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Advanced Neurology mTOR inhibition in epilepsy

seizure reduction of 73% at 12 weeks. In addition, 60% with most side effects being transient and mild-to-
of the patients experienced a ≥50% seizure reduction moderate, and manageable with dose adjustments or
in seizures, 35% had at least a 90% reduction, and 20% temporary discontinuation. Adverse events occurred
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achieved seizure freedom. 67 more frequently within the first 6 months of everolimus
The landmark EXIST-3 trial, a phase-3, double- treatment. Common adverse events included stomatitis
blind study, involved 366 patients with tuberous pyrexia (38.2%), stomatitis (36.0%), diarrhea (33.2%),
sclerosis complex-related refractory epilepsy. Patients oral ulceration (28.8%), upper respiratory tract infection
were randomly assigned to receive either a placebo, (26.6%), nasopharyngitis (26.0%), vomiting (22.2%),
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low-exposure everolimus (trough concentration of and cough (21.6%). The severity of adverse events was
3 – 7 ng/mL), or high-exposure everolimus (9 – 15 ng/mL). comparable across all age groups, except for pneumonia,
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The trial demonstrated that significantly more patients in which was more common and severe in children aged
the low-exposure (28.2%; P = 0.0077) and high-exposure <3 years. In this cohort, 38% of patients reported serious
everolimus (40%; P < 0.0001) groups achieved a ≥50% adverse events, with 21.3% considered to be everolimus-
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seizure reduction after 18 weeks of therapy compared to related. Common adverse events included pneumonia
the placebo group (15.1%). The open-label extension (10.5%), seizures (5.0%), and status epilepticus (4.2%).
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of the EXIST-3 trial (n = 361), conducted over 2 years, Four deaths were reported, two of which were due to
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showed sustained benefits of long-term everolimus use, treatment-related pneumonia and septic shock. Two
with an increasing response rate over time: 31% at week other deaths were attributed to non-treatment-related
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18, 46.6% at 1-year, and 57.7% at 2 years. 64 sudden unexpected death in epilepsy. Non-infectious
adverse events during everolimus treatment were less
In the post-extension phase study of the EXIST-3 trial, common but included non-infectious pneumonitis, a
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Franz et al. observed that the efficacy of everolimus is pro-coagulant state, angioedema with concurrent use
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usually maintained once a response is achieved. A post of angiotensin-converting enzyme inhibitors, renal
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hoc analysis by Curatolo et al. on the pediatric patients failure, myelosuppression, impaired wound healing,
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in this cohort showed findings similar to those in the hyperglycemia, dyslipidemia, and acne. 73
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adult population. In fact, younger children aged <6 years
appeared to derive greater benefits than older children A significant challenge during everolimus treatment is
aged ≥6 years, likely due to lower everolimus clearance in managing drug-drug interaction. Everolimus has significant
younger patients. 71 interactions with CYP3A4/p-glycoprotein (p-GP)
inducers and inhibitors. CYP3A4/p-GP inducers, such as
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In 2018, the U.S. FDA approved everolimus for the phenobarbital, phenytoin, rifampicin, and glucocorticoids,
treatment of tuberous sclerosis complex-related focal- reduce everolimus bioavailability, while CYP3A4/p-GP
onset seizures in adults and children aged ≥2 years. The inhibitors, such as erythromycin, ketoconazole, ritonavir,
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recommended starting dose of everolimus is 4.5 mg/m /d and verapamil, tend to increase everolimus serum levels.
2
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for SEGA and 5 mg/m /d for tuberous sclerosis complex- Consequently, dose modifications are often necessary,
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related focal-onset seizures. Although everolimus has with frequent therapeutic drug monitoring to guide
a better pharmacokinetic profile than rapamycin, both management. 79
drugs share a narrow therapeutic index. Dose titration
based on whole blood trough concentration from serial 6.1.3. Other mTOR inhibitors
therapeutic drug monitoring is recommended, with a target Several other mTOR inhibitors are currently under
range of 5 – 15 ng/mL. 16,54,72 Franz et al. concluded that development, progressing through various stages of clinical
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seizure reduction with everolimus improves progressively trials. Non-rapalog allosteric inhibitors suppress the
over time. Due to its disease-modifying effects, patients phosphorylation of both S6K1 and 4E-BP1, substrates of
receiving higher doses of everolimus may achieve a faster mTORC1. ATP-competitive mTOR inhibitors are gaining
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clinical response, whereas those on lower doses may reach popularity in research as they target the ATP-binding site
a similar response more slowly over a longer period. Franz of the catalytic domain of the mTOR protein, thereby
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et al. recommended starting everolimus at a low dose and inhibiting both mTORC1 and mTORC2. To overcome
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gradually increasing it, as tolerated, to minimize adverse resistance that may develop with long-term mTOR
events and enhance adherence. Temporary discontinuation inhibitor use, RapaLink-1, a dual-binding site inhibitor,
of everolimus is also advisable during febrile illnesses, before has been designed to simultaneously bind to the FRB
receiving live vaccines, and before surgical procedures. 73 domain and the ATP binding site of the mTOR protein.
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In the post-extension phase of EXIST-3, everolimus Dual-target mTOR inhibitors, such as dual mTOR/PI3K
demonstrated a tolerable long-term safety profile, inhibitors, dual mTOR/HDAC inhibitors, and ATR/
Volume 3 Issue 3 (2024) 11 doi: 10.36922/an.3568