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

Premoli, Isabella; Rossini, Pierre; Goldberg, Paul; Posadas, K.; Green, Louise; Yogo, Noah; Pimstone, Simon N.; Abela, Eugenio; Beatch, Gregory N.; Richardson, Mark P.

doi:10.1002/acn3.50896

Cited by 27 publications

(31 citation statements)

References 37 publications

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“…In a crossover design TMS placebo‐controlled study in adult healthy subjects, a 20‐mg single dose of XEN1101 increased resting motor threshold of maximum stimulator output by 4.4% at a plasma level of 44 ng/mL, 6 hours after dosing (Figure 7), and significantly decreased TMS evoked potential amplitudes, 59 indicating reduced corticospinal and cortical excitability.…”

Section: Xen1101mentioning

confidence: 99%

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Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Bialer

Johannessen

Koepp³

et al. 2020

Epilepsia

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Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with | 2341 BIALER Et AL. 1 | INTRODUCTION Despite the introduction of >20 second-generation antiepileptic drugs (AEDs) during the past 3 decades, including 10 new AEDs between 2008 and 2020, >30% of people with epilepsy do not attain seizure control with currently available medications, and for some epilepsy syndromes seizure outcome is even worse. 1 Hence, there is still an urgent need for newer, more effective treatments for epilepsy. Efforts to develop treatments with improved tolerability and safety are also warranted. Since 1992, the Eilat Conferences have provided a forum for stakeholders involved in clinical care, basic and clinical research, and regulatory agencies to meet on a biennial basis and discuss the latest advances in the discovery and development of new epilepsy treatments. Since 2016, sessions dedicated to discussion of novel therapeutic devices as well as devices for seizure monitoring were added to the Conferences' program. Because of the disruption caused by the COVID-19 pandemic, the 2020 Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held virtually on July 27-30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 participants from 63 countries attended the conference, with about 75% of attendees being health care professionals/academic researchers and 25% being professionals working in the pharmaceutical industry. The virtual format did not prevent lively interactions among participants, and presenters were able to address in real time the many questions raised by the audience. Nevertheless, the face-to-face discussions, the social interaction, and the networking opportunities made possible by the physical presence of participants were surely missed. Accordingly, the Organizing Committee is confident that the next conference scheduled for 2022 will revert to the traditional format and unique boutique a...

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Section: Xen1101mentioning

confidence: 99%

“…The objectives of the first ongoing phase 2 clinical study are to evaluate the efficacy, safety, tolerability, and pharmacokinetics of XEN1101 in adults with refractory focal seizures. Dose selection was guided by the results of the TMS study, 59 as well as XEN1101’s pharmacokinetic and side effect profile in phase 1 studies.…”

Section: Xen1101mentioning

confidence: 99%

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Bialer

Johannessen

Koepp³

et al. 2020

Epilepsia

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“…Five minutes before each postdrug measurement a blood sample was taken for every subject to evaluate drug plasma concentration. XEN1101 showed a pharmacokinetic profile characterized by a prolonged absorption and XEN1101 was detectable (<8.22 ng/mL) a week after administration, during the placebo experiment in those subjects who had placebo at the second visit 14 . Therefore, to investigate XEN1101 effects, we selected post-dose measures for TMS-EEG and resting EEG measurements taken during highest drug exposure (>8.22 ng/mL).…”

Section: Experimental Design and Proceduresmentioning

confidence: 99%

“…The experimental protocols and TEP modulation have already been published and they are described in more detail in previous reports 13,14 . In experiment 1, a single oral dose of lamotrigine (300 mg), a voltage-sensitive sodium channel blocker 19 , or levetiracetam (3,000 mg), a specific binder of synaptic vesicle protein 2A (SV2A) 20 , or placebo, were administered on separate occasions a week apart.…”

Section: Experimental Design and Proceduresmentioning

confidence: 99%

“…lamotrigine and carbamazepine) and type 2A synaptic vesicles (i.e. levetiracetam) [13][14][15] . More recently, TEPs were implemented in a commercial Phase I clinical trial to evaluate cortical excitability impact of XEN1101, a novel AED which potentiates the open state of potassium KCNQ2/3 channels 16 , which suppressed peaks at 30, 45 and 180 ms after TMS pulse.…”

Section: Introductionmentioning

confidence: 99%

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Cortical oscillations to measure anti-epileptic drug activity in clinical trials

Biondi¹,

Rocchi²,

Santoro³

et al. 2021

Preprint

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The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG), is a powerful tool to investigate changes in brain activity and excitability following the administration of antiepileptic drugs (AEDs). However, a systematic evaluation of the effect of AEDs on spontaneous and TMS-induced brain oscillations has not yet been provided. We studied the effects of lamotrigine, levetiracetam, and of a novel potassium channel opener (XEN1101) on TMS-induced and spontaneous brain oscillations in a group of healthy volunteers. Levetiracetam suppressed TMS-induced theta, alpha and beta power, whereas lamotrigine increased TMS-induced alpha power. XEN1101 decreased TMS-induced delta, theta and beta power. Resting-state EEG showed a decrease of theta band power after lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Different AEDs induce specific patterns of power changes in spontaneous and TMS-induced brain oscillations. Spontaneous and TMS-induced cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

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Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy

French,

Porter,

Perucca

et al. 2023

JAMA Neurol

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ImportanceMany patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.ObjectiveTo evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs).Design, Setting, and ParticipantsThis phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe.InterventionsPatients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose).Main Outcomes and MeasuresThe primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted.ResultsA total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P &lt; .001 vs placebo; IQR, −80.4% to −16.9%) for 25 mg, 46.4% (P &lt; .001 vs placebo; IQR, −76.7% to −14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, −61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, −37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported.Conclusions and RelevanceThe efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs.Trial RegistrationClinicalTrials.gov Identifier: NCT03796962

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

Cited by 27 publications

References 37 publications

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Cortical oscillations to measure anti-epileptic drug activity in clinical trials

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy

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