AUTHOR=Wu Jianhua , Zhang Liu , Zhou Xi , Wang Jiajun , Zheng Xiangyi , Hu Hankun , Wu Dongfang 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.980937

DOI=10.3389/fphar.2022.980937

ISSN=1663-9812

ABSTRACT=Abstract:
Purpose: Recently, the U.S. Food and Drug Administration 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 antiepileptic drugs in the treatment of DS.
Methods: We included randomized controlled trials (RCTs) evaluating the efficacy of antiepileptic drugs in direct comparisons with placebo or with each other for the treatment of DS. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched. 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 and serious adverse events during treatment. Relative ranking was assessed using the surface under the cumulative ranking curve (SUCRA) probabilities.
Results: Seven RCTs involving four antiepileptic drugs (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]. 
Conclusions: Based on the comparison of efficacy and safety, soticlestat is the best adjuvant antiepileptic drug, followed by fenfluramine. Although stiripentol has a positive effect on reducing seizures, it is also the most likely cause of adverse reactions. There are no significant advantages of cannabidiol in terms of efficacy and safety. The above conclusions must be verified in direct drug comparison clinical trials.
Keywords: Soticlestat; Stiripentol; Fenfluramine; Cannabidiol; Dravet syndrome