Overwater IE, Rietman AB, Bindels-de Heus K, Looman CW,
Rizopoulos D, Sibindi
TM, Cherian PJ, Jansen FE, Moll HA, Elgersma Y, de Wit MC.
Sirolimus for epilepsy
in children with tuberous sclerosis complex: A randomized
controlled trial.
Neurology. 2016 Sep 6;87(10):1011-8.
Abstract
OBJECTIVE:
To investigate whether mammalian target of rapamycin complex
1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous
sclerosis complex (TSC).
METHODS:
Due to slow inclusion rate, target inclusion of 30 children
was not reached. Twenty-three children with TSC and intractable epilepsy (age
1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus
treatment immediately or after 6 months. Sirolimus was titrated to trough
levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the
sixth month of sirolimus treatment.
RESULTS:
Intention-to-treat analysis showed sirolimus treatment
resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69%
to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis
of 14 children who reached sirolimus target trough levels in the sixth
sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%;
p = 0.06). Cognitive development did not change. All children had adverse
events. Five children discontinued sirolimus prematurely.
CONCLUSIONS:
We describe a randomized controlled trial for a non-antiepileptic
drug that directly targets a presumed causal mechanism of epileptogenesis in a
genetic disorder. Although seizure frequency decreased, especially in children
reaching target trough levels, we could not show a significant benefit. Larger
trials or meta-analyses are needed to investigate if patients with TSC with
seizures benefit from mTORC1 inhibition. This trial was registered at
trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation.
CLASSIFICATION OF EVIDENCE:
This study provides Class III evidence that sirolimus does
not significantly reduce seizure frequency in children with TSC and intractable
epilepsy. The study lacked the precision to exclude a benefit from sirolimus.
Curatolo P, Bjørnvold M, Dill PE, Ferreira JC, Feucht M, Hertzberg C, Jansen A, Jóźwiak S, Kingswood JC, Kotulska K, Macaya A, Moavero R, Nabbout R, Zonnenberg BA. The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions. Drugs. 2016 Apr;76(5):551-65.
ReplyDeleteAbstract
Tuberous sclerosis complex (TSC) is a genetic disorder arising from mutations in the TSC1 or TSC2 genes. The resulting over-activation of the mammalian target of rapamycin (mTOR) signalling pathway leaves patients with TSC susceptible to the growth of non-malignant tumours in multiple organs. Previously, surgery was the main therapeutic option for TSC. However, pharmacological therapy with mTOR inhibitors such as everolimus and sirolimus is now emerging as an alternate approach. Everolimus and sirolimus have already been shown to be effective in treating subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML), and everolimus is currently being evaluated in treating TSC-related epilepsy. In November 2013 a group of European experts convened to discuss the current options and practical considerations for treating various manifestations of TSC. This article provides evidence-based recommendations for the treatment of SEGA, TSC-related epilepsy and renal AML, with a focus on where mTOR inhibitor therapy may be considered alongside other treatment options. Safety considerations regarding mTOR inhibitor therapy are also reviewed. With evidence of beneficial effects in neurological and non-neurological TSC manifestations, mTOR inhibitors may represent a systemic treatment for TSC.
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From the article
The efficacy and safety data for mTOR inhibitors in the management of TSC-associated epilepsy from phase I/II and III everolimus clinical trials are summarised in Table 2. At present everolimus is not approved for use in this indication but a prospective, placebo-controlled, phase III clinical trial to evaluate the efficacy and safety of everolimus in patients with TSC who have refractory partial-onset seizures is ongoing and the first results are expected in 2016. According to the opinion of the expert clinicians, everolimus therapy needs to be continuous in order to obtain clinically meaningful seizure reduction. Again, the optimal duration of treatment is yet to be established. In a small study of children aged ≤3 years with TSC and AED-resistant epilepsy treated with everolimus, reductions in seizure frequency (at least 50 %) were reported in four of five children with active seizures at baseline. As patients with epilepsy are likely to be receiving AEDs, it is important to be aware that the combination of everolimus with AEDs requires caution because interactions with CYP3A4/p-glycoprotein (p-GP) inducers and/or inhibitors have been reported.
Kotulska K, Chmielewski D, Borkowska J, Jurkiewicz E, Kuczyński D, Kmieć T, et al. Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neurol. 2013;17(5):479–85
ReplyDeleteAbstract
BACKGROUND:
Tuberous sclerosis complex (TSC) is a genetic disorder characterized by increased mammalian target of rapamycin (mTOR) activation and growth of benign tumors in several organs throughout the body. In young children with TSC, drug-resistant epilepsy and subependymal giant cell astrocytomas (SEGAs) present the most common causes of mortality and morbidity. There are also some reports on the antiepileptic and antiepileptogenic potential of mTOR inhibitors in TSC. However, the data on everolimus efficacy and safety in young children are very limited.
AIMS:
To show the long-term safety data and the effect of everolimus treatment on epilepsy in children under the age of 3 who received everolimus for SEGAs associated with TSC.
METHODS:
We present the results of everolimus treatment in 8 children under the age of 3 who participated in EXIST-1 study. Five patients presented with active, drug-resistant epilepsy at baseline. The mean follow-up is 35 months (33-38 months) and all children are still on treatment.
RESULTS:
In 6 out of 8 children, at least a 50% reduction in SEGA volume was observed. In 1 child with drug-resistant epilepsy, everolimus treatment resulted in cessation of seizures and in 2 other children, at least a 50% reduction in the number of seizures was noted. The incidence of adverse events (AE) was similar to that observed in older children and adults.
CONCLUSIONS:
This study suggests that everolimus is effective and safe in infants and young children with epilepsy and SEGA associated with TSC and offers a valuable treatment option.
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 Sep 6. pii: S0140-6736(16)31419-2. doi:10.1016/S0140-6736(16)31419-2. [Epub ahead of print]
ReplyDeleteAbstract
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 NCT01713946.
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.