SKYLINE
Soticlestat as an adjunctive therapy in children and young adults with Dravet syndrome
Year of Publication: 2026
Authors: Sullivan J, Valente K, Villanueva V, et al.
Journal: Epilepsia
Citation: Epilepsia 2026;67(6):2796-2807. DOI: 10.1002/epi.70164
Link: https://doi.org/10.1002/epi.70164
PDF: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285253/pdf/
PDF: Clinical Question
In children and young adults with Dravet syndrome and treatment-resistant convulsive seizures, does adjunctive soticlestat (up to 300 mg BID, weight-adjusted) reduce monthly convulsive seizure frequency compared with placebo?
Bottom Line
In this global phase 3 trial, adjunctive soticlestat narrowly missed statistical significance for its primary endpoint of convulsive seizure frequency reduction in Dravet syndrome (placebo-adjusted -15.64%, p=0.061), though the responder rate (≥50% reduction) and multiple caregiver/clinician-reported outcomes numerically favored soticlestat with nominal significance. Safety was consistent with prior data. The totality of the data suggest at most a modest antiepileptic effect that did not clear the phase 3 primary bar.
Major Points
- Global, multicenter (53 sites, 17 countries), 1:1 randomized, double-blind, placebo-controlled phase 3 trial in children and young adults (2-21 y) with Dravet syndrome; 144 randomized (soticlestat 73, placebo 71); enrollment Dec 7, 2021 - Apr 11, 2024.
- Weight-adjusted soticlestat titrated over 4 weeks to a maximum of 300 mg BID (in participants ≥45 kg), followed by 12 weeks of maintenance (16-week total treatment).
- Primary endpoint (full treatment): median % change in convulsive seizure frequency/28 d was -22.16% soticlestat vs -8.64% placebo; placebo-adjusted -15.64% (95% CI -31.30 to 0.24), p=0.061 - narrowly missed.
- Primary endpoint (maintenance, EMA co-primary): -23.29% vs -11.99%; placebo-adjusted -14.29% (95% CI -30.51 to 1.53), p=0.089 - also not significant.
- Key secondary responder rate (≥50% reduction) 27.4% soticlestat vs 9.9% placebo (nominal p=0.008); >75% responders 10 vs 1.
- Care GI-I, CGI-I, and CGI-I Seizure Intensity and Duration all favored soticlestat (all nominal p≤.004); CGI-I Non-Seizure Symptoms and QI-Disability showed no meaningful difference.
- SCN1A+ exploratory subgroup (79% of participants; n=58 soticlestat vs 56 placebo): -23.34% vs -12.70%, diff -17.38% (95% CI -34.29 to -1.21, nominal p=0.045); responders 27.6% vs 8.9% (OR 4.31, 95% CI 1.32-14.02, nominal p=0.011).
- Post-hoc ASM-quartile analysis: benefit largest in participants with fewer prior ASMs (Q1: -34.9%; Q2: -30.1%; Q3: -22.5%) and adverse in the most refractory quartile (Q4 with ≥9 ASMs: +15.0% vs placebo).
- Any TEAE 80.8% (soticlestat) vs 74.6% (placebo); treatment-related TEAEs 43.8% vs 26.8%; most common drug-related events with soticlestat were somnolence (12.3%), change in seizure presentation (9.6%), decreased appetite (6.8%), and insomnia (5.5%).
- Serious TEAEs 9.6% (7/73) soticlestat vs 14.1% (10/71) placebo; TEAE-related discontinuations 15.1% (11/73) vs 5.6% (4/71); one SUDEP occurred on soticlestat, no deaths on placebo; no new safety signals.
Design
Study Type: Phase 3, global, multicenter, 1:1 randomized, double-blind, placebo-controlled, parallel-group, add-on trial
Randomization: 1
Blinding: Double-blind (participants, caregivers, investigators, and sponsor personnel blinded; matching placebo administered orally or via enteral feeding tube)
Enrollment Period: Dec 7, 2021 - Apr 11, 2024
Follow-up Duration: 16-week treatment (4-week titration + 12-week maintenance); 1-week taper + 2-week follow-up for those not entering open-label extension
Centers: 53
Countries: 17 countries (global; specific list not enumerated in main text)
Sample Size: 144
Power Calculation: Sample-size calculation based on the phase 2 ELEKTRA study and other prior data; the trial was described by the authors as adequately powered.
Analysis: Efficacy in modified intent-to-treat (randomized, ≥1 dose, ≥1 day of treatment-period seizure data). Primary analysis by rank ANCOVA with treatment, age stratum (≤6 y, >6 y), and rank of baseline convulsive seizure frequency as fixed effects; Hodges-Lehmann estimate reported. Hierarchical gatekeeping controlled type I error across the primary and six ordered key secondary endpoints; downstream comparisons after the primary miss are nominal. Safety analyses in all who received ≥1 dose.
Inclusion Criteria
- Age 2-21 years at screening
- Body weight ≥10 kg
- Clinical diagnosis of Dravet syndrome, independently adjudicated by The Epilepsy Study Consortium (TESC)
- Treatment-resistant seizures (failure of ≥1 appropriate ASM trial)
- Receiving stable antiseizure standard-of-care therapy with 0-4 concomitant ASMs
- ≥12 convulsive seizures in the 12 weeks prior to screening
- ≥4 convulsive seizures per 28 days during the 4-6-week prospective baseline
- Written informed consent from the participant or parent/legal guardian
Exclusion Criteria
- Admission to a medical facility and intubation for status epilepticus ≥2 times in the 3 months immediately before screening
- Additional inclusion/exclusion criteria specified in the study's Table (not enumerated in the main text)
Baseline Characteristics
| Characteristic | Placebo (n=71) | Soticlestat (n=73) |
|---|---|---|
| Age, years, mean (SD) | 10.5 (5.1) | 10.1 (5.0) |
| Male, n (%) | 36 (50.7) | 36 (49.3) |
| Female, n (%) | 35 (49.3) | 37 (50.7) |
| White, n (%) | 43 (60.6) | 39 (53.4) |
| Asian, n (%) | 24 (33.8) | 27 (37.0) |
| Hispanic or Latino, n (%) | 6 (8.5) | 5 (6.8) |
| SCN1A+, n (%) | 56 (78.9) | 58 (79.5) |
| Baseline ASMs = 3, n (%) | 36 (50.7) | 39 (53.4) |
| Baseline ASMs = 4, n (%) | 24 (33.8) | 18 (24.7) |
| Prior/baseline ASMs, median (range) | 8 (3-20) | 8 (3-27) |
| Valproic acid, n (%) | 47 (66.2) | 46 (63.0) |
| Clobazam, n (%) | 46 (64.8) | 40 (54.8) |
| Stiripentol, n (%) | 27 (38.0) | 27 (37.0) |
| Fenfluramine, n (%) | 13 (18.3) | 14 (19.2) |
| Pharmaceutical-grade cannabidiol, n (%) | 10 (14.1) | 11 (15.1) |
| Topiramate, n (%) | 15 (21.1) | 13 (17.8) |
| Ketogenic diet, n (%) | 4 (5.6) | 3 (4.1) |
| Vagal nerve stimulation, n (%) | 7 (9.9) | 8 (11.0) |
| Convulsive seizure frequency/28 d, median (IQR) | 10.8 (6.1-23.2) | 11.6 (6.3-23.3) |
| All-seizure frequency, median (IQR) | 15.9 (7.9-33.2) | 22.6 (10.0-63.2) |
Arms
| Field | Soticlestat | Control |
|---|---|---|
| Intervention | Weight-adjusted soticlestat BID up to a maximum of 300 mg BID: 40/60/100 mg BID (10 to <15 kg); 60/120/200 mg BID (15 to <30 kg); 80/140/200 mg BID (30 to <45 kg); 100/200/300 mg BID (≥45 kg); orally or via enteral feeding tube; add-on to 0-4 stable ASMs | Matching placebo BID on the same weight-based titration schedule as soticlestat, orally or via enteral feeding tube; add-on to 0-4 stable ASMs |
| N | 73 | 71 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Percentage change from baseline in convulsive seizure frequency per 28 days during the full 16-week treatment period (and, for EMA registration, during the 12-week maintenance period) | Primary | -8.64% (n=71) full treatment; -11.99% maintenance | -22.16% (n=73) full treatment; -23.29% maintenance | 0.061 | |
| ≥50% responders (full treatment period) | Secondary | 9.9% | 27.4% | 0.008 (nominal) | |
| Care GI-I improvement (minimally/much/very much improved) at end of full treatment | Secondary | reference | favored soticlestat | ≤.004 (nominal) | |
| CGI-I improvement at end of full treatment | Secondary | reference | favored soticlestat | ≤.004 (nominal) | |
| CGI-I Seizure Intensity and Duration at end of full treatment | Secondary | reference | favored soticlestat | ≤.004 (nominal) | |
| CGI-I Non-Seizure Symptoms (alertness, communication, disruptive behaviors) | Secondary | no meaningful difference | no meaningful difference | NS | |
| QI-Disability change from baseline | Secondary | no meaningful difference | no meaningful difference (no worsening) | NS | |
| SCN1A+ exploratory subgroup: % change in convulsive seizure frequency | Secondary | -12.70% (n=56) | -23.34% (n=58) | 0.045 (nominal) | |
| SCN1A- exploratory subgroup: % change in convulsive seizure frequency | Secondary | -5.02% (n=15) | -11.10% (n=14) | 0.713 (nominal) | |
| SCN1A+ ≥50% responders | Secondary | 8.9% | 27.6% | 4.31 | 0.011 (nominal) |
| SCN1A- ≥50% responders | Secondary | 13.3% | 28.6% | 2.59 | 0.325 (nominal) |
| Any TEAE | Safety | 53/71 (74.6%) | 59/73 (80.8%) | ||
| Treatment-related TEAE | Safety | 19/71 (26.8%) | 32/73 (43.8%) | ||
| Serious TEAE | Safety | 10/71 (14.1%) | 7/73 (9.6%) | ||
| Treatment-related serious TEAE | Safety | 2/71 (2.8%) | 2/73 (2.7%) | ||
| TEAE leading to study drug discontinuation | Safety | 4/71 (5.6%) | 11/73 (15.1%) | ||
| Somnolence (all) | Safety | 8/71 (11.3%) | 10/73 (13.7%) | ||
| Somnolence (treatment-related) | Safety | 8/71 (11.3%) | 9/73 (12.3%) | ||
| Change in seizure presentation (all) | Safety | 9/71 (12.7%) | 10/73 (13.7%) | ||
| Change in seizure presentation (treatment-related) | Safety | 4/71 (5.6%) | 7/73 (9.6%) | ||
| Nasopharyngitis | Safety | 9/71 (12.7%) | 9/73 (12.3%) | ||
| Pyrexia | Safety | 9/71 (12.7%) | 8/73 (11.0%) | ||
| Upper respiratory tract infection | Safety | 8/71 (11.3%) | 6/73 (8.2%) | ||
| Decreased appetite (all) | Safety | 4/71 (5.6%) | 5/73 (6.8%) | ||
| Insomnia (all) | Safety | 1/71 (1.4%) | 6/73 (8.2%) | ||
| Constipation | Safety | 0/71 (0) | 6/73 (8.2%) | ||
| Status epilepticus (all TEAE) | Safety | 4/71 (5.6%) | 2/73 (2.7%) | ||
| Status epilepticus (serious) | Safety | 4/71 (5.6%) | 2/73 (2.7%) | ||
| SUDEP | Safety | 0/71 (0) | 1/73 (1.4%) | ||
| Serious infections and infestations | Safety | 5/71 (7.0%) | 2/73 (2.7%) |
Subgroup Analysis
Prespecified SCN1A+ exploratory subgroup (79% of participants) showed a nominally significant placebo-adjusted reduction of 17.38% (95% CI -34.29 to -1.21, nominal p=0.045); SCN1A- subgroup showed no effect (-3.01%, nominal p=0.713). Post-hoc analysis by prior-ASM quartiles suggested larger benefit in patients with fewer prior ASMs (Q1: -34.9%; Q2: -30.1%; Q3: -22.5%) and an unfavorable effect in the most refractory quartile (Q4 ≥9 ASMs: +15.0% vs placebo).
Criticisms
- Primary endpoint not met - the trial narrowly missed statistical significance for both the full treatment period (p=0.061) and the maintenance period (p=0.089), so hierarchical testing means all downstream 'positive' key secondary results are nominal only.
- Placebo response was substantially higher than in the phase 2 ELEKTRA study (which showed a 50% placebo-adjusted reduction), likely diluting the observable treatment effect in phase 3.
- Population was more treatment-refractory than ELEKTRA (median 8 prior/current ASMs, range up to 27); post-hoc quartile analysis suggests the drug performs worst in patients on ≥9 ASMs (+15% vs placebo), raising questions about the target population.
- SCN1A genotype status was based on documented mutations - the ~20% classified as SCN1A- may include misdiagnosed patients and confounded the primary analysis; the SCN1A+ signal is exploratory and not adjusted for multiplicity.
- Sponsor (Takeda) designed, funded, and analyzed the trial, and 7 of 15 authors are Takeda employees/stockholders - risk of interpretation bias in framing a negative primary result as 'clinically meaningful.'
- Short 16-week treatment duration (4-week titration + 12-week maintenance) may not fully capture durability or long-term tolerability, particularly important for a chronic pediatric epilepsy.
- Post-hoc ASM-quartile analysis was not prespecified and is hypothesis-generating.
- Country/site-specific effects and cross-cultural differences in caregiver-reported outcomes (Care GI-I, CGI-I) across 17 countries were not detailed.
Funding
Takeda Development Center Americas (designed, funded, and analyzed the trial; several authors are Takeda employees and stockholders).
Based on: SKYLINE (Epilepsia, 2026)
Authors: Sullivan J, Valente K, Villanueva V, et al.
Citation: Epilepsia 2026;67(6):2796-2807. DOI: 10.1002/epi.70164
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