Adjunctive Everolimus Therapy for Treatment-Resistant Focal-Onset Seizures Associated with Tuberous Sclerosis

Ben Uphouse, Mercer University College of Pharmacy

Early human case reports have demonstrated beneficial effects of mechanistic target of rapamycin (mTOR) inhibitors on seizures.  Limited evidence was stated to be available on the optimal treatment of epilepsy in patients with tuberous sclerosis complex (TSC)  before the EXIST-3 study was conducted.  The previous EXIST studies evaluated the efficacy and safety of everolimus for TCS-associated subependymal giant cell astrocytomas and complex/sporadic lymphangioleiomyomatosis. (1,2)


Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomized, double-blind, placebo-controlled study [3]
Design Prospective, multicenter, randomized, double-blinded, placebo-controlled; N= 366
Objective To assess the efficacy and safety of everolimus as adjunctive therapy for treatment-resistant focal-onset seizures
Study Groups Low-exposure everolimus (n= 117); high-exposure everolimus (n= 130); placebo (n= 119)
Methods Patients aged 2–65 years with a confirmed diagnosis of TSC and treatment-resistant epilepsy, with 16 or more seizures during the 8-week baseline phase (with no continuous 21-day seizure-free period), and receiving between one and three antiepileptic drugs at a stable dose for at least 12 weeks before randomization were included.  Eligible patients were randomly assigned (1:1:1) to receive placebo, everolimus titrated to a target trough concentration (Cmin) of 3–7 ng/mL (low-exposure everolimus), or everolimus titrated to a target Cmin of 9–15 ng/mL (high-exposure everolimus), in addition to a stable regimen of one to three antiepileptic drugs.
Duration July 3rd, 2013 – May 29th, 2015
Primary Outcome Measure 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
Baseline Characteristics
Placebo Low-exposure everolimus High-exposure everolimus
Median age, yrs (range) 10.3 (2.2-52.0) 9.7 (2.2-56.3) 10.1 (2.3-50.5)
Male sex, n (%) 61 (51) 64 (55) 65 (50)
Race
White, n (%) 77 (65) 76 (65) 84 (65)
Black, n (%) 1 (1) 2 (2) 1 (1)
Asian, n (%) 27 (23) 29 (25) 31 (24)
Antiepileptic drugs failed prior to start, n (%)
2 5 (4) 4 (3) 8 (6)
3 13 (11) 15 (13) 9 (7)
4 16 (13) 22 (19) 27 (21)
5 22 (18) 22 (19) 25 (19)
6 10 (8) 10 (9) 17 (13)
>6 53 (45) 44 (38) 44 (34)
Results
Placebo Low-exposure everolimus High exposure everolimus
Response rate, n (%) 18 (15.1) 33 (28.2) 52 (40)
p-value N/A p= 0.0077 p< 0.0001
Median reduction in seizure frequency, % 14.9 29.3 39.6
p-value N/A p= 0.0028 p< 0.0001
Adverse Events Common Adverse Events: stomatitis (low-dose 55%, high-dose 64%), diarrhea (low-dose 17%, high-dose 22%), nasopharyngitis (placebo 16%, low-dose 14%, high-dose 16%), upper respiratory tract infection (low-dose 13%, high-dose 15%)
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: 3%
Study Author Conclusions 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.

As there have been few clinical trials assessing the use of mTOR inhibitors in TSC, this study could have a profound effect upon the potential role of mTOR inhibitors for TSC patients in a clinical setting.  The study focused on the short-term benefits of everolimus for patients with TSC; however, the long-term efficacy of everolimus needs to be assessed.

References

  1. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381(9861):125-32.
  2. Laguna MP. Re: everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. J Urol. 2014;191(3):626-7.
  3. French JA, Lawson JA, Yapici Z, et al. 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;
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