AES Poster Highlights Potential Efficacy of Soticlestat in Dravet Syndrome Despite Statistical Hurdle
New data from the phase 3 SKYLINE study suggests soticlestat as a promising adjunctive therapy for seizures among children and young adults living with Dravet syndrome.
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
Conducted by senior author
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.
REFERENCES
1. Murthy V, Khan Y, Castrillo C, et al. Soticlestat as Adjunctive Therapy in Children and Young Adults with Dravet Syndrome: The Phase 3 SKYLINE Clinical Trial. Presented at: AES 2024; December 6-10; Los Angeles, CA.
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