On April 10, 2018, the U.S. Food and Drug Administration approved everolimus tablets for oral suspension (Afinitor Disperz) for the adjunctive treatment of adult and pediatric patients aged ≥ 2 years with tuberous sclerosis complex–associated partial-onset seizures.^1,2 Tuberous sclerosis complex is a rare genetic disorder characterized by the growth of benign tumors in the brain, eyes, heart, kidneys, skin, lungs, and other organs, in some cases leading to serious health problems.

Supporting Efficacy Data

Approval was based on the double-blind phase III EXIST-3 trial involving 366 patients with tuberous sclerosis complex and tuberous sclerosis complex–associated partial-onset seizures who had inadequate seizure control on at least 2 sequential antiepileptic drug regimens.^2,3 Patients were required to have ≥ 16 partial-onset seizures during the 8-week baseline phase on a stable antiepileptic drug regimen.

Patients were randomly assigned (1:1:1) to everolimus tablets for oral suspension targeting a low-exposure trough (3–7 ng/mL; n = 117) or high-exposure trough (9–15 ng/mL; n = 130) concentration of everolimus or placebo (n = 119). Treatment was started with oral once-daily dosing of 3 to 6 mg/m² depending on age or further adjusted for concomitant P-glycoprotein (P-gp)/CYP3A4 inducer use. Doses were then titrated to achieve targeted trough concentrations. The major efficacy measure was percentage reduction in average weekly seizures during a 12-week treatment period vs the 8-week baseline period.

Patients had a median age of 10 years (range = 2.2–56 years), with 28% aged < 6 years, 31% aged 6 to < 12 years, 22% aged 12 to < 18 years, and 18% aged ≥ 18 years; 65% were white, and 52% were male. Patients received between one and three concomitant anti-epileptic drugs.

Median percentage reduction in seizures was 29.3% in the low-exposure group (P = .003 vs placebo) and 39.6% in the high-exposure group (P < .001 vs placebo) vs 14.9% in the placebo group. Proportions of patients with ≥ 50% reduction in seizure frequency during the 12-week treatment period compared with baseline were 28.2% of the low-exposure group and 40.0% of the high-exposure group vs 15.1% of the placebo group.

How It Works

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex. Everolimus binds to the intracellular protein FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity.

Everolimus reduces the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein, downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor, which results in ligand-independent activation of the receptor. In addition, everolimus inhibits expression of hypoxia-inducible factor (eg, HIF-1) and reduces expression of vascular endothelial growth factor. Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in both in vitro and in vivo studies.

The oncogene suppressors TSC1 and TSC2 are regulators of mTORC1 signaling. Loss or inactivation of TSC1 or TSC2 leads to activation of downstream signaling. In tuberous sclerosis complex, inactivating mutations in either TSC1 or TSC2 lead to hamartoma formation throughout the body, as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure, causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.

How It Is Used

Afinitor (standard tablets) and Afinitor Disperz (tablets for suspension) are two different dosage forms of everolimus. They should not be combined to achieve a total dose.

The recommended starting dosage of everolimus for oral suspension in tuberous sclerosis complex–associated partial-onset seizures is 5 mg/m² once daily, with treatment continued until disease progression or unacceptable toxicity. Therapeutic drug monitoring is required for treatment to attain everolimus whole blood trough concentrations of 5 to 15 ng/mL.

Product labeling provides specific instructions on drug monitoring and dose titration. It is recommended that the same assay and laboratory be used for drug monitoring throughout treatment. The recommended dosing in severe hepatic impairment is 2.5 mg/m² once daily, with dose adjusted based on everolimus trough concentrations.

Product labeling provides detailed instructions for dosage modification for grade 2 or 3 noninfectious pneumonitis, grade 2 or 3 stomatitis, grade 3 metabolic events (eg, hyperglycemia, dyslipidemia), other grade 2 or 3 nonhematologic toxicities, grade 2 to 4 thrombocytopenia, grade 3 or 4 neutropenia, and grade 3 febrile neutropenia. Everolimus tablets for oral suspension should be discontinued for clinically significant hypersensitivity; noninfectious pneumonitis of grade 2 that does not resolve or improve to grade 1 within 4 weeks, recurrent grade 3 pneumonitis, and any grade 4 pneumonitis; grade 4 stomatitis; grade 4 metabolic events; other recurrent grade 3 or any grade 4 nonhematologic toxicity; and grade 4 febrile neutropenia.

Concomitant use of P-gp/strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin) should be avoided, including grapefruit and grapefruit juice. The dose of everolimus tablets for oral suspension should be reduced in patients taking concurrent P-gp/moderate CYP3A4 inhibitors (eg, aprepitant, erythromycin, fluconazole) and increased in those taking concurrent P-gp/strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin). Product labeling provides detailed instructions on dosage modification in these situations. Concomitant use of the CYP3A4 inducer St. John’s wort should be avoided.

Safety Profile

The most common adverse events of any grade occurring in patients receiving everolimus tablets for oral suspension in EXIST-3 were stomatitis (55% in the low-exposure group and 64% in the high-exposure group vs 9% in the placebo group), diarrhea (17% and 22% vs 5%), pyrexia (20% and 14% vs 5%), and nasopharyngitis (14% and 16% vs 16%). The most common grade 3 or 4 adverse events (≥ 2%) were stomatitis (3% and 4% vs 0%), pneumonia, and irregular menstruation. The most common grade 3 or 4 laboratory abnormalities were neutropenia (4% and 6% vs 7%) and hypertriglyceridemia (2% and 2% vs 0%).

Adverse events led to treatment discontinuation in 5% of the low-exposure group and 3% of the high-exposure group, with the most common cause (≥ 1%) being stomatitis. Adverse events led to dose interruption or reduction in 24% of the low-exposure group and 35% of the high-exposure group, with the most common causes (≥ 3%) being stomatitis, pneumonia, and pyrexia.

Everolimus carries warnings/precautions for noninfectious pneumonitis, infections, severe hypersensitivity reactions, angioedema (with increased risk in patients taking angiotensin-converting enzyme inhibitors), stomatitis, renal failure, impaired wound healing, geriatric patients, metabolic disorders, myelosuppression, risk of infection or reduced immune response with vaccination, and embryofetal toxicity. Patients should be monitored for clinical symptoms or radiologic changes associated with noninfectious pneumonitis. Renal function, serum glucose and lipids, as well as hematologic parameters should be monitored prior to treatment and periodically thereafter. Everolimus is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves everolimus for tuberous sclerosis complex-associated partial-onset seizures. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm604351.htm. Accessed April 17, 2018.

2. Afinitor Disperz (everolimus tablets for oral suspension) prescribing information, Novartis Pharmaceuticals Corporation, April 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/022334s040,203985s013lbl.pdf. Accessed April 17, 2018.

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 388:2153-2163, 2016.