EXIST-3
Adjunctive Everolimus Therapy for Treatment-Resistant Focal-Onset Seizures Associated with Tuberous Sclerosis (EXIST-3): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study
Bottom Line
Everolimus significantly reduced seizure frequency in TSC-associated epilepsy. The high-trough group (9-15 ng/mL) achieved a 40.0% responder rate vs 15.1% placebo (p<0.001) and 39.6% median seizure reduction vs 14.9% placebo (p<0.001). However, the high AE burden (24% grade 3-4 events, majority with stomatitis), lack of improvement in quality of life or cognitive function despite seizure reduction, immunosuppressive risks, very low seizure-free rates (3.8-5.1%), and need for therapeutic drug monitoring limit its practical utility.
Major Points
- Everolimus significantly reduced seizure frequency in tuberous sclerosis complex (TSC)-associated epilepsy.
- Responder rate (≥50% reduction): 40% (high-exposure) vs 28.2% (low-exposure) vs 15.1% (placebo); P=0.0003 for high.
- Median seizure reduction: 39.6% (high) vs 29.3% (low) vs 14.9% (placebo).
- 366 patients (ages 2-65) with TSC and drug-resistant seizures. Phase 3, double-blind.
- Everolimus: mTOR inhibitor; targets the mTOR pathway dysregulated in TSC (TSC1/TSC2 mutations).
- Dose-response: higher everolimus trough levels (9-15 ng/mL) more effective than lower (3-7 ng/mL).
- AEs: stomatitis (28-31%), diarrhea (10-12%), mouth ulcers, nasopharyngitis. Serious infections 5-6%.
- Published JAMA 2016 (French et al.). Novartis sponsored.
- Led to FDA approval of everolimus as adjunctive therapy for TSC-associated seizures.
- First disease-specific (genotype-directed) therapy for epilepsy based on molecular pathway.
Design
Study Type: Phase 3, randomized, double-blind, placebo-controlled, three-arm, multicenter trial
Randomization: 1
Blinding: Double-blind
Enrollment Period: Randomization began April 29, 2013; primary completion October 25, 2017
Follow-up Duration: 8-week baseline + 18-week core treatment + 48-week extension
Centers: 99
Countries: 25 countries
Sample Size: 366
Analysis: Intention-to-treat; NCT01713946; co-primary endpoints for EMA (responder rate) and FDA (median % change)
Inclusion Criteria
- Age 2-65 years (minimum 1 year in Europe)
- Clinically definite TSC diagnosis (modified Gomez criteria)
- Partial-onset (focal) epilepsy per ILAE classification
- At least 16 reported quantifiable partial-onset seizures during 8-week baseline, no seizure-free period of 21 consecutive days
- Prior failure of 2 or more sequential AED regimens
- Stable AED medication for at least 4 weeks before baseline start
- Acceptable lab values: AST/ALT <2.5x ULN, creatinine <1.5x ULN, hemoglobin >=9 g/dL, platelets >=80,000/mm3
Exclusion Criteria
- Secondary seizures from metabolic, toxic, infectious, or psychogenic disorders
- TSC-related SEGA requiring immediate surgery
- Untreated infantile spasms (if <2 years)
- Status epilepticus within 52 weeks prior to randomization
- Seizure clusters preventing accurate counting within 26 weeks
- Rescue medication use >6 days during baseline
- Body weight <12 kg
- Coexisting malignancies (except treated cervical or non-melanoma skin cancers)
- Severe cardiac, pulmonary, hepatic, or renal conditions
- Uncontrolled diabetes or hyperlipidemia
- Active infections or bleeding disorders
- Prior systemic mTOR inhibitor use within 24 months
- Known hypersensitivity to everolimus or rapamycin analogues
- Score of 4 or 5 on Suicidal Ideation item of C-SSRS within 2 years
- Ketogenic diet (<40 g carbohydrates daily) within 3 months
Arms
| Field | Low-Trough Everolimus | High-Trough Everolimus | Control |
|---|---|---|---|
| Intervention | Everolimus dispersible tablets 2 mg, dose-titrated to target trough 3-7 ng/mL, added to 1-3 concurrent AEDs | Everolimus dispersible tablets 2 mg, dose-titrated to target trough 9-15 ng/mL, added to 1-3 concurrent AEDs | Matching placebo dispersible tablets, added to 1-3 concurrent AEDs |
| Duration | 18 weeks core + extension | 18 weeks core + extension | 18 weeks core |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Co-primary: EMA endpoint (>=50% seizure reduction, weeks 7-18) and FDA endpoint (median % change in weekly seizure frequency) | Primary | Placebo: 15.1% responder rate; -14.9% median change | Low-trough: 28.2% responder, -29.3% change; High-trough: 40.0% responder, -39.6% change | High-trough vs placebo: p<0.001 (both endpoints) | |
| Secondary | |||||
| Secondary | |||||
| Secondary | |||||
| Secondary | |||||
| Secondary | |||||
| Adverse | 11% (13) | Low-trough: 18% (21); High-trough: 24% (31) | |||
| Adverse | 3% (3) | Low-trough: 14% (16); High-trough: 14% (18) | |||
| Adverse | ~9% | Up to 63-100% depending on subgroup | |||
| Adverse | Not specified | ~38% | |||
| Adverse | Not specified | ~41% | |||
| Adverse | Not specified | ~30% | |||
| Adverse | Not specified | ~25% | |||
| Adverse | 2 (1.7%) | Low-trough: 1 (0.9%); High-trough: 2 (1.5%); Long-term (all everolimus): 4/361 (1.1%) | |||
| Adverse | 0 cases | Low-trough: 1 attempt, 2 preparatory, 3 ideation; High-trough: 1 ideation | |||
| Adverse | 2% (2) | Low-trough: 5% (6); High-trough: 3% (4) |
Subgroup Analysis
Pediatric subanalysis (Curatolo 2018): patients <6 years had 45% grade 3-4 AE rate, >=6 to <18 had 38%; pneumonia most common serious AE in children
Criticisms
- Entirely industry-funded (Novartis) with multiple Novartis employees as co-authors
- Despite significant seizure reduction, NO improvement in quality of life, adaptive functioning, or cognitive function
- Substantial AE profile: 24% grade 3-4 AEs in high-trough arm, stomatitis affecting majority, immunosuppressive effects
- 18-week core phase relatively short for assessing long-term efficacy sustainability and cumulative toxicity (4 deaths on everolimus in extension)
- Seizure-free rates very low (3.8-5.1%) even in treatment arms
- Complex trough-level-based dosing requiring regular therapeutic drug monitoring
- Suicidal ideation events occurred in everolimus arms (not placebo) during core phase
Funding
Novartis Pharmaceuticals Corporation -- industry-sponsored
Based on: EXIST-3 (The Lancet, 2016)
Authors: French JA, Lawson JA, Yapici Z, ..., Franz DN
Citation: French JA et al. Lancet. 2016;388(10056):2153-2163. DOI: 10.1016/S0140-6736(16)31419-2
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