A Randomized, Double-blind, Placebo-Controlled, Multicenter, Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 as Adjunctive Therapy in Primary Generalized Tonic-Clonic Seizures (X-ACKT)

The primary objective of this study is to evaluate the effect of **XEN1101** compared to placebo in reducing the frequency of **Primary Generalized Tonic-Clonic Seizures (PGTCS)** in subjects diagnosed with PGTCS. This objective is clinically relevant as it aims to determine the efficacy of XEN1101 as an adjunctive therapy, potentially offering a new treatment option for patients with this type of seizure, which can significantly impact quality of life.

Secondary objectives include:

• Assessing the effect of XEN1101 versus placebo on the frequency of PGTCS freedom in subjects with PGTCS.
• Evaluating the impact of XEN1101 compared to placebo on seizure impact in subjects with PGTCS.

The clinical trial involves a total of **106 participants** diagnosed with **Primary Generalized Tonic-Clonic Seizures**. The study population includes both male and female subjects, aged 12 years and older, with a **Body Mass Index (BMI)** of 40 kg/m² or less. Participants were selected based on their documented history of seizures, including a routine EEG within the past five years and prior neuroimaging. The trial includes individuals who have had the onset of seizures before the age of 40 and have experienced at least three seizures in the eight weeks preceding the study. Participants are required to be on a stable dose of one to three allowable antiseizure medications (ASMs) for at least one month prior to screening and throughout the study. The trial population also includes individuals with implanted neurostimulator systems, provided the devices were implanted at least five months before the study and remain unchanged. Participants must be able to maintain accurate seizure diaries and comply with contraception requirements. The study encompasses a vulnerable population, ensuring informed consent is obtained from all participants or their legal representatives.

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 **Primary Generalized Tonic-Clonic Seizures** (PGTCS). The trial is a Phase 3 study, which is confirmatory in nature, and involves multiple centers. The primary objective is to assess the effect of XEN1101 compared to placebo in reducing the frequency of PGTCS. The trial is expected to last until May 2025, with recruitment starting in September 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as age, seizure history, and current medication regimen. Following successful screening, participants will be randomized to receive either XEN1101 or a placebo, administered orally in capsule form. The study includes a double-blind period (DBP) where neither the participants nor the investigators will know the treatment assignments. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

The expected duration of participant involvement is up to 12 months, aligning with the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The primary endpoint is the proportion of subjects experiencing a 50% or greater reduction in monthly PGTCS frequency from baseline through the DBP. Secondary endpoints include changes in seizure frequency and overall improvement in clinical status as assessed by the Patient Global Impression of Change (PGI-C) scale.

The clinical trial involves the administration of the experimental medication **XPF-010**, which is formulated as a capsule for **oral use**. The active substance in XPF-010 is **azetukalner**, also known by its chemical name **N-[4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide**. This compound is classified under the ATC code **N03AX**, indicating its use as an antiepileptic agent. The trial includes multiple dosing regimens of XPF-010, with maximum daily doses of 10 mg, 15 mg, 20 mg, and 25 mg, administered over a treatment period of up to 12 weeks. The dosing schedule is designed to evaluate the safety, tolerability, and efficacy of the medication in reducing the frequency of Primary Generalized Tonic-Clonic Seizures (PGTCS).

In addition to the experimental medication, the study employs a placebo control to ensure the validity of the trial results. The placebo is a size 3 white opaque HPMC capsule, known as Capsugel VCaps® Plus White OP, containing 10 mg of Avicel® PH102 (microcrystalline cellulose). The placebo is indistinguishable from the active medication in appearance and is administered following the same oral route and dosing schedule as the experimental drug. This design allows for a double-blind comparison between the active treatment and placebo groups.

Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol. The trial is conducted under the sponsorship of Xenon Pharmaceuticals Inc., and all substances used in the study are of chemical origin. The trial's objective is to assess the effect of XEN1101, the active form of XPF-010, in comparison to placebo, on the reduction of PGTCS frequency in subjects diagnosed with this condition.

The efficacy of XEN1101 as an adjunctive therapy in reducing the frequency of **Primary Generalized Tonic-Clonic Seizures (PGTCS)** will be assessed in this randomized, double-blind, placebo-controlled, multicenter, Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the proportion of subjects experiencing a ≥50% reduction in monthly (28 days) PGTCS frequency from baseline through the double-blind period (DBP) for XEN1101 compared to placebo. Secondary endpoints include the mean percentage change (MPC) in monthly PGTCS frequency from baseline through the DBP, the proportion of subjects achieving PGTCS freedom, 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 throughout the study, with the primary focus on changes from baseline through the DBP. The PGI-C will be used as a tool to assess patient-reported outcomes regarding their perception of improvement. The trial is designed to ensure rigorous assessment of the therapeutic effect of XEN1101, with data collection scheduled to align with the study's objectives and endpoints.