Neurologist The Hospital For Sick Children, Canada
Rationale: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare childhood epilepsies that are often resistant to therapy by current antiseizure medication. Soticlestat (TAK-935/OV935) has demonstrated efficacy in preclinical seizure models, including those relevant to DS. ELEKTRA (ClinicalTrials.gov: NCT03650452) aimed to characterize the efficacy and safety of soticlestat in children with DS and LGS. Methods: ELEKTRA was a Phase 2, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in children aged two to 17 years with DS demonstrating ≥3 convulsive seizures per month, or LGS demonstrating ≥4 drop seizures per month at baseline. The study comprised a four to six week screening period followed by a 20-week treatment period, which included an eight-week dose optimization period and a 12‑week maintenance period. Participants either received soticlestat (up to 600 mg/day, weight-based for children < 60 Kg) or placebo twice daily. Study endpoints included the effect of soticlestat on seizure frequency compared with placebo during the maintenance period and throughout the full treatment period. Results: ELEKTRA enrolled 141 participants and 126 completed the study. The modified intent to treat population included 139 participants who received at least one dose of study drug and had at least one efficacy assessment over the full treatment period (DS, n=51; LGS, n=88). ELEKTRA achieved its primary endpoint, with the soticlestat group demonstrating a median placebo-adjusted reduction in seizure frequency of 30.5% during the maintenance period (p=0.0007, n=120). Over the full treatment period, children treated with soticlestat showed a 25.1% placebo-adjusted reduction in seizure frequency (p=0.0024, n=139). Over the full treatment period, children in the DS cohort treated with soticlestat demonstrated a 33.8% median reduction in convulsive seizure frequency compared with a 7.0% median increase in those who received placebo (median placebo-adjusted reduction in seizure frequency, 46.0%; p=0.0007). In the same period, children in the LGS cohort treated with soticlestat demonstrated a 20.6% median reduction in drop seizure frequency compared with a 6.0.% median reduction in those who received placebo (median placebo-adjusted reduction in seizure frequency, 14.8%; p=0.1279). Soticlestat appeared to be well tolerated and the incidence of treatment-emergent adverse events was similar between the soticlestat and placebo groups (80.3% vs. 74.3%). Serious adverse events were reported in 15.5% and 18.6% of participants in the soticlestat and placebo arms, respectively. No deaths were reported. The most frequent treatment emergent adverse events reported in soticlestat-treated patients with at least 5% difference from placebo were lethargy and constipation. Conclusions: In this Phase 2 study, soticlestat treatment resulted in a statistically significant reduction in median seizure frequency compared to baseline in children with DS, and in a directional reduction in seizure frequency in patients with LGS, and was generally well tolerated. Funding: Please list any funding that was received in support of this abstract.: Study funded by Takeda Pharmaceutical Company Limited and Ovid Therapeutics Inc.