Adjunctive soticlestat minimally beneficial in Lennox–Gastaut syndrome

Use of the cholesterol 24-hydroxylase inhibitor soticlestat as adjunctive therapy in patients with Lennox–Gastaut syndrome (LGS) falls short of reducing the frequency of major motor drop (MMD) seizures, according to the results of the phase III SKYWAY trial.

SKYWAY included 270 LGS patients aged 2–55 years (mean age 12.9 years, 60.4 percent male, 31.9 percent Asian) on stable background medication (95 percent receiving ≥2 antiseizure medications).

The patients were randomly assigned to receive either soticlestat (≤300 mg, weight-adjusted) or placebo (n=136) as an addition to background medication. Treatment was administered twice daily for 16 weeks (4-week titration phase plus 12-week maintenance phase).

The primary endpoint was percentage change from baseline in MMD seizure frequency per 28 days during the full 16-week treatment period and during the 12-week maintenance phase. MMD seizure was defined as an attack that either resulted in a fall or was likely to result in a fall if not prevented by body position, owing to involvement of major body areas such as the lower extremities. Secondary endpoints included treatment response (≥50-percent reduction in MMD seizures during the full treatment period and the maintenance period only) and effect on Clinical Global Impression of Improvement (CGI-I) domains, among others.

The median change in MMD seizure frequency did not differ between soticlestat and placebo during the full treatment period (difference, −1.17 percent; p=0.785) and the maintenance phase (difference, 2.43 percent; p=0.778).

Results for most secondary endpoints were also similar between the two treatment groups. There were numerical trends for small effects seen with soticlestat vs placebo in the proportions of patients showing improvement in the CGI-I Non-seizure Symptoms Disruptive Behaviors domain (odds ratio, 1.91; p=0.032) and CGI-I Seizure Intensity and Duration (odds ratio, 1.67; p=0.029).

In terms of safety, treatment-related adverse events (TEAEs) occurred in 74.6 percent of patients in the soticlestat group and in 68.4 percent of those in the placebo group. Most TEAEs were mild or moderate in severity, with the most common being somnolence. Three soticlestat-treated patients and one who received placebo experienced serious TEAEs.