A phase 3, prospective, open-label, multisite, extension of phase 3 studies to assess the long-term safety and tolerability of soticlestat as adjunctive therapy in subjects with Dravet Syndrome or Lennox-Gastaut Syndrome (ENDYMION 2)

The primary objective of this study is to assess the long-term **safety** and **tolerability** of **soticlestat** when administered as adjunctive therapy to standard of care (SOC) treatments, such as antiepileptic drugs, vagus nerve stimulation, ketogenic diet, and modified Atkins diet, in subjects with Dravet Syndrome (DS) or Lennox-Gastaut Syndrome (LGS). This is clinically relevant as it aims to ensure that soticlestat can be safely integrated into existing treatment regimens for these severe epileptic conditions, potentially improving patient outcomes without compromising safety.

Secondary objectives include:

• Assessing the effect of soticlestat on seizure frequency, specifically convulsive seizures in the DS cohort, major motor drop (MMD) seizures in the LGS cohort, and total seizure count for each cohort.
• Evaluating the effect of soticlestat on the Clinical Global Impression of Improvement (CGI-I) from both clinician and caregiver perspectives.
• Assessing the effect of soticlestat on CGI-I Seizure Intensity and Duration.
• Evaluating the effect of soticlestat on CGI-I Nonseizure Symptoms, completed by clinicians with input from caregivers.
• Assessing the effect on Quality of Life Inventory-Disability (QI-Disability).

The clinical trial involves a total of **250 participants** diagnosed with **Dravet and Lennox-Gastaut Syndromes**. The study population includes both male and female subjects, with an age range encompassing children and adolescents. Participants were selected based on their previous enrollment in a phase 3 soticlestat clinical study, having received at least 12 weeks of treatment with the study drug. The trial population is characterized by a vulnerable group, indicating the inclusion of individuals who may require additional considerations. Lifestyle factors such as adherence to specific diets, including the ketogenic or modified Atkins diet, and the use of adjunctive therapies like vagus nerve stimulation, are relevant to the study. The selection process ensured that participants had no serious adverse events related to the study drug that would contraindicate continued participation. The trial aims to assess the long-term safety and tolerability of soticlestat as an adjunctive therapy to standard care in this specific patient population.

The clinical trial is designed to evaluate the long-term safety and tolerability of **soticlestat** as an adjunctive therapy in subjects with Dravet Syndrome or Lennox-Gastaut Syndrome. This is a phase 3, prospective, open-label, multisite extension study. The trial will involve participants who have previously been enrolled in a phase 3 soticlestat clinical study and have received at least 12 weeks of treatment. The study is expected to last until December 21, 2025, with participant involvement potentially extending up to 52 weeks, depending on individual response and safety assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as prior participation in a related study and the absence of serious adverse events related to the study drug. Follow-up visits will be scheduled to monitor the incidence of treatment-emergent adverse events (TEAEs), changes in clinical laboratory test values, vital signs, and electrocardiogram (ECG) parameters. The primary endpoints include the incidence of TEAEs and changes from baseline in various clinical measures. Secondary endpoints focus on the percent change from baseline in seizure frequency and the effect on clinical global impression scales.

The study will require participants to comply with protocol requirements, including maintaining a daily seizure diary and attending all scheduled visits. Female participants of childbearing potential must agree to use effective contraception during the study and for 30 days after the last dose. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or non-compliance with study protocols. The trial aims to provide comprehensive data on the long-term use of soticlestat in managing these rare syndromes.

The clinical trial involves the administration of **soticlestat**, an experimental medication, as an adjunctive therapy for subjects with Dravet Syndrome or Lennox-Gastaut Syndrome. **Soticlestat** is provided in the form of a **tablet** and is administered **orally**. The maximum daily dose of **soticlestat** is 600 mg, with a total maximum dose of 214.2 grams over the course of the study. The treatment period extends up to 52 weeks. The active substance, **soticlestat**, is a chemical entity developed by Takeda Development Center Americas, Inc., and is identified by the sponsor product code TAK-935. The medication is classified as a new chemical entity and has been designated as an orphan drug under the designation number EU/3/21/2529.

In addition to the experimental treatment, participants may continue to receive standard-of-care (SOC) therapies, which may include antiepileptic drugs (ASMs), vagus nerve stimulation, ketogenic diet, or modified Atkins diet. These non-experimental treatments are allowed to ensure comprehensive management of the underlying conditions, Dravet Syndrome or Lennox-Gastaut Syndrome, during the trial. Compliance with the dosing schedule and administration of both the experimental and non-experimental treatments will be monitored throughout the study to ensure adherence and evaluate the long-term safety and tolerability of **soticlestat** as an adjunctive therapy.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. Primary endpoints include the incidence of **TEAEs** (treatment-emergent adverse events), incidence of abnormal values for clinical laboratory tests and electrocardiogram (ECG) evaluations, and changes from baseline in clinical laboratory test values, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS), and ECG parameters. Additionally, changes from baseline in height and weight for all age groups, absolute values for Tanner stage for children aged 6 to 17 years, and absolute values for IGF-1 for children aged 2 to 17 years will be evaluated.

Secondary endpoints focus on the percent change from baseline in total seizure frequency per 28 days for each cohort (Dravet Syndrome and Lennox-Gastaut Syndrome), as well as specific changes in convulsive seizure frequency for Dravet Syndrome and MMD seizure frequency for Lennox-Gastaut Syndrome. The trial will also assess the effect on the Clinical Global Impression-Improvement (CGI-I) and Care GI-I, seizure intensity and duration, non-seizure symptoms as completed by clinicians with input from caregivers, and the Quality of Life in Disability (QI-Disability) scale.