Takeda and Ovid Therapeutics Announce Positive Phase 2 ELEKTRA Trial Results for Soticlestat in Pediatric Dravet and Lennox-Gastaut Syndromes

Compiled by Keke

On August 25, Takeda and Ovid Therapeutics announced that the Phase 2 ELEKTRA clinical trial of soticlestat for the treatment of pediatric patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) had met its primary endpoint with high statistical significance.

ELEKTRA is an international, multicenter, randomized, double-blind, placebo-controlled Phase 2 clinical study designed to evaluate the efficacy of soticlestat in children aged 2–17 years with highly treatment-resistant epileptic seizures associated with Dravet syndrome (convulsive seizures) or Lennox-Gastaut syndrome (drop attacks). The study comprised a 4–6-week screening period to establish baseline seizure frequency, followed by a 20-week double-blind treatment period, including an 8-week dose-optimization phase and a 12-week maintenance phase. During the 8-week dose-optimization phase, patients were titrated from oral soticlestat 100 mg twice daily (BID), to 200 mg BID, and up to 300 mg BID (mg/kg dosing for patients weighing <60 kg). A total of 141 patients were enrolled in the study, and 126 completed it. A modified intent-to-treat (mITT) analysis was conducted on 139 patients to assess efficacy endpoints. Patients in the study were permitted to take 1–4 concomitant antiepileptic drugs (AEDs); most patients were receiving at least three AEDs concurrently, with the most common being sodium valproate, clobazam, levetiracetam, and topiramate.

Data from 120 patients with epilepsy in the efficacy analysis set showed that during the 12-week soticlestat maintenance treatment period, the median frequency of convulsive seizures (in DS) and drop seizures (in LGS) decreased by 27.8% compared with patients receiving placebo, whereas the median frequency of convulsive and drop seizures in the placebo group increased by 3.1% (the adjusted median decrease in the placebo group was 30.5%; p=0.0007). Furthermore, throughout the entire 20-week treatment period (titration plus maintenance), the median frequency of convulsive and drop seizures in patients treated with soticlestat decreased by 29.8%, while the median change in seizure frequency in the placebo group was 0.0% (a 25.1% decrease after placebo adjustment; p=0.0024).

In the DS cohort study (n=51), the median frequency of convulsive seizures decreased by 33.8% in patients treated with soticlestat throughout the treatment period, whereas it increased by 7.0% in the placebo group (a placebo-adjusted reduction of 46.0%; p=0.0007). Based on these data, the two companies plan to meet with regulatory authorities to discuss the registration plan for initiating Phase 3 clinical studies of soticlestat in patients with DS.

In the LGS cohort study (n=88), the median frequency of drop seizures during the entire treatment period decreased by 20.6% in patients receiving soticlestat, compared with a 6.0% decrease in the placebo group (a placebo-adjusted reduction of 14.8%; p=0.1279). Further analyses of this cohort are currently underway to better inform the next steps in the development of soticlestat for this highly heterogeneous patient population.

Furthermore, soticlestat demonstrated generally good tolerability in the ELEKTRA study, with a safety profile consistent with previous studies and no new safety signals identified. The most common treatment-emergent adverse events were somnolence and constipation. The incidence of serious adverse events was similar between the soticlestat and placebo groups (15.5% vs. 18.6%), and no deaths were reported. However, all patients who completed the ELEKTRA study continued into an open-label extension study, which will monitor the safety and tolerability of soticlestat over four years and also evaluate the long-term impact of the drug on seizure frequency.

DS and LGS are types of developmental and epileptic encephalopathies (DEEs), a group of rare epilepsy syndromes that typically become apparent in infancy or early childhood and are highly resistant to many antiepileptic drugs. DS is most commonly caused by mutations in the SCN1A gene and is characterized by prolonged focal seizures that may evolve into bilateral tonic-clonic seizures, along with an increased seizure burden in children with developmental impairments. Other common symptoms include changes in appetite, difficulty with balance, and a crouched gait. LGS is a heterogeneous disorder characterized by several different seizure types, most commonly atonic (drop attacks), tonic, and atypical absence seizures. Children with this condition may also exhibit cognitive impairment, delayed developmental milestones, and behavioral problems. LGS can be caused by various underlying conditions, but in some cases, the etiology remains unidentified.

Soticlestat is a potent, highly selective first-in-class inhibitor of cholesterol 24-hydroxylase (CH24H), with the potential to reduce seizure susceptibility and improve seizure control. Recent literature indicates that CH24H contributes to the hyperactivation of glutamate pathways by modulating NMDA receptors, and that increased CH24H expression can impair astrocytic glutamate reuptake, thereby leading to epileptogenesis and neurotoxicity. Inhibition of CH24H by soticlestat reduces neuronal levels of 24-hydroxycholesterol (24HC), which may restore the excitatory/inhibitory balance of NMDA receptor activity.

Ovid and Takeda are investigating soticlestat for the treatment of rare, highly refractory developmental and epileptic encephalopathies (DEEs), including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Data from ARCADE, an open-label Phase 2 clinical study in patients with two other highly refractory DEEs—CDKL5 deficiency disorder and Dup15q syndrome—are expected to be announced later this quarter. The two companies will share the development and commercialization costs and profits for soticlestat equally, each bearing 50%. It is reported that two drugs for DS have already received U.S. FDA approval this year, including GW Pharma’s cannabis-based extract Epidiolex (cannabidiol) and Zogenix’s Fintepla (fenfluramine oral solution).

Reference Source: Phase 2 ELEKTRA Study of Soticlestat (TAK-935/OV935) Meets Primary Endpoint Reducing Seizure Frequency in Children with Dravet Syndrome or Lennox-Gastaut Syndrome