FDA Approves Everolimus for TSC-Associated Partial-Onset Seizures

Approval was based on EXIST-3 (NCT01713946), a randomized, double-blind, multicenter trial in 366 patients with TSC-associated partial-onset seizures, inadequate seizure control with ≥ 2 sequential anti-epileptic drug (AED) regimens, and a TSC diagnosis (modified Gomez criteria). Additionally, eligible patients were required to have ≥ 16 partial-onset seizures during the 8-week baseline phase on a stable AED regimen.

Patients were randomized (1:1.09:1) to Afinitor Disperz targeting a low trough (LT, n=117) or high trough (HT, n=130) concentration of everolimus or placebo (n=119). Patients initiated treatment with Afinitor Disperz/matching placebo at 3 to 6 mg/m² (depending on age or further adjusted for concomitant CYP3A4/P-glycoprotein inducer use) orally once daily. Subsequent doses were titrated to achieve the targeted trough concentrations as directed by an automated system to maintain the study blind. The major efficacy measure was the percentage reduction in average weekly seizures during a 12-week treatment period compared with the average weekly seizures during the 8-week baseline period.

The trial demonstrated statistically significant reductions in seizures for each of the Afinitor Disperz arms (LT arm 29.3% [95% CI: 18.8, 41.9; p=0.003] and HT arm 39.6% [95% CI: 35, 48.7; p<0.001]) compared with the placebo arm (14.9% [95% CI: 0.1, 21.7]). The proportion of patients with 50% reduction in seizure frequency during the 12-week treatment period compared with baseline also was higher in the LT and HT Afinitor Disperz arms (28.2% and 40%, respectively) compared with the placebo arm (15.1%). 

The most common adverse reactions (occurring in at least 10% of patients receiving Afinitor Disperz in EXIST-3) were stomatitis, diarrhea, vomiting, nasopharyngitis, upper respiratory tract infection, pyrexia, cough, and rash.

The recommended starting dose of Afinitor Disperz for this indication is 5 mg/m² orally once daily with dose adjustments (in increments up to 5 mg) to achieve trough concentrations of 5-15 ng/mL. The dose of Afinitor Disperz should be reduced in patients with severe hepatic impairment or in patients taking concurrent p-glycoprotein and moderate CYP3A4 inhibitors. The dose of Afinitor Disperz should be increased in patients taking concurrent p-glycoprotein and strong CYP3A4 inducers.

Full prescribing information is available (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022334s040,203985s013lbl.pdf).

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