A phase 1b/2a study of soticlestat as adjunctive therapy in participants with developmental and/or epileptic encephalopathies

• DOI: 10.1016/j.eplepsyres.2021.106646
• Publication Date: 2021-04-22T22:49:43Z
• Authors: Jonathan J. Halford; Michael R. Sperling; Dimitrios Arkilo; Mahnaz Asgharnejad; Celia Zinger; Rengyi Xu; Matthew During; Jacqueline A. French
• Keywords: Tolerability; Lethargy

To evaluate the safety, tolerability, and pharmacokinetics of soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, in adults with developmental and/or epileptic encephalopathies (DEE). The study comprised 30-day, randomized, double-blind, placebo-controlled phase (Part A), followed by 55-day open-label B) (ClinicalTrials.gov ID: NCT03166215) . In Part A, patients DEE at least one bilateral motor seizure during 4-week prospective baseline period were randomized 4:1 to receive soticlestat or placebo, addition their usual antiseizure medication. B, all received soticlestat. Soticlestat doses titrated according tolerability maximum 300 mg twice daily (BID). Safety evaluations included incidence treatment-emergent adverse events (TEAEs). Plasma concentrations measured various times for determination multiple-dose 24S-hydroxycholesterol (24HC). Efficacy was assessed evaluation changes frequency from baseline. Eighteen (median age, 28.5 years) enrolled 14 (78 %) completed study. TEAEs occurred 71.4 % soticlestat-treated 100 placebo-treated patients. overall 68.8 %. that more than patient group dysarthria (n = 3, 21.4 %), lethargy 2, 14.3 upper respiratory tract infection fatigue headache %). Four discontinued treatment because TEAEs, whom two reported drug-related clusters as serious TEAEs. There no deaths. Pharmacokinetic analysis showed dose-dependent increases systemic exposure peak plasma concentrations. At end mean percent change 24HC −80.97 Changes median +16.71 +22.16 placebo groups, respectively, −36.38 participants B. well tolerated up BID associated reduction over duration. Further studies are warranted assess possible efficacy adjunctive therapy DEEs such Dravet syndrome Lennox–Gastaut syndrome.