Principal Investigator: Amir Arain
Keywords: Epilepsy , Seizure , Localized onset , Antiepileptic Drug , AED , Focal onset , Intractable seizures , Neurology , New drug , focal seizures Department: Neurology
IRB Number: 00121907 Co Investigator: Amir Arain
Specialty: Neurology, Neurology
Sub Specialties: Epilepsy,
Recruitment Status: Recruiting

Contact Information

Lilly Fagatele
Lilly.Fagatele@hsc.utah.edu
801-585-9266

Brief Summary

XEN1101 is a novel, small molecule, selective KCNQ2/3 (KV7.2/7.3) potassium channel positive allosteric modulator being developed for the treatment of partial onset (focal) epilepsy. Enhancing the open state of KCNQ2/3 in neurons favors a hyperpolarized resting state, which reduces rapid action potential spiking. This mechanism has been clinically proven to be effective for treatment of partial onset seizures in adults with epilepsy with the KCNQ2/3 opener, retigabine.

XEN1101 was investigated at single doses of 5, 15, 20, 25 and 30 mg, as well as multiple doses of 15 or 25 mg once daily for up to 10 days in healthy volunteers. The influence of single doses was also investigated for effects on cortical and corticospinal excitability using transcranial magnetic stimulation (TMS) techniques. XEN1101 was well tolerated, adverse events (AEs) were generally transient, dose/exposure related and the majority of AEs were mild. The most common related AEs were central nervous system (CNS) effects such as dizziness and sedation, consistent with this class of drugs (antiepileptics). The pharmacokinetics of XEN1101 were found to be suitable for once daily dosing, with absorption of the drug enhanced by food. The terminal elimination half-life was approximately 1 week after repeat dosing in healthy volunteers. The results from the TMS studies in healthy volunteers suggest that the plasma levels expected at the dose regimens to be used in this study are anticipated to decrease cortical excitability and may suppress seizures in epilepsy patients. For detailed summaries of the results of these studies please see the Investigator’s Brochure. 

The purpose of this phase 2 clinical trial is to evaluate the safety, tolerability and efficacy of XEN1101 as adjunctive therapy in adults with focal‑onset epilepsy. For this study, plasma levels expected at the doses chosen were shown to be well tolerated in the first‑in‑human (FIH) study (XPF‑008‑101a) and pharmacologically active in the brain in the companion transcranial magnetic stimulation (TMS) crossover study (XPF‑008‑101b).

OBJECTIVES

ENDPOINTS

Primary

 

To assess the efficacy of XEN1101 compared to placebo on focal seizure frequency in adults with focal epilepsy taking 1-3 AEDs in the double-blind period (DBP)

  • Median percent change (MPC) in monthly (28 days) focal seizure frequency from baseline to DBP for XEN1101 versus placebo

To assess the safety and tolerability of XEN1101 in adults with focal epilepsy taking 1-3 AEDs in the DBP

In the DBP:

  • Severity and frequency of associated adverse events/serious adverse events (AEs/SAEs)
  • Clinically significant changes in clinical laboratory findings
  • Clinically significant changes in 12-lead ECG
  • Increase in suicide risk as assessed by the C-SSRS including increase in suicidal thoughts or an attempt
  • Clinically significant changes in vital signs including blood pressure, pulse, or weight
  • Clinically significant changes in urological symptoms including retention as measured by the American Urological Association (AUA) Symptoms Index

Secondary

 

To evaluate the 50% XEN1101 response rates in comparison to placebo in the DBP

  • Responders are defined as patients experiencing ≥50% reduction in monthly (28 days) focal seizure frequency from baseline compared to DBP

To evaluate trends in focal seizure frequency over time in the DBP

  • Median absolute, change and percent change from baseline in weekly focal seizure frequency for each week of the DBP

To assess the effect of XEN1101 vs. placebo on seizure severity and impact  in adults with focal epilepsy taking 1-3 AEDs in the DBP

  • Clinical and Patient Global Impression of Change scores during the DBP

Exploratory

 

To assess the efficacy of XEN1101 on focal seizures in adults including the OLE for up to 1 year.

 

  • Median percent change (MPC) in monthly (28 days) focal seizure frequency from baseline compared to each 4-week period in the OLE.

To assess the safety and tolerability of XEN1101 in adults with focal epilepsy including the OLE for up to 1 year.

 

In the OLE:

  • Severity and frequency of associated adverse events/serious adverse events (AEs/SAEs)
  • Clinically significant changes in clinical laboratory findings
  • Clinically significant changes in 12-lead ECG
  • Increase in suicide risk as assessed by the C-SSRS including increase in suicidal thoughts or an attempt
  • Clinically significant changes in vital signs including blood pressure, pulse, or weight
  • Clinically significant changes in urological symptoms including retention as measured by the American Urological Association (AUA) Symptoms Index

To evaluate the pharmacokinetics and exposure response relationship of XEN1101

  • Evaluation of the steady-state PK of XEN1101 (and potentially other AEDs) using a population PK approach (refer to Section 8.3.6)
  • Correlation between XEN1101 plasma concentrations and changes in QTcF interval
  • XEN1101 plasma exposure-response relationship with safety and efficacy endpoints

To assess the impact of XEN1101 on quality of life in the DBP and OLE

  • Change from baseline in QOLIE-31 in the DBP and OLE.
  • Evaluate disease severity with CGI-S and PGI-S in the OLE

To evaluate the number of seizure-free days compared to baseline in the DBP and OLE

  • Median absolute, change and percent change in seizure-free days per month (28 days) from baseline to DBP and OLE.
  • Median absolute, change and percent change in seizure-free days per week for each week of the DBP and OLE compared to the average weekly rate during the entire baseline period.

To evaluate the impact of XEN1101 on specific seizure types or change in frequency or need for rescue medication in the DBP and OLE

  • Median absolute, change and percent change in seizure frequency per month (28 days) for each seizure subtype from baseline to DBP and OLE.
  • Median absolute, change and percent change in seizure frequency per week for each seizure subtype for each week of the DBP and OLE compared to overall average weekly rate of each subtype during the baseline period
  • Proportion of responders experiencing ≥75%/100% of reduction in monthly (28 days) seizure frequency from baseline for the DBP and OLE.
  • Incidence of new seizure types in patients without history of these seizure types (e.g., status epilepticus, myoclonic, absence) in the DBP and OLE
  • Incidence of use of rescue medications in the DBP and OLE.

To evaluate the time to reach the baseline monthly focal seizure count for XEN1101 compared to placebo through the end of the DBP and OLE

 

  • Number of days post-randomization to reach the same number of seizures as the baseline monthly focal seizure rate through the end of the DBP and OLE.

To assess time to withdrawal due to lack of efficacy in placebo compared to XEN1101 through the end of the DBP and OLE

  • Percent of participants and number of days post-randomization to withdrawal for lack of efficacy through DBP and OLE.

To explore epilepsy-associated genes and mode-of-action related pathways, safety and efficacy responses

  • Exploratory correlation of variants in genes known to cause epilepsies (e.g., variant enrichment in responders versus non‑responders) 
  • Exploratory analysis of variants in the genome to identify novel genes and variants that may cause epilepsies and correlate to response to XEN1101 (e.g., variant enrichment in novel genes in responders versus non‑responders)
  • Exploratory correlation of variants in specific drug metabolism genes on safety: number of adverse events, types of adverse events, events dependent on XEN1101 dose-by-gene interactions 
  • Exploratory correlation of variants in specific drug metabolism genes on efficacy: reduction on seizure frequency, type of seizures, and dose of XEN1101 required, efficacy dependent on XEN1101 dose-by-gene interactions

To explore the relationship between body fluid biomarkers with XEN1101 concentrations and clinical responses

  • Mean change from baseline in fluid biomarkers versus treatment, seizure frequency, and response status (e.g., responders versus non‑responders)
  • Correlation of exploratory fluid biomarkers with XEN1101 concentration

Detailed Description

The XEN1101 Phase 2 clinical trial is designed as a randomized, double-blind, placebo-controlled, multicenter study to evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive treatment in adult patients aged 18 to 75 years diagnosed with focal epilepsy. Approximately 300 patients will be randomized in a blinded manner to one of three active treatment groups or placebo in a 2:1:1:2 fashion (XEN1101 25 mg : 20 mg : 10 mg : Placebo). After screening, patients will have 8 weeks of baseline to assess frequency of seizures, followed by 8 weeks of treatment and a 4-week post treatment follow-up period. In order to be included in the study, patients must already be treated with a stable dose of 1 to 3 allowable current anti-epileptic drugs for at least one month prior to screening, during baseline, and throughout the duration of the study. During the treatment period, patients will be given XEN1101 or placebo once daily in the evening.

Inclusion Criteria

  1. Be properly informed of the nature and risks of the study and give informed consent in writing, prior to entering the study
  2. Male or female, 18 to 75 years of age (inclusive) with a BMI <37 kg/m2
  3. Diagnosis (≥2 years) of focal epilepsy according to the International League Against Epilepsy [ILAE] Classification of Epilepsy (2017)
  4. Prior neuroimaging within the last 10 years and  documentation is available
  5. Treatment with a stable dose of 1 to 3 allowable current AEDs for at least one month prior to screening, during baseline, and throughout the duration of the study
  6. Must be willing to comply with the contraception requirements as defined in Section 5.4
  7. Males must agree not to donate sperm from the time of the first administration of IMP until 6 months after the last dose of IMP. Females must agree not to donate ova from the time of the first administration of IMP until 6 months after the last dose of IMP
  8. Able to keep accurate seizure diaries
  9. Able to participate for the full term of the study

Exclusion Criteria

  1. Previously documented EEG which shows any pattern not consistent with focal etiology of seizures
  2. History of focal aware non-motor seizures only
  3. History of pseudoseizures or psychogenic seizures
  4. History of a primary generalized seizure
  5. Presence or previous history of Lennox-Gastaut syndrome
  6. Seizures secondary to illicit drug or alcohol use, ongoing infection, neoplasia, demyelinating disease, degenerative neurological disease, or central nervous system disease deemed progressive, metabolic illness, or progressive degenerative disease, progressive structural lesion or encephalopathy
  7. History of repetitive seizures within the 12-month period preceding study entry where the individual seizures cannot be counted
  8. Status epilepticus within the last 12 months prior to enrollment
  9. History of neurosurgery for seizures <1 year prior to enrollment, or radiosurgery <2 years prior to enrollment
  10. Schizophrenia and other psychotic disorders (e.g., schizophreniform disorder, schizoaffective disorder, psychosis not otherwise specified [NOS]), bipolar disorder, and/or obsessive-compulsive disorder, or other serious mental health disorders. Uncontrolled unipolar major depression where changes in pharmacotherapy are needed or anticipated during the study
  11. Active suicidal plan/intent in the past 6 months, or a history of suicide attempt in the last 2 years, or more than 1 lifetime suicide attempt
  12. History or presence of any significant medical or surgical condition or uncontrolled medical illness at screening including, but not limited to, hematologic, cardiovascular, pulmonary, renal, gastrointestinal, endocrine, hepatic or urogenital systems, or other conditions that would place the patient at increased risk as determined by the Investigator
  13. History of cancer within the past 2 years, with the exception of appropriately treated basal cell or squamous cell carcinoma
  14. Alanine transferase (ALT; SGPT) or aspartate transferase (AST; SGOT) levels >3 times the upper limit of normal (ULN) at screening or baseline
  15. Any clinically significant laboratory abnormalities or clinically significant abnormalities on pre-study physical examination, vital signs or ECG that in the judgment of the Investigator indicates a medical problem that would preclude study participation including but not limited to:
    1. History or presence of long QT syndrome; QTcF > 450 msec at baseline; family history of sudden death of unknown cause
    2. History of skin or retinal pigment epithelium abnormalities caused by ezogabine
  16. Females who are pregnant, breastfeeding or planning to become pregnant during the first administration of IMP until 6 months after the last dose of IMP
  17. History of illicit drug or alcohol abuse within 1 year prior to screening judged by the Investigator to be excessive or compulsive, or currently using drugs of abuse or any prescribed or over-the-counter medication in a manner that the Investigator considers indicative of abuse, dependence or habitual use
  18. Exposure to any other investigational drug or device within five half-lives or 30 days prior to screening, whichever is longer
  19. Use of vigabatrin in the last 5 years without stable visual fields tested twice over the 12 months after the last dose of vigabatrin (patients stopping vigabatrin more than 5 years prior to screening, must have no vigabatrin-related visual field abnormalities confirmed by examination within the past 6 months - concomitant use of vigabatrin is not allowed)
  20. If felbamate is used as a concomitant AED, patients must be on felbamate for at least 2 years, with a stable dose for 2 months (or no less than 49 days) prior to Screening. They must not have a history of white blood cell (WBC) count below 2500/µL (2.50 ´ 109/L), platelets below 100,000/mm3 (100 ´ 109/L), liver function tests (LFTs) above 3 times the upper limit of normal (ULN), or other indication of hepatic or bone marrow dysfunction while receiving felbamate. If patients received felbamate in the past, it must have been discontinued 2 months (or no less than 49 days) prior to Screening
  21. Have had multiple drug allergies or a severe drug reaction to an AED(s), including dermatological (e.g., Stevens-Johnson syndrome), hematological, or organ toxicity reactions
  22. Current use of a ketogenic diet
  23. Any medical condition or personal circumstance that in the opinion of the Investigator exposes the patient to unacceptable risk by participating in the study or prevents adherence to the protocol
  24. Employees of Xenon Pharmaceuticals Inc., the contract research organization (CRO), or study site personnel directly affiliated with this study and their immediate family members. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted