Soticlestat, previously called TAK-935 or OV935, is an investigational treatment developed by Takeda Pharmaceuticals in collaboration with Ovid Therapeutics to treat rare developmental and epileptic encephalopathies (DEE) including Dravet syndrome.
The U.S. Food and Drug Administration granted orphan drug status to soticlestat in 2017.
What is Dravet syndrome?
Dravet syndrome is a severe type of epilepsy characterized by frequent and prolonged epileptic seizures that usually begin in the first year of life. In nearly 80% of cases, the disease is caused by mutations in the SCN1A gene, which encodes for one of the essential proteins that are part of the sodium channels in nerve cells. Sodium channels regulate the uptake of sodium ions into the nerve cells and are responsible in part for generating and transmitting nerve impulses. The mutations in Dravet syndrome lead to hyperactivity of the nerve cells and cause epileptic seizures, which do not improve with anticonvulsant medications.
How does soticlestat work?
Soticlestat inhibits the activity of an enzyme called cholesterol 24-hydroxylase (CH24H), which is found at high levels in the brain where it plays a role in cholesterol metabolism. Research has shown that it is also involved in regulating a neurotransmitter or cell-signaling molecule called glutamate. One of the main neurotransmitters in the brain, glutamate can increase the initiation and spread of seizure activity. High levels of CH24H activate glutamate signaling pathways, so by inhibiting CH24H, soticlestat should be able to reduce the number and severity of seizures.
Soticlestat in clinical trials
Two Phase 1 clinical trials tested the safety and pharmacokinetics (movement in the body) of multiple increasing doses of soticlestat in healthy volunteers.
The results of the first trial (NCT02201056) showed that soticlestat was safe and well-tolerated up to a single dose of 1,350 mg. The most common side effects were headaches and nausea, and no severe adverse events were reported.
The results of the second trial (NCT02539134) showed that the treatment was well-tolerated up to 400 mg once per day for 14 days, with the most common side effects being headaches and attention disturbances.
A multicenter Phase 1b/2a clinical trial (NCT03166215) then studied the safety and tolerability of soticlestat for 12 weeks in 18 patients with rare epileptic disorders including Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex.
This trial was a two-part study: Part 1 was a randomized, double-blind, placebo-controlled study for 30 days, which included a drug-titration period for 20 days followed by a treatment period for 10 days. The target final dose of 300 mg twice daily could be reached after the 20-day titration period. Part 2 was a 60-day open-label study to explore the extent to which soticlestat reduced seizure frequency as well as its safety, tolerability, pharmacokinetics, and effect on estimated 24HC levels in the blood. Patients who rolled over to part 2 started at 200 mg soticlestat twice daily for 10 days (second titration period), which was then increased to 300 mg twice daily until day 85, followed by down titration until the end of the treatment period.
The results of this study showed that soticlestat was safe, well-tolerated, and effective, and produced a significant reduction in the levels of 24HC in the blood of treated patients compared to the placebo. The study also showed a correlation between 24HC levels and seizure frequency. By the end of the treatment period, there was a 69% decrease in seizure frequency in patients who showed an 80% reduction in 24HC levels compared with a 3% reduction in seizure frequency in those who did not show reduced 24HC levels. Adverse events were similar in both treatment and placebo groups.
Currently, Ovid and Takeda are conducting a Phase 2, prospective, open-label, multicenter, extension study called ENDYMION (NCT03635073) to assess the long-term safety and tolerability of soticlestat in patients with Dravet Syndrome, Lennox-Gastaut Syndrome, Dup15q Syndrome, and CDKL5 deficiency disorder. This study began in July 2018 and expects to enroll 176 participants including those who rolled over from the phase 1b/2a trial. The patients will undergo a dose optimization period of up to two weeks and then continue on the optimal dose for 103 weeks. After the last dose, patients will undergo a four-week safety follow-up including a two-week dose tapering period.
The trial is still recruiting participants in the U.S., Australia, China, Israel, Poland, and Spain, and is estimated to be completed in April 2023.
Ovid Therapeutics announced promising early data from this study in a news release in September 2019. At 12 weeks, the safety and tolerability profiles in the tested patients were similar to those observed during the completed Phase 1a/2b trial. The median seizure frequency was reduced by 86% by weeks 25–36 in six patients and by 90% at weeks 37–48 in four patients. One patient was seizure-free for 264 days, while another experienced no seizures for 150 consecutive days.
Ovid and Takeda are also conducting another Phase 2, multicenter, randomized, double-blind, placebo-controlled study called ELEKTRA (NCT03650452) to analyze the safety, tolerability, and efficacy of soticlestat in 126 children, 2 to 17 years old, with DEE, including those with Dravet syndrome. This study includes an eight-week dose optimization period followed by a 12-week maintenance period. The patients then have the option to continue in an open-label extension study, under a separate protocol. The primary outcome of the ELECTRA trial is the percent change in the frequency of seizures for 28 days after soticlestat treatment, when compared to a placebo.
This trial began enrollment in August 2018 and is still enrolling participants in the U.S., Australia, China, Israel, Poland, Portugal, and Spain. It’s expected to be completed in April 2021, with initial results to be announced in the second half of 2020.
A Phase 2, multi-center, open-label pilot study (NCT03694275) is underway to evaluate the safety and efficacy of soticlestat in 30 patients, ages 2 to 35, with epileptic seizures associated with CDKL5 deficiency disorder or Dup15q syndrome. This study consists of a four- to six-week screening period to establish baseline seizure frequency followed by a 20-week treatment period. The primary endpoint is the change in motor seizure frequency in patients treated with soticlestat.
The study is currently enrolling participants in the U.S. and is estimated to be completed by September 2020. The initial results are expected in the first quarter of 2020.
Last updated: Oct. 27, 2019
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