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LOS ANGELES -- The novel agent soticlestat flopped in a pair of phase III trials for rare seizure disorders, researchers reported here.

Among Dravet syndrome patients in the SKYLINE trial, the median change from baseline in convulsive seizure frequency over the full treatment period was -22.16% with soticlestat and -8.64% with placebo, a nonsignificant difference (P=0.061), reported Venkatesha Murthy, MD, of drug developer Takeda Development Center Americas in Cambridge, Massachusetts.

In addition, among Lennox-Gastaut syndrome patients in the SKYWAY trial, 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).

Results likewise came out neutral for seizure frequency during the maintenance period and for all secondary endpoints. Both trials were presented by Murthy's group at the American Epilepsy Society annual meeting.

Soticlestat had raised hopes as a first-in-class selective inhibitor of cholesterol 24-hydroxylase, which is a brain-specific enzyme that reduces glutamatergic hyperexcitability.

However, Takeda in June that the trials had missed their primary endpoints for Dravet syndrome and Lennox-Gastaut syndrome. The company worked with regulators to determine whether positive outcomes on secondary endpoints for certain patients .

In a prespecified exploratory analysis in the Dravet syndrome population, soticlestat did significantly reduce convulsive seizures in the subgroup of patients with the SCN1A gene mutation thought to be causative in the condition (difference of -17.38 percentage points vs placebo, P=0.045).

Most patients do have this mutation, which perhaps meant that this group had confirmed Dravet cases, Murthy suggested.

Caregiver- and clinician-rated improvement, as well as responder rates, also significantly improved with the investigational agent, although disability-related quality of life and non-seizure symptoms were unchanged.

However, Murthy told MedPage Today that the future looks dim for soticlestat. "Recently, we've heard [the FDA does] not see this evidence as providing substantial evidence of effectiveness," he said.

SKYLINE included 144 patients ages 2-21 years (mean age 10.5) with a Dravet syndrome diagnosis adjudicated independently by the Epilepsy Study Consortium. The trial enrolled patients with at least 12 convulsive seizures over 12 weeks before screening and at least four per 28 days during the baseline period. They had failure of at least one antiseizure medication before enrollment and could be taking up to four antiseizure medications at a stable dose.

SKYWAY included 270 patients ages 2-55 years (mean age 12.5) with a Lennox-Gastaut syndrome diagnosis, also adjudicated independently by the Epilepsy Study Consortium. They 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.

Both trials randomized patients to twice-daily doses of 300-mg soticlestat or placebo, both in addition to standard-of-care treatment, with a 4-week titration period and 12-week maintenance period.

Murthy noted that the trials were adequately powered, with SKYLINE being the largest trial to date in Dravet syndrome.

There are other drug candidates moving forward in the field, he noted, "so this is not going to be seen as disappointing news. But for us, it's really disappointing."