Use of Soticlestat Prevents Seizures, Sudden Death in Mouse Models

Margarida Maia PhD avatar

by Margarida Maia PhD |

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Treatment with soticlestat, an inhibitor of cholesterol turnover in the brain, protected against fever-induced seizures in two mouse models of Dravet syndrome, a study has found.

In one of the models, the experimental therapy also prevented sudden unexpected death in epilepsy (SUDEP), a rare complication of seizures — for which a cause has yet to be identified.

These results show soticlestat “has the potential for treatment” of Dravet and other severe types of epilepsies, the researchers said.

“Clinical translation of soticlestat” — taking such scientific discoveries made in the laboratory and transforming them into new therapies — “is ongoing,” the team wrote. But they added, “The current study supports further investigation of therapeutic potential in Dravet syndrome.”

The study, “Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice,” by a team of researchers in the U.S. and Japan, was published in the journal Epilepsia.

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Dravet syndrome is marked by frequent bursts of uncontrolled electrical activity between brain cells, or seizures. These seizures can be induced by multiple triggers, including fevers or any other factor leading to a rapid rise in body temperature, and are highly resistant to existing treatments.

“Uncontrolled seizures negatively affect brain development and are a leading risk factor for SUDEP,” the researchers wrote. “Novel treatments that provide better seizure control are needed to improve outcomes for individuals with Dravet.”

Soticlestat, previously known as TAK-935/OV935, is a potent, highly selective, first-in-class inhibitor of cholesterol 24-hydroxylase (CH24H). CH24H speeds the clearance of cholesterol, a type of fat present in all cells of the body, from the brain.

It also plays a role in regulating glutamate, a chemical messenger that sends signals from neurons to target cells, including other neurons. Too much glutamate, however, can lead to seizures. High levels of CH24H activate glutamate signaling pathways, which means that inhibiting CH24H with soticlestat could provide a strategy to reduce the number and severity of seizures.

To test how well soticlestat works against seizures, researchers used two types of mice — called Scn1a+/− and Scn1aRX/+ — that are susceptible to seizures induced by a rise in body temperature. These mice lack different sections of SCN1A, a gene that codes for a sodium channel protein that regulates brain cell activity; mutations in this gene are known causes of Dravet syndrome.

A group of mice received soticlestat mixed in food for seven days, while another group was fed their usual chow and served as controls.

The first step was to determine if soticlestat could increase the temperature at which a generalized tonic-clonic seizure is induced. Such seizures are characterized by convulsions and loss of consciousness.

The researchers placed the mice in a transparent box with small holes through which hot air was blown. Then, they recorded the number of mice who had a seizure as the temperature rose. They found that both types of soticlestat-treated mice had seizures at a temperature that was about a mean 1°C (1.8°F) higher than that of control mice.

Next, the researchers watched for changes in seizure frequency and severity. They found that most Scn1a+/− mice treated with soticlestat at a dose that lowered 24HC — a breakdown product of cholesterol — by half its normal levels in the brain had no spontaneous seizures. In turn, control mice had 1.4 seizures per day. Moreover, treatment with soticlestat reduced seizure severity.

A video electroencephalography (EEG) study to record brain activity confirmed the ability of soticlestat to reduce the number of seizures. However, the researchers observed no difference in seizure duration between the two groups of mice.

Finally, the researchers watched for changes in SUDEP. They found that most soticlestat-treated mice survived for the duration of the study compared with about half of control mice (95% vs. 55%).

“This suggests that soticlestat may reduce SUDEP risk in addition to providing anti-seizure [benefits],” the researchers wrote.

In clinical trials, including the global, Phase 2 ELEKTRA study (NCT03650452), soticlestat was found to be safe and effective for reducing seizure frequency in children with Dravet syndrome.

Ovid Therapeutics had originally developed soticlestat. However, in a May 2021 deal, Takeda Pharmaceuticals acquired the global rights to develop and market the therapy for Dravet and for Lennox–Gastaut syndrome,  another rare epilepsy.

Two Phase 3 clinical trials (NCT05163314 and NCT04940624), both sponsored by Takeda and investigating soticlestat in Dravet patients, have recently been launched, with one currently recruiting participants. More information on contacts and locations can be found here.