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Phase 3 Trials for Soticlestat Begin

What is soticlestat?

Soticlestat is an investigational medication that is currently in Phase 3 trials for the treatment of seizures in Dravet syndrome (1). Soticlestat works differently than any other current anti-seizure medications. Soticlestat blocks a molecule called ‘cholesterol 24-hydroxylase’ or ‘CH24H’, an important part of the pathway that processes cholesterol in the brain (2).

How is cholesterol related to the brain?

Cholesterol is an important component of the outer structure of cells in the body and is involved with signaling at the cell surface. Cholesterol in the brain is not the same as the cholesterol you take in through your diet. Because cholesterol cannot be transferred from the rest of the body into the tissues of the brain, it all has to be made (and later broken down) by the cells in the brain. For the most part, cholesterol in the brain remains quite stable and is not quickly broken down. However, when cholesterol in the brain does need to be broken down, the CH24H molecule is an important part of the process (2). When CH24H modifies cholesterol, the resulting molecule can impact the NMDA receptor and glutamate levels.

Why is the cholesterol pathway a target for treating seizures?

Soticlestat is thought to be effective for the treatment of epilepsy by ultimately modifying glutamate signaling. Increased glutamate levels are associated with increased excitation of neurons- too much excitability can lead to seizures. Blocking the CH24H molecule appears to reduce the increased glutamate often associated with seizures. Proof-of-concept of the potential for soticlestat as a therapeutic option to treat epilepsy has been shown in several mouse models including an Alzheimer’s disease mouse model that also had life-threatening seizures as a symptom (3), and two other induced mouse models of epilepsy. Additionally, soticlestat has been tested in two mouse models of Dravet syndrome where it reduced seizures and prevented premature lethality (4).

Initial trials of soticlestat showed efficacy for patients with Dravet syndrome.

Soticlestat (or also referred to as “TAK-935”) completed Phase 1b/2a trials in adult patients with developmental and/or epileptic encephalopathies (DEEs) showing the safety and tolerability of soticlestat and preliminary evidence to suggest it could be effective at seizure reduction in human patients (5). Recent Phase 2 trials went on to assess soticlestat in patients ages 2 to 17 years with Dravet syndrome and Lennox-Gastaut syndrome. The results of this trial again supported that soticlestat was well-tolerated and safe with the most common adverse event reports being lethargy and constipation. In the cohort of 51 patients with Dravet syndrome in the Phase 2 trial, there was a median reduction of seizure frequency of 46% for patients on soticlestat when compared to the placebo group. The open-label extension for this study supported that the effects on seizure reduction are maintained at least out to the 6-month time frame that was available at the time of the last report (6).

Phase 3 Clinical Trials for Soticlestat (TAK-935) are enrolling now.

The Skyline Study is a Phase 3 double-blind, placebo-controlled, clinical research study of soticlestat for children, teens, and young adults, ages 2 to 21, diagnosed with Dravet syndrome. The main goal of the study is to assess if use of soticlestat as an add-on therapy is effective at reducing convulsive seizures in children and young adults with Dravet syndrome. Additional outcome measures will further assess the impacts on seizures as well as non-seizure symptoms and quality of life. All participants will continue with their standard anti-seizure medication during the study. Throughout participation in the 25-week study, all study-related visits, tests, and the investigational medication will be provided at no cost. Reimbursement for expenses related to study participation such as travel, meals, etc., may also be available. Study staff will determine eligibility based on additional study criteria. To learn more about the clinical research study or to find out if your loved one may qualify, please visit the Skyline Study website at skyline-study.com or clinicaltrials.takeda.com.


  1. https://skyline.researchstudytrial.com
  2. Koike, T., Yoshikawa, M., Ando, H.K., Farnaby, W., Nishi, T., Watanabe, E., Yano, J., Miyamoto, M., Kondo, S., Ishii, T., Kuroita, T., 2021. Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H). J Med Chem 64, 12228–12244. https://doi.org/10.1021/acs.jmedchem.1c00864
  3. Nishi, T., Kondo, Shinichi, Miyamoto, M., Watanabe, S., Hasegawa, S., Kondo, Shigeru, Yano, J., Watanabe, E., Ishi, T., Yoshikawa, M., Ando, H.K., Farnaby, W., Fujimoto, S., Sunahara, E., Ohori, M., During, M.J., Kuroita, T., Koike, T., 2020. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice. Sci Rep-uk 10, 17081. https://doi.org/10.1038/s41598-020-74036-6
  4. Hawkins, N.A., Jurado, M., Thaxton, T.T., Duarte, S.E., Barse, L., Tatsukawa, T., Yamakawa, K., Nishi, T., Kondo, S., Miyamoto, M., Abrahams, B.S., During, M.J., Kearney, J.A., 2021. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice. Epilepsia 62, 2845–2857. https://doi.org/10.1111/epi.17062
  5. Halford, J.J., Sperling, M.R., Arkilo, D., Asgharnejad, M., Zinger, C., Xu, R., During, M., French, J.A., 2021. A phase 1b/2a study of soticlestat as adjunctive therapy in participants with developmental and/or epileptic encephalopathies. Epilepsy Res 174, 106646. https://doi.org/10.1016/j.eplepsyres.2021.106646
  6. https://www.globenewswire.com/news-release/2020/08/25/2083122/0/en/Phase-2-ELEKTRA-Study-of-Soticlestat-TAK-935-OV935-Meets-Primary-Endpoint-Reducing-Seizure-Frequency-in-Children-with-Dravet-Syndrome-or-Lennox-Gastaut-Syndrome.html
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