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Dravet Syndrome (DS)

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Experimental Therapies

Dravet syndrome (DS) is a rare, severe, and debilitating form of epilepsy that typically develops during the first year of life and is characterized by frequent and prolonged seizures that are often difficult to control with conventional antiseizure medications. As a result, patients with DS experience a significant reduction in their quality of life, with many suffering from developmental delays, cognitive impairment, and behavioral issues.1 

Recent advances in medical research have led to the development of several experimental therapies that show promising results in treating this neurological condition.1

Modulators of Serotonin Signaling

Clemizole (EPX-100), Belviq® (lorcaserin, EPX-200), and trazodone (EPX-300) are modulators of serotonin signaling that have been shown to reduce seizures in patients with DS. All 3 therapies have received Orphan Drug designation for DS from the US Food and Drug Administration (FDA).1,2

Clemizole/EPX-100

Clemizole is a first-generation antihistamine receptor antagonist with affinity for HTR2A and/or HTR2B receptors, and its antiseizure activity has been demonstrated using zebrafish models.1 A placebo-controlled, double-blind, phase 1 clinical trial (NCT04069689) has reported on both the safety and pharmacokinetics of this investigational therapy in healthy individuals.3 A phase 2 clinical trial is currently recruiting patients with DS aged 2 years and over to evaluate clemizole as an add-on therapy (NCT04462770, ARGUS).4

Belviq/EPX-200

Belviq is currently approved by the FDA for weight loss treatment.1 Similarly to clemizole, the antiseizure activity of this drug has been studied using zebrafish models. In clinical trials, Belviq has been studied as an off-label treatment in a small cohort of pediatric patients with DS. The study showed that the number of seizures was reduced, and the therapy demonstrated a favorable safety profile.5 A different study showed that Belviq reduced the frequency of motor seizures by 43% from baseline in patients with DS and other epilepsy syndromes.6 Currently, a phase 3 clinical trial is recruiting patients with DS to evaluate the use of Belviq as adjunctive therapy (NCT04572243, MOMENTUM 1).7

Trazodone/EPX-300

Trazodone is an antidepressant, anxiolytic, and sleep-inducing insomnia drug approved by the FDA.8 It was found to suppress spontaneous convulsive behavior and electrographic seizures in zebrafish models of DS.1,2 Depending on the concentration, trazodone is a 5-hydroxytryptamine (5-HT), or serotonin, receptor agonist or antagonist. Clinical studies are needed, however, to understand the safety and efficacy of this drug in humans.1

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Cholesterol 24-Hydroxylase Inhibitor

Soticlestat

Soticlestat (TAK-935/OV935) is a selective inhibitor of cholesterol 24-hydroxylase (CH24H). The connection between dysfunctional cholesterol metabolism and central nervous system diseases that cause seizures is being studied; therefore, soticlestat represents a potential new therapy in DS.1 

This experimental therapy demonstrated reduced seizure burden in mouse models, while its safety and pharmacokinetics were addressed in two phase 1 clinical trials (NCT02201056 and NCT02539134).1,9,10 A phase 2 clinical trial (NCT03635073, Endymion 1) is assessing the long-term safety and tolerability of soticlestat when used in combination with other antiseizure treatments.11 A randomized, double-blind, placebo-controlled, multicenter phase 2 trial (NCT03650452, ELEKTRA) involving 51 pediatric patients with DS was completed, showing a reduction in seizure frequency.1,12

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Gene Therapy

STK-001

Antisense oligonucleotides (ASOs) have been shown to reduce seizures when successfully delivered.1 STK-001 was developed by targeted augmentation of nuclear gene output

(TANGO) using ASOs, and its mechanism of action relies on an increase in productive messenger RNA (mRNA) levels, which leads to the expression of a protein that is reduced in patients with DS, the sodium channel Nav1.1 protein.1 

The effect of this investigational therapy has been shown in model mice, rats, and nonhuman primates. STK-001 is administered intrathecally in ongoing clinical trials. A phase 2 trial (NCT04442295, MONARCH)13 will evaluate the safety and pharmacokinetics of the potential treatment.1

ETX101

Gene therapy based on adeno-associated viral (AAV) vectors has been developed as a new therapy in DS. ETX101 is a nonreplicating, recombinant AAV vector serotype 9 (rAAV9) that contains a GABAergic regulatory element. The mechanism of action of ETX101 is based on the upregulation of SCN1A expression.1 

Using mouse models, ETX101 led to an increase in SCN1A mRNA levels and Nav1.1 protein levels, which resulted in a reduction in seizure frequency.14 The first phase 1/2 clinical trial on ETX101 is expected to recruit 22 participants (NCT05419492, ENDEAVOR).15

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References

1. Gao C, Pielas M, Jiao F, et al. Epilepsy in Dravet syndrome—current and future therapeutic opportunities. J Clin Med. 2023;12(7):2532. doi:10.3390/jcm12072532

2. Epygenix Therapeutics receives US FDA Orphan Drug designation for EPX-300 to treat patients with Dravet syndrome. News release. Epygenix Therapeutics, Inc; August 23, 2017.

3. Study of safety and pharmacokinetics of oral doses of EPX-100 in healthy subjects. ClinicalTrials.gov. August 28, 2019. Updated June 25, 2020. Accessed March 29, 2023.

4. EPX-100 (clemizole hydrochloride) as add-on therapy to control convulsive seizures in patients with Dravet syndrome (ARGUS). ClinicalTrials.gov. July 8, 2020. Updated March 22, 2023. Accessed March 29, 2023.

5. Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC. Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017;140(3):669-683. doi:10.1093/brain/aww342

6. Tolete P, Knupp K, Karlovich M, et al. Lorcaserin therapy for severe epilepsy of childhood onset: a case series. Neurology. 2018;91(18):837-839. doi:10.1212/WNL.0000000000006432

7. A study of lorcaserin as adjunctive treatment in participants with Dravet syndrome (MOMENTUM 1). ClinicalTrials.gov. October 1, 2020. Updated December 14, 2022. Accessed March 29, 2023.

8. Pipeline. Epygenix Therapeutics. Accessed March 29, 2023. 

9. Safety, tolerability, and pharmacokinetics of escalating single doses of TAK-935. ClinicalTrials.gov. July 25, 2014. Updated July 12, 2016. Accessed March 29, 2023.

10. TAK-935 multiple rising dose study in healthy participants. ClinicalTrials.gov. September 2, 2015. Updated July 12, 2017. Accessed March 29, 2023.

11. A study of soticlestat in adults and children with rare epilepsies (Endymion 1). ClinicalTrials.gov. August 17, 2018. Updated May 13, 2022. Accessed March 29, 2023.

12. 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 March 29, 2023.

13. An open-label study to investigate the safety of single and multiple ascending doses in children and adolescents with Dravet syndrome. ClinicalTrials.gov. June 22, 2020. Updated March 28, 2023. Accessed March 29, 2023.

14. Tanenhaus A, Stowe T, Young A, et al. Cell-selective adeno-associated virus-mediated SCN1A gene regulation therapy rescues mortality and seizure phenotypes in a Dravet syndrome mouse model and is well tolerated in nonhuman primates. Hum Gene Ther. 2022;33(11-12):579-597. doi:10.1089/hum.2022.037

15. A clinical study to evaluate the safety and efficacy of ETX101 in infants and children with SCN1A-positive Dravet syndrome (ENDEAVOR). ClinicalTrials.gov. June 15, 2022. Accessed March 29, 2023.

Reviewed by Harshi Dhingra, MD, on 3/31/2023.

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