Anti‐ictal Versus Mechanism Targeted Therapies

Michael A. Rogawski, M.D., Ph.D.Departments of Neurology and Pharmacology

School of MedicineUniversity of California, Davis

2018 Research Roundtable for EpilepsyEvolving concepts in endpoints and populationsin epilepsy trialsAmerican Institute of Architects, Washington, DCMay 17‐18, 2018

Epilepsy Therapy Discovery

• Protect against seizures• More or less broadly active among epilepsy syndromes

• 80 year‐old‐approach —30 approved antiseizure drugs

• Address epilepsy syndrome based on an understanding of thepathophysiologicalmechanisms

• Precision medicine• 1 approved drug*

Antiseizure activity /Target Seizure Mechanisms

Target Epilepsy Mechanism

Legacy Emerging

*April 10, 2018, FDA approved mTOR-inhibitoreverolimus for TSC-associated partial-onset seizures in adults and children >2 years.

Experimental Determination of the Anticonvulsant Properties of Some Phenyl Derivatives

Tracy J. Putnamand H. Houston MerrittHarvard Medical School

Science 85: 524-526, 1937

Current NIH Screening Algorithm

Animal Models and Drug Mechanism

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

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

Ongoing Transformation in Epilepsy Therapy Discovery

• Target seizures• Unbiased to epilepsy 

mechanism• May treat only certain 

seizure types in an epilepsy syndrome

• Unlikely to impact comorbidities

• Not disease modifying

• Target epilepsy• Informed by 

pathophysiology• Likely to treat all seizure 

types in a syndrome• May  impact 

comorbidities• May be disease 

modifying, but not necessarily

Legacy Model Emerging Model

January 1998

Mark Leppert

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

Yue C, Yaari Y. J Neurosci 24:4614–4624, 2004

Ezogabine Opens KCNQ Channels and Inhibits Epileptic Hyperexcitability

Ezogabine in KCNQ2 (Kv7.2) Encephalopathy

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. KCNQ2encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet. 2016 Aug 22;2(5):e96.

11 patients

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

0 20 40 60 80 1004 27 50

Ezogabine

XEN1101

mg/kg

Test

ed 1

h Po

st D

ose

Mous e ED50 or TD50 (Mean: 95% CI)

scPTZscPicrotoxin

scBicuculline

MES

6Hz 32mA

6Hz 44mA

Rotarod

mg/kg

Assay EC50 Function

KV7.2/KV7.3 27 nM CNS

KV7.3/KV7.5 94 nM CNS

KV7.4 113 nM Bladder

Acknowledgement: Xenon Pharmaceuticals

XEN1101

Ezogabine

Mouse ED50 or TD50 (mean ± 95% CI).Test 1 hour after dosing.

for KCNQ2 (Kv7.2) encephalopathy

Early‐Onset Epileptic Encephalopathy Due to Missense Mutation in GluN2 (GRIN2A L812M)

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;5:3251Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, Golas G, Simeonov DR, Holloman C, Tankovic A, KaramchandaniMM, 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):190-198.

Mutation in the linker region between the ligand-binding andtransmembranedomains.

Treatment With MemantineGluN2 (GRIN2A L812M) Early‐onset Epileptic Encephalopathy

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, TifftCJ, 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):190-198.

Memantine ~0.5 mg/kg (10 mg)per day without side effects

• >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

Early Infantile Epileptic Encephalopathy Type 13 (Pathogenic Gain‐of‐Function Mutations in SCN8A)

Veeramah et al., 2012

p. Asn1768Asp Mutation

XEN901 Highly Potent and Selective Inhibitor of NaV1.6 

0.001 0.01 0.1 1 10 100 1000

0.0

0.2

0.4

0.6

0.8

1.0

Concentration (M)

Frac

tiona

lbl o

ck

LacosamideCarbamazepine

PhenytoinLamotrigine

XEN901

0.001 0.01 0.1 1 10 100

0.0

0.2

0.4

0.6

0.8

1.0

XEN901 concentration (M)

Frac

tion

of N

a+ cur

rent

inhi

bite

d

hNaV1.6

hNaV1.1

hNaV1.2

hNaV1.7hNaV1.5hNaV1.4

hNaV1.3

[XEN901], µM[XEN901], µMFrac

tiona

l Blo

ck N

a+C

urre

nt

Frac

tiona

l Blo

ck N

a+C

urre

nt

Acknowledgement: Xenon Pharmaceuticals

High affinity and selectivity achieved by binding VSD4 in anextracellular site.

Conventional sodium channel blocking ASD in pore domain. Promiscuous, low affinity binding site.

XEN901 Provides Seizure Control in SCN8ATransgenic Mouse Model of EIEE Type 13

0.001 0.01 0.1 1 10 1000

2

4

6

8

10SCN8A mice 6Hz

BrainTotal Concentration (M)

Ave

rage

cum

ulat

ive

raci

ne s

core XEN901

PhenytoinCarbamazepineLacosamide

6 Hz Model in SCN8A p. Asn1768Asp Mutant

Veeramah et al., 2012

• SCN8A p. Asn1768Asp mutation• Heterozygous mice develop neonatal 

seizures and die prematurely

Acknowledgement: Xenon Pharmaceuticals

Motor Impairment TIXEN901 SCN8A: >66XEN901 MES: >25Phenytoin MES: <7

Future of Epilepsy Therapy Discovery

• 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 “mutation‐specific”

• Target modifier genes • Disease‐modifying gene 

therapies• Disease‐modifying cell 

therapies

Soon

The End