soticlestat (TAK-935) / Takeda, Ovid Therapeutics, Ligand - LARVOL DELTA

Study of TAK-935 as an Adjunctive Therapy in Participants With Developmental and/or Epileptic Encephalopathies (clinicaltrials.gov) - P1/2 | N=18 | Completed | Sponsor: Takeda | Phase classification: P1b/2a ➔ P1/2

Phase classification • CNS Disorders • Epilepsy

Study of TAK-935 as an Adjunctive Therapy in Adult Participants With Complex Regional Pain Syndrome (CRPS) (clinicaltrials.gov) - P2 | N=24 | Completed | Sponsor: Millennium Pharmaceuticals, Inc. | Phase classification: P2a ➔ P2

Phase classification • Musculoskeletal Pain • Pain

Antiseizure Medications in Development: Novel Mechanisms, Precision Therapy, and the Move Towards Disease Modification. (PubMed, Curr Issues Mol Biol) - "Functional-state-selective sodium channel modulation has emerged as a leading conceptual advance supported by converging mechanistic and early clinical evidence, exemplified by relutrigine (PRAX-562), a preferential persistent-current inhibitor for which a regulatory decision is pending in SCN2A/SCN8A-DEEs, and vormatrigine (PRAX-628), whose large open-label effect was not reproduced in a controlled (blinded) trial...Parallel advances include the selective Kv7 opener azetukalner; the dual-mechanism benchmark cenobamate; cholesterol-24-hydroxylase inhibition (soticlestat); selective serotonergic agonism (bexicaserin); glutamatergic precision agents (radiprodil); subtype-selective GABAA modulators (darigabat, ganaxolone); and gene-directed therapies (zorevunersen, elsunersen)... The pipeline reflects an ongoing shift from broad symptomatic agents toward mechanism-led, genotype-matched, and potentially disease-modifying treatments. This shift is tempered by a persistent..."

Journal • Review • CNS Disorders • Epilepsy • SCN8A

Exploring the caregiver journey through randomized controlled trials in dravet syndrome: insights from a cross-sectional survey. (PubMed, Epilepsy Behav) - "To our knowledge, this is the first survey exploring the caregivers' perceptions of participation in epilepsy clinical trials. Patient and stakeholder engagement is essential for optimizing trial recruitment, acceptance and understanding of the failures."

Journal • CNS Disorders • Epilepsy • Pediatrics

SKYLINE: A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome (clinicaltrials.gov) - P3 | N=0 | Completed | Sponsor: Takeda | N=21 ➔ 0

Enrollment change • CNS Disorders • Epilepsy • Pediatrics

Head-to-head comparison of [18F]CHL2205 versus [18F]T008 as PET radioligands to study brain cholesterol homeostasis in rodent models and nonhuman primates. (PubMed, Eur J Nucl Med Mol Imaging) - "Across species and models, both radioligands demonstrated appropriate characteristics for imaging C24H in vivo. However, [¹⁸F]CHL-2205 generally displayed higher specific binding and appeared more sensitive to detect moderate increases in C24H expression."

Head-to-Head • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Metabolic Disorders

Soticlestat for drug-resistant epilepsy: Current evidence and clinical perspectives. (PubMed, Seizure) - "These findings underscore the need for further research to elucidate the long-term benefits and potential synergy of soticlestat in combination with other antiseizure medications across diverse epilepsy syndromes. While challenges remain, soticlestat offers a promising therapeutic avenue for improving outcomes in DRE and warrants continued investigation as a potential adjunctive treatment."

Journal • Review • CNS Disorders • Epilepsy • Inflammation

A phase 3, randomized clinical trial of soticlestat as adjunctive therapy for Lennox-Gastaut syndrome. (PubMed, Epilepsia) - P3 | "Soticlestat did not demonstrate efficacy versus placebo in reducing MMD seizure frequency; the safety findings were consistent with those of previous studies. These data suggest that targeting cholesterol 24-hydroxylase is not a suitable pharmacotherapeutic strategy for LGS."

Clinical • Journal • P3 data • Behavior Disorders • CNS Disorders • Epilepsy

Soticlestat as an adjunctive therapy in children and young adults with Dravet syndrome. (PubMed, Epilepsia) - P3 | "Although statistical significance was narrowly missed, soticlestat showed a numerical benefit over placebo for convulsive seizure decrease. Clinically meaningful benefits across multiple secondary endpoints were observed. No new safety concerns emerged."

Clinical • Journal • CNS Disorders • Epilepsy • Insomnia • Sleep Disorder • STAT3

Endymion: A Study of Soticlestat in Adults and Children With Rare Epilepsies (clinicaltrials.gov) - P2 | N=165 | Recruiting | Sponsor: Takeda | Trial completion date: Dec 2020 ➔ Apr 2023 | Trial primary completion date: Jul 2020 ➔ Mar 2023

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Genetic Disorders

Endymion: A Study of Soticlestat in Adults and Children With Rare Epilepsies (clinicaltrials.gov) - P2 | N=165 | Recruiting | Sponsor: Takeda

New P2 trial • Epilepsy • Genetic Disorders

Endymion: A Study of Soticlestat in Adults and Children With Rare Epilepsies (clinicaltrials.gov) - P2 | N=156 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Nov 2024 ➔ May 2026 | Trial primary completion date: Nov 2024 ➔ May 2026

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Genetic Disorders

Endymion: A Study of Soticlestat in Adults and Children With Rare Epilepsies (clinicaltrials.gov) - P2 | N=156 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting | Trial completion date: Apr 2023 ➔ Nov 2024 | Trial primary completion date: Mar 2023 ➔ Nov 2024

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Genetic Disorders

Preclinical characterization of pharmacokinetics, enzyme occupancy, and pharmacodynamics of soticlestat (TAK-935), a novel cholesterol 24-hydroxylase inhibitor. (PubMed, J Pharmacol Exp Ther) - "The preclinical pharmacokinetic/enzyme occupancy/pharmacodynamic data for soticlestat provide comprehensive mechanistic and quantitative insights into clinical population models. Importantly, these data emphasize the potential of enzyme occupancy and pharmacodynamics as strategic tools for facilitating translational research in central nervous system drug development."

Journal • PK/PD data • Preclinical • CNS Disorders • Epilepsy

Structure-Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors. (PubMed, Molecules) - "Eventually, three compounds with a benzenesulfonamide moiety (in subseries C-4) that serves as an isostere of OH in soticlestat were discovered with very potent CYP46A1 inhibitory activities comparable to soticlestat, and an interesting flat SAR profile was observed in some subseries. The findings in the present study provide insight into the SAR of CYP46A1 inhibitors and should be valuable for the future design of novel CYP46A1 inhibitors."

Journal • CNS Disorders • Epilepsy • CYP46A1

Expanding the toolkit: An update on the evolution of new therapies for Lennox-Gastaut Syndrome. (PubMed, Semin Pediatr Neurol) - "The purpose of this paper is to address three such aspects of treatment evolution for LGS: (1) To review data supporting the repurposing of existing drugs for use in LGS, specifically, perampanel and cenobamate. (2) To present recent (soticlestat), ongoing (carisbamate, bexicaserin, clemizole) and upcoming (opakalim) clinical drug trials for LGS...With the richness of recent trial development for LGS combined with the nascence of clinical trials for specific genetic epilepsies comes a new era in which treatment options for LGS will continue to expand. Increasing understanding of the underlying genetic and molecular underpinnings of LGS should enable development of unique therapies, with the continued aims of sustained, durable seizure control and additional positive impact on central nervous system outcomes and beyond."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy

Evaluation of Pharmacological Treatments for Infantile Spasms: A Review of ClinicalTrials.gov (AES 2025) - "Key elements extracted included therapeutic agents, study design, primary endpoints, and reported efficacy and safety outcomes. The included trials assessed a range of pharmacologic agents, spanning both established therapies (ACTH, vigabatrin, prednisolone) and investigational compounds (cannabidiol, ganaxolone, TAK-935, tricaprilin, pyridoxine, lithium carbonate). This review highlights the diversity of pharmacologic interventions under investigation for IS and reinforces the role of both established and emerging therapies. While completed trials provide valuable insight into evolving treatment strategies, important gaps remain—particularly the lack of patient-level outcomes and long-term neurodevelopmental data. Future research should focus on stratified study designs, biomarker-informed approaches, and extended follow-up to optimize treatment selection and improve clinical outcomes in this high-risk pediatric population."

Clinical • Review • CNS Disorders • Epilepsy • Gastrointestinal Disorder

ENDYMION 2: A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome (clinicaltrials.gov) - P3 | N=352 | Terminated | Sponsor: Takeda | Trial completion date: May 2026 ➔ Sep 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2026 ➔ Sep 2025; Due to negative results from phase 3 SKYLINE and SKYWAY studies and unrelated to patient safety it has been determined that supplementary data from TAK-935-3003 study is no longer necessary. Therefore, Takeda has made a decision to close this study

Trial completion date • Trial primary completion date • Trial termination • CNS Disorders • Epilepsy • IGF1

Quantitative analysis of [18F]CHL2310, a novel PET ligand for cholesterol 24-Hydroxylase, in nonhuman primate brain. (PubMed, Eur J Nucl Med Mol Imaging) - "[18F]CHL2310 shows high in vivo specificity, favorable pharmacokinetic properties, and robust quantitative performance in non-human primates. These characteristics support its potential as a PET radiotracer for imaging CYP46A1 in human studies."

Journal • Alzheimer's Disease • CNS Disorders • Depression • Epilepsy • Huntington's Disease • Movement Disorders • Psychiatry • CYP46A1

Endymion: A Study of Soticlestat in Adults and Children With Rare Epilepsies (clinicaltrials.gov) - P2 | N=156 | Terminated | Sponsor: Takeda | Trial completion date: May 2026 ➔ Jul 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2026 ➔ Jul 2025; Due to negative results from phase 3 SKYLINE and SKYWAY studies and unrelated to patient safety it has been determined that supplementary data from TAK-935-18-001 study is no longer necessary. Therefore, Takeda has made a decision to close this study

Trial completion date • Trial primary completion date • Trial termination • CNS Disorders • Epilepsy • Genetic Disorders

Comprehensive in vitro assessment of drug-drug interactions of the major human metabolite of soticlestat. (PubMed, Xenobiotica) - "Moreover, soticlestat and TAK-935-G did not inhibit glucuronidation of the examined ASMs.Collectively, no notable concern exists regarding the clinical perpetrator risk of CYP, UGT and transporters with TAK-935-G, despite its high unbound plasma concentrations. The combined analysis of in vitro and clinical DDI results, alongside physiologically based pharmacokinetic modelling, exhibited a low DDI risk for soticlestat and TAK-935-G."

Journal • Preclinical • CNS Disorders • Epilepsy • CYP1A2

Development of a novel 18F-labeled radioligand for imaging cholesterol 24-hydroxylase (CYP46A1) (SNMMI 2025) - "The CYP46A1 inhibitor, Soticlestat, remarkably diminished the radioactivity in CYP46A1-rich regions and abolished the regional heterogeneity (Fig... The CYP46A1 inhibitor 5 was obtained in 6% yield over four steps (Fig. 1A). Compound 5 exhibited an excellent inhibition activity toward CYP46A1 (0.11 nM, Fig."

Alzheimer's Disease • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • CYP46A1

Efficacy, safety, and tolerability of soticlestat (TAK-935) as adjunctive therapy in pediatric patients with dravet syndrome and Lennox-Gastaut syndrome: a meta-analysis of 3 randomized controlled trials. (PubMed, Front Pharmacol) - "Nonetheless, for patients with LGS, the difference between soticlestat and placebo was not statistically significant. The incidence of SAE in patients receiving soticlestat was similar to those receiving placebo; however, substantially more patients allocated to soticlestat discontinued prematurely because of side effects."

Journal • Retrospective data • Review • CNS Disorders • Constipation • Epilepsy • Gastroenterology • Gastrointestinal Disorder • Pediatrics

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions of Soticlestat as a Victim of CYP Induction and Inhibition, and as a Perpetrator of CYP and P-Glycoprotein Inhibition. (PubMed, Clin Pharmacol Drug Dev) - "Model-simulated versus observed AUC0-inf and Cmax geometric mean ratios (GMRs) for soticlestat with/without itraconazole (potent cytochrome P450 [CYP] 3A inhibitor), and mefenamic acid (potent UDP glucuronosyltransferase [UGT] 1A9 inhibitor) were ≤1.10-fold. As soticlestat is primarily metabolized by UGT enzymes and Simulator v20 incorporates rifampin's induction of CYP3A only, the model underpredicted soticlestat's DDI with rifampin...Hence, the model was appropriate for evaluating DDIs with CYP3A inhibitors and inducers not evaluated in clinical DDI studies; all predicted DDIs were low/not clinically relevant (<50% impact on exposure). Furthermore, no clinically significant DDIs were predicted following coadministration of soticlestat with sensitive CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-glycoprotein substrates."

Journal • PK/PD data • CYP2C19 • CYP2C9 • CYP3A4

ENDYMION 2: A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome (clinicaltrials.gov) - P3 | N=400 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy • IGF1