Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial

David N Franz; John A Lawson; Zuhal Yapici; Hiroko Ikeda; Tilman Polster; Rima Nabbout; Paolo Curatolo; Petrus J de Vries; Dennis J Dlugos; Maurizio Voi; Jenna Fan; Alexandra Vaury; Diana Pelov; Jacqueline A French

doi:10.1212/CPJ.0000000000000514

Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial

Neurol Clin Pract. 2018 Oct;8(5):412-420. doi: 10.1212/CPJ.0000000000000514.

Affiliation

¹ 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.

Abstract

Background: 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.

Methods: 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).

Results: 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).

Conclusions: 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.

Classification of evidence: This study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.