A Randomized, Double-blind, Placebo-Controlled, Multicenter Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 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 **127 participants** diagnosed with **focal onset seizures**. The study population includes both male and female subjects, aged 18 years and older, with a body mass index (BMI) of 40 kg/m² or less. Participants were selected based on their ability to provide informed consent and their diagnosis of focal epilepsy for at least two years, as per the International League Against Epilepsy 2017 classification criteria. All subjects have undergone prior neuroimaging within the last decade and are on a stable dose of 1 to 3 allowable current antiseizure medications (ASMs) for at least one month prior to screening. The trial includes individuals with implanted vagal nerve stimulators, deep brain stimulation, or responsive neurostimulator systems, provided these devices have been stable for over a year. Participants are required to maintain accurate seizure diaries and comply with specific contraception requirements. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across a diverse group of individuals.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the safety, tolerability, and efficacy of XEN1101 as an adjunctive therapy in patients with **focal-onset seizures**. The trial is structured as a Phase 3 study and involves multiple centers. 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 until June 2027, with recruitment having commenced in May 2023.

Participants will be involved in the study for a maximum treatment period of 12 weeks. The study includes several key visits: an initial screening visit to determine eligibility, followed by regular follow-up visits to monitor safety and efficacy, and a final end-of-study visit. During the screening visit, participants will be evaluated based on inclusion criteria such as a confirmed diagnosis of focal epilepsy, stable medication regimen, and the ability to maintain accurate seizure diaries. Follow-up visits will occur at regular intervals to assess the primary endpoint, which is the proportion of subjects experiencing a 50% or greater reduction in monthly focal seizure frequency from baseline through the double-blind period (DBP).

Participants are required to adhere to the study protocol, including maintaining stable doses of current anti-seizure medications and complying with contraception requirements. The study drug, XEN1101, is administered orally in capsule form, with doses ranging from 10 mg to 25 mg daily, depending on the treatment group. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The study aims to provide robust data on the efficacy and safety of XEN1101, contributing to the understanding of its potential as a treatment for focal-onset seizures.

The clinical trial involves the administration of the experimental medication **XPF-010**, which contains the active substance **azetukalner**. This medication is provided in a **capsule** form and is intended for **oral use**. The trial includes several dosage regimens of XPF-010, with maximum daily doses of 10 mg, 15 mg, 20 mg, and 25 mg, respectively. Each dosage is administered once daily, and the treatment period extends up to 12 weeks. The active substance, azetukalner, is classified under the ATC code N03AX, indicating its role as an antiepileptic agent. The chemical origin of azetukalner is confirmed, and the product is manufactured by Xenon Pharmaceuticals Inc.

In addition to the experimental medication, the study employs a placebo control. The placebo is formulated as a size 3 white opaque HPMC capsule, known as Capsugel VCaps® Plus White OP, containing 10 mg of Avicel® PH102, which is microcrystalline cellulose. The placebo is designed to match the appearance of the XPF-010 capsules to maintain the double-blind nature of the trial. The placebo is administered orally, following the same dosing schedule as the experimental medication.

Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment protocol. The trial aims to evaluate the safety, tolerability, and efficacy of XPF-010 as an adjunctive therapy in patients with focal-onset seizures, comparing its effects to those of the placebo. The study is conducted in a randomized, double-blind, placebo-controlled, multicenter format to ensure robust and reliable results.

The efficacy of the investigational product XEN1101 in the treatment of **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 (PGIC) at Week 12.