Anti ictal Versus Mechanism Targeted Therapies

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1 2018 Research Roundtable for Epilepsy Evolving concepts in endpoints and populations in epilepsy trials American Institute of Architects, Washington, DC May 17 18, 2018 Anti ictal Versus Mechanism Targeted Therapies Michael A. Rogawski, M.D., Ph.D. Departments of Neurology and Pharmacology School of Medicine University of California, Davis

2 Epilepsy Therapy Discovery Legacy Antiseizure activity / Target Seizure Mechanisms Protect against seizures More or less broadly active among epilepsy syndromes 80 year old approach 30 approved antiseizure drugs Emerging Target Epilepsy Mechanism Address epilepsy syndrome based on an understanding of the pathophysiological mechanisms Precision medicine 1 approved drug* *April 10, 2018, FDA approved mtor-inhibitor everolimus for TSC-associated partial-onset seizures in adults and children >2 years.

3 Experimental Determination of the Anticonvulsant Properties of Some Phenyl Derivatives Tracy J. Putnam and H. Houston Merritt Harvard Medical School Science 85: , 1937

4 Current NIH Screening Algorithm

5 Animal Models and Drug Mechanism

6 Barker-Haliski ML, White HS. Antiepileptic drug development and experimental models (Chapter 42). Wyllie s Treatment of Epilepsy. Principles and Practice, 2015

7 Diversity of Epilepsy Pathogenesis Over 400 genes have been implicated in human epilepsy, and abnormal gene products can disrupt neural circuit function at various cell biological levels. Rao VR, Lowenstein DH. Epilepsy. Current Biology 25, R733 R752, 2015

8 Ongoing Transformation in Epilepsy Therapy Discovery Legacy Model Target seizures Unbiased to epilepsy mechanism May treat only certain seizure types in an epilepsy syndrome Unlikely to impact comorbidities Not disease modifying Emerging Model Target epilepsy Informed by pathophysiology Likely to treat all seizure types in a syndrome May impact comorbidities May be disease modifying, but not necessarily

9 January 1998 Mark Leppert

10 KCNQ2 (Kv7.2) Related Epilepsy KCNQ2 (Kv7.2) variants epilepsy of widely varying severity Benign familial neonatal epilepsy (BFNE) caused 5 30% loss of function Strong loss of function (60% 90% reduced current) causes neonatal onset epileptic encephalopathy (NOEE) NOEE mutations have dominant negative effects on channel gating, conduction, or surface targeting Ezogabine Opens KCNQ Channels and Inhibits Epileptic Hyperexcitability Yue C, Yaari Y. J Neurosci 24: , 2004

11 Ezogabine in KCNQ2 (Kv7.2) Encephalopathy 11 patients Millichap JJ, Park KL, Tsuchida T, Ben-Zeev B, Carmant L, Flamini R, Joshi N, Levisohn PM, Marsh E, Nangia S, Narayanan V, Ortiz-Gonzalez XR, Patterson MC, Pearl PL, Porter B, Ramsey K, McGinnis EL, Taglialatela M, Tracy M, Tran B, Venkatesan C, Weckhuysen S, Cooper EC. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet Aug 22;2(5):e96.

12 XEN1101 (1OP 2198) Second Generation Kv7 Opener No dimerization Predicted no skin and retinal pigmentation Not excreted unchanged in urine Predicted no bladder toxicity 10 50X in vitro potency Kv7.2/7.3 No activity on GABAA receptors Currently in clinical development for KCNQ2 (Kv7.2) encephalopathy Mo us e ED 50 or TD 50 (Mean: 95% CI) Assay EC 50 Function K V 7.2/K V nm CNS K V 7.3/K V nm CNS K V nm Bladder Tested 1h Post Dose XEN1101 XEN1101 Ezogabine Ezogabine Mouse ED50 or TD50 (mean ± 95% CI). Test 1 hour after dosing. scptz scpicrotoxin scbicuculline MES 6Hz 32mA 6Hz 44mA Rotarod Acknowledgement: Xenon Pharmaceuticals mg/kg mg/kg

13 Early Onset Epileptic Encephalopathy Due to Missense Mutation in GluN2 (GRIN2A L812M) Mutation in the linker region between the ligandbinding and transmembrane domains. Yuan H, Hansen KB, Zhang J, Pierson TM, Markello TC, Fajardo KV, Holloman CM, Golas G, Adams DR, Boerkoel CF, Gahl WA, Traynelis SF. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun. 2014;5:3251 Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, Golas G, Simeonov DR, Holloman C, Tankovic A, Karamchandani MM, Schreiber JM, Mullikin JC; PhD for the NISC Comparative Sequencing Program, Tifft CJ, Toro C, Boerkoel CF, Traynelis SF, Gahl WA. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):

14 Treatment With Memantine GluN2 (GRIN2A L812M) Early onset Epileptic Encephalopathy Memantine ~0.5 mg/kg (10 mg) per day without side effects Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, Golas G, Simeonov DR, Holloman C, Tankovic A, Karamchandani MM, Schreiber JM, Mullikin JC; PhD for the NISC Comparative Sequencing Program, Tifft CJ, Toro C, Boerkoel CF, Traynelis SF, Gahl WA. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):

15 Early Infantile Epileptic Encephalopathy Type 13 (Pathogenic Gain of Function Mutations in SCN8A) >50 mutations in NaV 1.6, >100 families), epileptic encephalopathy and intellectual disability, first identified in 2012 Seizure types: absence, hemiclonic, focal tonic, GTC SUDEP in 10% of patients Mothers may feel seizures in utero; has been detected before birth SCN8A encodes NaV1.6 expressed in neocortical and hippocampal pyramidal cells and also cerebellar Purkinje cells; Localized to AIS and nodes of Ranvier Gain of function: increased persistent sodium current, incomplete channel inactivation, depolarizing shift in the voltage dependence of steady state fast inactivation Phenytoin effective in individual cases p. Asn1768Asp Mutation Veeramah et al., 2012

16 XEN901 Highly Potent and Selective Inhibitor of NaV1.6 High affinity and selectivity achieved by binding VSD4 in an extracellular site. Conventional sodium channel blocking ASD in pore domain. Promiscuous, low affinity binding site. Fraction of Na + current Fractional Block Na+ inhibited Current XEN901 [XEN901], concentration µm ( M) hna V 1.6 hna V 1.7 hna V 1.5 hna V 1.4 hna V 1.3 hna V 1.2 hna V 1.1 Fractional Fractional Block Na+ block Current XEN Phenytoin 0.2 Lamotrigine Carbamazepine 0.0 Lacosamide [XEN901], µm Concentration ( M) Acknowledgement: Xenon Pharmaceuticals

17 XEN901 Provides Seizure Control in SCN8A Transgenic Mouse Model of EIEE Type 13 SCN8A p. Asn1768Asp mutation Heterozygous mice develop neonatal seizures and die prematurely Veeramah et al., 2012 Average cumulative racine score Hz Model SCN8A in SCN8A mice p. 6Hz Asn1768Asp Mutant Brain Total Concentration ( M) XEN901 Phenytoin Carbamazepine Lacosamide Acknowledgement: Xenon Pharmaceuticals Motor Impairment TI XEN901 SCN8A: >66 XEN901 MES: >25 Phenytoin MES: <7

18 Future of Epilepsy Therapy Discovery Soon Target epilepsy Informed by pathophysiology Likely to treat all seizure types in a syndrome Likely to impact comorbidities May be disease modifying, but not necessarily On the Horizon Personalized mutationspecific Target modifier genes Disease modifying gene therapies Disease modifying cell therapies

19 The End