Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
- Experimental Therapies
- Experimental Therapies
Lennox-Gastaut syndrome (LGS) is a severe childhood developmental epileptic encephalopathy (DEE) characterized by seizures of multiple types that are refractory to treatment with a specific brain wave pattern, as well as noted cognitive disability.1-3 Currently, there is no cure for LGS, and the therapeutic management of the disease relies on the use of antiseizure medications (ASMs). First-line therapies include Depakote® (valproate), Lamictal® (lamotrigine), and Onfi® (clobazam). Other drugs have been developed such as Topamax® (topiramate), Banzel® (rufinamide), Felbatol® (felbamate), Epidiolex® (cannabidiol), and Fintepla® (fenfluramine), while many others are under clinical study.3
Carisbamate is an experimental ASM being developed by SK Life Science for the potential treatment of LGS. It has received Orphan Drug designation from the US Food and Drug Administration (FDA).4
Although the mode of action of this investigational therapy is not fully understood, it is believed to reduce repetitive neuronal firing through the inhibition of voltage-gated sodium currents.4
The development of carisbamate for the treatment of LGS started with preclinical studies in animal models of epilepsy. Based on the important anticonvulsant activity observed in these models, carisbamate development has progressed to clinical trials involving patients with LGS.5
A phase 1 open-label, multicenter study in adult and pediatric patients with LGS
(NCT03731715) was first conducted with single- and multiple-dose pharmacokinetic assessments.6 A phase 3 clinical trial that is currently recruiting participants will evaluate the efficacy and safety of carisbamate in patients with LGS (NCT05219617).4,7 This global, multicenter, randomized, double-blind, placebo-controlled clinical trial expects to enroll over 250 patients with LGS to study the efficacy of 2 doses of the experimental treatment.4
Read more about LGS clinical trials
Xcopri® (cenobamate) is an ASM that was recently approved for the adjunctive management of focal-onset seizures with or without secondary generalization in adults with epilepsy who do not achieve adequate seizure control even after treatment with at least 2 ASMs.3
The mechanism of action of Xcopri may involve the inactivation of voltage-gated sodium channels by persistent inhibition rather than transient currents, as well as the positive allosteric modulation of GABAA receptor binding at nonbenzodiazepine sites.3
Preclinical studies showed that Xcopri has broad antiseizure activity in different rodent seizure models. In clinical studies, reports show a seizure freedom rate of approximately 20% in adult patients with uncontrolled focal epilepsy. Studies have also been performed in pediatric populations.3
The use of Xcopri in DEE is currently limited to Dravet syndrome.3 A recent study, however, examined the use of Xcopri as an adjunctive treatment in LGS.3 In this study, Xcopri presented a good efficacy and tolerability profile in a small cohort of patients with LGS. The baseline seizure frequency was reduced during treatment with Xcopri, but no seizure freedom was achieved. Although these are promising results, further research on the use of Xcopri in LGS is needed.3
Read more about LGS treatment
Soticlestat (TAK-935/OV935) is a first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase. This enzyme is mainly produced in the brain and is involved in the metabolism of cholesterol, reducing the plasma levels of 24S-hydroxycholesterol (24HC), which is an endogenous positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors.1,2 These receptors are involved in excitatory neurotransmission and synaptic plasticity in diseases such as epilepsy.2
Previous studies investigated the anticonvulsant activity of soticlestat in animal models, and a correlation between 24HC levels and seizure frequency has been established in a phase 1b/2a clinical study.2
A phase 2 clinical trial (ELEKTRA; NCT03650452) designed to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or LGS has been completed.8 In this study, soticlestat treatment led to statistically significant, clinically meaningful reductions from baseline in median seizure frequency and convulsive seizure frequency. The reported safety profile was similar to that observed in previous studies, and the most frequent adverse events experienced by the participants of the trial were lethargy and constipation.2,9
A phase 2 open-label study (ENDYMION 1; NCT03635073) is currently determining the long-term safety and tolerability of soticlestat as adjunctive therapy in patients with rare epilepsies who have participated in the phase 1b/2a study.2,10 Initial results showed a median seizure frequency reduction ranging from 46.4% to 90% after 13 to 48 weeks of treatment.2
A phase 3 clinical trial will evaluate the efficacy of soticlestat as an add-on therapy in children, teenagers, and adults with LGS, as well as the safety profile of the experimental treatment when used in combination with other therapies (NCT04938427).11
Read more about LGS therapies
1. Auvin S. Lennox-Gastaut syndrome: new treatments and treatments under investigation. Rev Neurol (Paris). 2020;176(6):444-447. doi:10.1016/j.neurol.2020.01.364
2. Strzelczyk A, Schubert-Bast S. Expanding the treatment landscape for Lennox-Gastaut syndrome: current and future strategies. CNS Drugs. 2021;35(1):61-83. doi:10.1007/s40263-020-00784-8
3. Falcicchio G, Lattanzi S, Negri F, de Tommaso M, La Neve A, Specchio N. Treatment with cenobamate in adult patients with Lennox-Gastaut syndrome: a case series. J Clin Med. 2022;12(1):129. doi:10.3390/jcm12010129
4. SK Life Science initiates phase 3 clinical trial of carisbamate for Lennox-Gastaut syndrome. News release. SK Life Science, Inc; January 6, 2022.
5. Steriade C, French J, Devinsky O. Epilepsy: key experimental therapeutics in early clinical development. Expert Opin Investig Drugs. 2020;29(4):373-383. doi:10.1080/13543784.2020.1743678
6. Carisbamate in adult & pediatric subjects with Lennox-Gastaut syndrome. ClinicalTrials.gov. November 6, 2018. Updated December 20, 2022. Accessed February 14, 2023.
7. Investigate efficacy and safety of carisbamate as adjunctive treatment for seizures associated with LGS in children and adults. ClinicalTrials.gov. February 2, 2022. Updated February 2, 2023. Accessed February 14, 2023.
8. A phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of TAK-935 (OV935) as an adjunctive therapy in pediatric participants with developmental and/or epileptic encephalopathies (ELEKTRA). ClinicalTrials.gov. August 28, 2018. Updated February 18, 2021. Accessed February 14, 2023.
9. Hahn CD, Jiang Y, Villanueva V, et al. 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). Epilepsia. 2022;63(10):2671-2683. doi:10.1111/epi.17367
10. A study of soticlestat in adults and children with rare epilepsies (Endymion 1). ClinicalTrials.gov. August 17, 2018. Updated May 13, 2022. Accessed February 14, 2023.
11. A study of soticlestat as an add-on therapy in children, teenagers, and adults with Lennox-Gastaut syndrome. ClinicalTrials.gov. June 24, 2021. Updated February 10, 2023. Accessed February 14, 2023.
Reviewed by Harshi Dhingra, MD, on 2/27/2023.