TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101.

Isabella Premoli,Paul Y Goldberg,Noah Yogo,Pierre G Rossini,Louise Green,Kristina Posadas,Eugenio Abela,Gregory N Beatch,Mark P Richardson,Simon Pimstone

doi:10.1002/acn3.50896

Abstract

ObjectiveTranscranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS‐evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials.MethodsTMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2‐, 4‐, and 6‐hours post drug intake in a double‐blind, placebo‐controlled, randomized, two‐period crossover study of 20 healthy male volunteers.ResultsConsistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15–55 msec after TMS) and at late (150–250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time‐dependent increase that correlated with the XEN1101 plasma concentration.InterpretationChanges from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early‐stage clinical trials.

Highlights

Epilepsy is a very common disorder in which approximately one third of patients do not respond to available antiepileptic drugs (AEDs).[1]
Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association
We found that XEN1101 had strong effects on resting motor threshold (RMT) and TMS-evoked EEG potentials (TEPs), which suggests that it reduces cortical excitability

Summary

Introduction

Epilepsy is a very common disorder in which approximately one third of patients do not respond to available antiepileptic drugs (AEDs).[1] There is a continued need to develop more efficacious AEDs. One of the crucial challenges for early-stage development of new AEDs is to assess whether the investigational compound can cross the blood brain barrier (BBB) and whether it is acting at the intended target. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

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