Dravet syndrome Yesterday Isn’t Soon Enough …

1. Dravet syndrome Yesterday Isn’t Soon Enough … Overview and Unmet Needs Presented to xxxxPharma May 8, 2009 Michelle Welborn, PharmD ICE Alliance

3. Phase 1

4. Phase 2

5. Activation/Inactivation Gates of the Na+ Channel

6. Phase 3

7. Phase 4

8. Neurotransmitters and Epilepsy Excitatory Neurotransmitters Glutamate Receptors: N-methyl-D-aspartate (NMDA); metabotropic; non-NMDA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] Estrogen reduces chloride conductance; agonist at NMDA receptors in the CA1 region of the hippocampus

9. Neurotransmitters Inhibitory Neurotransmitters GABAproduced by decarboxylation of glutamate mediated by the enzyme glutamic acid decarboxylase (GAD) receptors: GABA-A Progesteroneincreases chloride conductance at GABA-A receptors and attenuates glutamate excitatory response; alters messenger RNA for GAD and GABA-A receptor subunits SV2A(synaptic vessicle protein 2A binding) important for ability of calcium dependent neurotransmitter vessicles ; lack of SV2A results in decreased action potential dependent neurotransmission (levetiracetam)

10. The Playing Field • Na • K • Ca • Cl • Glutamate • GABA • Sex Hormones • SV2A – synaptic vesicle protein 2A

11. Epidemiology of Dravet syndrome – US Population US Population: 327,000,000 1-2% of US Population has Epilepsy US Population <19 = 73,210,000 65% “idiopathic” Population of children < 6 yrs old : 23,026,593 30% refractory to treatment Live births in US per year: 4, 270,000 Incidence of Dravet syndrome: 1:20,000 to 1:40,000 US Census 2006; Dravet el al. Severe myoclonic epilepsy of infancy - ILAE.

12. Epidemiology of Seizures and Epilepsy Seizures Incidence: 240,000 Lifetime incidence: 9% (1/3 febrile seizure) Epilepsy Prevalence: 2,500,000 to 3,000,000 Incidence: 135,000

13. Comparatively ……. Parkinson’s Disease Prevalence: 1,000,000 Incidence: 60,000 Cystic Fibrosis Prevalence: 25,000 Incidence: 850 Multiple Sclerosis Prevalence: 300,000 Incidence: 10,000 Breast Cancer Prevalence: 2,500,000 Incidence: 88,800

14. The Reality • 30% Epilepsy Drug Resistant • Sudden Unexplained Death 4x greater with epilepsy diagnosis • Sudden Unexplained Death 24x greater with refractory epilepsy diagnosis • 112,000 cases of SUDEP / year in US • 55,000 deaths due to status epilepticus

15. Dravet syndrome Etiology

16. Activation/Inactivation Gates of the Na+ Channel

17. Potential Mechanisms of Sodium Channel Mutation and Resulting Seizure Activity • Dramatic loss of sodium current in the hippocampalGABAergic inhibitory neurons causes reduced inhibitory neurotransmission • Mutation causes slow inactivation of sodium channel • Mutation enhances recovery from inactivation • Is there a traffic jam at the sodium channel? Yu et al. Reduced Sodium Current in GABAnergic Neurons in mouse model of severe myoclonic epilepsy of infancy. Nat Neurosc 9(11) 2006;1142-49 Stafstom C. Traffic Jam at the Sodium Channel. Epilepsy Currents 8(3):2008;81-82.

18. Genetics of Dravet syndrome • 79% have SCN1A mutation • 50% of SCN1A mutations in Ds are truncating • 50% are missense • 90% are denovo • GEFS+ parent may have Dravet child (10% inherited)

19. Genetics of Dravet syndrome • Haploinsufficiency causes diseases (one copy of gene functions normally) • Heterozygotic mutation (one allele) • Incomplete penetrance (some people carry the gene but do not express it and do not have symptoms or have slight symptoms)

20. Differential Diagnosis • RULE OUT: Trauma, hypoxia, sequelae of meningitis or hemorrhage, infectious or autoimmune cerebritis, vasculitis, paraneoplastic syndrome, toxins (including drug withdrawal), endocrinopathy, endocrinopathy pyridoxine- dependent seizures and B6-related epilepsies, folinic acid-responsive seizures, inborn errors of metabolism, including mitochondrial dysfunction, and glucose transporter type 1 deficiency should be ruled out before less obvious genetic mutations are implicated as cause of seizure activity. Consideration of differential diagnosis in positive family history of epilepsy including benign familial neonatal seizures, benign familial infantile seizures, benign childhood epilepsy with centrotemporal spikes, childhood occipital epilepsy, absence epilepsies is worthwhile.

21. Differential Diagnosis Consider SCN1A testing to confirm clinical diagnosis of Ds when infant < 12 months presents with or has medical history of: Infant onset, initial normal developoment, EEG, MRI, metabolic studies Clonichemiconvulsions, modest (80 degree) ambient temperature elevation and illness are triggers Episodes frequent, prolonged, and pharmacoresistant

22. A Screening test for the prediction of Dravet syndrome before one year of age Epilepsia Volume 49 Issue 4, Pages 626 - 633 Junri Hattori • Purpose: Our aim was to develop a screening test to predict Dravet syndrome before the first birthday based on the clinical characteristics of infants and the SCN1A mutation analysis. • Methods: Ninety-six patients who experienced febrile seizures before the age of one were enrolled. The patients were divided into two groups—the Dravet syndrome group (n = 46) and the non-Dravet syndrome group (n = 50). We compared the clinical characteristics before one year of age of the two groups. We analyzed all coding exons of the SCN1A gene by the direct sequencing method. Scores from 0 to 3 were assigned to each risk factor based on the odds ratio and p-value. • Results: An age of onset of febrile seizure ≤ 7 months, a total number of seizures ≥ 5, and prolonged seizures lasting more than 10 min. were regarded as significant risk factors for Dravet syndrome. Other factors highly predictive of this syndrome were hemiconvulsions, partial seizures, myoclonic seizures, and hot water–induced seizures. A total clinical score of six or above was the cutoff value indicating a high risk of Dravet syndrome. SCN1A missense and truncated mutations were detected significantly more often in the Dravet syndrome group than in the non-Dravet syndrome group. • Discussion: This simple screening test was designed to be used by general pediatricians. It could help to predict Dravet syndrome before one year of age. If the sum of the clinical risk score is ≥ 6, then the performance of an SCN1A mutation analysis is recommended.

23. Prognosis • 50% with IQ < 50 by age 4 • Comorbidities include abnormal gait leading to orthopedic problems, tremor, extreme light and heat sensitivity, chronic illnesses, low immunity • 20% mortality by age 20 • ½ SUDEP • ¼ Status Epilepticus • Other = accidents, illnesses

24. AEDs in Ds • Na : Worsens Seizures in Ds • K: ? • Ca : May be effective for absence seizures • Cl : ? • Glutamate: Topirimate is effective in Ds • GABA potentiators: Worsens myoclonics • Sex Hormones: ? • SV2A – synaptic vesicle protein 2A : Keppra may be effective

25. Anti-Epileptic Drugs

26. Evidence Based Treatment Kassi et al. Epilepsia 49(2):343-348, 2008.

27. Stiripentol Mechanism of Action • Increase GABA? • Drug Interaction with clobazam and valproate • “Magic Cocktail” : Stiripentol, clobazam and valproate

28. Other AEDs in Ds • Topirimate • Zonisamide • Levitiracetam • Other benzodiazepines • Ketogenic diet • Felbamate • Ethosuximide • Bromides

29. Drugs to Avoid Sodium Channel Blockers Phenytoin, fosphenytoin (IV), carbamazepine, oxcarbazapine, lamotrigine, rufinamide Selective GABA Reuptake Inhibitors/ GABA T inhibitors Vigabatrin, tiagabine

30. Unmet pharmacotherapy needs • Seizure control • FDA approval, insurance coverage stiripentol and clobazam • Acute seizure management pharmacotherapy • Stem cell therapy • Gene therapy

31. AED possibilities for Ds • Improved benzodiazepines • Non Sodium Channel AEDs • Glutamate Progesterone • K+ channel Ganaxolone • NMDA • Ca+ channel • SV2A • GABA • Cl

32. In Development • Perampanel (Eisai): AMPA glutamate receptor antagonist • Ganaxolone (Marinus): steroid drug that is agonist of GABA • Brivaracetam (UCB): SV2A • ICA-105665 (Icagen): KCNQ