A Phase 2, Prospective, Interventional, Open-Label, Multisite, Extension Study to Assess the Long-Term Safety and Tolerability of Soticlestat (TAK-935) as Adjunctive Therapy in Subjects with Developmental Epileptic Encephalopathies Including Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome (ENDYMION 1)

The primary objective of this study is to assess the long-term **safety** and **tolerability** of **soticlestat** when administered as adjunctive therapy to at least one anti-seizure therapy in subjects with rare epilepsies, including Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome. This is clinically relevant as it aims to ensure that soticlestat can be safely integrated into existing treatment regimens for these complex and severe forms of epilepsy, potentially improving patient outcomes.

The secondary objectives, in subjects receiving soticlestat as adjunctive therapy to at least one anti-seizure therapy, are the following:

• To assess the effect of soticlestat on **seizure frequency**.
• To assess the effect of soticlestat on the Clinical Global Impression of Severity (CGI-S) provided by the investigator.

The clinical trial involves a total of **105 participants** diagnosed with **epileptic encephalopathies**, including Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, Chromosome 15 Duplication Syndrome, and other adult developmental and epileptic encephalopathies (DEEs). The study population comprises both male and female subjects, with an age range that includes children and adults. Participants were selected based on their previous involvement in a soticlestat study, ensuring they either successfully completed a prior clinical study or received a minimum of 10 weeks of treatment without experiencing any serious adverse events related to the study drug. The trial includes individuals who are part of a vulnerable population, and the study aims to assess the long-term safety and tolerability of soticlestat as an adjunctive therapy to at least one anti-seizure treatment, such as antiepileptic drugs, vagal nerve stimulation, or specific dietary interventions like the ketogenic or modified Atkins diet.

The clinical trial is a Phase 2, prospective, interventional, open-label, multisite extension study designed to assess the long-term safety and tolerability of **soticlestat** as adjunctive therapy in subjects with developmental epileptic encephalopathies, including Dravet Syndrome, Lennox-Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome. The trial aims to evaluate the safety profile of soticlestat when administered alongside at least one anti-seizure therapy, such as antiepileptic drugs, vagal nerve stimulator, ketogenic diet, or modified Atkins diet. The study is expected to run from April 2019 to May 2026, with participants involved for a maximum treatment period of 96 weeks.

Participants eligible for inclusion must have previously participated in a soticlestat study and meet specific conditions, such as successful completion of a prior study or having received at least 10 weeks of treatment in a previous placebo-controlled, blinded soticlestat study without experiencing serious adverse events related to the study drug. The primary endpoints include the incidence of adverse events, changes from baseline in behavioral and adaptive functional measures, and clinical laboratory assessments. Secondary endpoints focus on the percent change from baseline in seizure frequency and changes in clinical global impression severity.

The trial involves a sequence of study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Follow-up visits are scheduled to monitor the safety and efficacy of the treatment, assess adverse events, and collect data on seizure frequency and behavioral changes. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any ongoing safety concerns are addressed. Participants may be terminated early from the study if they experience severe adverse events or if the investigator deems it unsafe for them to continue. The study is conducted in compliance with regulatory standards to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **soticlestat**, an experimental medication developed by Takeda Development Center Americas, Inc. Soticlestat is provided in a **tablet** form and is classified as a new chemical entity. The medication is administered **orally**. The maximum daily dose of soticlestat is 600 mg, with a total maximum dose of 1752 g over the course of the study. The treatment period extends up to 96 weeks. Soticlestat is available in both pediatric and non-pediatric formulations, and it has been designated as an orphan drug under the designation number EU/3/21/2529.

In addition to the experimental medication, participants in the study may receive non-experimental treatments as part of their standard-of-care therapy. These treatments include at least one anti-seizure therapy, which may consist of antiepileptic drugs (AEDs), a vagal nerve stimulator, a ketogenic diet, or a modified Atkins diet. The study aims to assess the long-term safety and tolerability of soticlestat when used as an adjunctive therapy in subjects with developmental epileptic encephalopathies, including Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome.

The efficacy of **soticlestat** in the clinical trial will be assessed using both primary and secondary endpoints. Primary endpoints include the incidence of adverse events (AEs), changes from baseline in behavioral and adaptive functional measures using the Vineland Adaptive Behavior Scale (VABS), and changes in behavior measures using total scores and subscale scores of the Aberrant Behavior Checklist-Community Edition (ABC-C) for subjects aged 6 years and older. Additionally, changes from baseline in the Columbia-Suicide Severity Rating Scale (CSSRS) categorization based on the Columbia Classification Algorithm of Suicide Assessment categories 1 through 5 for subjects aged 6 years and older will be evaluated. Absolute values and changes from baseline in clinical laboratory assessments, vital sign measurements, body weight, and electrocardiogram (ECG) parameters will also be monitored. The incidence of potentially clinically significant clinical safety laboratory test values, vital signs, weight, height, and ECG evaluations will be recorded.

Secondary endpoints focus on the percent change from baseline in all seizure 28-day frequency, drop seizure 28-day frequency for Lennox Gastaut Syndrome (LGS) subjects, convulsive seizure 28-day frequency for Dravet Syndrome (DS) subjects, and motor seizure 28-day frequency. Additionally, changes from baseline in the Clinical Global Impression-Severity (CGI-S) will be assessed. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the long-term safety and tolerability of soticlestat as adjunctive therapy in subjects with developmental epileptic encephalopathies.