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 (<scp>ELEKTRA</scp>)

Hahn, Cecil D.; Zhao, Yang; Villanueva, Vicente; Żołnowska, Marta; Arkilo, Dimitrios; Hsiao, Samuel; Asgharnejad, Mahnaz; Dlugos, Dennis J.

doi:10.1111/epi.17367

Cited by 38 publications

(60 citation statements)

References 34 publications

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“…The main characteristics of the included RCTs are presented in Table 2 . Among these, two studies on stiripentol were included ( Chiron et al, 2000 ; Hahn et al, 2022 ), and a total of 33 patients were randomly selected to receive the stiripentol treatment; two RCTs on cannabidiol were included ( Devinsky et al, 2017 ; Miller et al, 2020 ), with a total of 194 patients receiving the cannabidiol treatment; two studies of fenfluramine were included ( Lagae et al, 2019 ; Nabbout et al, 2020 ), with a total of 122 patients receiving fenfluramine; and one study of soticlestat was included ( Hahn et al, 2021 ), with 24 patients receiving soticlestat. Each drug was compared with a placebo in all experiments, and 261 patients were randomly assigned to the placebo group.…”

Section: Resultsmentioning

confidence: 99%

“…Overall, of the seven RCTs included in this study, five were considered to have a low risk of bias. The other two studies on stiripentol ( Chiron et al (2000) and Hahn et al (2022) ) were described as randomized, double-blind trials and blinded to participants and study performers; these lacked sufficient information on allocation concealment and blinded data handlers and were thus considered as uncertain with regard to risk of bias. The results of the risk of bias assessment in the literature are shown in Figure 2 .…”

Section: Resultsmentioning

confidence: 99%

“…A series of recently published randomized controlled trials reveals growing interest in the role of stiripentol, fenfluramine, cannabidiol, and soticlestat in DS treatment. Two double-blind, randomized, placebo-controlled trials of stiripentol as an adjuvant therapy for valproic acid and clobazam in France [STICLO-France ( Chiron et al, 2000 )] and Italy [STICLO-Italy ( Hahn et al, 2022 )] showed that DS patients over 3 years of age showed better responses to these drugs than placebo in both the ≥50% reduction in seizure frequency and complete control of seizures. The initial dose of stiripentol was 15–20 mg/(kg d), which was increased to a target dose of 50 mg/(kg d) in two to 4 weeks.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of adjunctive antiseizure medications for dravet syndrome: A systematic review and network meta-analysis

Zhang

et al. 2022

Front. Pharmacol.

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Purpose: Recently, the U.S. Food and Drug Administration (FDA) approved stiripentol, cannabidiol, and fenfluramine to treat patients with Dravet syndrome (DS). Moreover, soticlestat was determined as a promising new drug for the treatment of DS as it has good efficacy and safety. However, the efficacy and safety of these drugs have not yet been evaluated in “head-to-head” trials. This study aimed to compare and evaluate the efficacy and safety of these adjunctive antiseizure medications in the treatment of DS.Methods: We searched in PubMed, Embase, Cochrane Library, and Web of Science databases for randomized controlled trials (RCTs) and open-label extension (OLE) studies in patients with DS. We performed a random-effect meta-analysis of OLE studies and a network meta-analysis for RCTs to evaluate the efficacy and safety of antiseizure medications in the treatment of DS. Primary efficacy outcomes were defined as a ≥50% reduction in seizure frequency compared with baseline. Furthermore, safety evaluation indicators were defined as the incidence of adverse events (AEs) and serious adverse events (SAEs) during treatment. Relative ranking was assessed using the surface under the cumulative ranking curve (SUCRA) probabilities.Results: Seven RCTs involving four antiseizure medications (stiripentol, cannabidiol, fenfluramine, and soticlestat) and a total of 634 patients were included in the analysis. According to the SUCRA results, all four drugs significantly reduced the frequency of seizures compared with the placebo. Soticlestat was the most likely to reduce seizure frequency by ≥50% compared to the baseline [risk ratio (RR): 19.32; 95% confidence interval (CI): 1.20–311.40], followed by stiripentol and fenfluramine. Stiripentol was ranked highest for the near percentage reduction in the seizure rate from baseline [RR: 12.33; 95% CI: 1.71–89.17] and the occurrence of any treatment-emergent adverse events [RR: 3.73; 95% CI: 1.65–8.43] and serious adverse events [RR: 4.76; 95% CI: 0.61–37.28]. A total of ten OLE studies containing 1,121 patients were included in our study. According to the results of the meta-analysis, the order of probability of reducing seizure frequency by ≥50% was fenfluramine (0.715, 95% CI: 0.621–0.808), stiripentol (0.604, 95% CI: 0.502–0.706), cannabidiol (0.448, 95% CI: 0.403–0.493). And the probability of occurrence of AEs is ranked as fenfluramine(0.832, 95% CI: 0.795–0.869), cannabidiol (0.825, 95% CI:0.701–0.950), stiripentol (0.823, 95% CI: 0.707–0.938), soticlestat (0.688, 95% CI: 0.413–0.890).Conclusion: According to the results of indirect comparison of efficacy and safety, cannabidiol is slightly inferior to the other three antiseizure medications in terms of efficacy and safety. Soticlestat, fenfluramine, and stripentol may have little difference in efficacy, but soticlestat and fenfluramine are safer. Soticlestat is probably the best adjunctive antiseizure medication, followed by fenfluramine. This conclusion is consistent with the comparison of long-term efficacy and safety.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of adjunctive antiseizure medications for dravet syndrome: A systematic review and network meta-analysis

Zhang

et al. 2022

Front. Pharmacol.

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“…ASMs in clinical development include soticlestat and carisbamate. Soticlestat has recently successfully completed Phase 2 clinical deveopment as an adjunctive therapy in pediatric patients with DS or LGS [ 85 ], with Phase 3 trials underway (NCT04938427 and NCT05163314). A Phase 3 clinical trial assessing carisbamate in patients with LGS has also been initiated (NCT05219617).…”

Section: Discussionmentioning

confidence: 99%

The burden of illness in Lennox–Gastaut syndrome: a systematic literature review

Strzelczyk

Zuberi

Striano

et al. 2023

Orphanet J Rare Dis

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Background Lennox–Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with multiple seizure types starting in childhood, a typical slow spike-wave pattern on electroencephalogram, and cognitive dysfunction. Methods We performed a systematic literature review according to the PRISMA guidelines to identify, synthesize and appraise the burden of illness in LGS (including “probable” LGS). Studies were identified by searching MEDLINE, Embase and APA PsychInfo, Cochrane’s database of systematic reviews, and Epistemonikos. The outcomes were epidemiology (incidence, prevalence or mortality), direct and indirect costs, healthcare resource utilization, and patient and caregiver health-related quality of life (HRQoL). Results The search identified 22 publications evaluating the epidemiology (n = 10), direct costs and resource (n = 10) and/or HRQoL (n = 5). No studies reporting on indirect costs were identified. With no specific ICD code for LGS in many regions, several studies had to rely upon indirect methods to identify their patient populations (e.g., algorithms to search insurance claims databases to identify “probable” LGS). There was heterogeneity between studies in how LGS was defined, the size of the populations, ages of the patients and length of the follow-up period. The prevalence varied from 4.2 to 60.8 per 100,000 people across studies for probable LGS and 2.9–28 per 100,000 for a confirmed/narrow definition of LGS. LGS was associated with high mortality rates compared to the general population and epilepsy population. Healthcare resource utilization and direct costs were substantial across all studies. Mean annual direct costs per person varied from $24,048 to $80,545 across studies, and home-based care and inpatient care were significant cost drivers. Studies showed that the HRQoL of patients and caregivers was adversely affected, although only a few studies were identified. In addition, studies suggested that seizure events were associated with higher costs and worse HRQoL. The risk of bias was low or moderate in most studies. Conclusions LGS is associated with a significant burden of illness featuring resistant seizures associated with higher costs and worse HRQoL. More research is needed, especially in evaluating indirect costs and caregiver burden, where there is a notable lack of studies.

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“…Additional novel treatments that target the underlying pathogenesis of both seizures and the neurodevelopment comorbidities would also be welcome. In this respect, soticlestat, which has a novel mechanism of action as an inhibitor of cholesterol 24-hydroxylase, is in clinical development as adjunctive therapy in children with DS or LGS [ 333 ]. To date, soticlestat has been found to be well tolerated and was associated with significant reductions in seizure frequency in patients with DS and LGS [ 333 ].…”

Section: Discussionmentioning

confidence: 99%

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

Strzelczyk

Schubert‐Bast

2022

CNS Drugs

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The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous h...

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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)

Cited by 38 publications

References 34 publications

Efficacy and safety of adjunctive antiseizure medications for dravet syndrome: A systematic review and network meta-analysis

Efficacy and safety of adjunctive antiseizure medications for dravet syndrome: A systematic review and network meta-analysis

The burden of illness in Lennox–Gastaut syndrome: a systematic literature review

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

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