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Therapeutic advances in Dravet syndrome: a

targeted literature review

Adam Strzelczyk & Susanne Schubert-Bast

To cite this article: Adam Strzelczyk & Susanne Schubert-Bast (2020) Therapeutic advances
in Dravet syndrome: a targeted literature review, Expert Review of Neurotherapeutics, 20:10,
1065-1079, DOI: 10.1080/14737175.2020.1801423

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EXPERT REVIEW OF NEUROTHERAPEUTICS
2020, VOL. 20, NO. 10, 1065–1079
https://doi.org/10.1080/14737175.2020.1801423

REVIEW

Therapeutic advances in Dravet syndrome: a targeted literature review

a,b a,b,c
Adam Strzelczyk and Susanne Schubert-Bast
a
Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, Frankfurt am Main, Germany; bLOEWE
Center for Personalized and Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany; cDepartment of
Neuropediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany

ABSTRACT ARTICLE HISTORY

Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy Received 22 May 2020
(DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in Accepted 23 July 2020
motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures KEYWORDS
remain poorly controlled, and there has been a considerable unmet need for effective and tolerable Cannabidiol; Dravet
treatments. syndrome; epileptic
Areas covered: This targeted literature review aims to highlight recent changes to the therapeutic encephalopathy; epilepsy;
landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data fenfluramine; stiripentol;
from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important mile­ rare diseases
stones for DS treatment, together with the latest findings of other pharmacotherapies in development.
In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and
fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are gen­
erally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in
convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was
associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine
of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and
clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense
oligonucleotides beginning to emerge from preclinical studies.
Expert opinion: Despite the challenges of drug development in rare diseases, this is an exciting time
for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may
pave the way for treatment advances in other DEEs.

1. Introduction motor, atypical, myoclonic, and absence) together with cogni­

tive, behavioral and motor impairments; the third ‘non-
The developmental and epileptic encephalopathies (DEEs) are
epileptic progressive stage’, occurring from 5 years of age
a heterogeneous group of rare but devastating early onset
into adulthood, is marked by a decrease in convulsive seizures
childhood epilepsy syndromes characterized by pharmacore­
which are now mainly nocturnal; however mental, motor, and
sistant seizures, cognitive dysfunction, and a poor prognosis
mobility impairments become more prominent in adult
[1]. One of the most well-characterized DEE is Dravet syn­
patients, with a consequential high level of dependency [6].
drome (DS), previously known as severe myoclonic epilepsy
SE, a state of prolonged seizure that requires emergency
of infancy (SMEI), which is predominantly caused by mutations
medical intervention, is common especially in the first years
in the SCN1A gene, which codes for the α-1 subunit of the
of life [7]. DS is also associated with a significantly higher risk
neuronal, voltage-gated sodium channel [2–4]. Based on
of premature mortality, due to SE, accidents, and sudden
advancements in the understanding of the molecular mechan­
unexpected death in epilepsy (SUDEP) [8].
isms and clinical features of DS, it is widely thought to be
DS is a rare condition, with a reported incidence of between 1
a clinically relevant model for other genetic diseases with
in 15,000 and 1 in 33,000 live births [9–11], however for those
epilepsy [5].
affected persons and their families the burden of this severe
DS, which typically starts in the first year of life in an
condition is immense [12–17]. Persons with DS have a poor
otherwise healthy infant, generally progresses in three stages
health-related quality of life (HRQoL), which is worse in those
[4]: the first ‘febrile stage’ is characterized by prolonged com­
with persisting and severe seizures and with comorbidities
plex febrile seizures (mostly clonic generalized and unilateral
[12,13], and the daily life of family caregivers are also profoundly
motor seizures) and status epilepticus (SE); during the second
affected, with demands on their physical and emotional states,
‘worsening stage’, occurring between the ages of 1 and
financial resources and personal time [14–17]. DS is also asso­
5 years, additional seizure types appear (e.g. generalized
ciated with higher direct healthcare costs than patients with

CONTACT Adam Strzelczyk strzelczyk@med.uni-frankfurt.de Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt, Frankfurt am Main 60528,
Germany
Supplemental data for this article can be accessed here.
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
1066 A. STRZELCZYK AND S. SCHUBERT-BAST
Article highlights
● Dravet syndrome is a prototypical example of a developmental and
epileptic encephalopathy (DEE).
● There is an unmet need for effective and tolerable treatments for DS
and other DEEs.
● Stiripentol, cannabidiol, and fenfluramine are new effective and well-
tolerated pharmacological treatments for DS.
● Pharmacologic treatment may also be supported by a ketogenic diet
or vagus nerve stimulation.
● Further treatment options with new drug approaches are under
development.
● The high research activity for DS will also benefit other DEEs, helping
to find effective therapeutic approaches in other entities.
other drug-resistant epilepsy [15], and high seizure burden and
comorbidities are related to higher healthcare costs [16,18].
DS is highly drug resistant, and seizure freedom is rare. The aim
of treatment is to reduce the frequency of seizures, particularly the
prolonged convulsive seizures which cause the most injuries and
hospitalizations [13,19], while minimizing the side effects of treat­
ment [3]. Valproate (VPA) and clobazam (CLB) are the generally
accepted first-line anti-epileptic drugs (AEDs) for DS, however,
these conventional AEDs are usually insufficient for most patients
[3]. Indeed, despite treatment with multiple AEDs, seizures often
remain poorly controlled [20–22]. To further complicate matters,
AEDs that block sodium channels are inappropriate for the treat­
ment of DS as they can worsen the condition [3,23]. Overall, there
has been a considerable unmet need for effective and tolerable
treatments that reduce seizures and improve QoL. Even now not
all therapeutic agents that have been developed for the treatment
of DS are available in all regions and there is also some divergency
in the indications (Figure 1).
Figure 1. Pharmacologic agents approved or in development for Dravet syndrome.
Footnote: CLB, clobazam; CNS, central nervous system; DS, Dravet syndrome, LGS, Lennox-Gastaut syndrome; VPA, valproic acid.
This review aims to highlight the recent changes to the
therapeutic landscape for DS by summarizing the most up-to-
date, evidence-based research, identified via a literature
review. This review supports previous recent reviews on the
treatment of DS [7,19,24–28], but includes a comprehensive
update of the data from the clinical development of stiripentol
(STP), cannabidiol (CBD) and fenfluramine (FFA) (including
newly-published key data from the pivotal phase III regulatory
trials of CBD and FFA), which are important milestones for the
treatment of seizures associated with DS, together with the
latest findings of other pharmacotherapies in development
(Figure 1). In addition, we sought to identify recent studies
on the efficacy and safety of non-pharmacological agents
(ketogenic diet [KD] and vagus nerve stimulation [VNS]).
2. Methods
The literature review was designed to capture clinical trials
and observational studies reporting on interventions in DS.
Studies were identified by a systematic search of MEDLINE
(Ovid interface). The search took the following form: ((search
terms for Dravet Syndrome) and (study design literature
search filters for randomized or controlled clinical studies (1)
OR observational studies (2) OR a pragmatic search for sys­
tematic reviews)). The search was run from database inception
(1946) to 31 March 2020, and it was not limited by language.
In addition, reference lists of relevant publications were
searched manually, and trial registries and regulatory websites
(the FDA and European Medicines Agency [EMA]) were also
searched for further studies. In addition, conference proceed­
ings from the American Epilepsy Society and the American
Academy of Neurology annual meetings for the years 2018 to
2020 were searched for updates to the pivotal RCTs identified

in the main search so that the most up-to-date evidence that
may not yet have been published in full could be included.
Only articles written in English were included. The inclusion
and exclusion criteria (PICOS criteria) used to screen the arti­
cles identified in the electronic searches are provided in
Supplemental Table S1. The publications were screened by
a single reviewer according to the PICOS criteria. Initially, titles
and abstracts were reviewed and articles were excluded if they
were not clearly relevant. Subsequently, the full articles of all
potentially relevant articles were retrieved and were reviewed
for inclusion. Finally, each article was summarized according to
the area of focus. The search terms are available in the
Supplemental information. The search was not a true systema­
tic review, and emphasis was placed on articles that included
pertinent information on treatment options. In addition, there
were some limitations that may have resulted in missing
articles: only the MEDLINE database was searched (not
EMBASE).
The electronic database search initially identified 954 arti­
cles. After the initial screening, a total of 168 articles were
retrieved for full-text assessment, of which 45 publications met
the eligibility criteria and were included in the review. Manual
searches identified an additional 21 documents, including 7
regulatory documents, 5 from clinical trial registries, and 9
conference abstracts.
3. Pharmacological agents
3.1. Stiripentol
STP is approved in conjunction with VPA and CLB as adjunc­
tive for DS in Europe, Canada, and Japan, and in the USA in
conjunction with CLB (Figure 1). The efficacy and safety of STP
has been evaluated in two phase III double-blind, placebo
controlled RCTs in patients aged ≥3 years with DS who were
experiencing at least four clonic or (tonic-clonic) generalized
seizures per month despite ongoing treatment with CLB and
VPA (Table 1) [29–32].
The trials showed that the addition of STP to VPA+CLB was
associated with significantly higher responder rates (at least
a 50% reduction in the frequency of convulsive seizures)
compared with placebo: 71% vs 5% (p < 0.0001) in STICLO-
France and 67% vs 9% (p = 0.0094) in STICLO-Italy (Table 2)
[29–32]. In addition, STP was superior to placebo for the
number of seizure-free patients (Table 2) [29–32]. The long-
term efficacy of STP has been demonstrated into adulthood in
patients who originally participated in the STICLO-France
study (Supplemental Table S2) [33].
Overall, STP was generally well tolerated. The largest differ­
ence between the STP and placebo treatment groups in the
two trials (>10%) was seen for somnolence, decreased appe­
tite, weight decreased, dysarthria, and nausea (Figure 2) [32].
Drug–drug interactions are also an important safety considera­
tion (Figure 3). Of note, STP increases the plasma concentra­
tion of CLB and its metabolite through metabolic inhibition of
CYP3A4 and CYP2C19, and therefore in case of adverse reac­
tions (i.e. drowsiness, hypotonia, and irritability in young chil­
dren) dose reductions of CLB of 25% every week are
recommended [29,34]. STP is both an inhibitor and inducer
EXPERT REVIEW OF NEUROTHERAPEUTICS 1067
of several CYP enzymes, and drug–drug interactions regarding
drugs that are substrates of these CYPs also need to be
considered, including CYP1A2 substrates (e.g. theophylline,
caffeine), CYP2B6 substrates (e.g. sertraline, thiotepa), and
CYP3A4 substrates (e.g. midazolam, triazolam, quinidine)
[29,34]. In addition, due to potential inhibition of enzyme/
transporter activity, dose reductions may be required in case
of adverse reactions for substrates of CYP2C8, CYP2C19 (e.g.
diazepam, clopidogrel), P-gp (e.g. carbamazepine), an BCRP
(e.g. methotrexate, prazosin, glyburide) [29,34]. Furthermore,
induction-based interactions leading to decreases in STP may
occur when co-administered with a potent CYP1A2, CYP3A4,
or CYP2C19 inducer, such as rifampin, phenytoin, phenobarbi­
tal and carbamazepine [29,34].
A number of observational studies have generally con­
firmed the long-term efficacy and tolerability of add-on STP
treatment in DS patients for up to 24 years (Supplemental
Table S2). Studies have reported reduced frequency and sever­
ity of seizures, and responder rates generally of between 49%
to 60% across studies [35–37]. Seizure freedom has been
reported in 2–10% of patients across studies with various
follow-up periods [33,35,37]. However, DeLiso reported that
in patients treated with STP (follow-up of up to 22 years,
median 8 years), 38% of patients (n = 20/52) treated with
STP still experienced ongoing weekly seizures (>3/month),
and 40% experienced monthly seizures [38], and Balestrini
et al reported responder rates of only 23% after 36 months
of treatment in a study of 13 adults with DS [39].
3.2. Cannabidiol
Although the mechanisms of action by which CBD exerts its
anti-seizure effects are still being fully elucidated, CBD pos­
sesses affinity for multiple targets that result in reductions in
neuronal excitability relevant to the pathophysiology of the
disease (Figure 1) [40]. CBD was first approved as adjunctive
therapy of seizures associated with Lennox-Gastaut syndrome
(LGS) or DS for patients 2 years of age and older in the USA in
2018 [41]; subsequently CBD gained approval in Europe in
2019 [42], but in conjunction with CLB based on clinical trial
data showing that the combination of CBD and CLB resulted in
greater efficacy than in the subgroup of patients not taking
CLB (Table 2) [42]. The FDA and EMA approvals were based on
data from two phase III double-blind, placebo-controlled RCTs
in patients aged 2–18 years with DS with seizures not con­
trolled with current AEDs: GWPCARE1 part B (referred to here
as GWPCARE1) and GWPCARE2 [43,44]. In GWPCARE1 patients
were randomized to receive either CBD oral solution at a dose
of 20 mg/kg/day or placebo, in addition to standard antiepi­
leptic treatment (Table 1) [43]. In GWPCARE2, patients were
randomized to receive CBD at a dose of 10 mg/kg per day
(CBD10 group) or 20 mg/kg/day (CBD20 group) or matched
placebo, in addition to current antiepileptic treatment
(Table 1) [44]. Of note, the recommended maintenance dose
of CBD is 10 mg/kg/day, with dose increases up to 20 mg/kg/
day allowed [41,42].
Overall, these pivotal trials demonstrated that adjunctive CBD
resulted in a greater reduction in convulsive-seizure frequency
 1068

Table 1. Study and baseline characteristics of the pivotal phase III studies for the treatment of Dravet syndrome.
Age: mean Seizure frequency per Previous AEDs: Concomitant
Author (year), study Intervention/ (SD) [range or 28 days: mean (SD) mean (SD) AEDs: mean (SD) Primary
name, location Study design Population Comparator (n) IQR], years Male, n (%) [median: range or IQR] [median: range]a [median: range]a outcome
Stiripentol
Chiron [30,31] Phase III, double-blind, Patients with SMEI (DS) STP(+CLB+VPA) 9.4 (4) [IQR: 6 (29) 17.9 (17.3) [18: IQR: 4–7; 6.6 (2.5) [3–11] NR Response rateb
STICLO-France multicentre placebo (≥3 years) (n = 21) 3–16.7] range 3.9–72.9]
controlled, RCT Placebo (+CLB 9.3 (4.86) 11 (55) 18.5 (17.0) [19: IQR 4–76; 7.5 (2.9) [3–13] NR
+VPA) (n = 20) [IQR:3.2–20.7] range 4.1–76.2]
STICLO-Italy [31] Phase III, double-blind, Patients with SMEI (DS) STP(+CLB+VPA) 9.17 (3.63) 8 (66.7) 33.6 (28.2) [2.14–86.1] NR NR Response rateb
multicentre placebo (≥3 years) (n = 12)
controlled, RCT Placebo (+CLB 8.72 (4.43) 5 (45.5) 27.4 (28.6) [3.75–101] NR NR
+VPA) (n = 11)
Cannabidiol
Devinsky [43] Phase III, double-blind, Patients with DS CBD 20 mg/kg/day 9.7 (4.7) 35 (57) [12.4: 3.9–1717]b 4.6 (4.3) 3.0 (1.0) Change from
A. STRZELCZYK AND S. SCHUBERT-BAST

GWPCARE1 part multinational placebo (2–18 years) with (n = 61) [2.5–18.0] baseline
B (NCT02091375), controlled, RCT seizures Placebo (n = 59) 9.8 (4.8) 27 (46) [14.9: 3.7–718]c 4.6 (3.3) 2.9 (1.0) MCSF
Europe & USA not controlled with [2.3–18.4]
current AEDs
Miller [44] Phase III, double-blind, Patients with DS CBD 10 mg/kg/day 9.2 (4.3) 27 (41) [14: IQR 6–31]c [4: 0–19] [3: 1–5] Change from
GWPCARE2 multinational placebo (2–18 years) with (n = 66) [2.3–17.7] baseline
(NCT02224703), controlled, RCT seizures CBD 20 mg/kg/day 9.3 (4.3) 36 (54) [9: IQR: 6–21]c [4: 0–11] [3: 1–4] MCSF
Europe, USA and not controlled with (n = 67) [2.2–18.9]
Australia current AEDs Placebo (n = 65) 9.6 (4.6) 31 (48) [17: IQR: 7–51.1]c [4: 0–11] [3: 1–5]
[2.2–18.1]
Fenfluramine
Lagae [47] Identical phase III, Patients (2–18 years) with FFA 8.8 (4.4) [2–18] 21 (52) 31.4 (30.6) [20.7: 4.8–124]c NR 2.3 (0.9) Change from
NCT02682927 USA multinational, double- DS with seizures not 0.7 mg/kg/day baseline
and Canada and blind, placebo controlled, completely (n = 40) MCSF
NCT02826863 RCTs controlled by current FFA 9.0 (4.5) [2–17] 22 (56) 45.5 (99.8) [17.5: NR 2.5 (1.1) (FFA 0.7 mg/kg
Europe and AEDs and 0.2 mg/kg/day 4.7–623.5]c per day vs
Australia other therapies. (n = 39) placebo)
FFA Study 1 Placebo (n = 40) 9.2 (5.1) [2–18] 21 (52) 44.2 (40.2) [27.3: NR 2.5 (0.9)
3.3–147.3]c
Nabbout [48] Phase III, double-blind, Patients with DS FFA 0.4 mg/kg/day 8.8 (4.6) [2–18] 23 (53) 27.9 (36.9) [14.0: 3–213]c NR NR (2 = 2%; Change from
NCT02926898, multinational placebo (2–18 years) with (n = 43) 3 = 44%; baseline in
Europe, USA and controlled, RCT seizures 4 = 37%; MCSF vs
Canada poorly controlled with 5 = 16%) placebo
FFA Study ZX008- current AEDs, Placebo (n = 44) 9.4 (5.1) [2–19] 27 (61) 21.6 (27.6) [10.7: 3–163]c NR NR (2 = 2%;
1504 including STP+CLB or 3 = 59%;
VPA 4 = 36%;
5 = 2%)
a
In STICLO France and Italy, patients were being treated with VPA and CLB [29–32]. In GWPCARE1 part B the most common AEDs at baseline were CLB (65%), VPA (59%), STP (42%), levetiracetam (28%), and topiramate (26%)
[43]. In GWPCARE2 the most common concomitant AEDs were VPA (70.2%), CLB (63.6%), STP (36%), levetiracetam (27%), and topiramate (23%) [44]. In FFA Study 1, the most common AEDs at baseline included VPA (60%),
CLB (59%), topiramate (25%), and levetiracetam (22%); 49% patients had previously been treated with STP and 26% with CBD [47]. In FFA Study ZX008-1504, as per protocol, all patients had and continued to be treated with
STP; other concomitant AEDs included CLB (94%), VPA (89%), topiramate (24%) and levetiracetam (13%) [48]. b Responder is defined as a patient with a greater than 50% decrease in frequency of generalized tonic-clonic or
clonic seizures; c Convulsive seizures.
AEDs, antiepileptic drug regimens, CBD, cannabidiol; CLB, clobazam, DS, Dravet syndrome; FFA, fenfluramine; IQR, inter-quartile range; MCSF, monthly convulsive seizure frequency; NR, not reported; SD, standard deviation;
STP, stiripentol; SMEI, severe myoclonic epilepsy in infants; VPA, valproic acid.
Table 2. Efficacy in the pivotal phase III studies for the treatment of Dravet syndrome.
Percentage change in Difference from placebo ≥50% reduction in MCSF from
MCSF in MCSF baseline, n (%) Percentage change in total seizure frequency Seizure free patients
Study: Treatment Median (95% CI); n (%) Median (range); Change from placebo
period/follow-up Study arms Median (range) p value [95% CI] OR (95% CI; p value p value (95% CI); p value n (%) [95% CI]; p value
Stiripentol
Chiron [29–31] STP (+CLB+VPA) (n = 21) Mean (SD): −69 (42) 0.0002 15 (71) p < 0.0001 NR NR 9 (43) [21.9 to 65.9]; p = 0.0013
STICLO-France Median (range): −91 [52.1 to
2-month (8 week) (−100 to 28)a 90.7]
treatment period Placebo (+CLB+VPA) (n = 20) Mean (SD): 7.6 (38) - 1 (5) - NR NR 0 [0.0 to 13.9]
Median (range): 7.4 (−75 [0 to
to 65) 14.6]
STICLO-Italy [29,31] STP(+CLB+VPA) (n = 12) Mean (SD): 0.0056 8 (66.7) p = 0.0094 NR NR 3/11 (27); p = 0.05
2-month (8 week) -74 (27) [34.9 to
treatment period Median (range): −81 90.2]
(−100 to −33)a
Placebo (+CLB+VPA) (n = 11) Mean (SD): −13 (62) - 1 (9.1) - NR NR 0/9 (0)
Median (range) [0.0 to
-27 (−87 to 140) 41.3]
Cannabidiol
Devinsky [43] CBD 20 mg/kg/day (n = 61) −38.9 (−100 to 337) −22.8 (−41.1 to −5.4); 26 (43) 2.00 (0.93 to 4.30); −28.6 −19.20 (−39.25 to −1.17); 3 (5); p = 0.08
GWPCARE1 part B; p = 0.01 p = 0.08 p = 0.03
GWEP1332B Placebo (n = 59) −13.3 (−91.5 to 230) - 16 (27) - −9.0 - 0
NCT02091375 CBD 20 mg/kg/day + CLB 53.6 42.8 (17.4 to 60.4) 19 (47.5) p = 0.0382 NRb NR NR
14-week treatment subgroup (n = 40) p = 0.0032
period Placebo + CLB subgroup 18.9 9 (23.7) - NR NR NR
(n = 38)
Miller [44] CBD 10 mg/kg/day (n = 66) −48.7 29.8 (8.4 to 46.2); 29 (43.9) 2.21 56.4; 38.0 2
GWPCARE2/ p = 0.01 (1.06 to 4.62); (20.1 to 51.9);
GWEP1424/ p = 0.03 p < 0.001
NCT02224703 CBD 20 mg/kg/day (n = 67) −45.7 25.7 (32.9 to 43.2); 33 (49.3) 2.74 (1.32 to 5.70); 47.3 25.1 (3.5 to 41.9); 2
14-week treatment p = 0.03 p = 0.007 p = 0.03
period Placebo (n = 65) −26.9 - 17 (26.2) - 29.7 - 1
CBD 10 mg/kg/day + CLB 60.9 37.4 (13.9 to 54.5); 25 (55.6) p = 0.0623 NRb NR NR
subgroup (n = 45) p = 0.0042
CBD 20 mg/kg/day + CLB 56.8 30.8 (3.6, 50.4); 25 (62.5) p = 0.0130 NR NR NR
subgroup (n = 40) p = 0.0297
Placebo (n = 65) + CLB 37.6 - 15 (36.6) - NR NR NR
subgroup (n = 41)
Fenfluramine
Lagae [47] FFA −74.9 (−100 to 196.4); −62.3 (−47.7 to −72.8); 27 (68) 15.0 (4.5 to 50.0); −68.3 (−100 to p < 0.0001 3 (8)
NCT02682927 0.7 mg/kg/day (n = 40) p < 0.0001 p < 0.0001 p < 0.0001 35.6) (≤1 convulsive seizure: 10 (25))
NCT02826863 FFA −42.3 (−100 to 197.6); −32.4 (−6.2 to −51.3); 15 (38) 4.8 (1.5 to 15.0); −41.1 (−100 to p = 0.0202 3 (8)
FFA Study 1 0.2 mg/kg/day p = 0.2035 p = 0.0209 p = 0.0091 292); (≤1 convulsive seizure: 5 (12.8))
14-week treatment (n = 39)
period Placebo (n = 40) −19.2 (−76.1 to 51.8) - 5 (12) - −16.2 (−77.6 to - 0
601) (≤1 convulsive seizure: 0)
Nabbout [48] FFA 0.4 mg/kg/day (n = 43) 63.1 (−100.0 to −54.0 (35.6–67.2; 23 (54) 26.0 (5.5–123.2); −41.1 (−100.0 p = 0.003 1 (2) [0.1–12.3]; p = 0.49
NCT02926898 115.0); p < 0.001 p < 0.001 to 133.2) (≤1convulsive seizure: 5 (12)
FFA Study ZX008- p < 0.001 [3.9–25.1]; p = 0.03)
1504 Placebo (n = 44) 1.1 (−82.8% – 435.1%) - 2 (5) - −5.9 (−73.8 to - 0 (0) [0.0–8.0]
EXPERT REVIEW OF NEUROTHERAPEUTICS

Combined titration 375.6) (≤1convulsive seizure: 0 (0)

(3 weeks) and [0.0–8.0])
maintenance
period (12 weeks)
a
1069

Frequency of generalized tonic-clonic or clonic seizures during month 2

b
The SmPC for CBD reported that in a subgroup of patients treated with concomitant CLB patients receiving CBD experienced a greater percentage reduction in total seizures compared with placebo (66% 10 mg/kg/day, 54%
to 58% 20 mg/kg/day, 27% to 41% placebo; p = 0.0003 for 10 mg/kg/day and p = 0.0341 and 0.0211 for 20 mg/kg/day vs. placebo) [42].
CBD, cannabidiol; CI, confidence interval; FFA, fenfluramine; MCSF, monthly convulsive seizure frequency; NR, not reported; OR, odds ratio; STP, stiripentol.
1070 A. STRZELCZYK AND S. SCHUBERT-BAST

Figure 2. Treatment-emergent adverse events occurring in ≥10% patients in the pivotal Dravet syndrome phase III trials.
Footnote: CBD10 and 20, cannabidiol 10, and 20 mg/kg per day; CI, confidence interval; FFA0.2, 0.4 and 0.7, fenfluramine 0.2, 0.4, and 0.7 mg/kg per day; PBO, placebo; STP, stiripentol.

Figure 3. Drug interactions with stiripentol, cannabidiol and fenfluramine.

Footnote: From [29,34,41,42,49,57,58]: CLB, clobazam; PK, pharmacokinetic; VPA, valproic acid.

than placebo (Table 2) [43,44]. In GWPCARE1 the median fre­
quency of convulsive seizures per month decreased from base­
line with an adjusted median difference vs placebo of −22.8%
(95% CI −41.1 to −5.4; p = 0.01) [43]. Likewise, in GWPCARE2 the
percentage reduction from baseline in convulsive seizure fre­
quency was significantly greater with CBD (both CBD10 and
CBD20) compared to placebo, with a percentage reduction
from placebo of 29.8% (95% CI 8.4%-46.2%; p = 0.01) for CBD10
and 25.7% (95% CI 2.9%-43.2%; p = 0.03) for CBD20 [44]. Both
trials also reported significant percentage reductions in total
seizure frequency with CBD vs placebo (Table 2). In addition,
the proportion of patients achieving at least a 50% reduction
from baseline in convulsive seizure frequency during the treat­
ment period was significantly greater with CBD than placebo
(Table 2). In GWPCARE1 freedom from convulsive seizures during
the 14-week treatment period was achieved by 3 patients in the

CBD group and none in the placebo group (p = 0.08), and in
GWPCARE2 in 2 patients each in the CBD10 and CBD20 groups vs
1 in the placebo group. The use of rescue medication and
inpatient hospitalizations due to epilepsy were reported in
GWPCARE1: rescue medication was used by 59% in the CBD
group vs 69% in the control group, and there were no change
from baseline in inpatient hospitalizations due to epilepsy com­
pared to placebo (difference [95% CI]: 0.0 [0.0 to 0.1]).
Compared with placebo, caregivers of CBD-treated patients
were significantly more likely to report an improvement in
overall condition, assessed using the Caregiver Global
Impression of Change (CGIC) (Table 3) [43,44]. In both trials
there was no significant difference between groups in the
sleep-disruption score and Epworth Sleepiness Scale score,
suggesting that there was no negative effect of CBD on
sleep. In addition, the Quality of Life in Childhood Epilepsy
and Vineland Adaptive Behavior Scales II scores showed no
significant difference between CBD and placebo [43,44].
As mentioned above, the efficacy of CBD was greater in the
subgroup of patients treated with concomitant CLB with
regard to median percentage reduction in convulsive seizures
compared with placebo, responder rates, reductions in total
seizures, and CGIC-assessed improvements (Tables 2 and 3)
[42]. In addition, CBD+CLB was associated with an increase in
the number of convulsive seizure-free days during the treat­
ment period in each trial, equivalent to 2.7 days per 28 days
(10 mg/kg/day) and 1.3 to 2.2 days per 28 days (20 mg/kg/
day) [42].
The long-term efficacy and safety of CBD is being assessed
in GWPCARE5 (NCT02224573), an open label extension study
of CBD, which includes patients who completed GWPCARE1
Part A (NCT02091206) or Part B, or GWPCARE2 [45]. Overall,
264 patients with DS were treated with long-term CBD (mean
modal dose 21 mg/kg/d, median treatment 274 days, with
a median of 3 concomitant AEDs). CBD improved the long-
term seizure frequency up to 48 weeks of treatment; the
median reduction in monthly convulsive seizure frequency
from baseline to Week 12 was 37.5%, which was maintained
at weeks 13-24, 25-36, and 37-48 (42.9%-44.3%). In addition, 5/
104 (4.8%) patients were convulsive seizure-free in their last
12 weeks of treatment, and 44%-45% of patients had convul­
sive seizure-frequency reductions of ≥50% across each 12-
week visit window up to 48 weeks. Of note, the long-term
efficacy and safety of CBD has also been confirmed in an
expanded access program in the US in children and adults
with DS (n = 54) or LGS, (n = 152), although the data were only
presented for the pooled DS/LGS population (Supplementary
Table S2).
The most common TEAEs with CBD across trials, including
the OLE trial, included somnolence, decreased appetite, diar­
rhea, vomiting, fatigue, and pyrexia (Figure 2) [43–45].
Elevated liver transaminase levels occurred more frequently
in the CBD groups across both trials, with all affected patients
taking concomitant VPA. Of note, CBD lacks appreciable affi­
nity or activity at the cannabinoid receptors and lacks the
psychoactivity of the archetypal cannabinoid, tetrahydrocan­
nabinol [43]. No instances of suicidal ideation have been
reported, as assessed using the Columbia Suicide Severity
EXPERT REVIEW OF NEUROTHERAPEUTICS 1071
Rating Scale in patients ≥6 years of age, when appropriate
[43]. However, because suicidal behavior and ideation have
been reported in patients treated with AEDs in several indica­
tions, the SmPC and the US prescribing information for CBD
(and for STP) advises that patients should be carefully mon­
itored for suicidal behavior and thoughts [41,42]. Other warn­
ings include that concomitant use of VPA and higher doses of
CBD increase the risk of transaminase elevations (Figure 3),
and that there is a need to monitor patients for somnolence
and sedation, the occurrence of which is higher with conco­
mitant CLB [41,42]. The combination of CBD with CLB results in
a bidirectional drug-drug interaction that increases levels of
active metabolites of both compounds (Figure 3), and reduc­
tions in the dose of CLB are recommended if somnolence or
sedation are experienced when the two are co-administered.
CBD also has the potential to affect several CYP and UGT
substrates (Figure 3).
3.3. Fenfluramine
FFA is also a promising new ‘targeted’ treatment for DS, with
evidence that it exerts its anti-epileptic activity by multiple
mechanisms including stimulating multiple 5-HT receptor sub-
types through the release of serotonin, as well as acting as
a positive modulator of sigma-1 receptors (Figure 1) [27,46].
The efficacy and safety of FFA has been assessed in three
phase III double-blind, placebo-controlled RCTs in patients
aged 2–18 years with DS: NCT02682927 (Study ZX008-1501),
NCT02826863 (Study ZX008-1502) (identical trials with merged
datasets before unblinding of results and analysis) [Study 1])
and NCT02926898 (Study ZX008-1504) [47,48]. Based on the
data from these studies, FFA has recently been approved by
the FDA (June 2020) [49], and is currently awaiting a decision
by the EMA.
In FFA Study 1 patients were randomized in a 1:1:1 ratio to
FFA 0.2 mg/kg per day (FFA0.2 group) or 0.7 mg/kg per day
(FFA0.7 group), or placebo in addition to existing AED regi­
mens; treatment with STP was an exclusion criterion due to
a lack of pharmacokinetic (PK) data to evaluate dosage mod­
ifications needed to compensate for an expected FFA-STP
drug interaction. However, given the widespread use of STP
for DS, NCT02926898 (Study ZX008-1504) was later designed
to enroll patients with DS receiving a stable, STP-inclusive AED
regimen where patients were randomized in a 1:1 ratio to
receive a lower dose of FFA (0.4 mg/kg per day [FFA0.4]
based on PK data) or matching placebo, in addition to their
AED regimen.
The studies showed that FFA was associated with signifi­
cant improvements in monthly convulsive seizure frequency in
patients with DS [47,48]. In FFA Study 1 the adjusted median
difference in mean monthly convulsive seizure frequency vs
placebo was 62.3% (95% CI 47.7–72.8, p < 0.0001) for FFA0.7,
32.4% (95% CI 6.2–51.3, p = 0.0209) for FFA0.2, and in Study
ZX008-1504 54.0% (95% CI 35.6%-67.2%; p < 0.001) for FFA0.4
[47,48]. FFA was also associated with greater reductions from
baseline in total seizure frequency (Table 2). Significantly more
patients treated with FFA than placebo experienced a clinically
meaningful (≥50%) reduction in mean convulsive seizure
Table 3. Additional secondary efficacy outcomes in pivotal phase III studies.
1072

Percentage change in nonconvulsive seizure Seizure-

frequency per 28 days free days Seizure free interval CGIC
Median (range); Change from placebo Median Treatment differences vs Very much or much
Study: Treatment period/follow-up Study arms p value (95% CI); p value N; p value (range) placebo, median (95% CI) improved Any improvement
Stiripentol
Chiron (2000) STP(+CLB+VPA) NR NR NR NR NR NR NR
STICLO-France (n = 21)
2-month (8 week) treatment period Placebo (+CLB NR NR NR NR NR NR NR
+VPA) (n = 20)
STICLO-Italy STP(+CLB+VPA) NR NR NR NR NR NR NR
2-month (8 week) treatment period (n = 12)
Placebo (+CLB NR - NR NR NR NR NR
+VPA) (n = 11)
Cannabidiol
Devinsky (2017) CBD20 mg/kg/ NR 0.00 (−21.36 to 31.59); NRa NR NR NR Parent/caregiver rating:
GWPCARE1 part B; GWEP1332B day (n = 61) 0.88 37/60 (62); p = 0.02b
A. STRZELCZYK AND S. SCHUBERT-BAST

NCT02091375 Placebo (n = 59) NR - NR NR NR NR Parent/caregiver rating:

14-week treatment period 20/58 (34)
Miller (2020) CBD 10 mg/kg/ NR 40.7 (12.4 to 59.9) NRa NR NR Parent/caregiver rating: Parent/caregiver rating:
GWPCARE2/GWEP1424/NCT02224703 day (n = 66) 21/66 (32) 45/66 (68.2);
14-week treatment period p < 0.001b
CBD 20 mg/kg/ NR 20.6 NR NR NR Parent/caregiver rating: Parent/caregiver rating:
day (n = 67) (−18.1 to 46.6) 24/66 (36) 40/66 (60.6);
p = 0.03
Placebo (n = 65) NR - NR NR NR Parent/caregiver rating: Parent/caregiver rating:
9/65 (14) 27/65 (41.5)
Fenfluramine
Lagae (2020) FFA −76.0 (−100 to NR NR 25.0 (2 to 15.5 (6 to 25); p = 0.0001 Parent/caregiver rating: NR
NCT02682927 NCT02826863 0.7 mg/kg/day 69.2); 97) 22 (55); p < 0.0001
FFA Study 1 (n = 40) p = 0.0458 c Investigator rating: 25
14-week treatment period (62); p < 0.0001
FFA −50.6 (−100 to 534); NR NR 15 (3 to 4.5 (0 to 9); p = 0.0352 Parent/caregiver rating: NR
0.2 mg/kg/day p = 0.7585 c 106) 16 (41); p = 0.0036
(n = 39) Investigator rating: 16
(41); p = 0.0032
Placebo (n = 40) −55.6 (−100 to NR NR 9.5 (2 to - Parent/caregiver rating: 4 NR
723.6)c 23) (10)
Investigator rating: 4 (10)
Nabbout (2019) FFA 0.4 mg/kg/ −0.5 (−100.0 to NR 24.4 22.0 NR; p = 0.004 Parent/caregiver rating: Parent/caregiver rating:
NCT02926898 day (n = 43) 611.2); p = 0.18 [1.9–28.0]; (3.0–105.0) 14 (33); 26 (61); p = 0.009
FFA Study ZX008-1504 p = 0.001 p = 0.14 Investigator rating: 31
Combined titration (3 weeks) and Investigator rating: 19 (72); p < 0.001
maintenance period (12 weeks) (44); p = 0.008
Placebo (n = 44) −49.7 (−100.0 to NR 20.3 13.0 - Parent/caregiver rating: 9 Parent/caregiver rating:
529.4) [0.0–26.4] (1.0–40.0) (21) 16 (36)
Investigator rating: 7 (16) Investigator rating: 14 (32)
a
The SmPC for CBD reported that in a subgroup of patients treated with concomitant CLB, CBD was associated with an increase in the number of convulsive seizure-free days during the treatment period in each trial,
equivalent to 2.7 days per 28 days (10 mg/kg/day) and 1.3 to 2.2 days per 28 days (20 mg/kg/day).
b
The SmPC for CBD reported that in a subgroup of patients treated with concomitant CLB greater improvements in overall condition were reported by caregivers and patients with both doses of cannabidiol (73% on 10 mg/kg/
day, 62 to 77% on 20 mg/kg/day, 30% to 41% on placebo; p = 0.0009 for 10 mg/kg/day
and p = 0.0018 and 0.0136 for 20 mg/kg/day vs. placebo).
c
Other seizure types, which included focal seizures without clearly observable motor signs, absence or atypical absence, myoclonic, atonic, and other or unclassifiable
CGIC, Caregiver Global Impression of Change; CBD, cannabidiol; CI, confidence interval; FFA, fenfluramine; NR, not reported; NS, non-significant; OR, odds ratio

frequency (Table 2). In Study 1 seizure freedom during the
entire 14-week treatment period was observed in 3 (8%)
patients in the FFA0.7 group, 3 (8%) patients in the FFA0.2
group, and no patients in the placebo group, with only one
seizure reported during the entire 14-week treatment period
by 7 (18%) patients in the FFA0.7 group, 2 (5%) patients in the
FFA0.2 group compared to none in the placebo group [47].
Likewise in Study ZX008-1504, statistically significant increases
in the number of patients experiencing no more than a single
convulsive seizure during the treatment period were reported:
5 (12%) vs 0 (p = 0.03) [48]. FFA was associated with a greater
reduction in days of rescue medication in both studies.
FFA was associated with significantly longer seizure-free
intervals (Table 3). In addition, the median number of convul­
sive seizure-free days was significantly higher in patients trea­
ted with FFA than placebo [48].
Patients who completed one of the phase III clinical trials
could enroll in an open-label extension (OLE) study
(NCT02823145; Study ZX008-1503), with results reported at
12 months [50], and 2 years [51]. FFA has continued to provide
clinically meaningful and substantial reductions in convulsive
seizure frequency over a median duration of treatment of
445 days (range, 7–899 days; n = 330 patients). The
median percent reduction in monthly convulsive seizure fre­
quency over the entire OLE treatment period as compared
with the baseline frequency established in the core phase III
studies was 83.3%. Overall, 62% of patients demonstrated
a 50% reduction in convulsive seizure frequency.
Using the CGIC, significantly more patients receiving FFA
than placebo were rated as having any improvement by both
investigators and caregivers [48], or as having much improved
or very much improved by both caregivers and investigators
(Table 3) [47]. In addition, in the OLE trial, 66.1% of caregivers
and 65.9% of investigators rated patients as ‘much improved’
or ‘very much improved’ after 12 months of treatment [50].
In Study ZX008-1504 no significant differences were
reported between FFA and placebo for the Quality of Life in
Childhood Epilepsy Scale, Pediatric Quality of Life Inventory,
and Behavior Rating Inventory of Executive Function (BRIEF)
[48]. In FFA Study 1, while there was no difference between
FFA and placebo in the Quality of Life in Childhood Epilepsy
instrument, the Pediatric Quality of Life Inventory showed
improvement in both FFA groups compared with placebo
[47]. In addition, patients in the FFA0.7 group had significant
improvements from baseline in the BRIEF Behavioral
Regulatory Index and Global Executive Composite score [47].
A post-hoc analysis of 77 patients who completed the BRIEF2
showed statistically significant and clinically meaningful
improvements in behavior regulation and emotion regulation,
and some components of cognitive regulation (i.e. plan/orga­
nize) [52]. Further analysis in the OLE study confirmed that
reduction in monthly convulsive seizure frequency (MCSF)
after 1 year of treatment with add-on FFA was associated
with improvement in overall executive function assessed
using the BRIEF2 tool, and in particular, patients who had
profound reduction in MCSF (≥75%) were significantly more
likely to show clinically meaningful improvements in overall
executive function than patients who had minimal reduction
in MCSF (<25%) [53].
EXPERT REVIEW OF NEUROTHERAPEUTICS 1073
The most common TEAEs with FFA across the two trials
included decreases in appetite, weight loss, diarrhea, fati­
gue, lethargy, and pyrexia (Figure 2) [47,48]. In the OLE
trial, TEAEs occurring in ≥15% of patients with up to
2 years of FFA treatment were nasopharyngitis (23%), pyr­
exia (23%), decreased appetite (21%), and diarrhea (15%)
[51]. FFA was previously marketed as an appetite suppres­
sant, but was withdrawn from the market in 1997 for this
indication due to reports of cardiac valve disease, however,
FFA doses were high (up to 120 mg/day compared to
a licensed maximum dose of 26 mg/day for DS), and it
was frequently given off-label with phentermine which
itself has an influence on valvular disease [54–56]. No
cases of valvular heart disease or pulmonary arterial hyper­
tension have been reported in the FFA studies, including
the long-term OLE study [55]. That being said, cardiovas­
cular safety will still need to be carefully monitored in DS
patients treated with FFA. Studies have reported that FFA
has no significant impact on the PK of STP, CLB, VPA [57],
and CBD [58], although the STP+VPA+CLB regimen
increased the peak plasma levels and systematic exposure
of FFA demonstrating the need to reduce the dose of FFA
when administered in combination with the STP regimen
(Figure 3) [57].
Of note, results from a compassionate use program granted
by a Belgian Royal Decree in 2002, which allowed patients
with DS given FFA under a treatment protocol, have also
provided evidence that daily FFA for up to 27 years provides
sustained, clinically significant reductions in seizure frequency,
without evidence of cardiopulmonary disease, as reported by
Ceulemans 2012 and Ceulemans 2016 (Supplementary Table
S2) [59,60].
4. Non-pharmacological agents
4.1. Ketogenic diet (KD)
The KD is a high-fat, adequate-protein and low carbohydrate
diet that mimics the biochemical response to starvation so
that ketone bodies rather than glucose are the main fuel for
the brain [61]. The mechanism of action of the KD in redu­
cing seizures is still being investigated, however multiple
mechanisms affecting neuronal structure and/or function
have been suggested [62]. Several retrospective and prospec­
tive studies have provided evidence on the efficacy and
tolerability of the KD. The KD is associated with reductions
in the frequency of convulsive and other seizures [63–69],
even leading to some patients being seizure-free [63–
65,67,68], and is well tolerated [63–69]. Responder rates of
between 38 and 85% have been reported across studies
[63,65–67,69,70]. The effect of the KD appears to be inde­
pendent of age at initiation [63,67–69], however, some stu­
dies have noted issues in adhering to the diet [63,64],
especially in solid fed older children compared with infants
treated with the liquid ketogenic formula [63]. KD may also
be beneficial on behavior disturbances including hyperactiv­
ity [65], cognitive, and other neuropsychological develop­
mental aspects [69,70], and quality of life [67].
1074 A. STRZELCZYK AND S. SCHUBERT-BAST
4.2. Vagus nerve stimulation
VNS consists of intermittent electrical stimulation of the left
cervical vagus nerve by an implanted helical electrode that is
connected to a pulse generator [71]. Dibué-Adjei et al. per­
formed a meta-analysis of 68 patients with DS; overall 52.9%
of patients experienced a ≥ 50% reduction of seizures, and
while the rates varied between 0 and 100% across all 13
studies, they were similar in nearly all studies with more
than 6 DS patients (75%, 67%, 50%, 38%, 50%, 38%) [71].
Hoarseness was the most frequently reported side-effect.
Overall, VNS appears to be beneficial in a proportion of
patients with DS.
5. Potential future treatments: therapeutic agents in
development
A number of agents are in development for the treatment of
DS (Figure 1). Soticlestat (TAK-935/OV935), a novel highly
selective first-in-class inhibitor of the brain-specific enzyme
cholesterol 24-hydroxylase (CH24H) [72], is being evaluated
in two phase II trials for DEEs including DS: the ELEKTRA trial
(NCT03650452) [73], and the ENDYMION trial [74]. Ataluren,
which is already indicated for the treatment of Duchenne
muscular dystrophy, where it promotes readthrough of
a nonsense mutation to produce full-length functional dystro­
phin protein [75], is being evaluated in a phase II trial in
patients with DS resulting from a nonsense mutation
(NCT02758626) [76]. Verapamil, a voltage-gated calcium chan­
nel blocker currently used to treat hypertension, angina, and
certain heart rhythm disorders [77], showed a partial (reduc­
tion of 50–99%) response for all types of seizures over a 14-
month period in a pilot study in 3/4 patients with DS [77].
Verapamil has also been assessed in a phase II trial in children
and young adults with DS (NCT01607073) [78], although while
the trial was completed in 2015, the data have yet to be
reported. Phenotypic screening of drug libraries in
a preclinical model using zebrafish scn1 mutants identified
the serotonin (5-HT) modulators clemizole (EPX-100), lorca­
serin (EPX-200) and trazodone (EPX-300) as potential clinical
treatments for DS [79,80], with clemizole being assessed in
a phase I trial in healthy subjects (NCT04069689) [81].
Strategies to treat the underlying cause of DS, including
gene therapy [82,83], and antisense oligonucleotides (ASO)
[84,85] are also beginning to emerge from preclinical studies.
While gene therapy should be amenable for SCN1A-related DS,
progress has been hampered by current technologies that
have limited cell-type selectivity and cannot accommodate
large, complex genes like SCN1A. To overcome these limita­
tions, the development of an adenoassociated viral vector
containing an engineered transcription factor for the upregu­
lation of endogenous SCN1A controlled by a GABA-selective
human regulatory element has been reported [82,83]. When
administered to SCN1A+/− mice the novel vector significantly
reduced hyperthermic seizures, decreased the frequency and
duration of electrographic seizures, and significantly reduced
the risk for SUDEP by 89% [82,83]. Antisense oligonucleotides
(ASOs) are also a valuable technology for the treatment of
severe genetic diseases that work by targeting RNA splicing to
increase gene expression. TANGO (Targeted Augmentation of
Nuclear Gene Output) is an ASO-based therapy being devel­
oped for DS, designed to increase the SCN1A protein to
normal levels by upregulating NaV1.1 protein expression
from the non-mutant copy of the SCN1A gene; it has shown
promising preclinical results [84,85], which is expected to
shortly advance to clinical development.
6. Conclusions
Overall, STP, CBD and FFA have all shown significant efficacy
for seizure control and are generally well tolerated, with
acceptable safety profiles. However, head-to-head trials
would be needed to fully decipher the comparative efficacy,
although indirect treatment comparison and network-meta-
analysis studies could also be useful for evidence-based
healthcare decision making. In the STP trials responder rates
were 67%-71%, and in the FFA trials they were 68% with
FFA0.7 and 54% with FFA0.4; however, they were lower for
CBD especially in the overall trial population (43–49% across
trials and doses) compared to the subgroup of patients with
CLB (48%-63%), which has implications in the US where the
indication does not specify concomitant CLB, in contrast to the
EU. In this respect, the interaction between CBD and CLB has
also led to the speculation that the efficacy of CBD may simply
reflect a CBD-associated increase in the plasma concentration
of CLB. However, recent systematic reviews and meta-analyses
of trials in patients with DS and LGS has provided evidence
that CBD has therapeutic effects that are (at least partly)
independent of its interaction with CLB; while improvement
in seizure control over placebo was greatest in patients with
CBD plus CLB, seizure control was also improved vs placebo in
patients with other medications [86–88].
STP, CBD and FFA have demonstrated convulsive seizure-
freedom and additional seizure-free days/intervals in the pivotal
clinical trials and/or observational studies (Tables 2 and 3 and
Supplemental Table S2). Increases in seizure-free time are likely
to help reduce the burden of care for family/caregivers, even
allowing some free time, while also providing time for the child
to attend rehabilitation programs [22]. With regards to improve­
ments in quality of life, both FFA and CBD were associated with
improvements in the CGIC. Reducing seizure frequency may also
alleviate some health-related costs of treating DS, especially
those associated with hospitalizations [89].
In addition to being a severe epileptic syndrome, impairment
in cognition and neurodevelopment are also important conse­
quence of DS, with negative impacts on QoL and independence.
These impairments are believed to be in part due to the under­
lying etiology of the disease and in part as a consequence of the
seizures themselves [2,90]; therefore reductions in the severity
and frequency of seizures might have benefits on this additional
impairment. To date, there is a paucity of evidence on the impact
of treatments on cognition and behavior, although these can be
challenging outcomes to assess, especially in short-term trials
[22]. Longer-term evidence suggests that STP and the KD may
not have a beneficial impact on cognitive abilities, although
further studies are needed [33,70]. However, there is some pre­
liminary evidence that FFA may have positive impacts on aspects
of executive function, including behavior and emotion, as

assessed using the BRIEF or BRIEF2 tool [47,52,53]. In addition,
recent in vivo data suggest that FFA may protect against chemi­
cally induced neurocognitive damage by positively modulating
sigma-1 receptors [46].
SE is a cause of substantial morbidity as well as mortality
[91–93]. As with cognition, effects on SE can be difficult to
assess in short-term trials because of the rarity of the outcome
during that time period. However, longer-term observational
studies have shown that STP is associated with low rates of SE
in those with a prior history (Supplemental Table S2). Further
long-term observational studies on the effects of CBD and FFA
are needed as these agents become more widely used upon
approval. Of interest, a recent case report reported that FFA
was beneficial for the acute treatment of SE in one patient;
after 4 days of FFA, the patient became more responsive, with
cessation of seizures and paroxysmal activity, and after
1 month, seizures remained in remission and the EEG had
improved [94].
Overall, this review summarizes the current and emerging
treatment landscape in DS and is an important contribution to
the evidence in this rare severe disease.
7. Expert opinion
7.1. Changes to the treatment paradigm for Dravet
Syndrome
As of 2017, a North American consensus panel recommends
VPA and/or CLB as first-line treatment for DS, and if seizures
are inadequately controlled, STP or topiramate are recom­
mended as adjunctive treatment (Figure 4) [3]. The KD could
also be considered as a second-line treatment in patients with
suboptimal response to clobazam and valproic acid, with the
traditional diet considered appropriate for children ≤12 years,
and alternatives (e.g. the Modified Atkins diet) being the
better option in teens and adults [3]. According to the con­
sensus panel, later therapeutic options in patients with sub­
optimal response to first – and second-line therapies may
include clonazepam, levetiracetam, zonisamide, rufinamide,
acetazolamide, or bromides [3]. VNS, which is less efficacious
than the KD, may also be considered if first- and second-line
therapies have failed. Of note, a number of AEDs are to be
avoided for the treatment of DS due to exacerbating seizures
[3], and developmental outcomes are reported to be worse in
children who have been treated with sodium channel blockers
for longer periods of time (Figure 4) [23]; this highlights the
importance of early diagnosis and initiation of appropriate
treatment for improving the long-term outcomes of patients
with DS. Medication to use for emergency rescue for pro­
longed seizures is also a concern, but is beyond the scope of
this review; this topic has recently been reviewed by Cross et
al., 2020 [19].
While the consensus forms a good basis for treatment
guidance, therapeutic strategies will need to be adapted
according to the availability of drugs in different countries,
including newer therapies as they become approved, while
also taking into account clinicians’ experience and indivi­
dual patient factors. Real-world evidence in Europe and
beyond has shown that VPA, CLB, STP, topiramate,
EXPERT REVIEW OF NEUROTHERAPEUTICS 1075
lamotrigine, and bromide are all commonly AEDs prescribed
in DS patients. Despite there being ‘no consensus’ regarding
bromide in the North American recommendations, it was
the second most used AED in patients in a study in
Germany, and has been shown to be effective in patients
with DS in other studies [95–97]. In addition, levetiracetam
(strong consensus in the North American recommendations)
was rarely prescribed in the German study [21], and while
the lifetime prevalence of levetiracetam is high, the low
current prevalence suggests there may be a lack of efficacy
and/or tolerability issues where patients only use this AED
for a short time [98]. In this respect, a study reported similar
response rates for the STP+CLB+VPA (89%), bromides (78%)
and KD (70%), but significantly lower rates for levetiracetam
(30%) [63].
Since its approval in the EU in 2007, STP has become
a mainstay of treatment [18,21,99]. However, persisting sei­
zures remain a burden in many patients, and there are limited
treatment options in such patients. Given that the conse­
quences of DS can be catastrophic, and that higher seizure
burden is associated with increased comorbidities and lower
QoL [13], this unmet need is extremely pertinent. The two
additional agents, CBD and FFA, are therefore welcome
(potential) additions to the treatment armamentarium for DS.
CBD and FFA have been assessed in patients aged ≥2 years
experiencing high numbers of seizures at baseline despite being
treated with a variety of AEDs, including STP, and could there­
fore be initiated at any position in the treatment pathway, where
the indication allows (Figure 4). Together with STP, CBD and FFA
are likely to become mainstays of treatment, with treatments
tailored to the individual patients, taking into account the dif­
ferent risks and benefits, personal preferences, previous lines of
therapy, and drug–drug interactions (Figure 3) [19,100].
7.2. Implications for other DEEs
Mutations in genes encoding voltage-gated ion channels,
including SCN1A, are a major cause of DEEs, the so-called chan­
nelopathies [101]. DS, as a clinically and genetically defined
entity, can be a model for other DEEs with regard to targeted
therapy. CBD is already approved for the treatment of LGS and
approval for treatment of seizures in tuberous sclerosis complex
is anticipated; FFA is also being trialed as a possible treatment in
patients with LGS. In addition, the technologies being devel­
oped for DS, including the use of gene therapy and ASOs, may
also be able to be applied to other DEEs.
Overall, it is hoped that via early diagnosis and the timely
use of new efficacious therapeutics such as STP, CBD and FFA,
that positive outcomes can be achieved including reductions
in seizures, and positive impacts on QoL for both patients and
caregivers. However, despite new treatments, the burden of
the disease is still heavy for patients and caregivers. The future
of treatment for DEE should consider not only the number of
seizures but also cognition and behavior; the ideal treatment,
possibly through a disease-modifying technology such as
gene therapy or ASOs, should be able to act on the neurobio­
logical process of the disease. Overall, the advances in DS may
also stimulate advances in other genetic epilepsy syndromes.
1076 A. STRZELCZYK AND S. SCHUBERT-BAST
Figure 4. Current and potential future treatment pathway in Dravet syndrome.
Footnote: Adapted from Wirrel et al 2017 [3]; Wirrel and Nabbout 2019 [22] and Cross et al. 2019 [19]The current treatment strategy is based on the recommendations from the North
American consensus panel [3], however not all therapies are available in all regionsaAgreed upon by strong consensus; bAgreed upon by moderate consensus; cNot approved for use in all
jurisdictions; dKetogenic diet is not suitable for all patients, its use is not required before moving to third-line therapies; e No consensus, however, of note bromide was the second most
commonly used AED in a real-world study in Germany commonly used in second-line, whereas levetiracetam (strong consensus) was rarely prescribed [21]; the efficacy of bromide has also
been demonstrated in other studies [95–97]AEDs, antiepileptic drugs; CLB, clobazam; STP, stiripentol; VNS, vagus nerve stimulation; VPA, valproic acid.
Acknowledgments
The authors would like to thank Amanda Prowse (Lochside Medical
Communications Ltd) for providing editorial assistance and Chris Cooper
for developing the search terms.
Funding
Medical writing assistance was funded by Zogenix GmbH, Germany.
Declaration of interest
A Strzelczyk reports personal fees and grants from Arvelle Therapeutics,
Desitin Arzneimittel, Eisai, GW Pharmaceuticals, LivaNova, Marinus
Pharmaceuticals, Medtronic, Sage Therapeutics, UCB Pharma, and
Zogenix. S Schubert-Bast reports personal fees from Eisai, Desitin
Pharma, GW Pharmaceuticals, LivaNova, UCB Pharma, and Zogenix. The
authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or conflict with the
subject matter or materials discussed in this manuscript apart from those
disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Adam Strzelczyk http://orcid.org/0000-0001-6288-9915
Susanne Schubert-Bast http://orcid.org/0000-0003-1545-7364
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