Soticlestat is a potential first-in-class oral medicine that is intended to reduce seizure susceptibility and improve seizure control for people living with Lennox-Gastaut syndrome and Dravet syndrome. Soticlestat is currently being evaluated in two Phase 3 trials. Ovid co-developed soticlestat through Phase 2 studies and then sold its rights to Takeda. Ovid retains financial interests to soticlestat.
mechanism of action
Soticlestat is a potent, highly selective inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H). CH24H is predominantly expressed in the brain where it converts cholesterol into 24S-hydroxycholesterol (24HC) to adjust the homeostatic balance of brain cholesterol. 24HC has multiple functions in the brain, one of which is as a positive allosteric modulator of the NMDA receptor. Glutamate is the main excitatory neurotransmitter in the brain and has been shown to play a role in the initiation and spread of seizure activity. Studies suggest that 24HC is involved in over-activation of the glutamatergic pathway through modulation of the NMDA receptor and disruption of astrocytic glutamate amino acid transporter 2 (EAAT2), resulting in epileptogenesis. Inhibition of CH24H by soticlestat reduces the neuronal levels of 24HC and may improve the excitatory/inhibitory balance in the brain, thereby reducing seizure susceptibility and improving seizure control.
Ovid Therapeutics designed and conducted a robust clinical program for soticlestat in individuals with developmental and epileptic encephalopathies (DEE). A Phase 1b/2a study in adults with DEE yielded positive results. Additionally, Ovid completed two Phase 2 studies with soticlestat:
- The Phase 2 ARCADE study in pediatric patients with CDKL5 deficiency disorder or Dup15q syndrome was completed and yielded positive results.
- The Phase 2 ELEKTRA study in pediatric patients with Lennox-Gastaut syndrome or Dravet syndrome was completed and yielded positive results.
Further development and research of soticlestat is being led by Takeda, including two ongoing Phase 3 studies in children and adults with Dravet syndrome (NCT04940624) and Lennox-Gastaut syndrome (NCT04938427) and the ongoing open-label ENDYMION extension study (NCT05163314).
For additional information on soticlestat clinical and non-clinical data, please click here »
Soticlestat is currently being developed for Dravet syndrome and Lennox-Gastaut syndrome. See below to learn more about these syndromes:
- Dravet syndrome is most commonly caused by a genetic mutation in the SCN1A gene
- Dravet syndrome is estimated to affect approximately 1 in 15,000 in the US (Wu et al 2015)
- Dravet syndrome is characterized by prolonged focal seizures that can evolve to convulsive tonic-clonic seizures
- Children with Dravet syndrome experience developmental disabilities as seizures increase. Other common symptoms include changes in appetite, difficulty balancing and a crouched gait when walking.
Reference: 1. Wu YW, Sullivan J, McDaniel SS, Meisler MH, Walsh EM, Li SX, Kuzniewicz MW. Incidence of Dravet Syndrome in a US Population. Pediatrics. 2015
- Lennox-Gastaut syndrome is estimated to affect approximately 1 in 11,000 individuals in the US (Trevathan, 1997)
- Lennox-Gastaut syndrome is a heterogeneous condition, characterized by several different types of seizures, most commonly atonic (drop), tonic and atypical absence seizures
- Children with Lennox-Gastaut syndrome may also develop cognitive dysfunction, delays in reaching developmental milestones and behavioral problems
Reference: 1. Trevathan E, Murphy CC, Yeargin-Allsopp M. Prevalence and descriptive epidemiology of Lennox-Gastaut syndrome among Atlanta children. Epilepsia. 1997