Abstracts

Rationale: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy associated with treatment-resistant seizures of several different types and developmental delay with > 80% having a SCN1A gene mutation. Despite recent approval of antiseizure medications (ASMs) specifically indicated for DS, seizures often remain uncontrolled and polytherapy can lead to drug–drug interactions and an increase in adverse events. As such, there remains an unmet need for efficacious medications with a good safety and tolerability profile. Soticlestat (TAK-935) is a first-in-class potent and selective inhibitor of cholesterol 24-hydroxylase (CH24H), an enzyme primarily expressed in the brain that catabolizes cholesterol to 24S-hydroxycholesterol (24HC) resulting in a reduction in glutamatergic hyperexcitability. SKYLINE evaluated the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in children and young adults diagnosed with DS.

Methods: SKYLINE (NCT04940624) was a phase 3, global, multicenter, randomized, double-blind, placebo-controlled, parallel group trial that evaluated the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in pediatric and young adult participants with DS. The primary endpoint was percent change from baseline in convulsive seizure frequency per 28 days in participants receiving soticlestat compared with placebo during the full treatment period. Key secondary endpoints included evaluation of effects on treatment response, Caregiver Global Impression of Improvement (GI-I), Clinical GI-I, and Clinical GI-seizure intensity and duration. The diagnosis of DS was adjudicated independently by the Epilepsy Study Consortium. The treatment period was 16 weeks including a 4-week titration period and 12-week maintenance period. Participants aged 2 to 21 years were randomized 1:1 to receive either soticlestat or matching placebo twice daily (BID). Upon completion of the study, participants had the option to enroll in an ongoing open-label extension study, ENDYMION 2 (NCT05163314).

Results: One hundred and forty-four participants enrolled globally with 123 (85.4%) completing the study. The mean (SD) age was 10.3 (5.0) years and 72 (50%) were male; 117 (81.3%) participants were on three or more ASMs, 7 (4.9%) were on a ketogenic diet, and 15 (10.4%) were utilizing Vagus Nerve Stimulation therapy. The median convulsive seizure frequency per 28 days at baseline was 11.13 and all-seizure frequency was 17.9. The full data analysis is ongoing and will be presented at the congress.

Conclusions: These forthcoming data will be the first from the phase 3 SKYLINE study and will provide valuable information on the efficacy and safety of soticlestat as a potential treatment for seizures associated with DS.

Funding: Takeda Development Center Americas, Inc.