Franz David N, Lawson John A, Yapici Zuhal, Ikeda Hiroko, Polster Tilman, Nabbout Rima, Curatolo Paolo, de Vries Petrus J, Dlugos Dennis J, Voi Maurizio, Fan Jenna, Vaury Alexandra, Pelov Diana, French Jacqueline A
Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy Center, Germany; Reference Centre for Rare Epilepsies (RN), Hospital Necker-Enfants Malades, Paris Descartes University, France; Tor Vergata University Hospital (PC), Rome, Italy; Division of Child and Adolescent Psychiatry (PJdV), University of Cape Town, South Africa; Departments of Neurology and Pediatrics (DJD), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Novartis Pharmaceuticals Corporation (MV, JF, DP), East Hanover, NJ; Novartis Pharmaceuticals SAS (AV), Rueil-Malmaison, France; and NYU Comprehensive Epilepsy Center (JAF), New York.
Neurol Clin Pract. 2018 Oct;8(5):412-420. doi: 10.1212/CPJ.0000000000000514.
EXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures.
After completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3-15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR).
Of 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2-36.1; N = 352) at week 18, 46.6% (95% CI, 40.9-52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7-65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5-36.1) at week 18, 46.7% (95% CI, 40.2-54) at 1 year, and 56.9% (95% CI, 50-68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5-35.2; N = 361) at week 18, 38.8% (95% CI, 33.7-44.1; N = 358) at 1 year, and 41% (95% CI, 34.6-47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock).
Sustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns.
This study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.
结节性硬化症3期依维莫司研究（EXIST - 3）表明，与安慰剂相比，依维莫司显著降低了癫痫发作频率（SF）。在本研究中，我们评估了依维莫司用于治疗结节性硬化症复合物（TSC）相关的难治性癫痫的长期疗效和安全性。
在核心阶段完成后，患者可进入开放标签扩展阶段，并接受依维莫司（目标暴露量，3 - 15 ng/mL）治疗≥48周。疗效终点包括平均每周癫痫发作频率相对于基线的变化，以缓解率（RR，降低≥50%）和中位降低百分比（PR）表示。
366例患者中，361例在核心/扩展阶段接受了依维莫司治疗。第18周时缓解率为31%（95%置信区间，26.2 - 36.1；N = 352），1年时为46.6%（95%置信区间，40.9 - 52.5；N = 298），2年时为57.7%（95%置信区间，49.7 - 65.4；N = 163）。第18周时癫痫发作频率的中位降低百分比为31.7%（95%置信区间，28.5 - 36.1），1年时为46.7%（95%置信区间，40.2 - 54），2年时为56.9%（95%置信区间，50 - 68.4）。95例患者（26.3%）在2年前停用了依维莫司；103例（28.5%）在研究截止时随访时间不足2年，40%的患者接受依维莫司治疗≥2年。将停药患者分类为无反应者的分析显示，第18周时缓解率为30.2%（95%置信区间，25.5 - 35.2；N = 361），1年时为38.8%（95%置信区间，33.7 - 44.1；N = 358），2年时为41%（95%置信区间，34.6 - 47.7；N = 229），表明随着时间推移持续获益。3/4级不良事件（任何原因）的发生率为40.2%，13%的患者因不良事件停药（肺炎[1.7%]和口腔炎[1.4%]）。2例死亡疑似与治疗相关（肺炎和感染性休克）。
辅助使用依维莫司可使TSC相关的难治性癫痫发作随时间持续减少。安全性与核心阶段一致，无新的安全问题。
本研究提供了IV类证据，表明长期依维莫司治疗可降低TSC相关难治性癫痫患者的癫痫发作频率。
