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.
https://www.medscape.com/viewarticle/895069
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.
Abstract
BACKGROUND:
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.
METHODS:
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>.
FINDINGS:
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.
INTERPRETATION:
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.
FUNDING:
Novartis Pharmaceuticals Corporation.
See: http://childnervoussystem.blogspot.com/2016/04/everolimus-data-for-seizures-in.html#comment-form
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