Treating Epilepsy: Key Takeaways From AES 2020 - Episode 4
Evaluating long-term safety, efficacy, and tolerability of soticlestat (TAK-935/OV935) as adjunctive therapy, as seen in the phase 2 ELEKTRA study, for pediatric patients with Dravet and Lennox-Gastaut syndromes.
Trevor J. Resnick, MD: This abstract being discussed is on a new drug, TAK-935 or soticlestat, and it looks at the efficacy, safety, and tolerability of a new molecule as adjunctive therapy in pediatric patients with Dravet syndrome and Lennox-Gastaut syndrome. The first author was Cecil Hahn, [MD, MPH,] and the study name was ELEKTRA.
TAK-935 is a molecule that inhibits cholesterol hydroxylase. Cholesterol hydroxylase converts cholesterol to 24S-hydroxycholesterol. That’s important because 24S-hydroxycholesterol is an allosteric modulator of the NMDA [N-methyl-D-aspartate] receptor, and it over activates or simulates the glutaminergic pathway. The rationale for the study, specifically in patients with Dravet syndrome and Lennox-Gastaut syndrome, is to see whether a different mechanism of action with TAK-935 has demonstrated efficacy—it already demonstrated efficacy in preclinical seizure models, including those relevant to Dravet syndrome—so this trial was to see whether in clinical practice that rolled over. Whether the efficacy and safety in children with Dravet syndrome and Lennox-Gastaut syndrome was similar to that noted in the preclinical models.
ELEKTRA was a phase 2, multicenter, randomized placebo-controlled, double-blind parallel group study in children 2 to 17 years of age with Dravet syndrome, demonstrating at least 3 convulsive seizures per month, and with the Lennox-Gastaut group, demonstrating more than 4 drop seizures per month at baseline. This study is more similar to the pivotal study, and it comprised a 4-to-6-week screening period, followed by a 20-week treatment period. In that 20-week treatment period, there was an 8-week dose optimization, and then a 12-week maintenance period. The participants either received TAK-935 up to 600 mg per day, or placebo, and the study end points included the effect of TAK-935 on seizure frequency, compared with placebo during the maintenance period and throughout the full treatment period.
There were 141 patients enrolled in the study, the modified intent-to-treat population was 139 patients, and 126 patients completed the study. Fifty-one patients out of the group had Dravet syndrome, and 88 had Lennox-Gastaut syndrome. With the TAK- 935 group, the efficacy demonstrated a medium placebo-adjusted reduction in seizure frequency of 30.5% during the maintenance period. Over the full treatment period, children in the Dravet syndrome cohort treated with TAK-935 demonstrated a 33.8% median reduction, and those in the Lennox-Gastaut group, a 20.6% median reduction in drop seizures. The Dravet syndrome group had a statistically significant difference as compared to the placebo, whereas in the Lennox-Gastaut group there was directionality for the TAK-935, but it did not reach statistical significance.
The summary of the study and the conclusion is that the TAK-935 resulted in a statistically significant reduction in median seizure frequency compared to baseline in children with Dravet syndrome, and a directional reduction in seizure frequency in patients with Lennox-Gastaut syndrome. And importantly, it was well tolerated. There was no difference in adverse events as compared to placebo. It’s a different molecule with a different mechanism of action, it was statistically significantly effective in patients with Dravet syndrome, and it was well tolerated with no real difference in [adverse] effects as compared to the placebo group. The only 2 adverse events that specifically separated from placebo were lethargy and constipation. TAK-935 is an interesting new molecule that we will be hearing about in the near future.