Treatment with soticlestat (OV935/TAK-935) safely led to a clinically meaningful reduction in the frequency of hard-to-treat seizures in a group of children with Dravet and Lennox-Gastaut (LGS) syndromes, according to top-line data from a Phase 2 trial.
Soticlestat is an experimental oral therapy currently being developed by Takeda Pharmaceuticals and Ovid Therapeutics for the treatment of rare and severe forms of epilepsy, such as LGS and Dravet, that often fail to respond to treatment with anti-seizure medications.
“We are extremely encouraged by these results, which show … a trend for seizure reduction in Lennox-Gastaut patients,” Amit Rakhit, MD, MBA, president and chief medical officer of Ovid, said in a press release.
The medication works by blocking the activity of the enzyme cholesterol 24-hydroxylase that plays a major role in clearing cholesterol from the brain. By inhibiting this enzyme, soticlestat is thought to lower the activation of a signaling pathway in the brain — known as glutamatergic signaling — that is thought to play a role in the onset and spread of seizures.
The safety and effectiveness of soticlestat at lowering the frequency of seizures experienced by young patients with Dravet and LGS were assessed in a Phase 2 trial called ELEKTRA (NCT03650452).
The study, which completed patient enrollment earlier this year, involved a total of 141 children and adolescents, ages 2-17, with highly refractory (treatment-resistant) seizures associated with either LGS or Dravet. The children with LGS experienced drop or atonic seizures, while those with Dravet had convulsive seizures.
ELEKTRA comprised an initial four- to six-week screening period to establish seizure frequency, followed by a 20-week treatment period; that was subdivided into an eight-week dose optimization period, followed by a 12-week maintenance period. During the dose optimization period, patients had their soticlestat doses increased from 100 mg to 200 mg, and then to 300 mg twice daily.
The main goal of the study was to determine if soticlestat could be superior to a placebo at lowering the frequency of seizures during the 12-week maintenance period.
The 126 patients who completed ELEKTRA had the opportunity to enroll in the trial’s open-label, long-term, Phase 2 ENDYMION (NCT03635073) extension study. Participants in the extension study can continue treatment with soticlestat for up to four years.
Top-line data from ELEKTRA now revealed the study met its primary goal of demonstrating soticlestat’s superiority at reducing the frequency of seizures over a placebo.
Data from 139 patients — 88 with LGS and 51 with Dravet syndrome — who received at least one dose of soticlestat or placebo were used to evaluate treatment effectiveness.
During the 12-week maintenance period, soticlestat lowered the frequency of convulsive and drop seizures by a median of 27.8% since the start of the trial, while the placebo only lowered seizure frequency by a median of 3.1%.
Similar findings were observed for the entire 20-week treatment period, with soticlestat lowering the frequency of both types of seizures by a median of 29.8%. Meanwhile, no changes were seen among those given a placebo.
In the subset of Dravet patients, soticlestat lowered the frequency of convulsive seizures by a median of 33.8% over the entire 20-week treatment period, while the placebo only lowered seizure frequency by a median of 7.0%.
However, reductions in drop seizure frequency associated with soticlestat during the same period of time were milder in the subset of patients with LGS, compared with the placebo. The median reduction was 20.6% versus 6.0%.
Ovid officials were “extremely encouraged” by the overall results, which showed “a clear statistically significant reduction of seizures in Dravet syndrome patients treated with soticlestat,” and the trend for seizure reduction in LGS, according to Rakhit.
“We look forward to continuing our collaboration with Takeda to initiate a Phase 3 registrational program for soticlestat in patients with DS, while continuing to analyze the data from patients with LGS in the ELEKTRA and ENDYMION studies to define potential next steps,” Rakhit said.
Soticlestat also was found to be safe and well-tolerated during the trial, with a safety profile that was similar to those reported in previous studies. No new safety concerns, nor deaths were reported during ELEKTRA.
Moreover, the incidence of both treatment-emergent and serious adverse events were found to be similar among children and adolescents receiving soticlestat and those receiving a placebo.
“Children with developmental epileptic encephalopathies like DS and LGS need more options to manage their treatment-resistant seizures,” said Cecil Hahn, MD, MPH, child neurologist at The Hospital for Sick Children and associate professor of pediatrics at the University of Toronto.
“The results of the ELEKTRA study are very promising, particularly for children with DS and represent a clinically significant reduction in seizure burden. Moreover, soticlestat was well-tolerated in this study,” Hahn said.
All 126 patients who completed the trial opted to enroll in ENDYMION. So far, data from the extension study support the findings from the original trial.
Among those originally assigned to soticlestat, seizure frequency remains low during the extension study. Meanwhile, seizure frequency dropped in those who received a placebo in ELEKTRA and only started treatment with the investigative therapy in ENDYMION. No new safety signals have been identified yet in ENDYMION.
Based on the particularly strong results in children with Dravet, the companies plan to meet with regulatory authorities to discuss the launch of a Phase 3 registrational program of soticlestat in that patient population.