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

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

Evaluation of the Abuse Potential of the Cholesterol-24-Hydroxylase Inhibitor, Soticlestat, in Drug-Discrimination and Self-Administration Tests (CPDD 2024) - "These non-clinical models have well established translational validity. The results demonstrate that soticlestat does not induce ketamine-like effects in humans and does not produce reinforcing effects."

CNS Disorders • Epilepsy

Human Abuse Potential Study of the Novel Antiepileptic Drug Soticlestat in Recreational Drug Users (CPDD 2024) - ": Randomized, double-blind, placebo- and active-controlled, single-dose crossover study with 300 mg (therapeutic dose), 600 mg, and 900 mg soticlestat, 2 mg alprazolam, and placebo in nondependent, male and female recreational CNS depressant users. The results of this study demonstrated that soticlestat has no abuse potential in recreational CNS depressant users. This is the first human study examining abuse potential of this novel drug class."

CNS Disorders • Epilepsy

Assessment of Withdrawal-Induced Physical Dependence in Rats After Administration of the Potent Cholesterol-24-Hydroxylase Inhibitor, Soticlestat (CPDD 2024) - "This non-clinical model has well established translational validity. The results demonstrate that soticlestat does not pose a risk for withdrawal-induced dependence in humans at plasma concentrations up to 20-fold that of the maximum recommended clinical dose."

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Epilepsy

Testing of putative antiseizure medications in a preclinical Dravet syndrome zebrafish model. (PubMed, Brain Commun) - "Thus far, we have screened more than 3000 drug candidates in scn1lab zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g. Food and Drug Administration-approved drugs, with clinical application in the Dravet syndrome population...Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat...Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications."

Journal • Preclinical • CNS Disorders • Epilepsy

A Study of Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome (clinicaltrials.gov) - P3 | N=144 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Epilepsy • Pediatrics

Physiologically-based Pharmacokinetic Modeling to Predict Drug–drug Interactions of Soticlestat (AAN 2024) - "For soticlestat administered with and without itraconazole (strong CYP3A4 inhibitor), the model-simulated versus observed AUC0-inf and Cmax GMRs were 1.05 and 1.10-fold, respectively. For soticlestat with and without coadministration of rifampin (strong CYP3A4 inducer), the model under-predicted the DDI, with simulated AUC0-inf and Cmax GMRs of >2.9-fold of observed values. Our verified PBPK model reasonably predicted DDIs and will support the clinical development of soticlestat and regulatory submissions."

PK/PD data • CNS Disorders • Epilepsy • Metabolic Disorders • CYP2C19 • CYP2C9 • STAT3 • UGT1A9

Proposed Mechanism of Action of Soticlestat as an Antiseizure Medication (AAN 2024) - "Soticlestat is a first-in-class ASM that inhibits CH24H, reduces postsynaptic levels of 24HC which correlates with reductions in TNF-α levels, and is associated with increased functional EAAT2 in peri-synaptic astrocytes. These effects act to decrease extra synaptic glutamate, decrease neuronal hyperexcitability, and reduce seizure susceptibility. Further understanding of soticlestat's MOA will provide a foundation for developing new ASMs and help elucidate the underlying pathophysiology of epilepsy."

CNS Disorders • Epilepsy • Oncology • TNFA

Soticlestat in Vitro Metabolism and Drug-drug Interactions: Comprehensive Investigations Display Minimal Notable Interactions (AAN 2024) - "Soticlestat has well-characterized metabolism and limited victim and perpetrator DDI potential leading to minimal concern of clinical DDI risk."

Preclinical • CNS Disorders • Colon Cancer • Colorectal Adenocarcinoma • Epilepsy • Gastrointestinal Cancer • Oncology • CYP1A2 • CYP2C19 • CYP2C9 • CYP3A4 • UGT1A9 • UGT2B17