
==== Front
Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

39196806
AIAN-27-352
10.4103/aian.aian_49_24
AIAN Review
Advancements in Dravet Syndrome Therapeutics: A Comprehensive Look at Present and Future Treatment Horizons: A Focused Review
Mahesan Aakash
Kamila Gautam
Gulati Sheffali
Centre of Excellence and Advanced Research for Childhood Neurodevelopmental Disorders, Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
Address for correspondence: Prof. Sheffali Gulati, Centre of Excellence and Advanced Research for Childhood Neurodevelopmental Disorders, Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. E-mail: sheffaligulati@gmail.com
Jul-Aug 2024
16 8 2024
27 4 352357
18 1 2024
17 5 2024
07 7 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Dravet syndrome (DS) is a developmental epileptic encephalopathy, characterized by fever-triggered focal or hemiclonic seizures at onset with various associated comorbidities like intellectual disability, gait abnormalities, and behavioral issues. It typically advances to drug-refractory epilepsy with multiple seizure semiology. In this review, we give a focused narrative on the treatment aspects of DS. We searched the PubMed database for articles on DS. More than 500 articles were reviewed, of which 55 relevant articles are included in this review. ClinicalTrials.gov database was also accessed for data on ongoing trials. Majority are caused by mutations in the SCN1A gene. Valproate and clobazam are the most commonly used traditional antiseizure medications. Stiripentol, fenfluramine, and cannabidiol are recently approved drugs with promising results. Ketogenic diet and vagus nerve stimulation are commonly tried nonpharmacologic modalities that have shown significant responses. Antisense oligonucleotides and viral vector-mediated gene transfer therapies are on the horizon. This review outlines the current existing treatment rationale, evidence for newly approved drugs, and the future scope of gene therapy in DS.

Dravet syndrome
future therapeutics
SCN1A
==== Body
pmcINTRODUCTION

Dravet syndrome (DS), formerly known as severe myoclonic epilepsy of infancy, is an infantile-onset developmental epileptic encephalopathy characterized by fever-triggered prolonged focal clonic or hemiclonic seizures with varying focality, eventually progressing to afebrile seizures with multiple semiologies like myoclonic, atonic, atypical absence and generalized tonic clonic seizures.[1] It is accompanied by developmental delay and numerous comorbidities like intellectual disability, behavioral issues with autistic traits, gait abnormality, hypotonia, sleep disorders, sudden unexpected death in epilepsy (SUDEP), brady/tachyarrhythmias, dysautonomia, recurrent infections, and poor growth.[2] Up to 80% of DS is caused by mutation in the SCN1A gene leading to abnormalities in the alpha subunit of sodium channel. Most of them are caused by de novo truncating mutations.[3] SCN1A mutations can have varying phenotypical presentations ranging from mild familial febrile seizures, febrile seizure plus, genetic epilepsy febrile seizure plus to severe phenotypes like DS, myoclonic astatic epilepsy, and early infantile migrating focal seizures.[4] Other reported genes for DS and DS-like phenotypes include SCN2A, SCN8A, SCN9A, HCN1, CDH2, PCDH19, GABAG2, GABRA1, STXBP1, KCNA2, and SCN1B.[5] The estimated incidence is 1:15,700–1:46,000 and prevalence is 1 in 22,000–1 in 45,000, thus making it a rare disease.[678] It contributes to significant strain on health-care expenditure as well as quality of life of both the patient as well as the caregiver.[9] Probability risk scores for screening for DS help in early identification, genetic diagnosis, and treatment initiation.[10] In this review, we shall take a comprehensive look at the current approved treatment options and future scope for new therapeutic targets.

SEARCH METHODS

MEDLINE/PubMed literature searches were made using the search terms “Dravet syndrome,” OR “SCN1A” AND “Treatment,” “Future” for the last 10 years. The latest articles and those with robust methodology and evidences were given preference. We reviewed more than 500 citations, of which 55 are included in this review. In addition to the future drugs on the horizon, searches were made in Google Scholar also, so that even conference presentations are not missed. ClinicalTrials.gov database was also searched for information on any ongoing trials, their phases, and current status.

CURRENT TREATMENT METHODS

Traditional antiseizure medications, precautions, and vaccination

A recent consensus statement by international league against epilepsy (ILAE) recommended sodium valproate to be the first-line antiseizure medication (ASM), followed by benzodiazepines like clobazam.[11] Sodium channel blockers like carbamazepine, oxcarbamazepine, lamotrigine, and phenytoin should be avoided in children with DS for treating daily seizures.[11] Vigabatrin, eslicarbazepine, rufinamide, lacosamide, pregabalin, and gabapentin are also best avoided.[12] Lamotrigine may be beneficial in some adult patients with DS in whom all other drugs are exhausted.[1113] Levetiracetam, topiramate, zonisamide, and ethosuximide for atypical absences may be considered as next-line ASMs.[14] All children with DS need home rescue medication and a seizure action plan.[11] Rectal diazepam and intranasal/buccal midazolam have good efficacy as rescue therapy.[15] In status epilepticus, the standard drugs like intravenous (IV) benzodiazepines, sodium valproate, and levetiracetam are recommended. IV phenytoin can be given during status epilepticus if all the three drugs fail.[11] In addition to the above medical management, one must also try to avoid provoking factors like hot baths, overexertion, flashing lights, visual patterns, and overexcitement.[1617] Although many children with DS had their first episode of seizure associated with fever post-vaccination, it is still vital to protect them from infections. The frequency of further such episodes may be reduced by prophylactic use of antipyretics and dosing ASMs near the time of vaccination.[11]

NEWER APPROVED DRUGS

Stiripentol

Stiripentol was first approved by the US Food and Drug Administration (FDA) in 2018 for use in DS for patients 6 months of age and above. The approved dose is 25 mg/kg/day in two divided doses for less than 10 kg body weight and up to 50 mg/kg/day in three divided doses for >10 kg body weight. The proposed mechanism of action is enhanced GABAergic neurotransmission. Coadministration with clobazam increases the drug levels of both the drugs and may cause sedation.[18] The first randomized controlled trial (RCT) showed that 71% responded (>50% seizure reduction) in the stiripentol add-on group versus 5% in the placebo group, with drowsiness and loss of appetite being the most common adverse effects.[19] A recent meta-analysis concluded that stiripentol had a greater rate of seizure freedom compared to placebo (odds ratio [OR]: 19.86, 95% CI: 2.40–164.45) and showed a higher seizure response rate than pharmaceutical-grade cannabidiol (OR: 14.07, 95% CI: 2.57–76.87) and good safety and tolerability.[20] As per the recently updated ILAE consensus statement, it is recommended as a second-line ASM in the treatment of DS, next to sodium valproate along with clobazam.[11]

Cannabidiol

Pharmaceutical-grade cannabidiol (Epidiolex) was approved by the FDA for use in DS in 2018 for children at least 1 year of age and by the central drugs standard control organisation (CDSCO), India in 2023. The recommended dose starts from 5 mg/kg/day in two divided doses, slowly hiking in weekly 5 mg/kg/day (two divided doses) increments up to a maximum of 20 mg/kg/day in two divided doses. Many cases may attain adequate seizure control at the maintenance dose of 10 mg/kg/day in two divided doses. The antiseizure activity of the drug is proposed to be mediated via action on three targets, namely transient receptor potential vanilloid-1, orphan G-protein-coupled receptor-55 (GPR55), and equilibrate nucleoside transporter 1 (ENT-1).[21] The median seizure reduction in the cannabidiol group was 43.9% (interquartile range [IQR] -69·6 to -1·9) compared to 21.8% (IQR -45.7 to 1.7) in the placebo group.[22] Somnolence, diarrhea, loss of appetite, and vomiting were the most common side effects.[22] In a recent meta-analysis, it was observed that cannabidiol showed greater reduction in seizure frequency than placebo, but had more treatment discontinuation due to side effects.[20] As per the ILAE consensus, it is a third-line ASM after stiripentol and fenfluramine.[11]

Fenfluramine

Fenfluramine was first approved by the FDA in 2020 for use in DS for children aged 2 years and above. The dosing starts from 0.1 mg/kg twice daily, hiked slowly every week up to a maximum of 0.35 mg/kg twice daily (max 26 mg/day). With concomitant stiripentol and clobazam use, the maximum dose is 0.2 mg/kg twice daily (max 17 mg/day). Initially developed as an appetite suppressant, it was later withdrawn due to its cardiac valvular side effects. However, it later made a comeback in drug-refractory epilepsy like DS. It is thought to act by a plethora of mechanisms via serotonin and sigma 1 receptor modulation, maintaining a balance between glutamate and gamma amino butyric acid (GABA), causing antiseizure effects, and reducing related comorbidities like SUDEP.[23] In an RCT where fenfluramine was used in two dosage arms of 0.2 and 0.7 mg/kg versus placebo add-on therapy, median seizure reduction of 42.3%, 74.9%, and 19.2% was noted, respectively.[24] Decreased appetite, diarrhea, fatigue, lethargy, somnolence, and decreased weight were the common side effects. No cardiac side effects were noted, and echocardiogram (ECHO) was normal in all.[24] A dose of 0.7 mg/kg/day of fenfluramine had a better response than 0.2 mg/kg/day (OR: 3.32, 95% CI: 1.32–8.37), and cannabidiol had lower seizure reduction rate than fenfluramine (OR: 0.20, 95% CI: 0.07–0.54).[20] As per the ILAE consensus, it is a second-line ASM along with stiripentol and clobazam.[11]

NONPHARMACOLOGIC METHODS

Ketogenic diet

Ketogenic diet (KD) therapy has been in use for drug-refractory epilepsies and more so in children. A Cochrane review of 13 RCTs showed the promising role of KD, with studies reporting seizure freedom as high as 55% and seizure reduction up to 85%, favoring the use of KD in comparison to standard therapy alone in drug-resistant epilepsies including DS.[25] The common side effects are gastrointestinal symptoms like constipation, diarrhea, vomiting, poor palatability, and dyslipidemia.[25] With less-restrictive diet regimens like modified Atkins diet and low glycemic index diet therapy, more compliance via reduction of side effects with almost similar efficacy can be obtained.[26] The mechanism of action of KD in epilepsy is thought to be multimodal, mediated via ketone bodies, mitochondrial function enhancement, increasing GABA, reducing glutamate, and altering bioamines like adenosine and serotonin.[27] A study conducted on KD in DS as early as 2005 had shown that up to 77% of the study group achieved >75% seizure reduction and nearly 15% became seizure free.[28] A recent meta-analysis of seven studies and 167 patients showed 60% responder rate by 6 months of therapy, and the therapy was found to be safe as well as tolerable.[29] It is considered as a fourth-line therapy as per the recent ILAE consensus statement.[11]

Vagus nerve stimulation

Vagus nerve stimulation (VNS) is an approved adjunctive treatment for drug-refractory epilepsy, with a meta-analysis showing up to 45% reduction in seizure frequency.[30] VNS via afferent vagal nerve projections to the locus coeruleus and raphe nucleus, altering the norepinephrine and serotonin levels has been proposed to mediate antiseizure effect.[31] A meta-analysis of 68 DS patients showed that 52.9% participants had >50% reduction in seizure frequency.[32] A long-term study in 22 patients showed progressive and time-dependent improvement with up to 13.6% showing seizure freedom and 63.2% having >50% seizure reduction 3 years post-VNS, with hoarseness of voice being the most common side effect.[33]

NEWER DRUGS UNDER TRIAL

Following the success of fenfluramine, serotonin receptors as a potential target of action have been tried on multiple models of zebra fish, which is an approved model for epilepsy since it has up to 85% of known genes implicated in human epilepsy syndromes.[34] These drugs have been granted orphan drug status by the FDA for DS.

Clemizole (EPX 100)

Clemizole is a potent first-generation antihistaminic drug, which also modulates serotonin receptors. Zebra fish models have shown the potential role of the drug in DS, with proven affinity for HTR2A and HTR2B.[3536] It is currently under trial (NCT04462770 ARGUS Phase 2 trial) as an adjunctive therapy versus placebo for children aged above 2 years and adults, as a part of a multicentric RCT.

Lorcaserin (EPX 200)

It is a 5-hydroxytryptamine 2C (5-HT2C) receptor agonist, which is FDA approved for weight reduction.[37] A retrospective case series of 20 DS patients showed up to 43% reduction in seizures, with decreased appetite and weight loss being the major side effects.[38] A recent meta-analysis suggests an increase in trend toward lung and pancreatic cancer on long-term usage of this drug.[39] A Phase 3 trial (NCT04572243 MOMENTUM 1) is currently ongoing for lorcaserin in children with DS above 2 years of age.

Trazodone (EPX 300)

This is an FDA-approved drug for depression, anxiety, and insomnia and acts via blockade of 5-HT2A receptors as well as H1 histamine receptors and α1 adrenergic receptors in low doses and blockade of serotonin transporter in higher dose.[40] Zebra fish models have again demonstrated possible use of this drug in DS.[3541] In a case report of trazodone being used for a 25-year-old woman with DS for insomnia, she showed seizure reduction as well as neurophysiological improvement.[42]

LP352

This is a 5-HT2C super-agonist that has currently completed Phase 1b/2a PACIFIC trial with established safety in adults with developmental and epileptic encephalopathy including DS. Headache, somnolence, dizziness, micturition urgency, and orthostatic hypotension were the common side effects.[43] Phase 2 open-label extension and Phase 3 multicentric studies are planned to be initiated.

Soticlestat (TAK 935)

Soticlestat is a selective inhibitor of cholesterol 24-hydroxylase and is being investigated for the treatment of both DS and Lennox–Gastaut syndrome. It has neuromodulatory effects, suppressing glutamate and reducing the hyperexcitable state.[44] Initial preclinical studies established drug safety.[45] A Phase 2 ELEKTRA trial of 51 participants with DS showed up to 30% reduction in median seizure frequency, with constipation and lethargy being the most common side effects.[46] An interim data of the long-term extension phase of this trial with 80 weeks of exposure in 47 DS participants showed sustained seizure frequency reduction and consistent safety profile.[47] A Phase 3 trial (NCT04940624 Skyline study) is currently ongoing for soticlestat as an add-on therapy versus placebo in DS patients aged 2–21 years.

Other drugs with orphan drug status from the FDA or in preclinical studies and on which many details are yet to be known include NT102 that targets mitochondrial dysfunction, BMB101, a 5-HT2C agonist, SPN-817 (Huperzine A), a brain penetrant acetylcholine esterase inhibitor, ReS3-T, acting on the delta subunit of rod-specific photoreceptor cGMP phosphodiesterase (PDE6D), and NCT-10004 and DSP-0378, targeting GABA-A–positive allosteric modulators.

DISEASE-TARGETING THERAPIES

Ataluren

Ataluren promotes ribosomal readthrough of nonsense mutations and hence it can help in those non sense mutations otherwise causing a premature termination of RNA translation.[48] A Phase 2 controlled crossover trial over 12 weeks with ataluren versus placebo in DS and CDKL5 epilepsy failed to demonstrate efficacy in seizure reduction, although it had a tolerable side effect profile.[49]

Antisense oligonucleotide (STK-001)

Antisense oligonucleotides (ASOs) regulate RNA processing and thus gene expression, and have found a vital place in the treatment and management of diseases like spinal muscular atrophy (nusinersen) and DMD (eteplirsen, golodirsen, viltolarsen, and casimersen).[50] STK-001 is an ASO that is structured to increase the sodium channel protein (Nav1.1) expression, which is reduced in patients with DS, using a novel technology called targeted augmentation of nuclear gene output, thus ameliorating the disease. ASOs in rat/mouse models with SCN1A defects have shown improvement in seizure and SUDEP.[5152] NCT04442295, MONARCH; NCT04740476, SWALLOWTAIL, an open-label extension of MONARCH; and NCT04442295, ADMIRAL are the various currently ongoing human trials with the drug being administered intrathecally. Irritability, vomiting, and elevated cerebrospinal fluid proteins are the commonly reported adverse events. Initial trial findings suggest a favorable outcome in seizure reduction, cognition, and behavior. OPK88001 (CUR-1916) was an ASO designed to displace an indigenous repressor of SCN1A transcription, thus enhancing the gene expression (up to 30%) in a mouse model and significantly reducing seizures, but no further development is available on this drug.[53]

Gene therapy (ETX 101)

Gene therapy in basic sense is the replacement of defective gene by a functional gene, often mediated by a viral vector like an adenovirus.[54] The existing gene therapies like Zolgensma for spinal muscular atrophy (SMA) and Elevidys for DMD show promising results in their respective fields. CRISPR-Cas9 gene editing technologies have greatly enhanced our understanding and feasibility of various gene therapies. ETX101 is an adeno associated virus (AAV) vector encoding a small engineered transcription factor targeted to GABAergic interneuron, thus bypassing the hurdle of transmitting an otherwise large gene.[55] Initial mouse model demonstrated significant reduction in seizures and prolonged survival with widespread vector distribution and no serious adverse effects.[56] ENDEAVOUR (NCT05419492) Phase 1/2 trial is currently ongoing for children with DS aged 6–36 months, evaluating the intracerebroventricular administration of ETX101.

Other gene therapy modalities in preclinical stages include mRNA modulation via tRNA-based AAV gene therapy and NAV1.1 activators. Based on the discussion above, a treatment algorithm for suspected DS has been provided in Figure 1. The current list of various drugs in their phases of clinical trials are given in Figure 2.

Figure 1 Treatment algorithm for suspected DS. ASM = antiseizure medication, DS = Dravet syndrome

Figure 2 List of drugs in their phases of clinical trials

CONCLUSION

Treatment modalities for DS are evolving. We now have better evidence on the use of current ASMs. Repurposing of drugs with newer mechanisms of action like serotonin receptor modulation, cholesterol 24-hydroxylase inhibition, along with targeted gene therapies have improved the current outlook toward therapeutic options in DS. Though most of the newer studies are based on small sample size, the early results are promising, and many pharmaceutical companies are taking increasing interest in conducting drug trials for DS. Future drugs should not only focus on controlling the seizures, but also on overall improvement in the quality of life, including improved cognition and behavioral profile in children with DS. Clinical research across various geographic populations will aid in faster integration of newer treatment modalities into regular practice and help in bringing out better treatment guidelines for DS population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
==== Refs
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