Takeda and Ovid Report Soticlestat Reduces Seizure Frequency in Children with Dravet or Lennox-Gastaut Syndromes

Rare Daily Staff

Takeda Pharmaceutical and Ovid Therapeutics reported positive topline results from the mid-stage ELEKTRA study of soticlestat in children with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS).

Ovid’s shares jumped 49 percent on the news and the company quickly took advantage of the bump up of its share price to put together a $50 million follow-on public offering.

The randomized, placebo-controlled study achieved its primary endpoint of a statistically significant reduction of seizures from baseline compared to placebo in the Dravet syndrome population, and numeric reductions in seizure frequency in children with Lennox-Gastaut syndrome that did not achieve statistical significance.

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 anti-seizure 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. It 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.

Soticlestat is a potent, highly selective, oral, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H) that is being investigated by Ovid and Takeda for the treatment of rare developmental and epileptic encephalopathies (DEEs), a group of highly refractory epilepsy syndromes including DS and LGS.

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 DS (convulsive seizures) or LGS (drop seizures), which enrolled 141 patients, 126 of whom completed the study. 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.

A modified intent-to-treat 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 could be on one to four concomitant anti-epileptic drugs, with the majority of patients concomitantly treated with at least three anti-epileptic drugs. The most common anti-epileptic drugs taken by the patients were valproate, clobazam, levetiracetam and topiramate.

The ELEKTRA study achieved its primary endpoint with high statistical significance, demonstrating a 27.8 percent median reduction from baseline in convulsive seizure (Dravet syndrome) and drop seizure (Lennox-Gastaut syndrome) frequency compared to a 3.1 percent median increase in patients taking placebo during the 12-week maintenance period. In addition, DS and LGS patients treated with soticlestat demonstrated a 29.8 percent median reduction in convulsive seizure (Dravet syndrome) and drop seizure (Lennox-Gastaut syndrome) frequency compared to no change in median seizure frequency in patients taking placebo during the full 20-week treatment period of the study.

In the Dravet syndrome cohort, patients treated with soticlestat demonstrated a 33.8 percent median reduction in convulsive seizure frequency compared to a 7.0 percent median increase in patients taking placebo during the full 20-week treatment period of the study. Based on these data, the companies plan to meet with regulatory authorities to discuss initiation of a phase 3 registrational program for soticlestat in patients with DS.

In the Lennox-Gastaut cohort, patients treated with soticlestat demonstrated a 20.6 percent median reduction in drop seizure frequency compared to a 6.0. percent median reduction in patients taking placebo during the full 20-week treatment period of the study. Additional analyses are being conducted to better understand the potential next steps for the development of soticlestat in this highly heterogenous patient population.

Soticlestat was generally well-tolerated and demonstrated a safety profile consistent with those of previous studies, with no new safety signals identified. All patients who completed the study elected to enroll into the open-label extension study to assess the long-term safety and tolerability of soticlestat over four years of treatment in patients with rare epilepsies, and to evaluate its effect on seizure frequency over time. Six months into this study, the data continue to support the results of the phase 2 study.

“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, head, Neuroscience Therapeutic Area Unit at Takeda. “Soticlestat and its novel mechanism of action were discovered at Takeda and we are enthusiastic about continuing to advance the science and clinical programs as one aligned team, in strong partnership with Ovid Therapeutics.”

Takeda and Ovid are sharing in the development and commercialization costs of soticlestat on a 50/50 basis and, if successful, the companies will share in the profits on a 50/50 basis. Takeda will be responsible for commercialization in Japan and has the option to take responsibility for commercialization in other countries in Asia and other selected countries. Ovid will be responsible for clinical development activities and commercialization of soticlestat in the United States, Europe, Canada and Israel. Under the terms of the agreement, Takeda received equity in Ovid and may be eligible to receive certain milestone payments based on the advancement of soticlestat.

Photo: Sarah Sheikh, head, Neuroscience Therapeutic Area Unit at Takeda