1.285 Efficacy of Sodium Channel Inhibitors as Anticonvulsants in the Rat MES Assay is Predictive of the Therapeutic Plasma Concentration in Humans Charles J. Cohen; Parisa Karimi Tari; Karen Nelkenbrecher; Matthew Waldbrook; Gina de Boer; Rainbow Kwan, Céline Dubé; Thilo Focken; Christoph Dehnhardt; Noah Shuart; Samuel Goodchild; Luis Sojo; Raymond Winquist;James R. Empfield; JP Johnson Jr. Xenon Pharmaceuticals, 200-3650 Gilmore Way, Burnaby, BC V5G 4W8 Canada
INTRODUCTION Maximal Electroshock Seizure (MES) Model Potency in MES Assay Correlates with Inhibition • Sodium channel inhibitors are widely used as antiepileptic drugs (AEDs) but seizure control is often inadequate at maximally tolerated of NaV1.6 in Brain
doses. • Highly predictive of clinical efficacy of NaV inhibitors against human seizures. n 1 . 0
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s a
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• Clinically effective concentration of nonselective Na inhibitors at 1-3 times EC in rat MES assay. m t
• Currently available NaV AEDs are nearly equipotent inhibitors of V 50 i
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isoforms widely expressed in the CNS (Na 1.1, Na 1.2, Na 1.6). A
V V V
0 . 6 f • XEN901 is well tolerated at a plasma concentration 32-times higher than the EC in the rat MES assay. b
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• Loss of function mutations in Na 1.1 cause Dravet Syndrome, d 0 . 4
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indicating that NaV1.1 is the dominant NaV channel in inhibitory c
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GABAergic neurons (Catterall et. al., 2010). Thus, inhibition of h
t
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Na 1.1 is likely counter-productive for treatment of epilepsy. w n
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• Reduced expression of Na 1.6 reduces seizures in epilepsy models s
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a n V n
[ B r a i n ] ( M )
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e m
(Blumenfeld et al., 2009; Makinson et al., 2014; Wong et al., 2018). m t
0 . 8 t 0 . 8
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• XEN901 is highly selective for inhibition of Na 1.6. 0 . 6 W e l l t o l e r a t e d 0 . 6 f
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• We explored whether plasma levels in the Maximal Electroshock 0 . 4 0 . 4 a
c o n c e n t r a t i o n n
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Stimulus assay correlate with therapeutic plasma concentration for t
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nonselective sodium channel inhibitors, thereby enabling an a 0 . 6
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r s t u d y
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estimate of the necessary concentration of XEN901. F
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i n i X E N 9 0 1
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n t i P h e n y t o in Selective Inhibition of Na 1.6 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 c
V H
a
r 0 . 2 C a r b a m a z e p i n e
h
t
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d 1 . 0 H u m a n P l a s m a [ X E N 9 0 1 ] ( M ) P l a s m a [ C a r b a m a z e p i n e ] ( M )
e L a c o s a m i d e
w t i 0 . 8
b 0 . 0
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0 . 6 n
I 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0
n 0 . 4
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t
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c 0 . 2 ( [ B r a i n ] / N a 1 . 6 I C ) R a t i o
a V 5 0
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r i 0 . 0 i
F 1 . 0 1 . 0
s
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l s s • Upper panel: Efficacy in the MES assay increased with brain concentration of
0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0
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[ X E N 9 0 1 ] ( M ) compounds.
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e M o u s e • Lower panel: Dividing the brain concentration by the in vitro potency on
t
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f f
b Na 1.6 results in close overlay of all curves. 0 . 6 b
n V
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n 0 . 4
m
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l n n • IC concentration in vivo corresponds to a brain concentration approximately c 0 . 2 50
a 0 . 4 0 . 4
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o d
0 . 0 o
F i
i 0.3-5 fold the IC50 for NaV1.6 in vitro. The greater potency of XEN901 in the
n
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t
t i
0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 i c
c MES assay can be accounted for by the greater potency for inhibition of NaV1.6 H
[ X E N 9 0 1 ] ( M ) 0 . 2 H 0 . 2
a
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r in the brain.
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d 1 . 0 0 . 0 0 . 0
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w • After the MES assay, animals were euthanized and plasma and brain
0 . 8 b i 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0
h 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 . 6
n concentrations were measured by mass spectrometry. All points represent
I
n 0 . 4 o
i results of 5-8 animals in a single study group. Error bars on the x-axis are t P l a s m a [ P h e n y t o i n ] ( M )
c 0 . 2 P l a s m a [ L a c o s a m i d e ] ( M ) a r standard errors of the mean but in many cases are smaller than the symbols.
0 . 0 F
0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 [ P h e n y t o i n ] ( M ) CONCLUSIONS
d 1 . 0 • Efficacy in the rat MES Assay is plotted vs measured plasma concentrations for XEN901, Carbamazepine,
e t
i 0 . 8 b
i Phenytoin, and Lacosamide. The vertical dotted line in the plot for XEN901 corresponds to the highest plasma • Clinical efficacy of nonselective sodium channel inhibitors is achieved at 1- 3 h
0 . 6
n I concentration achieved in a phase I study with healthy humans, achieved at a well tolerated dose. times the EC in the rat MES assay.
n 0 . 4 50
o
i t
c 0 . 2
a r 0 . 0 F • The shaded areas on the graphs for Carbamazepine, Phenytoin, and Lacosamide correspond to reported • Nonselective sodium channel inhibitors are effective at approximately the same 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0
[ C a r b a m a z e p i n e ] ( M ) effective plasma concentrations for human patients. multiple of IC50 for NaV1.6 as the selective inhibitor, XEN901.
d 1 . 0
e t
i 0 . 8 b
i • Binary seizure readout – animals are monitored for presence/absence of tonic-clonic seizure. • NaV1.6 inhibition is likely the primary driver of the efficacy of non-selective NaV h
0 . 6
n I
inhibitors in the rat MES assay.
n 0 . 4
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c 0 . 2 • Seizures were induced by a constant current stimulus applied to cornea of 150 mA, consisting of 0.5 ms pulses
a r 0 . 0 F delivered at 60 Hz for 200 ms. • The rat MES assay suggests that therapeutically effective plasma 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 concentrations of XEN901 may be attained in humans without toxicity. [ L a c o s a m i d e ] [ M ]
RESEARCH POSTER PRESENTATION DESIGN © 2015 www.PosterPresentations.com Presented at the 72nd Annual Meeting of the American Epilepsy Society, November 30 - December 4, 2018, New Orleans, LA