A phase 3, randomized clinical trial of soticlestat as adjunctive therapy for Lennox–Gastaut syndrome

Abstract Objective There remains a need for new treatments for Lennox–Gastaut syndrome (LGS), a developmental and epileptic encephalopathy with a heterogenous patient population that often requires polytherapy. The phase 3, randomized SKYWAY study (NCT04938427) investigated the efficacy and safety of the cholesterol 24‐hydroxylase inhibitor soticlestat (TAK‐935) in participants with LGS. Methods This global, double‐blind, placebo‐controlled trial enrolled participants aged 2–55 years with LGS (adjudicated by the Epilepsy Study Consortium). Participants were randomized 1:1 to stable background medication plus either soticlestat (≤300 mg twice daily, weight‐adjusted) or placebo over 16 weeks (4‐week titration plus 12‐week maintenance). The primary endpoint was percentage change from baseline in major motor drop (MMD) seizure frequency per 28 days. Results SKYWAY enrolled 270 participants (placebo, n = 136; soticlestat, n = 134); mean age was 12.9 years; 95% were receiving ≥2 antiseizure medications. The difference in median change from baseline in MMD seizure frequency for soticlestat versus placebo was −1.17% ( p = .785) during the full treatment period and 2.43% ( p = .778) during maintenance. No meaningful difference was observed between soticlestat and placebo for most key secondary endpoints; numerical trends for small effects favoring soticlestat were seen in the proportions of participants showing improvement in the Clinical Global Impression of Improvement (CGI‐I) Non‐seizure Symptoms Disruptive Behaviors domain (odds ratio = 1.91, nominal p = .032) and CGI‐I Seizure Intensity and Duration (odds ratio = 1.67, nominal p = .029). Treatment‐related adverse events (TEAEs; mostly mild or moderate) were reported in 68.4% of placebo‐treated and 74.6% of soticlestat‐treated participants; the most frequent treatment‐related TEAE with soticlestat was somnolence. Serious treatment‐related TEAEs occurred in one placebo‐treated and three soticlestat‐treated participants. Significance Soticlestat did not demonstrate efficacy versus placebo in reducing MMD seizure frequency; the safety findings were consistent with those of previous studies. These data suggest that targeting cholesterol 24‐hydroxylase is not a suitable pharmacotherapeutic strategy for LGS.