Soticlestat (TAK-935): A Paradigm Shift in Epilepsy Treatment Strategies

• Takeda and Ovid Therapeutics with soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, holds promise for transformative therapy marking a milestone in advancing treatment options for individuals with refractory epilepsies associated with Dravet syndrome and Lennox-Gastaut syndrome. 
• Soticlestat by modulating cholesterol homeostasis and glutamatergic pathways, presents a pioneering approach to reducing seizure susceptibility and improving seizure control.  

Current treatments for epilepsy predominantly address symptomatic seizure control, frequently falling short in targeting fundamental disease mechanisms, thus leaving approximately one-third of patients without adequate seizure management. Bridging this clinical gap for disease-modifying therapies requires dedicated research concentrating on targets that achieve a nuanced equilibrium between efficacy and safety. 

At the 76th annual meeting of the American Academy of Neurology (AAN) 2024, held in Denver from April 13 to 18, the company presented posters detailing soticlestat’s mechanism of action as an anti-seizure medication, and its in-vitro metabolism and drug-drug interactions, shown in DS and LGS patients up to 2 years. It also presented details about the physiologically based pharmacokinetic (PBPK) model, developed to predict drug-drug interactions. 

Soticlestat (TAK-935) by Takeda and Ovid Therapeutics, targets brain-specific cholesterol 24-hydroxylase (CH24H) enzyme, crucial in regulating neuronal functions linked to seizure hyperexcitability. The enzyme primarily found in the brain, facilitates the conversion of cholesterol into 24S-hydroxycholesterol (24HC), thus regulating brain cholesterol homeostasis. This 24HC serves as a positive regulator of the NMDA receptor, impacting glutamatergic signaling. Activation of CH24H decreases excitatory amino acid transporter 2 function, which in turn reduces glutamate reuptake from the peri-synaptic space and potentially contributes to exaggerated neuronal hyperexcitability. 

Reduced postsynaptic levels of 24HC correlate with reductions in tumor necrosis factor-alpha (TNF-α) levels, and an increase in functional excitatory amino acid transporter 2 (EAAT2) in peri-synaptic astrocytes. These decrease extrasynaptic glutamate, decrease neuronal hyperexcitability, and reduce seizure susceptibility

According to the data from the PBPK model, offering predictions on potential DDIs involving soticlestat, the simulated area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) and maximal drug concentration (C_max) based on the final PBPK model for all doses evaluated were within 2-fold of observed values from single- and multiple-rising-dose studies. For soticlestat 300 mg, the model-simulated AUC0-inf and C_max geometric mean ratios (GMRs) were 0.88 and 0.78‑fold of the observed values, respectively, which were not clinically significant. For soticlestat administered with and without itraconazole (strong CYP3A4 inhibitor), the model-simulated versus observed AUC0-inf and C_max 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 C_max GMRs of >2.9-fold of observed values, representing a  weak-to-moderate interactions. This PBPK model accurately predicted DDIs and will help with the clinical development and regulatory submissions of soticlestat.  

Takeda also provided information on the metabolism of soticlestat. The in-vitro investigations conducted in human hepatocytes (HHep), in human hepatocytes (HHep), liver microsomes (HLM), embryonic kidney (HEK), and colon adenocarcinoma clone 2 (Caco-2) cells using standard methodology, established that soticlestat has well-characterized metabolism, with limited victim and perpetrator DDI potential leading to minimal concern of clinical DDI risk. It demonstrated that soticlestat-glucuronide accounted for about 66% of total metabolism after 6 hours, with 34% attributed to cytochrome P450 and CYP3A being the only CYP responsible for soticlestat metabolism. Studies in human liver microsomes stated that UGT2B4 accounted for maximum UGT metabolism, almost 89.7%. Reversible CYP inhibition studies with soticlestat in HLMs showed notable inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4, but were not time-dependent. 

Soticlestat’s unique mechanism as a CH24H inhibitor represents an innovative avenue in treating epilepsy, with a significant impact on neurosteroid synthesis regulation. Its advancement for conditions like Dravet Syndrome and Lennox–Gastaut syndrome suggests a potential breakthrough in addressing rare epilepsies with transformative therapeutic prospects.