Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures

Figures & data

Table 1. Overview of AEDs used in clinical studies for treatment of TSC-associated partial-onset seizures.

Agent	Type/Mechanism of Action	Efficacy	Safety concerns
Vigabatrin [19–26]	GABAergic; irreversible inhibition of GABA-T	16–46% with seizure freedom	Retinal nerve fiber layer thinning, visual field deficits, cortical visual loss
Clobazam [27]	GABAergic; benzodiazepine	≥50% response rate: 69% (between 1 week to 3 months); 21% at 12 months	Sleepiness/sedation
Lamotrigine [28]	Glutamatergic; voltage-gated sodium channel blocker	>50% response rate: 79% Seizure freedom: 49%	Rash
Levetiracetam [29,30]	Glutamatergic; unknown, correlated with binding to SV2A	≥50% response rate: 40% Seizure freedom: 20%	Irritability, hyperactivity, insomnia

GABA: γ-aminobutyric acid.

Figure 1. Mechanism of action of (a) mTORC1 in the pathophysiology of TSC and (b) the mTORC1 inhibitor everolimus for TSC-associated seizures.

Akt: protein kinase B; AMPK: 5ʹ adenosine monophosphate-activated protein kinase; IGF: insulin growth factor; mTORC1: mammalian target of rapamycin complex 1; PI3K: phosphoinositide-3 kinase; PTEN: phosphatase and tensin homolog on chromosome 10; Rheb: Ras homolog enriched in brain; STRAD^α: STE20-related kinase adapter alpha; TSC: tuberous sclerosis complex; TSC1: tuberous sclerosis complex 1 protein; TSC2: tuberous sclerosis complex 2 protein.

Table 2. Phase 1–3 clinical studies evaluating mTOR inhibitors for treatment of TSC-associated seizures.

Drug	Study/Phase	N/Study population	Everolimus dose	Study duration/everolimus exposure	Efficacy and safety data in seizures
Everolimus	Krueger et al. Phase 1/2 Core phase [47] Extension analysis [48] Final analysis [49]	28; patients with growing TSC-associated SEGA	Initial dose: 3 mg/m^2 Maintenance dose: titrated to blood trough 5–15 ng/ml	Core phase: 6 months Extension analysis: median exposure 34.2 months Final analysis: median exposure 67.8 months	Efficacy Core phase● Median change of −1 seizure (p = 0.02)● Of 16 patients with available video EEG data: ● 9 decrease in seizures ● 6 no change ● 1 increase in seizures Extension analysis● 38.5% seizure-free at baseline vs 65.2% at 24 months● 26.9 with ≥1 seizure/day at baseline vs 13.0% at 24 months Final analysis● 50% seizure-free at 60 months● 11.1% with ≥1 seizure/day at 60 monthsSafety Final analysis● Most common AEs: upper respiratory tract infection (67.9%), sinusitis (42.9%), cellulitis (32.1%), otitis media (32.1%), stomatitis (28.6%), and gastroenteritis (25.0%)
Everolimus	Krueger et al. Phase 1/2 Core phase [50] Final analysis [51]	20; patients with TSC-associated refractory seizures	Initial dose: 5 mg/m^2 Maintenance dose: titrated to blood trough 5–15 ng/ml	Core phase: 12 weeks Final analysis: everolimus duration 50.9 months	Efficacy Core phase● Among 20 patients ● 60% responders (≥50% reduction) ● 15% partial responders (25% to <50% reduction) ● 35% with ≥90% reduction) ● 20% seizure-free● Median seizure frequency – 73% (p = 0.020)Final analysis● ≥50% responders ● Month 12 (n = 17): 76% ● Month 24 (n = 16): 75% ● Month 36 (n = 15): 80% ● Month 48 (n = 14): 93% Safety Final analysis● Most common AEs: infections (38.9%) and gastrointestinal/oral (24.9%)^a
Everolimus	EXIST-1 [52]	78 (everolimus), 39 (placebo); patients with growing TSC-associated SEGA Presence of seizure on baseline EEG: 27 (everolimus), 13 (placebo)	Initial dose: 4.5 mg/m^2 Maintenance dose: titrated to blood trough 5–15 ng/ml	Median duration: 41.9 weeks (everolimus), 36.1 weeks (placebo)	Efficacy● Median baseline seizure frequency ● Everolimus: 11.0/24 h ● Placebo: 5.9/24 h● Median change from baseline to week 24 seizure frequency: everolimus vs placebo  ● –2.9/24 h (95% CI −4.0 to −1.0) vs −4.1/24 h (95% CI, −10.9 to 5.8); p = 0.2988 Safety● Most common AEs (everolimus only): mouth ulceration (32%), stomatitis (31), convulsion (23%), and pyrexia (22%)
Everolimus	EXIST-3 Core phase [15] Extension analysis [54]	Core phase 130 (everolimus HE), 117 (everolimus LE), 119 (placebo); patients with TSC-associated refractory partial-onset seizures Extension analysis 361 (everolimus in core and/or extension phases)	Trough concentrations Core phase Everolimus HE: 9–15 ng/ml Everolimus LE: 3–7 ng/ml Extension analysis Everolimus 3–15 ng/ml	Core phase: 18 weeks Extension analysis: median everolimus exposure ~21 months	Efficacy Core phase● Median percentage reduction in seizure frequency from baseline (p value vs placebo)  ● Everolimus HE: 39.6% (p < 0.0001) ● Everolimus LE: 29.3% (p = 0.0028) ● Placebo: 14.9%● Response rate: ≥50% reduction from baseline in seizure frequency (p value vs placebo) ● Everolimus HE: 40.0% (p < 0.0001) ● Everolimus LE: 28.2% (p = 0.0077) ● Placebo: 15.1% Extension analysis● Median percentage reduction in seizure frequency from baseline ● Week 18 (n = 352): 31.7% ● 1 year (n = 298): 46.7% ● 2 years (n = 163): 56.9%  ● Response rate: ≥50% reduction from baseline in seizure frequency ● Week 18 (n = 352): 31% ● 1 year (n = 298): 46.6% ● 2 years (n = 163): 57.7% Safety Extension analysis● Most common AEs (everolimus only): stomatitis (35.2%), pyrexia (34.6%), diarrhea (28.5%), mouth ulceration (27.7%), nasopharyngitis (23.8%), and upper respiratory tract infection (22.4%)
Sirolimus	Overwater et al. [43]	23 (12 received sirolimus during first period of 6 months, 11 received sirolimus during second period of 6 months); patients with TSC ≥1 epileptic seizure per week and resistant to ≥2 AEDs	Titrated to target blood trough levels of 5–10 ng/mL.	Study duration: 12 months Exposure: 6 months of adjunctive sirolimus and 6 months standard of care in crossover design	Efficacy● 41% fewer seizures compared with standard care (95% CI – 69% to +14%; p = 0.11)● Mean seizure frequency reduction of 61% (95% CI – 86% to +6%; p = 0.06 Safety● Most common AEs: upper respiratory tract infection (87%), gastrointestinal (83%), acne-like skin lesions (74%), other infection (52%), aphthous ulcer (30%), fever (26%)

AE, adverse event; EEG: electroencephalogram; HE: high exposure; LE: low exposure; SEGA: subependymal giant cell astrocytoma; TSC: tuberous sclerosis complex.

^aInfections included upper respiratory tract infection, gastroenteritis, and cellulitis. Gastrointestinal/oral included mucositis and stomatitis.

Figure 2. (a) Response rate over time from the start of everolimus. Bars represent 95% confidence intervals obtained using Clopper–Pearson method. (b) Median percentage reduction in seizure frequency over time from the start of everolimus. Bars represent 95% confidence intervals based on bootstrap percentiles. Reprinted with permission from Franz DN et al. Everolimus for treatment-refractory seizures in TSC. Extension of a randomized controlled trial. Neurology Clinical Practice. Volume 8, Issue 5, Pages 412–420. https://cp.neurology.org/ [54].

Table 3. Adverse reactions reported in ≥10% of Everolimus-treated patients with TSC-associated partial-onset seizures in EXIST-3 [15].

	Everolimus HE (n = 130)		Everolimus LE (n = 117)		Placebo (n = 119)
Adverse event, %	All grades	Grade 3/4	All grades	Grade 3/4	All grades	Grade 3/4
Gastrointestinal
Stomatitis^a	64	4^b	55	3^b	9	0
Diarrhea	22	0	17	0	5	0
Vomiting	10	2^b	12	0	9	0
Infections
Nasopharyngitis	16	0	14	0	16	0
Upper respiratory tract infection	15	0	13	0	13	0.8^b
General
Pyrexia	14	0.8^b	20	0	5	0
Respiratory, thoracic and mediastinal
Cough	10	0	11	0	3	0
Skin and subcutaneous tissue
Rash	10	0	6	0	3	0

HE: high exposure; LE: low exposure.

^aIncludes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain.

^bNo grade 4 adverse events reported.

Table 4. Comparison of everolimus characteristics with potential competitors for treatment of TSC-associated partial seizures.

Characteristic	Everolimus [16,17]	Cannabidiol	Vigabatrin [21]
Mechanism of action	mTORC1 inhibitor	Unknown [35]	Irreversible inhibitor of GABA-T
Usage for seizures	Refractory seizures associated with TSC	Dravet syndrome, LGS, TSC, and IS (currently only approved in Dravet syndrome and LGS) [35]	Adjunctive for rCPS, not as first line IS
Ages of use	≥2 years	1–65 years [37]	≥10 years (for rCPS) 1 month to 2 years (for IS)
Dosage forms	Oral tablet Tablet for oral suspension	Oral solution [37,38]	Oral tablet Oral solution
Dose frequency	Once daily	Twice daily [37,38]	Twice daily
Common AEs	Stomatitis, diarrhea, nasopharyngitis, pyrexia, upper respiratory tract infection, cough, rash, vomiting^a	Drowsiness, ataxia, diarrhea, agitation, poor sleep, irritability, appetite suppression, confusion, vomiting, increased self-stimulation, behavioral difficulties [38]	Refractory complex seizures^b Pediatrics (age 10 to 16 years): weight gain, upper respiratory tract infection, tremor, fatigue, aggression, and diplopia Adults: permanent vision loss, fatigue, somnolence, nystagmus, tremor, blurred vision, memory impairment, weight gain, arthralgia, abnormal coordination, and confused state IS^c Somnolence, bronchitis, ear infection, and acute otitis media
Boxed warning	None	Not established	Permanent bilateral concentric visual field constriction and decreased visual acuity
Warnings/ Precautions	Increased risk of noninfectious pneumonitis, infections, hypersensitivity reactions, angioedema, stomatitis, hemorrhage, renal failure, impaired wound healing, laboratory test alterations, embryo-fetal toxicity. Avoid live vaccinations	Increased risk of hepatocellular injury, somnolence and sedation, suicidal behavior and ideation, hypersensitivity reactions, withdrawal of AEDs [35]	Increased risk of abnormal MRI signal changes, suicidal ideation, withdrawal of AEDs, anemia, somnolence, and fatigue

AED: antiepileptic drug; GABA-T: γ-aminobutyric acid transaminase; LGS: Lennox–Gastaut Syndrome; IS: infantile spasms; MRI: magnetic resonance imaging; rCPS: refractory complex partial seizures; TSC: tuberous sclerosis complex.

^aIncidence ≥10% in either high-dose or low-dose treatment groups.

^bIncidence ≥5% over placebo.

^cIncidence >5% and greater than on placebo.

Sirven JI, Noe K, Hoerth M, et al. Antiepileptic drugs 2012: recent advances and trends. Mayo Clin Proc. 2012;87(9):879–889.

 PubMed Web of Science ®Google Scholar

Riikonen R, Rener-Primec Z, Carmant L, et al. Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study. Dev Med Child Neurol. 2015;57(1):60–67.

 PubMed Web of Science ®Google Scholar

Greiner HM, Lynch ER, Fordyce S, et al. Vigabatrin for childhood partial-onset epilepsies. Pediatr Neurol. 2012;46(2):83–88.

 PubMed Web of Science ®Google Scholar

Jennesson M, van Eeghen AM, Caruso PA, et al. Clobazam therapy of refractory epilepsy in tuberous sclerosis complex. Epilepsy Res. 2013;104(3):269–274.

 PubMed Web of Science ®Google Scholar

Franz DN, Tudor C, Leonard J, et al. Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia. 2001;42(7):935–940.

 PubMed Web of Science ®Google Scholar

Collins JJ, Tudor C, Leonard JM, et al. Levetiracetam as adjunctive antiepileptic therapy for patients with tuberous sclerosis complex: a retrospective open-label trial. J Child Neurol. 2006;21(1):53–57.

 PubMed Web of Science ®Google Scholar

Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801–1811.

 PubMed Web of Science ®Google Scholar

Krueger D, Care M, Agricola K, et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 2013;80(6):574–580.

 PubMed Web of Science ®Google Scholar

Franz DN, Agricola K, Mays M, et al. Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol. 2015;78(6):929–938.

 PubMed Web of Science ®Google Scholar

Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74(5):679–687.

 PubMed Web of Science ®Google Scholar

Krueger DA, Wilfong AA, Mays M, et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology. 2016;87(23):2408–2415.

 PubMed Web of Science ®Google Scholar

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):125–132.

 PubMed Web of Science ®Google Scholar

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;388(10056):2153–2163.

 PubMed Web of Science ®Google Scholar

Franz DN, Lawson JA, Yapici Z, et al. Everolimus for treatment-refractory seizures in TSC. Extension of a randomized controlled trial. Neurol Clin Pract. 2018;8(5):412–420.

 PubMedGoogle Scholar

Overwater IE, Reitman AB, Bindels-de Heus K, et al. Sirolimus for epilepsy in children with tuberous sclerosis complex: a randomized controlled trial. Neurology. 2016;87(10):1011–1018.

 PubMedGoogle Scholar

Prescribing Information for Afinitor®. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022334s6lbl.pdf

 Google Scholar

Summary of Product Characteristics for Votubia. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022334s6lbl.pdf

 Google Scholar

Prescribing Information for Sabril®. Availbale from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020427s010s011s012,022006s011s012s013lbl.pdf

 Google Scholar

Prescribing Information for Epidiolex®. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf

 Google Scholar

Clinicaltrials.gov. A randomized controlled trial of cannabidiol (GWP42003-P, CBD) for seizures in tuberous sclerosis complex (GWPCARE6). NCT02544763. Available from: https://clinicaltrials.gov/ct2/show/NCT02544763

 Google Scholar

Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(10):1617–1624.

 PubMed Web of Science ®Google Scholar