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)

Dravet syndrome (DS) or severe myoclonic epilepsy in infancy is one of the most
well-described disorders of epileptic encephalopathies. Clinically, DS is
characterized at onset by frequent convulsive febrile seizures, followed by
frequent status epilepticus and nonfebrile seizures that are mainly clonic,
unilateral, and of long duration.
Lennox-Gastaut syndrome (LGS) is one of the most severe forms of childhood
epilepsy. The syndrome usually has its onset between the ages of 1 and 8 years,
but occasionally it occurs in children who are older than 8 years, or even into
adulthood. LGS includes the presence of multiple seizure types: the hallmark
tonic-atonic drop seizures. Other seizure types include atypical absence
seizures, but tonic-clonic, myoclonic, and partial seizures are also frequently
present.

Soticlestat is a first-in-class small molecule inhibitor of cholesterol-24
hydroxylase (CH24H) in the brain. Based on the efficacy, safety, and
tolerability data collected in the phase 2 ELEKTRA study, combined with the
safety and tolerability data from phase 1 and other completed or ongoing
studies (please see the IB), soticlestat is being proposed as adjunctive
therapy in pediatric and adult subjects with DS or LGS, highly impacted
populations with great unmet need.

This is a multisite, phase 3, open-label extension (OLE) study designed to
obtain additional safety and tolerability data related to soticlestat
administered long-term in subjects who participated in an antecedent
soticlestat phase 3 clinical study. Additional aims are to assess efficacy in
terms of seizure frequency, non-seizure-related symptoms, impact on quality of
life, and the pharmacokinetics (PK) and pharmacodynamics (concentration of
24Shydroxycholesterol [24HC]) of soticlestat administration in pediatric and
adult subjects with DS or LGS, as well as assessing palatability and
acceptability of soticlestat in the pediatric population.

This study has been transitioned to CTIS with ID 2022-502802-34-00 check the CTIS register for the current data.

Primary Objective:
To assess the long-term safety and tolerability of soticlestat when
administered as adjunctive therapy to standard of care (SOC) (eg, antiseizure
medications [ASMs], vagus nerve stimulation, ketogenic diet, or modified Atkins
diet) in subjects with DS or LGS.

Secondary Objectives:
- To assess the effect of soticlestat on seizure frequency (convulsive seizures
for the DS cohort, MMD seizures for the LGS cohort, and total seizure count for
each cohort).
- To assess the effect of soticlestat on the Clinical Global Impression of
Improvement (CGI-I) (clinician) and Caregiver Global Impression of Improvement
(Care GI-I).
- To assess the effect of soticlestat on CGI-I Seizure Intensity and Duration.
- To assess the effect of soticlestat on the CGI-I Nonseizure Symptoms
completed by clinician with input from the caregiver.
- To assess the effect on Quality of Life Inventory-Disability (QI-Disability).

This is a multisite, phase 3, open-label extension (OLE) study designed to obtain additional safety and tolerability data related to soticlestat administered long-term in subjects who participated in an antecedent soticlestat phase 3 clinical study. Additional aims are to assess efficacy in terms of seizure frequency, non-seizure-related symptoms, impact on quality of life, and the pharmacokinetics (PK) and pharmacodynamics (concentration of 24Shydroxycholesterol [24HC]) of soticlestat administration in pediatric and adult subjects with DS or LGS, as well as assessing palatability and acceptability of soticlestat in the pediatric population. After an initial 2-week titration period, the planned treatment duration is approximately 4 years, or until the study is stopped at the discretion of the sponsor, or the product is approved for marketing. The total daily dose of soticlestat will be calculated based on body weight at Visit 1 and given twice daily (BID). Subjects will receive the initial dose of the study drug (200 mg BID adult reference dose, weight-based dosing for weight <45 kg) for the first 7 days of the dose titration period; the study drug dose will then be increased to the target dose (300 mg BID adult reference dose, weight-based dosing for weight <45 kg). If the subjects do not experience any tolerability issues, they will remain on the target dose for the remaining 7 days of the titration period, followed by a safety follow-up phone call. The minimum dose allowed during the study is 100 mg BID (weight-based dosing <45 kg). Subjects who cannot tolerate the minimum dose will be discontinued from the study. The dose may be adjusted every 6 months, depending on the subject's weight. Dose changes (increased or decreased) during the maintenance period are allowed as assessed by the investigator; however, if possible, dose changes due to safety or tolerability may need to be discussed with the medical monitor and/or the sponsor. In the absence of weight change or safety or tolerability considerations, the final dose tolerated by the end of the 2-week titration period should be maintained until the end of the maintenance period. At the end of the maintenance period, whether after the full duration or for early termination, the dose will be tapered for approximately 1 week (unless already at the lowest dose), followed approximately 2 weeks later by a safety follow-up visit or phone call.

Soticlestat will be available as yellow-red colored, film-coated tablets and
mini-tablets. Soticlestat (tablets/mini-tablets) can be swallowed whole or can
be crushed and mixed well in applesauce or a thick liquid. Soticlestat should
be taken by you 2 times a day (morning and evening). Soticlestat can be taken
orally, with or without food, or via a gastrostomy tube (G tube) or via a
percutaneous endoscopic gastrostomy tube (PEG tube).

The following side effects are common:
- Feeling tired and sluggish
- Difficulty sleeping
- Headache
- Nausea or feeling like you need to vomit
- Difficulty paying attention or confusion
- Feeling constantly tense, on guard, or abnormally aware of one*s environment
- Difficulty speaking
- Sleepiness or drowsiness (somnolence)
- Decreased appetite
- Abnormal bowel movements (constipation and diarrhea)


Potential discomforts from the measurements are:
- Blood draw: Obtaining blood may sometimes cause pain/discomfort, bruising, or
bleeding at the site where the blood is drawn, occasional light-headedness,
and, rarely, infection or fainting.
- ECG: The ECG sticky patches or suction cups placed on the skin may cause
slight discomfort during their placement and removal. The patient may also feel
a little embarrassed as some upper clothing may need to be removed.
- Ophthalmological assessments: The patient may feel temporary discomfort
during the eye examinations due to the bright lights and with the drops which
will be put in your eyes before performing any examinations to make the pupils
larger.
- Questionnaires about well-being, behavior, quality of life and risk for
suicide: Some questions may cause distress or make the patient feel
uncomfortable.