A Phase 3 Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Azetukalner as Adjunctive Therapy in Focal-Onset Seizures

The primary objective of this study is to evaluate the effect of **XEN1101** compared to placebo in reducing the frequency of **focal onset seizures**. This is clinically relevant as focal onset seizures are a common type of epilepsy, and effective management can significantly improve patient quality of life and reduce the risk of seizure-related complications.

Secondary objectives include:

• Assessing the early treatment effect of XEN1101 versus placebo on focal seizure frequency.
• Evaluating the effect of XEN1101 versus placebo on seizure impact.

The clinical trial involves a total of **192 participants** diagnosed with **focal onset seizures**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of focal epilepsy for at least two years, as per the International League Against Epilepsy 2017 classification criteria. All subjects have previously undergone adequate trials of at least two antiseizure medications (ASMs) at therapeutic doses without achieving sustained seizure freedom. Additionally, participants are required to be on a stable dose of one to three allowable ASMs for at least one month prior to screening and throughout the double-blind period. The trial includes a vulnerable population, and subjects must be capable of maintaining accurate seizure diaries. The selection process ensures that participants are properly informed of the study's nature and risks, providing informed consent in writing before entering the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety, tolerability, and efficacy of XEN1101 as an adjunctive therapy in patients with **focal-onset seizures**. The trial will involve multiple centers and is classified as a Phase III confirmatory study. The primary objective is to assess the effect of XEN1101 compared to placebo in reducing the frequency of focal seizures. The trial is expected to run from May 15, 2023, to April 30, 2025, with a maximum treatment period of 12 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of focal epilepsy for at least two years and a stable dose of 1 to 3 allowable current anti-seizure medications (ASMs). Following the screening, eligible participants will be randomized to receive either XEN1101 or a placebo, administered orally in capsule form. The study will include regular follow-up visits to monitor safety, tolerability, and efficacy, with the primary endpoint being the proportion of subjects experiencing a 50% or greater reduction in monthly focal seizure frequency from baseline through the double-blind period (DBP).

The end-of-study visit will conclude the participant's involvement, which is expected to last up to 12 weeks. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. Secondary endpoints include changes in weekly seizure frequency and patient-reported improvements in the Patient Global Impression of Change (PGI-C) at Week 12. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings.

The clinical trial involves the administration of **XPF-010**, an experimental medication formulated as a capsule. The active substance in XPF-010 is **azetukalner**, classified under the ATC code N03AX, which denotes it as part of the "Other Antiepileptics" category. The pharmaceutical form of XPF-010 is a capsule, and it is intended for **oral use**. The dosing regimen varies, with maximum daily doses of 25 mg, 20 mg, 15 mg, and 10 mg, depending on the specific protocol arm. The maximum treatment period for each dosing regimen is 12 weeks. The medication is manufactured by Xenon Pharmaceuticals Inc. and is not a pediatric formulation.

The trial also includes a **placebo** control, which is a size 3 white opaque HPMC capsule (Capsugel VCaps® Plus White OP) containing 10 mg of Avicel® PH102, a form of microcrystalline cellulose. The placebo is designed to match the appearance of the XPF-010 capsules to maintain the double-blind nature of the study. The placebo is administered orally, following the same schedule as the experimental medication, to ensure consistency in the treatment protocol.

The efficacy of XEN1101 as an adjunctive therapy in patients with focal-onset seizures will be assessed through a randomized, double-blind, placebo-controlled, multicenter Phase 3 study. The primary endpoint for evaluating efficacy is the proportion of subjects experiencing a ≥50% reduction in monthly (28 days) focal seizure frequency from baseline through the double-blind period (DBP) for XEN1101 compared to placebo. Secondary endpoints include the mean percentage change (MPC) in monthly focal seizure frequency from baseline through the DBP, the proportion of subjects experiencing a ≥50% reduction in weekly (7 days) focal seizure frequency from baseline to Week 1, and the proportion of subjects experiencing "at least much improved" status in the Patient Global Impression of Change (PGI-C) at Week 12.

Efficacy parameters will be collected and analyzed at specified timepoints, including baseline, Week 1, and Week 12. The PGI-C will be utilized as a tool for assessing patient-reported outcomes regarding improvement in seizure frequency and overall condition. The study aims to provide comprehensive data on the efficacy of XEN1101 in reducing seizure frequency and improving patient outcomes in focal epilepsy.