Clinical Failure Validates a Fifth Predictive Preclinical Antiseizure Medicine Discovery Model

Soticlestat as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome Sullivan J, Valente K, Villanueva V, Strzelczyk A, Nabbout R, Nakagawa E, Zhang Y, Zolnowska M, Khan Y, Dong C, Hsiao S, Sheikh SI, von Rosenstiel P, Asgharnejad M, Murthy V. Epilepsia . 2026 Mar 5. doi: 10.1002/epi.70164 . Epub ahead of print. PMID: 41784472. Objective: This study evaluated the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in children and young adults with Dravet syndrome (DS). Methods: SKYLINE (NCT04940624) was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that enrolled patients with DS aged 2–21 years with uncontrolled convulsive seizures (≥4/month despite adequate treatment). Participants received oral soticlestat 300 mg (weight adjusted) or matching placebo twice daily. The total study duration was 16 weeks, comprising 4-week dose titration and 12-week maintenance treatment periods. The primary endpoint was a comparison of monthly convulsive seizure frequency between baseline and the titration/maintenance periods. Key secondary endpoints included several modified Caregiver and Clinical Global Impression of Improvement (GI-I) scales for DS. Results: One hundred forty-four participants were randomized (71 placebo, 73 soticlestat) with a mean (SD) age of 10.3 (5.0) years; 72 (50%) were male, and 117 (81.3%) were receiving ≥3 antiseizure medications. Median change from baseline in convulsive seizure frequency over the full treatment period was −8.64% with placebo ( n = 71) and −22.16% with soticlestat ( n = 73), a difference of −15.64% ( p = .061); in the maintenance treatment period, these changes were −11.99% with placebo and −23.29% with soticlestat, a difference of −14.29% ( p = .089). The proportion of participants with ≥50% reduction in convulsive seizures was 9.9% with placebo and 27.4% with soticlestat (nominal p = .008). Soticlestat showed clinically meaningful results in the Caregiver and Clinical GI-I, and Clinical GI-I Seizure Intensity and Duration scales over the 16-week treatment period (all nominal p -values ≤ .004). The most commonly reported treatment-emergent adverse events related to study drug were somnolence, change in seizure presentation, decreased appetite, and insomnia. Significance: Although statistical significance was narrowly missed, soticlestat showed a numerical benefit over placebo for convulsive seizure decrease. Clinically meaningful benefits across multiple secondary endpoints were observed. No new safety concerns emerged.