President, Clinical Research and Medical Affairs, CNS

05 March, 2010


Stedesa eslicarbazepine acetate regulatory status

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 31st, 2009 and accepted for standard review, but still pending approval.


Firing sequence of voltage gated sodium channels vgsc

Firing Sequence of Voltage-gated Sodium Channels (VGSC)

Resting/normal(channel recovering)

Inactive(channel closed)

Active(channel open)

  • 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 state1

  • The activity of ESL is therefore concentrated on rapidly-firing channels, rather than those which are not actively firing1

1.Bonifacio MJ, et al. Epilepsia 2001;42(5):600-608


Eslicarbazepine acetate metabolic profile

ESL, Eslicarbazepine Acetate

H

C

3

O

O

First-pass Hydrolysis

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

Eslicarbazepine Acetate — Metabolic Profile

  • Eslicarbazepine is the predominant metabolite in both plasma and urine1

  • Glucuronidation is the main metabolic pathway2

  • Eslicarbazepine and its glucuronide correspond to 92% of the total drug material excreted in urine2

  • The main metabolic pathway of ESL generates no epoxide metabolites, which are associated with toxic effects3

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


Higher brain plasma exposure ratio of eslicarbazepine 1

Higher Brain/Plasma Exposure Ratio of Eslicarbazepine1

Brain exposure of Eslicarbazepine is twice that of R-licarbazepine1

Brain to Plasma ratio

*

*

*

0.45

Eslicarbazepine

R-licarbazepine

*p <0.05

0.30

Brain to plasma ratio

0.15

Vehicle

Probenecid

Verapamil

Lower brain exposure of R-licarbazepine is due to its susceptability to be back transported by P-glycoprotein (a verapamil-sensitive process)

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,


An overview of eslicarbazepine acetate esl as adjunctive therapy for partial onset seizures

Phase II, 12 Week, Double-blind, Adjunctive Fixed Dose Escalation Study (400-1200 mg daily doses)1

Responder* Rate – Intention to treat population (ITT)1

60

P =0.008

50

P = 0.12

40

30

% of Responders

20

10

0

ESL

QD (n = 50)

ESL

BID (n = 46)

Placebo

(n = 47)

*subjects with a 50% reduction from baseline in seizure frequency

1.Elger C, et al. Epilepsia 2007;48(3):497-504


Integrated results from phase iii studies primary endpoint 1 2

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

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


Integrated results from phase iii studies secondary endpoint 1 2

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 period1,2

1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-429

2.Data on file. BIAL-ESL Phase III - Integrated Clinical Report


Incidence rate of cns related teaes affecting 2 of patients in any group 1 2

Incidence rate of CNS-related TEAEs affecting >2% of patients in any group1,2

1.Elger C, et al. Epilepsia. 2008;49(suppl.7):428-429

2.Data on file. BIAL-ESL Phase III - Integrated Clinical Report


High completion rates for phase iii 1 year open label extension 1 3

High Completion Rates for Phase III 1-Year Open-Label Extension1- 3

  • Halász P, et al. Epilepsia. 2008;49(suppl.7):435-436

  • Gabbai AA ,et al. Epilepsia. 2008;49(suppl.7):432-433

  • Lopes-Lima J, et al. Epilepsia. 2008;49(suppl.7):441-442


Eslicarbazepine acetate in partial onset epilepsy summary of results 1

Eslicarbazepine Acetate in Partial-Onset Epilepsy – Summary of Results1

  • 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


Eslicarbazepine acetate ongoing and planned studies

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


St valentine patron saint of the falling sickness epilepsy

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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