Abstracts

Rationale: Epilepsy is a disabiling and often long-term manifestation of Tuberous Sclerosis Complex (TSC). Everolimus is an mTORC1 inhibitor with demonstrated benefit in several aspects of TSC, including epilepsy. We report the four-year outcome of the first prospective human clinical trial using everolimus for the treatment of refractory epilepsy in TSC patients.Methods: Patients who successfully completed a prospective, multi-center, open-label, phase I/II clinical trial, have been followed in a controlled extension phase. Patients ≥2 years of age with confirmed diagnosis of TSC and medically-refractory epilepsy were initially treated for a total of 12 weeks. Those with at least a 25% reduction in seizure burden were eligible to continue in open-label extension up to an additional 4 years. The primary measure is percent reduction in seizure frequency compared to baseline. Secondary endpoints assessed safety and impact on behavior and quality of life.Results: 18 of 20 patients who completed the initial treatment were eligible to continue treatment in the extension phase. 14 of the 18 patients (78%) completed the extension phase or were still on treatment at time of data cut-off (12/31/2014), with median treatment duration of 48.1 months. Seizure frequency was reduced by ≥50% in 14 of 18 subjects at 12 months, 13 of 16subjects at 24 months, 12 of 16 subjects at 36 months, and 8 of 9 subjects at 48 months continued treatment with everolimus. Overall, seizures were reduced by a median of 90% after 12 months (range +16% to =100%, p<0.01) and 96% after 48 months (range -37% to -100%, p<0.01). Frequency of reported adverse events was 0.75 per patient-month of treatment and decreased each year during extension. Infections (38.9%), gastrointestinal symptoms (24.9%), and constitutional complaints (7.4%) were most commonly encountered. The vast majority (94%) of AEs were mild or moderate (CTCAE grade 1 or 2) in severity and no patient discontinued treatment due to adverse events.Conclusions: Seizure control was maintained up to 4 years in the majority of TSC patients with medically-refractory epilepsy during treatment with everolimus. Treatment was safe and well-tolerated. Everolimus has sustained efficacy as a therapeutic option for refractory epilepsy in this population.