Objective:

To provide a comprehensive overview of the science supporting the mechanism of action (MOA) of soticlestat (TAK-935).

Background:

Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol (24HC). 24HC is a positive allosteric modulator of the N-methyl-D-aspartate receptor that can contribute to neuronal hyperexcitability. Activation of CH24H decreases excitatory amino acid transporter 2 (EAAT2) function, which in turn reduces glutamate reuptake from the peri-synaptic space and potentially contributes to exaggerated neuronal hyperexcitability. In addition, increased levels of tumor necrosis factor-alpha (TNF-α) is reported to enhance vesicular release of glutamate into the synaptic cleft and decrease glutamate reuptake, further increasing peri-synaptic glutamate levels. Soticlestat is a first-in-class, selective CH24H inhibitor currently in phase 3 trials for treatment of Dravet and Lennox-Gastaut syndromes.

Design/Methods:

A literature search and data generated on soticlestat to date were used to describe the MOA of this novel potential anti-seizure medication (ASM).

Results:

Soticlestat binds CH24H in the brain with high specificity, which directly correlates with reductions in brain and plasma 24HC levels. This reduction in 24HC reduces neuronal hyperexcitability. In addition, soticlestat inhibits conversion of membrane cholesterol to 24HC preserving the cholesterol-rich lipid raft in the plasma membrane of reactive astrocytes. Furthermore, preclinical results have shown a significant correlation between reductions in 24HC levels and TNF-α levels in the hippocampus in soticlestat-treated mice that may contribute to the reduction of seizure susceptibility caused by excess glutamate neuronal hyperexcitation and neuroinflammation.

Conclusions:

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.