Strzelczyk Adam, Schubert-Bast Susanne
Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt , Frankfurt am Main, Germany.
LOEWE Center for Personalized and Translational Epilepsy Research (CePTER), Goethe-University Frankfurt , Frankfurt am Main, Germany.
Expert Rev Neurother. 2020 Oct;20(10):1065-1079. doi: 10.1080/14737175.2020.1801423. Epub 2020 Aug 16.
Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments.
This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones 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 generally 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.
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.
德雷维特综合征（DS）是一种典型的发育性和遗传性癫痫性脑病（DEE），其特征为早期出现难治性癫痫发作，同时伴有运动控制、行为和认知障碍。即使使用多种传统抗癫痫药物，癫痫发作仍难以得到有效控制，因此对于有效且耐受性良好的治疗方法存在相当大的未满足需求。
本针对性文献综述旨在通过总结最新的循证研究，突出DS治疗领域的近期变化，包括司替戊醇、大麻二酚和芬氟拉明临床开发的关键数据，这些是DS治疗的重要里程碑，以及其他正在研发的药物疗法的最新研究结果。在III期双盲、安慰剂对照随机试验中，司替戊醇、大麻二酚和芬氟拉明已显示出惊厥发作频率有临床意义的降低，且总体耐受性良好。当与丙戊酸和氯巴占联合使用时，司替戊醇的缓解率（惊厥发作频率降低超过50%）为67%-71%；大麻二酚的缓解率为43%-49%（与氯巴占联合使用时为48%-63%），芬氟拉明在各项研究中的缓解率为54%-68%。正在研发的疗法包括索替司他、阿他芦醇、维拉帕米和氯咪唑，治疗DS潜在病因的策略，包括基因治疗和反义寡核苷酸，已开始从临床前研究中崭露头角。
尽管罕见病药物开发面临挑战，但对于DS治疗而言，这是一个令人兴奋的时期，有望出现新的有效且耐受性良好的疗法，这可能为其他DEE的治疗进展铺平道路。
