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

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

A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat. (PubMed, Epilepsia) - "The data support three potential mechanisms of action: (1) normalization of the seizure threshold via reduction of 24HC levels in the brain; as 24HC acts as a potent and selective positive allosteric modulator of glutamate N-methyl-D-aspartate receptors, reduction of 24HC levels by soticlestat may lead to decreased hyperexcitability and elevated seizure thresholds; (2) restoration of glutamate sequestration from the synaptic cleft; accumulation of glutamate in the synaptic cleft enhances neural excitation and can contribute to neurotoxicity; soticlestat may inhibit conversion of cholesterol to 24HC in the membrane lipid raft microdomain and help to preserve it, consequently reducing excessive glutamate excitation; and (3) suppression of neuroinflammation via reduction of inflammatory cytokine release. These potential mechanisms of action warrant further investigation."

Journal • Review • CNS Disorders • Epilepsy • Inflammation • CYP46A1

Broad perspective on the relationship between soticlestat and QT interval in patients with epilepsy. (PubMed, Eur J Hosp Pharm) - No abstract available

Journal • CNS Disorders • Epilepsy

Soticlestat as Adjunctive Therapy in Children and Young Adults with Dravet Syndrome: The Phase 3 SKYLINE Clinical Trial (AES 2024) - P3 | "These forthcoming data will be the first from the phase 3 SKYLINE study and will provide valuable information on the efficacy and safety of soticlestat as a potential treatment for seizures associated with DS."

Clinical • P3 data • CNS Disorders • Developmental Disorders • Epilepsy • Pediatrics

Soticlestat vs Placebo as Adjunctive Therapy for Lennox-gastaut Syndrome: Results from the Phase 3, Randomized SKYWAY Clinical Trial (AES 2024) - P3 | "In the SKYWAY study of individuals with LGS, soticlestat did not demonstrate efficacy vs placebo on the primary or multiple secondary endpoints. Soticlestat was well tolerated with a safety profile that was consistent with previous studies."

Clinical • P3 data • CNS Disorders • Epilepsy

Population Pharmacokinetics, Enzyme Occupancy, and Pharmacodynamic Modeling of Soticlestat in Patients with Dravet Syndrome and Lennox-gastaut Syndrome (AES 2024) - "Strong CYP3A inducers (ASMs) had minimal impact on soticlestat PK exposures so suggesting dose adjustments may not be required. All soticlestat doses tested achieved efficacious levels of occupancy and 24HC reductions. These robust models offer a solid foundation for guiding clinical decision-making and optimizing dosing strategies."

Clinical • PK/PD data • CNS Disorders • Epilepsy • Pediatrics

ENDYMION 2: Phase 3, Open-label Extension Study Assessing Long-term Safety, Tolerability and Secondary Outcomes of Adjunctive Soticlestat in Individuals with Dravet Syndrome or Lennox-gastaut Syndrome (AES 2024) - P3 | "In the ENDYMION 2 study, soticlestat was well tolerated with a safety profile consistent with previous studies in DS and LGS. A sustained reduction in convulsive seizure frequency and improvements in Caregiver and Clinical GI-I measures were reported for participants with DS who remained in the study, though we acknowledge the absence of a control group, and potential for adjustments to background antiseizure therapies and selection bias. LGS data must be considered with caution as the double-blind, placebo-controlled SKYWAY study did not demonstrate efficacy in this population."

Clinical • P3 data • CNS Disorders • Epilepsy

Caregiver Preferences for Dravet Syndrome and Lennox-gastaut Syndrome Treatments Across the USA, UK, and Germany (AES 2024) - "Primary caregivers of patients with DS (2–21 years old) or LGS (2–55 years old) completed an online stated-preference survey to elicit benefit-risk tradeoffs among 3 unlabeled hypothetical treatments A (soticlestat-like), B (cannabidiol-like), and C (fenfluramine-like) defined by attributes with varying levels (Table 1). Findings from the stated-preference exercise and focus groups suggested DS or LGS caregivers may prefer a treatment with fewer medication interactions and no additional monitoring requirements. Caregivers made tradeoff decisions that consistently tried to maximize benefits while minimizing risks. The study highlights the need for new treatment options that address the complexities of care for individuals with DS or LGS while improving quality of life and treatment burden."

CNS Disorders • Epilepsy

A Study of Soticlestat in Healthy Adult Nondependent Recreational Drug Users With Central Nervous System (CNS) Depressant Experience (clinicaltrials.gov) - P1 | N=100 | Completed | Sponsor: Takeda | N=67 ➔ 100

Enrollment change

Concentration-QTc analysis of soticlestat in healthy adults: An alternative to a thorough QT study. (PubMed, Br J Clin Pharmacol) - P1 | "There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety/PK findings aligned with previous soticlestat clinical studies."

Journal • Hepatology • STAT3

TAK-935-3004: A Study Evaluating Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine (clinicaltrials.gov) - P3 | N=1 | Terminated | Sponsor: Takeda | N=45 ➔ 1 | Trial completion date: Jan 2027 ➔ Aug 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2027 ➔ Aug 2024; Business decision unrelated to patient safety.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • CNS Disorders • Epilepsy

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development. (PubMed, Epilepsia) - "These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve..."

Journal • Metastases • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry • NAV1

Innovative drug discovery strategies in epilepsy: integrating next-generation syndrome-specific mouse models to address pharmacoresistance and epileptogenesis. (PubMed, Expert Opin Drug Discov) - "Syndrome-specific models, including Scn1a variant models of Dravet syndrome and APP/PS1 mice associated with familial early-onset Alzheimer's disease, have already led to the discovery of two mechanistically novel treatments for developmental and epileptic encephalopathies (DEEs), namely cannabidiol and soticlestat, respectively...The percentage of patients with pharmacoresistant epilepsy has remained unchanged despite over 30 marketed ASMs. Consequently, there is a high unmet need to reinvent and revise discovery strategies to more effectively address the remaining needs of patients with specific epilepsy syndromes, including drug-resistant epilepsy and DEEs."

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

Phase 1 pharmacokinetic and safety study of soticlestat in participants with mild or moderate hepatic impairment or normal hepatic function. (PubMed, Pharmacol Res Perspect) - P1 | "TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment."

Journal • P1 data • PK/PD data • Hepatology

Characterization of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in acute and chronic neurodegeneration models. (PubMed, Neurosci Res) - "Herein, we discuss the interplay among 24S-hydroxycholesterol production, neuroinflammation, and excitotoxicity. Effects on neurodegeneration and neuroinflammation demonstrated in two preclinical models suggest that soticlestat is effective in ameliorating seizures and addressing cognitive dysfunction in seizure disorders."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy • Inflammation • Oncology • TNFA

A Study Evaluating Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine (clinicaltrials.gov) - P3 | N=45 | Recruiting | Sponsor: Takeda

New P3 trial • CNS Disorders • Epilepsy