A Multicenter, Open-label, Long-term, Safety, Tolerability, and Efficacy Study of XEN1101 in Subjects Diagnosed With Epilepsy (X-TOLE4)

The primary objective of this study is to evaluate the **safety** and **tolerability** of long-term therapy with XEN1101 in subjects diagnosed with **focal-onset seizures** (FOS) or **primary generalized tonic-clonic seizures** (PGTCS) who have completed previous studies (XPF-010-301, XPF-010-302, or XPF-010-303). This is clinically relevant as it aims to ensure that the extended use of XEN1101 does not result in adverse effects, thereby supporting its potential as a sustainable treatment option for epilepsy.

Secondary objectives include: - Assessing the efficacy of long-term treatment with XEN1101 on seizure frequency, which is crucial for determining the therapeutic benefit of the medication in reducing seizure occurrences. - Evaluating the change in disease severity, which provides insights into the progression or improvement of the condition under treatment. - Assessing the impact of long-term treatment with XEN1101 on the quality of life in subjects aged ≥18 years at study entry, which is important for understanding the broader implications of the treatment on patients' daily living and overall well-being.

The clinical trial involves a total of **434 participants** who have been diagnosed with **primary generalized tonic-clonic seizures** or **focal-onset seizures**. The study population includes both male and female subjects, encompassing a diverse age range. Participants were selected based on their successful completion of previous studies, specifically Study XPF-010-301, XPF-010-302, or XPF-010-303, without early termination or significant protocol deviations. The trial includes individuals who are capable of maintaining accurate seizure diaries and are willing to adhere to specific contraception requirements. The population is characterized by a mix of age groups, and it includes a vulnerable population, indicating a careful consideration of ethical standards in participant selection. The health status of participants is generally stable, as they have met all eligibility requirements and have been deemed suitable for long-term therapy assessment by the investigator. Lifestyle factors such as diet and physical activity are not specified, but participants are expected to comply with study schedules and requirements.

The clinical trial is designed to evaluate the **safety** and tolerability of long-term therapy with XEN1101 in subjects diagnosed with **epilepsy**, specifically those with primary generalized tonic-clonic seizures and focal-onset seizures. This is a Phase III, open-label study, which means that both the researchers and participants know which treatment is being administered. The trial is expected to run until January 26, 2032, with recruitment starting on October 15, 2023. Participants will be involved in the study for a maximum treatment period of up to 36 months, depending on the dosage group they are assigned to.

The trial involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as successful completion of prior studies and the ability to maintain accurate seizure diaries. Following the screening, participants will undergo regular follow-up visits to monitor the severity and frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and other safety parameters such as vital signs, laboratory findings, and electrocardiograms (ECGs). The end-of-study visit will conclude the participant's involvement, assessing the overall impact of the treatment on seizure frequency and quality of life.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study requirements, or choose to withdraw consent. The primary endpoints focus on the safety profile of XEN1101, while secondary endpoints include changes in seizure frequency and quality of life assessments. The study drug, XPF-010, containing the active substance **azetukalner**, is administered orally in capsule form, with varying dosages up to a maximum of 25 mg per day. The trial aims to provide comprehensive data on the long-term use of XEN1101 in managing epilepsy, contributing to the understanding of its efficacy and safety in this patient population.

The clinical trial involves the administration of the experimental medication **XPF-010**, which contains the active substance **azetukalner**. This medication is provided in the form of a capsule and is intended for **oral use**. The trial includes several dosing regimens of XPF-010, each with specific dosage and treatment duration parameters. The first regimen involves a maximum daily dose of 15 mg, with a total treatment period of up to 36 weeks. The second regimen allows for a maximum daily dose of 10 mg, with a treatment duration of 12 weeks. The third regimen permits a maximum daily dose of 20 mg, also over a 12-week period. Lastly, the fourth regimen involves a maximum daily dose of 25 mg, with a treatment period extending to 36 weeks. Each regimen is designed to assess the safety, tolerability, and efficacy of long-term therapy with XPF-010 in subjects diagnosed with epilepsy.

In addition to the experimental medication, the study may include the use of standard-of-care therapies as deemed necessary by the clinical investigators. These therapies are not specified in the trial data but are typically administered in accordance with established medical guidelines for the management of epilepsy. The trial does not utilize a placebo or comparator treatment, focusing solely on the evaluation of XPF-010.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. This monitoring is crucial for the accurate assessment of the medication's effects and the collection of reliable data on its safety and efficacy. The trial is conducted under the sponsorship of Xenon Pharmaceuticals Inc., and the medication is classified under the ATC code N03AX, indicating its categorization as an "Other Antiepileptics" agent.

The efficacy of the clinical trial will be assessed using several secondary endpoints. These include the percent change in monthly seizure rate recorded at baseline compared to each 4-week assessment period during the treatment phase of the study. Additionally, the proportion of responders, defined as subjects experiencing a ≥50% reduction in seizure frequency from baseline, will be evaluated in each consecutive 4-week assessment period. Changes in the Clinical Global Impression-Severity (CGI-S) and Patient Global Impression-Severity (PGI-S) scores over time will also be measured, alongside changes in the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) scores.

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial. The assessment of seizure frequency and responder rates will be based on data collected during each 4-week period. The CGI-S, PGI-S, and QOLIE-31 scores will be evaluated over time to monitor changes in the subjects' condition and quality of life. These assessments will provide a comprehensive evaluation of the efficacy of the investigational product, XPF-010, in subjects diagnosed with epilepsy.