LOS ANGELES -- Soticlestat, a novel agent targeting cholesterol 24-hydroxylase, has failed to meet its primary endpoints in two Phase III trials, SKYLINE and SKYWAY, for the treatment of rare seizure disorders, Dravet syndrome and Lennox-Gastaut syndrome, respectively.
SKYLINE Trial Results in Dravet Syndrome
The SKYLINE trial, involving 144 patients aged 2-21 years with Dravet syndrome, assessed the efficacy of soticlestat as an adjunctive therapy. The median change from baseline in convulsive seizure frequency over the full treatment period was -22.16% with soticlestat and -8.64% with placebo. This difference was not statistically significant (P = 0.061), according to Dr. Venkatesha Murthy of Takeda Development Center Americas, who presented the findings at the American Epilepsy Society (AES) annual meeting.
The trial included patients who had experienced at least 12 convulsive seizures over 12 weeks before screening and at least four per 28 days during the baseline period, despite treatment with at least one antiseizure medication. Patients were randomized to twice-daily doses of 300-mg soticlestat or placebo, in addition to their standard-of-care treatment, with a 4-week titration period and 12-week maintenance period.
SKYWAY Trial Results in Lennox-Gastaut Syndrome
The SKYWAY trial, which included 270 patients aged 2-55 years with Lennox-Gastaut syndrome, also yielded negative results. The drug did not significantly reduce the frequency of major motor drop seizures during the treatment period, with a percentage change difference of -1.17% from baseline compared with placebo (P = 0.785). Similar neutral results were observed for seizure frequency during the maintenance period and for all secondary endpoints.
Patients in the SKYWAY trial had to have failure of at least one antiseizure medication at baseline and at least eight major motor drop seizures per 28 days during the 4-week minimum prospective baseline period. The dosing regimen was the same as in the SKYLINE trial.
Exploratory Analysis and Future Prospects
An exploratory analysis in the Dravet syndrome population revealed that soticlestat significantly reduced convulsive seizures in the subgroup of patients with the SCN1A gene mutation (difference of -17.38 percentage points vs placebo, P = 0.045). This mutation is thought to be causative in the condition, and most patients with Dravet syndrome have it.
Despite these findings, Dr. Murthy indicated that the FDA does not consider this evidence as providing substantial evidence of effectiveness, casting doubt on the future development of soticlestat. While caregiver- and clinician-rated improvement and responder rates significantly improved with soticlestat, disability-related quality of life and non-seizure symptoms remained unchanged.
Dr. Murthy acknowledged the disappointment of the results but noted that other drug candidates are moving forward in the field. The trials were funded by Takeda Development Center Americas, and Dr. Murthy and other authors disclosed employment by Takeda.
