Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3

David N Franz; John A Lawson; Zuhal Yapici; Hiroko Ikeda; Tilman Polster; Rima Nabbout; Paolo Curatolo; Petrus J de Vries; Dennis J Dlugos; Fabian Herbst; Severine Peyrard; Diana Pelov; Jacqueline A French

doi:10.1111/epi.17099

Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3

Epilepsia. 2021 Dec;62(12):3029-3041. doi: 10.1111/epi.17099. Epub 2021 Oct 25.

Authors

Affiliations

¹ Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
² Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children's Hospital, Randwick, New South Wales, Australia.
³ Division of Child Neurology, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁴ National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.
⁵ Pediatric Epileptology, Bethel Epilepsy Center, Mara Hospital, Bielefeld, Germany.
⁶ Necker-Enfants Malades Hospital, Paris Descartes University, Paris, France.
⁷ Tor Vergata University Hospital, University of Rome Tor Vergata, Rome, Italy.
⁸ Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa.
⁹ Department of Neurology and Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Novartis Pharma AG, Basel, Switzerland.
¹¹ Novartis Pharmaceuticals SAS, Rueil-Malmaison, France.
¹² Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
¹³ New York University Comprehensive Epilepsy Center, New York, New York, USA.

PMID: 34693520
DOI: 10.1111/epi.17099

Abstract

Objective: Epilepsy is highly prevalent in patients with tuberous sclerosis complex (TSC). Everolimus showed higher efficacy than placebo for seizures in the primary analysis of the EXIST-3 study. Here, we present the long-term outcomes of everolimus at the end of the postextension phase (PEP; data cutoff date: October 25, 2017).

Methods: After completion of the extension phase, patients were invited to continue everolimus in the PEP with everolimus (targeted trough concentration = 5-15 ng/ml, investigator-judged). Efficacy assessments included changes in seizure status during the PEP collected at 12-week intervals as parent/caregiver-reported data through a structured questionnaire.

Results: Among 361 patients, 343 entered the extension phase and 249 entered the PEP. After 12 weeks in the PEP, 18.9% (46/244) of patients were seizure-free since the last visit of the extension phase and 64.8% (158/244) had a stable/improved seizure status. At 24 weeks, the corresponding percentages were 18.2% (42/231) and 64.5% (149/231). Among 244 patients, the response rate was 32.8% (80/244) during the 12-week maintenance period of the core phase and 63.9% (156/244) at the end of the extension phase. Of the 149 responders at the end of the extension phase, 70.5% were seizure-free or had stable/improved seizure status. Long-term efficacy data showed persistent responses were observed in 183 of 361 patients (50.7%); 63.9% of these patients had a response that lasted at least 48 weeks. The most frequent Grade 3-4 adverse events (≥2% incidence) reported throughout the study were pneumonia, status epilepticus, seizure, stomatitis, neutropenia, and gastroenteritis. Four patients died during the study.

Significance: The final analysis of EXIST-3 demonstrated the sustained efficacy of everolimus as adjunctive therapy in patients with TSC-associated treatment-refractory seizures, with a tolerable safety profile.

Keywords: EXIST-3; epilepsy; everolimus; postextension phase; tuberous sclerosis complex.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Combined Modality Therapy
Epilepsy* / drug therapy
Everolimus / adverse effects
Humans
Seizures / chemically induced
Seizures / etiology
Treatment Outcome
Tuberous Sclerosis* / complications
Tuberous Sclerosis* / drug therapy

Substances

Everolimus