The investigational oral therapy Soticlestat (OV935/TAK-935), developed by Ovid Therapeutics and Takeda Pharmaceuticals, safely and effectively lowers seizure frequency in children with Dravet syndrome and Lennox‑Gastaut syndrome (LGS), according to top-line data from a Phase 2 clinical trial.
“We are extremely encouraged by these results, which show a clear statistically significant reduction of seizures in Dravet syndrome patients treated with soticlestat, as well as a trend for seizure reduction in Lennox-Gastaut patients,” Amit Rakhit, MD, Ovid’s president and chief medical officer, said in a press release.
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 this patient population.
“It is exciting to see these positive results and to advance soticlestat into late stage clinical development — initially for the potential treatment of children with Dravet syndrome who need more options to manage treatment-resistant seizures,” said Sarah Sheikh, MD, head of Takeda’s neuroscience therapeutic area unit.
Soticlestat is a potent, highly-selective, first-in-class suppressor of cholesterol 24-hydroxylase (CH24H), an enzyme that plays a major role in clearing brain cholesterol. Its byproduct activates NMDA receptors — an ion-channel receptor found at most excitatory synapses, or nerve cell junctions — making nerve cells more prone to fire electrical signals.
By blocking CH24H and subsequently reducing NMDA receptor activation, soticlestat is thought to potentially lower seizure susceptibility in patients with rare developmental and epileptic encephalopathies (DEEs), including Dravet, LGS, CDKL5 deficiency disorder, and Dup15q syndrome.
The global, placebo-controlled Phase 2 ELEKTRA study (NCT03650452) evaluated the safety and effectiveness of soticlestat in 141 children and adolescents (2 to 17 years old) who experienced seizures associated with Dravet or LGS. The children and adolescents with Dravet had convulsive seizures while those with LGS experienced drop or atonic seizures.
The participants’ seizure frequency was established during a four-to-six-week observation period. Following that, the patients were randomly assigned to receive either soticlestat or a placebo for 20 weeks. This 20-week period included eight weeks of dose optimization (from 100 mg to 200 and 300 mg twice daily) followed by a 12-week period of maintenance treatment.
One to four simultaneous anti-seizure medications were allowed for each patient, with most receiving at least three such therapies. The most commonly given therapies were valproate, clobazam, levetiracetam, and topiramate.
Data from 139 patients — 51 with Dravet syndrome and 88 with LGS — who received at least one dose of soticlestat or placebo were used to evaluate treatment effectiveness.
The top-line results showed that soticlestat was significantly superior to the placebo in dropping the seizure rate among these young patients during the 12-week maintenance period, achieving the trial’s main goal. The patients receiving soticlestat saw a median drop of 27.8% in their seizure rate versus a 3.1% median increase in participants given the placebo.
A similar superiority was found during the full 20-week treatment period, with soticlestat-treated patients showing a 25.1% placebo-adjusted reduction in seizure frequency.
Notably, Dravet patients receiving soticlestat showed a 33.8% median drop in convulsive seizure frequency, compared with a 7% median increase in those on a placebo, reflecting a significant, placebo-adjusted 46% reduction in the seizure rate.
While soticlestat also dropped the seizure frequency in LGS patients, this change was not statistically different from that observed in the placebo group. Further analyses are being conducted to determine the potential next steps for soticlestat development in this highly diverse patient population.
The therapy was generally well tolerated, with a safety profile consistent with those reported in previous trials. There were no new safety concerns. Adverse events (side effects), including those considered serious, were reported in a similar proportion of patients in both the soticlestat and placebo groups.
Tiredness and constipation were the most frequent adverse events among soticlestat-treated patients, compared with those in the placebo group. No patients died during the study.
All 126 participants who completed the ELEKTRA trial entered the ENDYMION open-label extension study (NCT03635073), in which all patients receive the therapy. The extension trial is evaluating soticlestat’s long-term safety, tolerability, and effectiveness over four years in people with rare DEEs.
Data from the ELEKTRA participants who rolled over into ENDYMION showed that a lower seizure frequency was maintained over six months in those who were originally randomly selected to receive soticlestat. The lower seizure frequency also was achieved by those previously assigned to the placebo group. No new safety signals were reported.
“Children with developmental epileptic encephalopathies like DS [Dravet syndrome] and LGS need more options to manage their treatment-resistant seizures,” said Cecil Hahn, MD, a pediatric neurologist at The Hospital for Sick Children, in Toronto, Canada, 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,” he added.
Importantly, data from a previous Phase 1b/2a clinical trial (NCT03166215) highlighted that soticlestat may interact with the anti-seizure medicine perampanel, sold under the brand Fycompa by Eisai. That means that the two therapies should not be taken together.
Top-line results from the completed, open-label Phase 2 ARCADE study (NCT03694275) are expected to be announced later this year, Rakhit said. ARCADE tested soticlestat in patients with CDKL5 deficiency disorder and Dup15q syndrome.
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