To evaluate long-term safety, tolerability and efficacy of soticlestat in patients with Dravet syndrome (DS) or Lennox–Gastaut syndrome (LGS).

Soticlestat, a selective inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase, was well tolerated and reduced seizure frequency in patients with DS and LGS in the phase 2 study ELEKTRA, with phase 3 studies ongoing.

ENDYMION 1 (NCT03635073) is an ongoing phase 2, open-label extension study of adjunctive soticlestat (≤300 mg BID, weight-adjusted in children) enrolling patients with DS or LGS who completed ELEKTRA, or had received ≥10 weeks of treatment. ENDYMION 1 patients undergo 1–2 weeks of dose optimization, followed by a long-term maintenance period. Those discontinuing undergo a 1-week dose taper and a 4-week safety follow-up. Primary endpoints include incidence of treatment-emergent adverse events (TEAEs); secondary endpoints include change in seizure frequency from baseline.

At the time of analysis, 47 DS patients and 83 LGS patients were enrolled, with median soticlestat exposures of 80.1 (range 1.4–134.0) and 88.3 (range 1.0–178.0) weeks, respectively. For DS and LGS respectively, TEAEs were experienced by 41 (87.2%) and 72 (86.7%) patients; 21 (44.7%) and 36 (43.4%) patients experienced ≥1 drug-related TEAE, which were serious in 1 (2.1%) and 5 (6.0%) patients. Three (6.4%) DS and 10 (12.0%) LGS patients discontinued soticlestat owing to drug-related TEAEs. At weeks 1–12, 49–60, and 97–108 median changes in all seizure frequency from baseline of ELEKTRA were –28.0% (n=46), –59.6% (n=28), and –53.4% (n=22) in DS patients, respectively, and –28.4% (n=79), –17.7% (n=49), and –27.7% (n=35) in LGS patients, respectively.

Safety findings from an interim analysis of ENDYMION 1 were consistent with those from previous studies, with no new safety signals identified. Soticlestat was associated with sustained seizure reductions over the interim period presented here.

Study funded by Takeda Pharmaceutical Company Limited.