XEN1101

Brief Summary

XEN1101 is a novel, small molecule, selective KCNQ2/3 (K_V7.2/7.3) 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).

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 body mass index (BMI) ≤40 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 DBP.
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. (A new EEG is not required, if not available.)
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 (eg, 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 ms 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 5 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 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 (eg, 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