Soticlestat Explained

Soticlestat (TAK-935, OV-935) is an experimental anticonvulsant and cholesterol 24-hydroxylase inhibitor being investigated as a treatment for Dravet syndrome, Lennox–Gastaut syndrome, tuberous sclerosis complex, dup15q syndrome, and CDKL5 deficiency disorder.^{[1] [2]} The development rights to the drug were purchased by Takeda Pharmaceuticals from Ovid Therapeutics in 2021.^[3]

Soticlestat was designated as an orphan drug by the FDA in 2017 for the treatment for both Dravet syndrome and Lennox–Gastaut syndrome.^[4] In a phase 2 study called ELEKTRA, soticlestat was well tolerated and reduced seizure frequency in patients with Dravet syndrome and Lennox–Gastaut syndrome.^[5]

Mechanism of action

Soticlestat functions by blocking cholesterol 24-hydroxylase (CH24H, also known as CYP46A1), an enzyme in the brain that converts cholesterol to the oxysterol 24S-hydroxycholesterol (24S-HC). Reduction of 24S-HC has been shown to reduce glutamatergic signaling, which reduces seizures.^{[1] [2]} Soticlestat may also have neuroprotective and anti-inflammatory properties via glial cell modulation.^[2]

Notes and References

1. Hong W, Haviland I, Pestana-Knight E, Weisenberg JL, Demarest S, Marsh ED, Olson HE . CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment . . 36 . 6 . 591–604 . June 2022 . 35633486 . 9876658 . 10.1007/s40263-022-00921-5 .
2. Pong AW, Ross J, Tyrlikova I, Giermek AJ, Kohli MP, Khan YA, Salgado RD, Klein P . Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials . . 27 . 1 . 75–90 . March 2022 . 35341431 . 10.1080/14728214.2022.2059464. 247763576 .
3. Web site: Takeda buys epilepsy treatment rights from Ovid for up to $856 million . . 3 March 2021 . 2 October 2023.
4. Web site: Pena . Ana . Soticlestat Can Reduce Seizure Frequency in Adults With Dravet, Other Rare Epilepsies, Initial Data Shows . Dravet Syndrome News . 22 October 2019 . 2 October 2023.
5. Hahn CD, Jiang Y, Villanueva V, Zolnowska M, Arkilo D, Hsiao S, Asgharnejad M, Dlugos D . A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox–Gastaut syndrome (ELEKTRA) . . 63 . 10 . 2671–2683 . October 2022 . 35841234 . 9804149 . 10.1111/epi.17367 .