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Soticlestat, a small molecule that inhibits the activity of cholesterol 24-hydroxylase, one of several enzymes responsible for catabolism of cholesterol, has the potential to translate into a useful therapy for epilepsy, but more research from clinical trials are needed, experts said.

A compound that inhibits cholesterol catabolism has potential as an antiseizure drug, according to a study published March 22 in Epilepsia. The compound, soticlestat, reduced seizure frequency in a standard preclinical model, and appeared safe after prolonged dosing. Clinical trials of soticlestat in Dravet syndrome and Lennox-Gastaut syndrome are ongoing, sponsored by the manufacturer, Takeda, and initial results are promising.

“This is a new mechanism for treatment of epilepsy,” commented Edward H. Bertram, MD, FAAN, professor of neurology at the University of Virginia, who was not involved in the study. “But as with many drugs in development, the preclinical data, which look good, are not necessarily predictive of clinical benefit.”

Soticlestat is a small molecule that inhibits the activity of cholesterol 24-hydroxylase (CH24H), one of several enzymes responsible for catabolism of cholesterol. Inhibition of the enzyme lowers the level of 24S-hydroxycholesterol, a brain-specific metabolite that modulates a wide variety of receptors and ion channels, including the NMDA receptor, according to lead author Toshiya Nishi, DVM, principal scientist in neuroscience drug discovery at Takeda Pharmaceuticals.

Previous work by Dr. Nishi and colleagues demonstrated the antiseizure potential of reducing CH24H activity in a mouse carrying two Alzheimer’s disease genes, presenilin-1 and amyloid precursor protein, known for both seizures and sudden death. When crossed with a CH24H knockout mouse, the offspring not only had fewer seizures but also a lower risk of sudden death.

Mutations in the sodium channel gene are a cause of Dravet syndrome; previous work has shown that soticlestat reduced seizures and sudden death in a mouse model of the syndrome. “These results are encouraging, “Dr. Nishi noted, “but this model is not yet part of the standard suite of epilepsy models used to test the antiseizure potential of new drugs, and there is relatively little historical data from the model to help evaluate new candidates.”

Study Details

For that reason, he and his team tested tested soticlestat in four of the canonical seizure models. Because of the slow turnover of 24S-cholesterol in the brain, soticlestat was administered for three days prior to provoking seizures. Doses were chosen to achieve a 50 percent reduction in 24S-cholesterol, which the previous study showed was necessary for effective seizure reduction. Sixteen animals were tested in each model, with half of each group receiving soticlestat.

There was no evidence of seizure protection in three of the models, although in the maximum electroshock seizures model, six mice died in the untreated group, compared with none in the soticlestat group. In contrast, in the audiogenic seizure model, seven of eight mice were protected against seizures by soticlestate, compared with none in the untreated group.

“Antiseizure medications do not necessarily work in all animal models of seizures,” Dr. Nishi noted, and it is common in epilepsy drug development to advance candidates that only show benefit in some models.

Next, the team explored the effects of both dose and pretreatment duration on seizure reduction in the audiogenic seizure model. They found that the highest degree of protection occurred with the maximum pretreatment period (three days prior to seizure induction) and at the highest dose (30 mg/kg), although significant benefit was observed at lower doses as well.

Dr. Nishi noted that, unlike in the other models, mice in the audiogenic model, so-called Fring’s mice, have an underlying genetic pathology that predisposes them to seizures. That suggests that blockade of CH24H by soticlestat “may be modifying the neurologic conditions behind seizure susceptibility, rather than addressing the basic pathology of audiogenic seizures,” he explained.

That hypothesis led him to ask whether soticlestat might reduce susceptibility to “kindling,” or the increase in frequency and severity over time often seen in mice (and patients) with an untreated seizure disorder. He found that prolonged treatment at certain doses did indeed retard the development of kindling, although only temporarily, as generalized seizures eventually appeared in most treated mice.

At the end of the study, an analysis of 24HS levels indicated a reduction in the brain at all soticlestat levels tested, up to 92 percent at the highest dose. “Studies thus far published consistently agree that a 50 percent to 60 percent reduction in 24S-hydroxycholesterol is explicitly required for efficacy in preclinical models, Dr. Nishi said. “Here, the greater the reduction in 24S-hydroxycholesterol, the greater the progressive effect on reducing seizure severity.”

Even at the highest dose, soticlestat did not cause sedation or other overt adverse effects, he added.

In phase 2 clinical trials for Dravet syndrome and Lennox-Gastaut syndrome, soticlestat has been well tolerated, Dr. Nishi said, “especially during the up-titration that is common with all antiseizure medications.” The treatments in those trials were administered for 20 weeks; they were followed by long-term open-label extension studies, which are ongoing. The drug is now entering phase 3 trials for both conditions. The clinical dose currently under investigation is expected to consistently achieve a 24SH lowering greater than 60 percent.

“Since patients with these conditions are usually on multiple drugs to control their seizures, we believe that soticlestat, due to its novel mechanism of action, will effectively complement the treatment algorithms currently used to treat epileptic encephalopathies,” Dr. Nishi said.

Expert Commentary

This study is interesting, and the proposed mechanism is plausible, given the multiple known effects of 24S-cholesterol in the nervous system, including potentiation of glutamatergic receptors, commented Pavel Klein, MD, FAAN, director of the Mid-Atlantic Epilepsy and Sleep Center in Bethesda, MD. “The study is very comprehensive, using standard models for epilepsy, and the investigators are well established,” Dr. Klein said.

The results are discordant, but that is not necessarily problematic, Dr. Klein said. He noted that levetiracetam also displayed varied effectiveness in preclinical models, with virtually no effect on acute seizures in genetically normal mice, before going on to become the most widely prescribed antiseizure medication. “This is an intriguing parallel,” he added.

“The short answer is we don’t know” how predictive these results will be for clinical efficacy of soticlestat, said Dr. Bertram, who researches mechanisms of epilepsy. “Although we can find a potential mechanism for many of the medicines we use to treat epilepsy, we aren’t always sure that it is the actual one. And finding a specific mechanism doesn’t guarantee success in the clinic. And some drugs that look only weakly effective preclinically go on to be quite successful.”

Nonetheless, the results of this study indicate some promise, Dr. Bertram said, with a clear effect on brain activity, modest but good seizure reduction, and reassuring toxicology. “This is a new mechanism for epilepsy, which has the potential to translate into a clinically useful compound. But there are many steps ahead before it proves to be so.”

Source: journals.lww.com, Richard Robinson

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