The US Food and Drug Administration (FDA) has approved everolimus tablets for oral suspension (Afinitor Disperz, Novartis) for the adjunctive treatment of adults and children aged 2 years and older with tuberous sclerosis complex (TSC)–associated partial-onset seizures.
Everolimus tablets for oral suspension become the first approved pharmacologic therapy in the United States specifically indicated for the treatment of this condition, the company said in a news release.
In the EXIST-3 (EXamining everolimus In a Study of TSC) phase 3 study, everolimus tablets for oral suspension, when used as an adjunctive therapy, significantly reduced the frequency of treatment-resistant seizures associated with TSC compared with placebo.
Response rates, defined as a 50% or greater reduction in seizures, were also greater with everolimus than with placebo. The most common adverse events seen with everolimus included stomatitis, diarrhea, nasopharyngitis, upper respiratory tract infection, and pyrexia.
TSC is a rare genetic disorder affecting up to 1 million people worldwide. More than 60% of patients with TSC experience seizures that have become resistant to available antiepileptic therapies.
TSC is caused by defects in the TSC1 and TSC2 genes that negatively control the mammalian target of rapamycin (mTOR). Everolimus inhibits mTOR. In animal models of mTOR dysregulation, treatment with an mTOR inhibitor resulted in prolonged survival, seizure suppression, prevention of new-onset seizures, and prevention of premature death.
Everolimus was granted accelerated FDA approval in 2010 to treat subependymal giant cell astrocytoma in patients with TSC. The agency approved a pediatric dosage form of everolimus in 2012.
French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Oct 29;388(10056):2153-2163.
Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex.
In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2-65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov, number <a href="http://clinicaltrials.gov/show/NCT01713946" title="See in ClinicalTrials.gov" >NCT01713946</a>.
Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2-22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3-37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5-49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1-21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8-41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0-48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group.
Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures.
Novartis Pharmaceuticals Corporation.