Primary objectives of this Phase 1b/2a trial were safety and tolerability of soticlestat (TAK-935/OV935) in adult patients with DEE. Exploratory objectives were 24S-hydroxycholesterol (24HC) plasma levels and change in seizure frequency.

Soticlestat is an inhibitor of cholesterol 24-hydroxylase that converts neuronal cholesterol to 24HC, which is a positive allosteric modulator of NMDA receptors. Soticlestat may also reduce inflammation through glial modulation and neuroprotection.

Patients were randomized in the double-blind controlled phase to placebo or soticlestat (30 days; target dose oral 300 mg BID) and then could enter an open-label phase in which all patients received soticlestat up to 60 days. The seizure frequency data presented are from the 60-day open-label phase.

Eighteen patients were randomized (mean age 29 years [range 19-45], male n=14) with heterogeneous types of DEE. Fourteen of 18 patients (78%) completed the study; four withdrawals occurred (two in each phase). During the open-label period, 11 patients (69%) experienced a treatment-emergent adverse event (TEAE).  The majority of TEAEs were mild. Five serious TEAEs, all seizure cluster related, were reported among three subjects receiving soticlestat. ITT analysis in the open-label phase of all 16 patients receiving at least one dose of soticlestat showed a 36% median reduction in seizure frequency from baseline to day 85 (end of maintenance). Three patients on perampanel had increases in seizure frequency, potentially related to a pharmacodynamic interaction. A post hoc analysis of the median seizure reduction, excluding patients on perampanel, in the last 28 days on open-label TAK-935 was 46.6% (n=13). Two patients (12.5%) became seizure free in the last four weeks. Mean 24HC levels decreased 81% from baseline to Day 85 (n=9), representing a potential biomarker for drug effect. 

Soticlestat was well tolerated, with initial evidence of possible efficacy and with measurement of a promising peripheral biomarker.