Soticlestat Improves Caregiver and Clinical Measures in ENDYMION 2 Trial of Dravet Syndrome and LGS

Author(s):

Key Takeaways

ENDYMION 2 trial showed soticlestat was safe in DS and LGS, with improvements in caregiver and clinician-reported outcomes.
Phase 3 SKYLINE and SKYWAY trials did not demonstrate significant efficacy for soticlestat in these populations.
Most treatment-emergent adverse events in ENDYMION 2 were mild or moderate, with some serious events leading to discontinuation.
Soticlestat showed some benefits over placebo in seizure frequency reduction, but statistical significance was not achieved.
Takeda plans to engage with regulatory authorities to discuss the totality of the data for soticlestat's future.

Most treatment-emergent adverse events were mild or moderate, with low rates of serious TEAEs leading to discontinuation (1.7% in DS and 2.2% in LGS patients).

Julia Jacobs, MD, PhD

New data from the open-label ENDYMION 2 trial (NCT05163314) revealed that investigational soticlestat (Takeda) was safe in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), with treated patients showing improvements in Caregiver and Clinical Global Impression of Improvement (GI-I) scales. These data should be considered with caution, as the phase 3 SKYLINE (NCT04940624) and SKYWAY (NCT04938427) trials did not show demonstrate efficacy in these populations.¹

ENDYMION 2 was a follow-up, open-label study for participants who completed either SKYLINE or SKYWAY. In this study, patients received their standard antiseizure therapy plus no more than 300 mg of soticlestat, with primary end points focused on long-term safety, specifically treatment-emergent adverse events (TEAEs). At the interim analysis time point (April 12, 2024), 121 participants with DS and 231 with LGS had enrolled, of which 93 (DS: 76.9%) and 136 (LGS: 58.9%) were ongoing.

Presented at the 2024 American Epilepsy Society (AES) Annual Meeting, held December 6-10, in Los Angeles, California, TEAEs were reported in 75.2% (n = 91) of participants with DS and 80.1% (n = 185) in LGS. Most of the TEAEs reported were mild (DS: 29.8%; LGS: 28.6%) or moderate (DS: 33.9%; LGS: 38.5%). Seizure frequency, a secondary end point, was reduced over the study period as well.

Led by Julia Jacobs, MD, PhD, a professor of neurology at the University of Calgary, the ongoing study spans 17 countries, beginning initially in March 2022. In the study, drug-related TEAEs occurred in 44 (36.4%) and 77 (33.3%) participants with DS or LGS, respectively, and serious TEAEs leading to study drug discontinuation in 2 (1.7%) and 5 (2.2%) patients.

At 26, 52, and 78 weeks, caregiver-reported improvements (very much, much, or minimally improved) were observed in 74.1% (n = 58), 72.4% (n = 29), and 92.9% (n = 14) of patients with DS and 58.4% (n=161), 77.7% (n = 94), and 63.4% (n = 41) of patients with LGS. Clinician-reported improvements over the same time points were 72.4% (n=58), 65.5% (n = 29), and 92.9% (n = 14) for DS, and 60.0% (n = 160), 73.4% (n = 94), and 68.3% (n = 41) for LGS.

SKYLINE and SKYWAY, the core trials of ENDYMION 2, were global, placebo-controlled studies evaluating soticlestat as an adjunctive therapy for pediatric and young adult patients with DS and LGS, respectively. The primary endpoint in SKYLINE is the percentage reduction in convulsive seizure frequency, while SKYWAY targets seizure frequency in monthly median drop (MMD) seizures, with identical secondary outcomes across the two populations.

Updated results from these trials presented at AES 2024 showed that soticlestat demonstrated a benefit over placebo on the primary end point, although statistical significance was missed. In SKYLINE (n = 144), median change in convulsive seizure frequency over the full treatment period, which includes a 4-week titration period and 12-week maintenance phase, was –22.16% with soticlestat and –8.64% with placebo (P = .061). In the SCN1A positive subgroup, the median change was –23.34% with soticlestat and –12.70% with placebo (nominal P = .045). Overall, a greater proportion of patients experienced at least a 50% reduction in convulsive seizures with soticlestat vs placebo (27.4% vs 9.9%).²

SKYWAY featured 270 participants with a mean age of 12.9 years (SD, 8.1), of whom 190 (70.4%) were on 3 antiseizure medications. Overall, treatment with soticlestat led to a nonsignificant median change in seizure frequency vs placebo (–6.11% vs –6.69%; P = .785). Secondary outcomes also showed no meaningful differences, though a higher proportion of participants on soticlestat reported improvements in seizure intensity and duration (49.2%) compared with placebo (OR, 1.67; P = .029).

In the original announcement of these data in June, Takeda noted it will engage with regulatory authorities to discuss the totality of the data to determine next steps for the investigational agent.

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REFERENCES
1. Jacobs J, Ciliberto M, Jiang Y, et al. ENDYMION 2: Phase 3, Open-label Extension Study Assessing Long-term Safety, Tolerability and Secondary Outcomes of Adjunctive Soticlestat in Individuals with Dravet Syndrome or Lennox-Gastaut Syndrome. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 1.485
2. Murthy V, Khan Y, Castrillo C, et al. Soticlestat as Adjunctive Therapy in Children and Young Adults with Dravet Syndrome: The Phase 3 SKYLINE Clinical Trial. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 2.375
3. Auvin S, Guerrini R, Hahn C, et al. Soticlestat vs Placebo as Adjunctive Therapy for Lennox-gastaut Syndrome: Results from the Phase 3, Randomized SKYWAY Clinical Trial. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 1.489