Discontinued Soticlestat ‘narrowly missed’ trial goal, data show
Treatment eased seizure activity for some patients, SKYLINE data show
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A clinical study showed that Soticlestat, when added to standard treatment, tended to reduce convulsive seizures in children and young adults with Dravet syndrome compared with a placebo, although the study “narrowly missed” its main statistical goal, according to research led by Takeda Pharmaceuticals.
The company decided last year to stop developing soticlestat based on early data from the Phase 3 clinical study SKYLINE (NCT04940624). The full set of clinical data was reported in the study, “Soticlestat as an adjunctive therapy in children and young adults with Dravet syndrome,” published in Epilepsia.
Dravet syndrome usually begins in infancy and causes frequent seizures, delayed development, problems with sleep, and difficulty controlling body temperature. For most patients, this is caused by mutations in the SCN1A gene, which disrupt sodium channels in the brain, leading to the excessive nerve cell firing that triggers seizures.
Soticlestat is designed to block the activity of an enzyme in the brain called cholesterol 24-hydroxylase (CH24H). This enzyme normally helps regulate glutamate, a signaling molecule whose abnormal activity is thought to contribute to seizures. By blocking CH24H, soticlestat aims to reduce excessive nerve cell firing and help ease symptoms of Dravet syndrome.
The SKYLINE clinical study involved 144 children and young adults with Dravet syndrome, ages 2 to 21, from 17 countries. They were randomly assigned to receive either soticlestat or a placebo twice daily for 16 weeks (about four months). Of the 144 patients, 73 received soticlestat, and 71 received the placebo. Most patients (79.2%) tested positive for mutations in the SCN1A gene.
Convulsive seizures
To enter the study, patients had to experience at least four convulsive seizures per month despite receiving standard treatment. Convulsive seizures involve sudden muscle contractions that cause the body to stiffen and lose consciousness. Most patients were receiving three or more antiseizure medications, most commonly valproic acid (sold as Depacon, among others ) and Onfi (clobazam).
During the first four weeks, doses were gradually increased to help the body adjust to the medication and reduce side effects. After that, patients continued on a stable dose for 12 weeks (maintenance period). The dose depended on body weight and was taken by mouth as tablets or through a feeding tube.
The main goal was to monitor changes in the percent change in convulsive seizure frequency from the study’s start. Over the full treatment period, monthly convulsive seizures were reduced by a median of 22.2% in the soticlestat group and by 8.6% in the placebo group. Although the reduction was greater with soticlestat, the difference did not reach statistical significance. A similar, nonsignificant difference was observed during the maintenance period (23.3% vs. 12%).
The study did meet some secondary goals. The proportion of patients whose convulsive seizures were reduced by at least half, called responders, was significantly higher among those who received soticlestat compared with placebo during the full treatment period (27.4% vs. 9.9%) and the maintenance period (30.4% vs. 11.8%).
The researchers also monitored overall progress using scales completed by caregivers and doctors. Patients receiving soticlestat showed greater reductions in symptoms, as well as in the severity and duration of their seizures, which “captured beneficial changes with soticlestat beyond the outcome on seizures,” the researchers wrote.
Although most patients (77.8%) reported side effects during the clinical study, most were mild or moderate. The most common side effects in the soticlestat group were sleepiness, changes in how seizures appeared, reduced appetite, and insomnia. Eleven patients in the soticlestat group discontinued treatment due to side effects, but most improved or resolved by the end of the study.
While the SKYLINE clinical study did not meet its main statistical goal, the data showed a numerical reduction in convulsive seizures and improvements in several clinical measures with soticlestat. “Soticlestat may have modest antiepileptic effects, which failed to achieve statistical significance in patients with [Dravet syndrome],” the researchers concluded.
