Takeda Reveals Phase 3 Results for Soticlestat in Dravet and Lennox-Gastaut Syndrome

Takeda Pharmaceuticals recently released top-line results from its SKYLINE and SKYWAY studies, evaluating the efficacy and safety of soticlestat in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Despite narrowly missing primary endpoints, the studies showed promising secondary outcomes and consistent safety profiles.

The SKYLINE study was a Phase 3 trial exploring the efficacy of soticlestat combined with the standard of care against a placebo in patients with refractory DS. Although the primary endpoint—reduction in convulsive seizure frequency from baseline—was not met (p=0.06), soticlestat demonstrated notable results in key secondary endpoints. These included the responder rate, caregiver and clinician global impression of improvement, and measures of seizure intensity and duration over the 16-week treatment period (all p-values ≤ 0.008).

The SKYWAY study, also a Phase 3 trial, evaluated soticlestat plus standard care versus placebo in patients with refractory LGS. Unfortunately, the trial did not meet its primary endpoint of reducing the frequency of Major Motor Drop (MMD) seizures from baseline. However, some pre-specified subgroups did show significant treatment effects on both primary and secondary endpoints, including caregiver and clinician global impressions of improvement and measures of seizure intensity and duration over the 16-week period.

Both studies highlighted the drug's favorable safety and tolerability, consistent with previous research findings. "We are thankful to all participants, their families, investigators, and clinical staff involved in these crucial studies," stated Sarah Sheikh, Head of the Neuroscience Therapeutic Area Unit at Takeda. Sheikh acknowledged the ongoing challenges patients with DS and LGS face, including persistent seizure burdens and treatment tolerability issues. Despite not meeting primary endpoints, she remained optimistic about the positive outcomes observed in secondary measures and the overall data.

The SKYLINE and SKYWAY trials have provided valuable information for Takeda as it plans to engage with regulatory authorities to discuss the cumulative data and determine future steps. The company also intends to present these findings at an upcoming scientific conference.

Previously, in a Phase 2 study named ELEKTRA, soticlestat showed a statistically significant reduction in seizures from baseline compared to placebo in both DS and LGS study populations. These positive results were particularly pronounced in the DS cohort, which achieved a significant reduction in convulsive seizure frequency (p=0.0007). A pooled analysis of the SKYLINE and Phase 2 ELEKTRA DS cohort reaffirmed soticlestat's efficacy in lowering convulsive seizure frequency (p=0.001).

Takeda is also evaluating the financial implications of these study outcomes on its first-quarter results ending June 30, 2024, including potential impairment losses for intangible assets. Further announcements will be made as necessary.

Soticlestat (TAK-935) is an investigational drug that inhibits cholesterol 24-hydroxylase (CH24H), primarily found in the brain. This enzyme breaks down cholesterol to 24-S hydroxycholesterol (24HC), thereby reducing glutamatergic hyperexcitability, a key factor in neural hyperexcitation.

Dravet syndrome and Lennox-Gastaut syndrome are severe forms of developmental and epileptic encephalopathies (DEEs), notoriously resistant to many anti-seizure medications. Both conditions often manifest in infancy or early childhood and are marked by frequent, debilitating seizures and a high burden of non-seizure symptoms, impacting cognitive and behavioral development.

Dravet syndrome usually results from a mutation in the SCN1A gene, affecting about 1 in 15,000 to 21,000 people in the United States. The syndrome is characterized by prolonged focal seizures that can evolve into tonic-clonic seizures and various developmental disabilities.

Lennox-Gastaut syndrome is rarer, affecting fewer than 1 in 1,000 people in the U.S. It presents a variety of seizure types, including atonic, tonic, and atypical absence seizures, and is often accompanied by cognitive dysfunction and behavioral problems.

The SKYLINE and SKYWAY trials aimed to assess soticlestat's potential as an adjunctive therapy in these populations, enrolling 144 and 270 participants respectively, aged from young children to adults. Both trials followed a double-blind, placebo-controlled design to evaluate efficacy, safety, and tolerability over a 16-week treatment period.

Takeda remains committed to its mission of improving health and advancing treatment options for patients with rare and complex conditions like DS and LGS. The company continues to focus on its diverse therapeutic areas, including neuroscience, and aims to deliver transformative treatments worldwide.