Preclinical In Vitro and In Vivo Comparison of the Kv7 Activator XEN1101 with Ezogabine.
Abstract number :
654
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2020
Submission ID :
2422995
Source :
www.aesnet.org
Presentation date :
12/7/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Richard Dean, Xenon Pharmaceuticals; Sophia Lin - Xenon Pharmaceuticals; Girish Bankar - Xenon Pharmaceuticals; Kuldip Khakh - Xenon Pharmaceuticals; Janette Mezeyova - Xenon Pharmaceuticals; Jenny Li - Xenon Pharmaceuticals; Andrea Lindgren - Xenon Pharm
Rationale:
The KV7.2/ KV7.3 activator ezogabine (retigabine) has been shown to reduce seizures in patients with focal (partial) epilepsy and has been suggested to reduce seizures in pediatric patients with KCNQ2-developmental encephalopathic epilepsy (DEE). However, since ezogabine was removed from the market in 2017 for commercial reasons, no KV7 activating drugs are currently available for the treatment of epilepsy. XEN1101 is a next-generation, differentiated novel chemical entity that enhances activation of neuronal KV7 (KCNQ2-5) potassium channels and is currently in a Phase 2b clinical trial in adults with focal seizures. Because of the overlap in mechanism of action, assessment of XEN1101 and ezogabine was conducted to compare their preclinical in vitro and in vivo profiles.
Method:
In vitro, HEK cells expressing KV7.x were used to examine the potency of XEN1101 and ezogabine using a K+ flux assay and Sophion Qube 384 patch clamp electrophysiology. Characterization of the biophysical mechanisms of XEN1101 and ezogabine was also conducted using the Sophion Qube 384. In vivo, we evaluated the ability of administered XEN1101 and ezogabine to prevent electrically induced seizures in a Maximal Electroshock Stimulus (MES) mouse model of seizures.
Results:
XEN1101 was shown to engage the same critical Trp236 residue in the core of the Kv channel as ezogabine however, it offers substantial differentiation. 1) XEN1101 is ~20-fold more potent for potentiation of KV7.2/KV7.3 heterotetramers compared to ezogabine by both K+ flux assays (XEN1101 KV7.2/KV7.3 EC50=0.034 µM and ezogabine EC50=0.950 µM) and electrophysiology (XEN1101 KV7.2/KV7.3 EC50=0.042 µM and ezogabine EC50=0.920 µM). 2) XEN1101 reduces the voltage threshold for channel opening by 15% more than ezogabine. Although XEN1101 speeds the kinetics of activation to a similar degree as ezogabine, XEN1101 slows deactivation of the channel by ~2-fold more than ezogabine, enhancing its ability to reduce hyper excitability. 3) In line with the in vitro data, XEN1101 requires ~15-fold less brain exposure than ezogabine for half-maximal activity in a MES mouse model of seizures. 4) Unlike ezogabine, XEN1101 does not possess the requisite structural features for the formation of chromophoric phenazinium-type dimers, which have been implicated in the pigmentary abnormalities observed with long-term ezogabine exposure.
Conclusion:
XEN1101 is a novel chemical entity that has a strong rationale and multiple predicted benefits over ezogabine as a potential anti-epileptic drug. XEN1101 provides a mechanism of action not currently available for the treatment of epilepsy and top line data in a large adult focal seizure trial should be available in H1, 2021.
Funding:
:N/A
Basic Mechanisms