Authors :
Presenting Author: Naga Venkatesha Murthy, MD – Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
H Steve White, PhD – Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA; Mahnaz Asgharnejad, PharmD – Takeda Pharmaceutical Company Limited, Cambridge, MA, USA; Arturo Benitez, MD, MBA – Takeda Pharmaceutical Company Limited, Cambridge, MA, USA; Kosuke Nakashima, PhD – Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan; Shinichi Kondo, PhD – Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
Rationale:
Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol (24HC). 24HC is a positive allosteric modulator (PAM) of the N-methyl-D-aspartate receptor (NMDAR) that can contribute to neuronal hyperexcitability. Activation of CH24H leads to a decrease in excitatory amino acid transporter 2 (EAAT2) function, which in turn reduces glutamate reuptake. This reduction of EAAT2 in the peri-synaptic space is thought to contribute to exaggerated neuronal hyperexcitability. In addition, increased levels of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine associated with hyperexcitability in neural networks in epilepsy, is reported to enhance vesicular release of glutamate into the synaptic cleft and decrease glutamate reuptake, thereby further increasing peri-synaptic glutamate levels.
Soticlestat is a first-in-class, selective inhibitor of the enzyme CH24H currently in phase three trials for the treatment of Dravet and Lennox-Gastaut syndromes. Herein, we provide a comprehensive overview of the science supporting the mechanism of action (MOA) of soticlestat.
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 levels of 24HC. A reduction in 24HC, a PAM of NMDAR in the brain, reduces neuronal hyperexcitability. In addition, soticlestat inhibits conversion of membrane cholesterol to 24HC; an effect that preserves the cholesterol-rich lipid raft in the plasma membrane of reactive astrocytes. Lipid rafts are thought to be important for the functioning of EAAT2 that clears glutamate from peri-synaptic space. Furthermore, preclinical results have shown a significant correlation between reductions in 24HC levels and TNF-α levels in the hippocampus in soticlestat-treated mice. This reduction in 24HC levels by soticlestat and concomitant reduction of TNF-α 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, and is associated with increased functional EAAT2 in peri-synaptic astrocytes. These effects act to decrease extra synaptic glutamate and are correlated with decreases in TNF-α, decreased neuronal hyperexcitability and reduced seizure susceptibility. Further understanding of soticlestat’s MOA will provide a foundation for developing new ASMs and help to elucidate the underlying pathophysiology of epilepsy.Funding:
Takeda Pharmaceutical Company Limited