Everolimus for epilepsy and autism spectrum disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan.

Background: Epilepsy and autism spectrum disorder (ASD) are the common neurological manifestations of tuberous sclerosis complex (TSC). EXIST-3 study has recently demonstrated that everolimus reduces seizures in patients with TSC and refractory epilepsy. Here we report the efficacy and safety of everolimus for treatment-refractory seizures in Japanese patients of EXIST-3, along with the exploratory analysis evaluating the everolimus effect on comorbid ASD symptoms in these patients.

Methods: Primary endpoint was change in seizure frequency from baseline defined as response rate (≥50% reduction) and median percentage reduction in the seizure frequency. Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores were assessed at baseline and at week-18 for ASD symptoms.

Results: Overall, 35 Japanese patients were randomized to everolimus low-exposure (LE; n = 10), everolimus high-exposure (HE; n = 14), or placebo (n = 11). The response rate was 30.0% and 28.6% versus 0% with the everolimus LE and HE versus placebo arm, respectively. Similarly, the median percentage reduction in seizure frequency was 6.88% and 38.06% versus -6.67%. Stomatitis was the most frequently reported adverse event (everolimus LE, 100%; HE, 78.6%; placebo, 9.1%). Four of 11 patients with ASD in the everolimus arms and 1 of 8 patients with ASD in the placebo arm showed ≥5 point decrease in PARS scores.

Conclusions: Adjunctive everolimus treatment improved seizure frequency with a tolerable safety relative to placebo among 35 Japanese patients with TSC-associated refractory seizures, consistent with the results of overall EXIST-3 study involving 366 patients. A favorable trend towards the improvement of ASD symptoms was observed.