Ovid Tumbles as Takeda’s Soticlestat Misses in Phase 3 Studies in Rare Epilepsies

Rare Daily Staff

Takeda said its experimental therapy soticlestat narrowly missed it primary endpoint of a reduction in convulsive seizure frequency in Dravet syndrome while showing clinically meaningful and nominally significant effects in multiple key secondary efficacy endpoints.

Takeda’s study in Lennox-Gastaut syndrome missed its primary endpoint of reduction in major motor drop seizures as compared to placebo.

The results are a blow to Ovid Therapeutics, which sold Takeda rights to soticlestat for $196 million and is eligible for $660 million in regulatory and commercial milestones, as well as royalties. Shares in Ovid fell nearly 80 percent to $1.03 in early trading. Takeda’s shares were up nominally.

Takeda said it will engage with regulatory authorities to discuss the totality of the data generated by its studies to determine next steps. Takeda will also plan to present results of both phase 3 studies of soticlestat in Dravet syndrome and Lennox- Gastaut syndrome at an upcoming scientific congress.

Dravet syndrome and Lennox-Gastaut syndrome are types of developmental and epileptic encephalopathies (DEEs), a group of rare epilepsy syndromes that typically become apparent during infancy or early childhood and are highly drug-resistant to many antiseizure medications. Individuals with these conditions also suffer from common non-seizure symptoms such as problems with alertness, communication, and disruptive behavior.

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 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 (TAK-935) is an experimental, first-in-class potent and selective inhibitor of cholesterol 24-hydroxylase (CH24H), an enzyme primarily expressed in the brain that catabolizes cholesterol to 24-S hydroxycholesterol (24HC) resulting in a reduction in glutamatergic hyperexcitability.

SKYLINE was a multicenter, randomized, double-blind phase 3 study that evaluated soticlestat plus standard of care versus placebo plus standard of care in patients with refractory Dravet syndrome.

SKYWAY was a multicenter, randomized, double-blind phase 3 study that evaluated soticlestat plus standard of care versus placebo plus standard of care in patients with refractory Lennox-Gastaut syndrome.

In SKYLINE and SKYWAY, some pre-specified subgroups of patients also showed nominally significant treatment effects on the primary and secondary efficacy endpoints of caregiver and clinician global impression of improvement, and seizure intensity and duration scales over the 16-week treatment period. Further analyses are being conducted.

Soticlestat was generally well tolerated in both SKYLINE and SKYWAY studies and demonstrated a safety profile consistent with the findings of previous studies.

In the phase 2 study, ELEKTRA, soticlestat demonstrated a statistically significant reduction of seizures from baseline compared to placebo in the combined DS and LGS study population during the full treatment period. In the DS cohort, statistically significant reduction in convulsive seizure frequency from baseline compared to placebo was also achieved. In a pooled analysis of SKYLINE and the DS cohort of the phase 2 ELEKTRA study, soticlestat also showed a reduction from baseline in convulsive seizure frequency compared to placebo.

“Even with currently available therapies, we know that many patients with developmental encephalopathies like DS and LGS still experience persistent unmet need across multiple dimensions, such as seizure burden and treatment tolerability,” said Sarah Sheikh, head of Neuroscience Therapeutic Area Unit and head of Global Development at Takeda. “While we would have wished for more declarative results on the primary endpoints, we are encouraged by positive outcomes seen in the totality of the data and are looking forward to engaging health authorities to determine the best path forward.”

Photo: Sarah Sheikh, head of Neuroscience Therapeutic Area Unit and head of Global Development at Takeda