Abstract
BackgroundEpilepsy 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. MethodsPrimary 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. ResultsOverall, 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. ConclusionsAdjunctive 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.
Highlights
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in either TSC1 or TSC2 gene, and involves multiple organs in the body, including the brain, heart, kidneys, lungs, eyes, and skin [1]
The pivotal EXIST-3 study (EXamining everolimus In a Study of tuberous sclerosis complex (TSC)) demonstrated that everolimus, as an adjunctive therapy, significantly improves the seizure frequency when compared to placebo in patients with treatment-refractory seizures associated with TSC [18]
This paper presents the results from an exploratory analysis of EXIST-3, first of its kind in a randomized setting, assessing the efficacy of everolimus for the treatment of symptoms related to autism spectrum disorder (ASD) in patients from the same population
Summary
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in either TSC1 or TSC2 gene, and involves multiple organs in the body, including the brain, heart, kidneys, lungs, eyes, and skin [1]. Epilepsy is the most common neurological symptom of TSC, affecting 72% to 85% of patients [1]. Onset of epilepsy in TSC is associated with an increased risk of neurodevelopmental disorders, such as intellectual disability and autism spectrum disorder (ASD) [2]. ASD is very common in patients with TSC [3], with a prevalence rate of 17–63% [4]. Autism is more frequent in TSC children with early-onset seizures, and is occasionally noted in those without epilepsy. In patients with TSC, an abnormal brain circuitry has been implicated in both ASD and epilepsy [5]. 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. 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
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