Soticlestat Lowers Seizure Frequency for Dravet Children in Phase 2 Trial
Treatment with soticlestat significantly reduced seizure frequency for children with Dravet syndrome or Lennox-Gastaut syndrome (LGS), another childhood disorder that causes seizures, in a Phase 2 clinical trial called ELEKTRA.
Trial results were in the study, “A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox–Gastaut syndrome (ELEKTRA),” published in Epilepsia.
The work was funded by Takeda Pharmaceuticals, which acquired the rights to develop soticlestat for Dravet and LGS last year. The experimental therapy is designed to modulate the activity of a seizure-related brain signaling molecule called glutamate by inhibiting a protein called CH24H. Soticlestat has been shown to reduce seizures in mouse models of Dravet syndrome.
“As a first-in-class selective inhibitor of CH24H, soticlestat has the potential to provide therapy via a different mechanism of action from existing available therapies,” the researchers wrote.
ELEKTRA (NCT03650452) was a Phase 2 study that enrolled 141 children, ages 2 to 17, with Dravet syndrome or LGS across 35 sites in Australia, Canada, China, Israel, Poland, Portugal, Spain, and the U.S.
Following a screening period, participants were randomized to take soticlestat or a placebo for 20 weeks, including an eight-week dose-optimization period followed by 12 weeks of steady-dose maintenance treatment. The experimental therapy was given twice daily by mouth or a feeding tube. During the dose-optimizing study part, patients were treated with increasing doses of soticlestat, up to a maximum of 300 mg twice daily for patients weighing 60 kg (133 pounds) or more, with weight-based maximums for those weighing less.
At the study’s end, 80.3% of treated patients were given soticlestat at the 300 mg twice daily dose.
Seizure frequency drops with soticlestat in trial
ELEKTRA’s main goal was to assess the effect of treatment on seizure frequency during the maintenance period, as measured with a seizure diary kept by patients or their caregivers. Results were available for 139 patients (two did not complete the diaries): 51 with Dravet syndrome and 88 with LGS. About two-thirds of the patients were male, with an average age of 9.5 years.
At the study’s start (baseline), the average rate of convulsive seizures among children with Dravet syndrome was just over 13 seizures per month. Participants reported “a wide range of seizure frequencies at baseline, although this was especially pronounced in patients with LGS,” the researchers noted.
During the 12-week maintenance period, treatment with soticlestat was seen to reduce seizure frequency significantly, by 50% compared to placebo among the Dravet patients. Similar results were seen comparing the entire 20-week treatment period, with a 45.95% reduction in convulsive seizure frequency.
Just less than 1 in 3 (30.8%) Dravet syndrome patients on soticlestat experienced a reduction in seizure frequency of 50% or higher. No patients on placebo reported a similar drop in seizure frequency. More patients on soticlestat than placebo also experienced a marked improvement in overall functional status, as assessed by clinicians (26.9% vs 8%) or by caregivers (57.7% vs 32%).
The results were generally comparable for children on LGS, indicating that soticlestat lowered seizure frequency and improved functional status, though the reduction in seizures for these children was not statistically significant.
Side effects deemed by investigators related to the investigative treatment were reported in just less than half (45.4%) of study participants. Three serious adverse events were reported in two children given soticlestat — one child with serious speech disorder and seizure, another with serious septic shock.
Three patients on soticlestat discontinued treatment due to side effects — the patient who had experienced speech disorder and seizures, as well as one who experienced excessive sleepiness and another with unusual apathy reported.
Most side effects were considered mild or moderate, with lethargy and constipation being most commonly reported among children given soticlestat.
“Soticlestat had a safety profile that was consistent with previous studies … no new safety signals were identified,” the researchers wrote.
“These findings support the further evaluation of soticlestat as a potential therapy for [Dravet syndrome] and LGS in phase 3 clinical studies,” the researchers concluded.
Takeda recently initiated a Phase 3 study called Skyline to further test soticlestat in children and young adults with Dravet syndrome.
The Skyline trial (NCT04940624) is testing soticlestat as an add-on therapy in up to 142 Dravet patients, ages 2–21, with repeated and recent convulsive seizures not controlled despite the use of at least two anti-seizure medications. Enrollment is underway for this global study, including sites in the U.S., Europe, Canada, and Japan. Site and contact information are available.
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