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

Jonathan J Halford,Michael R Sperling,Dimitrios Arkilo,Mahnaz Asgharnejad,Celia Zinger,Rengyi Xu,Matthew During,Jacqueline A French

doi:10.1016/j.eplepsyres.2021.106646

Abstract

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

Highlights

The primary endpoint was the percentage of participants with at least one treatment-emergent adverse event (TEAE), as reported by the participant or participants’ caregivers or observed by the investigator
Given that there is no known reason for a pharmacokinetic interaction between soticlestat and perampanel, the increased seizure frequency observed in the patients taking concomitant perampanel might be due to a phar macodynamic interaction, or because of the variability in seizures associated with the developmental and/or epileptic encephalopathies (DEE) itself
Soticlestat was generally well tolerated in this study at dosages up to 300 mg twice daily (BID) for up to 90 days, as measured by the inci dence of primarily mild treatmentemergent adverse event (TEAE) in adults with DEE

Summary

Introduction

Making an early diagnosis is often critical as many patients with DEE experience daily seizures, which cause significant morbidity and quick deterioration of quality of life These rare neurodevelopmental conditions often cause seizures that are difficult to control and are highly resistant to multiple conventional antiseizure medications (ASMs) (Scheffer et al, 2017; Steward et al, 2019), representing a significant unmet medical need. The investigational drug soticlestat (TAK-935/OV935) is a first-inclass, selective inhibitor of cholesterol 24-hydroxylase (CH24H) being evaluated for adjunctive treatment of seizures in association with DEE This novel mechanism of action is thought to have the potential to reduce seizure frequency and severity, with therapeutic benefit in epi lepsy and disorders associated with overactivated glutamatergic regu lation (Nishi et al, 2020), presumably through the inhibition of CH24H and associated reduction of the cholesterol metabolite 24S-hydrox ycholesterol (24HC)

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