AES Poster Highlights Potential Efficacy of Soticlestat in Dravet Syndrome Despite Statistical Hurdle

Newly presented data from the phase 3 SKYLINE study (NCT04940624) of investigational soticlestat (Takeda Pharmaceuticals), also known as TAK-935, showed that the antiseizure medication (ASM) had a benefit over the placebo on the primary end point, although statistically significant was narrowly missed, among children and young adults diagnosed with Dravet syndrome (DS). These data provide valuable information on the efficacy of soticlestat as a potential adjunctive therapy for seizures associated with DS in this patient population.¹

Recently presented at the 2024 American Epilepsy Society Annual Meeting, held December 6-10, in Los Angeles, California, results revealed that median change from baseline in convulsive seizure frequency was -22.16% with soticlestat (n = 73) and -8.64% with placebo (n = 71) over the full treatment period (P = 0.061). In the SCN1A positive subgroup, the median change from baseline in convulsive seizure frequency over the full treatment period was –23.34% with soticlestat and –12.70% with placebo (nominal P = 0.045).

Conducted by senior author Joseph Sullivan, MD, FAES, professor of neurology and pediatrics, and director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco, and colleagues, the proportion of treatment responders (at least 50% reduction in convulsive seizures from baseline) was 27.4% with soticlestat and 9.9% with placebo (nominal P = 0.008). Notbaly, soticlestat showed clinically meaningful and nominally significant results in the secondary end point measures over the 16-week treatment period (P-values less than 0.004).

In the phase 3, global, multicenter, randomized, double-blind, placebo-controlled, parallel group SKYLINE trial, the primary end point was percent change from baseline in convulsive seizure frequency per 28 days in patients who received soticlestat compared with placebo during the full treatment period. Researchers included assessment of effects on treatment response, Caregiver Global Impression of Improvement (GI-I), Clinical GI-I, and Clinical GI-seizure intensity and duration as key secondary end points in the study.

All told, the diagnosis of DS for participants in the trial was adjudicated independently by the Epilepsy Study Consortium. Authors noted that the treatment period was 16 weeks which included a 4-week titration period and 12-week maintenance period. Investigators randomized participants aged between 2 years and 21 years 1:1 to receive either soticlestat or matching placebo twice daily. In addition, participants had the option to enroll in the ongoing open-label extension ENDYMION 2 study (NCT05163314) upon completion of the study.

Among 144 participants enrolled in SKYLINE, 123 (85.4%) of participants completed the study (mean age; 10.3 [SD, 5.0] years; men, n = 72). Authors noted that 117 (81.3%) participants were on 3 or more ASMs, 7 (4.9%) were on a ketogenic diet, and 15 (10.4%) utilized Vagus Nerve Stimulation therapy. Additionally, researchers observed that the median number of prior of current antiseizure medications was 8, underscoring this as a highly refractory study population. Moreover, investigators reported that the median convulsive seizure frequency per 28 days at baseline was 11.13 and all-seizure frequency was 17.9.

DS is a rare developmental and epileptic encephalopathy characterized by treatment-resistant seizures of various types and developmental delays, with over 80% of patients harboring a SCN1A gene mutation. Despite the recent approval of ASMs specifically indicated for DS, many patients continue to experience uncontrolled seizures. Additionally, polytherapy with multiple ASMs can result in drug-drug interactions and an increased risk of adverse events. Consequently, there remains a significant unmet need for effective therapies with an improved safety and tolerability profile.

Soticlestat is a first-in-class potent and selective inhibitor of cholesterol 24-hydroxylase, an enzyme primarily expressed in the brain that catabolizes cholesterol to 24S-hydroxycholesterol resulting in a reduction in glutamatergic hyperexcitability. These recently presented results on soticlestat suggest that the study population in SKYLINE was pharmacoresistant, according to the researchers. Furthermore, authors noted that the findings showed soticlestat was well tolerated, displaying a safety profile consistent with the results from previous studies.