ELEKTRA was an international, multi-center, randomized, double-blind, placebo-controlled study designed to evaluate treatment with Soticlestat in pediatric patients, aged 2 to 17 years, with highly refractory epileptic seizures associated with Dravet syndrome [ DS ] ( convulsive seizures ) or Lennox-Gastaut syndrome [ LGS ] ( drop seizures ).
The study consisted of a four- to six-week screening period to establish baseline seizure frequency, followed by a 20-week double-blind treatment period, including an 8-week dose optimization period and a 12-week maintenance period.
During the 8-week dose optimization period, patients were titrated from 100mg twice daily ( BID ), to 200mg BID to 300mg BID ( mg/kg dosing for less than 60 kg ) of orally administered Soticlestat.

A total of 141 patients were enrolled in ELEKTRA and 126 completed the study. A modified intent-to-treat ( mITT ) analysis of 139 patients was performed to evaluate the efficacy endpoints, which includes any patient who enrolled in the study and received at least one dose of study drug.
Patients in the study were allowed to be on one to four concomitant anti-epileptic drugs ( AEDs ), with the majority of patients concomitantly treated with at least three AEDs.
The most common AEDs taken by the patients were Valproate, Clobazam, Levetiracetam and Topiramate.

The study achieved its primary endpoint, demonstrating a 27.8% median reduction from baseline in convulsive seizure ( DS ) and drop seizure ( LGS ) frequency compared to a 3.1% median increase in patients on placebo during the 12-week maintenance period ( median placebo-adjusted reduction=30.5%; p=0.0007, based on the efficacy analysis set of 120 patients with seizure data in the maintenance period ).
During the full 20-week treatment period of the mITT DS patient population, the median percent change from baseline was a 33.8% decrease in seizure frequency compared to a 7.0% increase in seizure frequency for patients receiving placebo ( median placebo-adjusted reduction=46.0%; p=0.0007 ).
During the full treatment period of the mITT LGS patient population, the median percent change from baseline was a 20.6% decrease in seizure frequency compared to a 6.0% decrease in patients receiving placebo ( median placebo-adjusted reduction=14.8%; p=0.1279 ).

Soticlestat was well tolerated in this study. These findings were consistent with previous studies and no new safety signals were identified.
The incidence of treatment emergent adverse events was similar in both the treatment and placebo groups with 57 ( 80.3% ) of Soticlestat patients experiencing at least one treatment emergent adverse event compared to 52 ( 74.3% ) placebo patients.
The most frequent treatment emergent adverse events reported in Soticlestat-treated patients with 5% or more difference from placebo were lethargy and constipation.
The incidence of serious adverse events was similar in both Soticlestat and placebo groups, with 11 ( 15.5% ) in Soticlestat experiencing at least one treatment emergent serious adverse event compared to 13 ( 18.6% ) in placebo.
There were no deaths reported.

Soticlestat is a potent, highly selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase ( CH24H ), with the potential to reduce seizure susceptibility and improve seizure control.
CH24H is predominantly expressed in the brain, where it converts cholesterol into 24S-hydroxycholesterol ( 24HC ) to adjust the homeostatic balance of brain cholesterol.
24HC is a positive allosteric modulator of the NMDA receptor and modulates glutamatergic signaling associated with epilepsy.
Glutamate is one of the main neurotransmitters in the brain and has been shown to play a role in the initiation and spread of seizure activity.
Recent literature indicates that CH24H is involved in over-activation of the glutamatergic pathway through modulation of the NMDA channel and that increased expression of CH24H can disrupt the reuptake of glutamate by astrocytes, resulting in epileptogenesis and neurotoxicity.
Inhibition of CH24H by Soticlestat reduces the neuronal levels of 24HC and may improve excitatory/inhibitory balance of NMDA channel activity.

Dravet syndrome and Lennox-Gastaut syndrome are types of developmental and epileptic encephalopathies, a heterogeneous group of rare epilepsy syndromes.
Dravet and Lennox-Gastaut syndrome typically become apparent during infancy or early childhood and are highly refractory to many antiseizure medications.

Dravet syndrome is most commonly caused by a genetic mutation in the SCN1A gene and affects approximately 1 in 15,000 to 1 in 21,000 people in the United States.
Dravet syndrome is characterized by prolonged focal seizures that can evolve to convulsive tonic-clonic seizures.
Children with Dravet syndrome experience developmental disabilities as seizures increase. Other common symptoms include changes in appetite, difficulty balancing and a crouched gait when walking.

Lennox-Gastaut syndrome is estimated to affect approximately 1 in 11,000 people in the United States.
Lennox-Gastaut syndrome is a heterogeneous condition and characterized by several different types of seizures, most commonly atonic ( drop ), tonic and atypical absence seizures.
Children with Lennox-Gastaut syndrome may also develop cognitive dysfunction, delays in reaching developmental milestones and behavioral problems.
Lennox-Gastaut syndrome can be caused by a variety of underlying conditions, but in some cases no cause can be identified. ( Xagena )

Source: Ovid Therapeutics & Takeda Pharmaceutical, 2020

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