Takeda’s Epilepsy Drug Stumbles in Back-to-Back Phase III Rare Disease Failures

Deerfield - Circa June 2019: Takeda Pharmaceutical Company. Takeda recently acquired Irish drugmaker Shire I

Deerfield - Circa June 2019: Takeda Pharmaceutical Company. Takeda recently acquired Irish drugmaker Shire I

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Takeda’s soticlestat, licensed from Ovid Therapeutics, did not significantly reduce seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome, respectively, according to two late-stage readouts on Monday.

Pictured: Takeda sign at its office in Massachusetts/iStock, jetcityimage

Takeda on Monday revealed two disappointing Phase III readouts for its investigational drug soticlestat, which failed to hit the primary efficacy endpoints in the SKYLINE study in Dravet syndrome and the SKYWAY trial in Lennox-Gastaut syndrome.

The Japanese multinational did not provide much data in its announcement, only revealing that soticlestat “narrowly missed” its bar in SKYLINE. Compared with placebo, the drug candidate demonstrated a reduction in convulsive seizure frequency from baseline, though this effect was shy of statistical significance, with a p-value of 0.06, according to Takeda.

In terms of secondary endpoints, soticlestat also showed “clinically meaningful” benefit in responder rate and seizure intensity and duration, as well as in caregiver and clinician global impressions of improvement. Soticlestat’s treatment effects in these endpoints were “nominally significant,” according to Takeda’s announcement, with p-values all lower than or equal to 0.008.

By contrast, soticlestat appeared to be even less effective in the Lennox-Gastaut syndrome trial, with Takeda noting that the drug candidate failed to significantly reduce Major Motor Drop seizure frequency—SKYWAY’s primary outcome—versus placebo.

In terms of safety, soticlestat was well-tolerated overall in both SKYLINE and SKYWAY, with an adverse even profile consistent with what had been previously established.

“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,” Sarah Sheikh, head of global development at Takeda, said in a statement.

The pharma is currently conducting additional analyses of both studies and will share its final findings at an upcoming scientific meeting. Takeda will also work with regulatory authorities to discuss the totality of data for soticlestat and determine the next best steps for the drug candidate.

In the interim, Takeda will also assess the financial impacts of these Phase III failures on its first-quarter earnings for the three months ending June 30, the company said.

Soticlestat is a potent and highly selective blocker of the cholesterol 24-hydoxylase (CH24H) enzyme with first-in-class potential. CH24H is central to the homeostatic regulation of brain cholesterol levels and modulates glutamate signaling, which is known to be associated with epilepsy and the spread of seizure. Soticlestat’s mechanism of action allows it to normalize the disrupted balance of excitatory and inhibitory signals in the brain.

Takeda bought the global development and commercialization rights to soticlestat fron Ovid Therapeutics in March 2021. The Japanese pharma paid $196 million upfront and pledged up to $660 million in certain developmental, regulatory and sales milestones. Ovid is also eligible for tiered royalties of up to 20% on soticlestat sales.

In a separate announcement on Monday, Ovid CEO Jeremy Levin said that the biotech has used Takeda’s upfront payment in 2021 to build “an exciting and differentiated pipeline, which we believe will generate multiple value-creating opportunities in the near-term.”

“Our R&D and financial strategy is independent of soticlestat’s outcome,” Levin said.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Tristan is an independent science writer based in Metro Manila, with more than eight years of experience writing about medicine, biotech and science. He can be reached at tristan.manalac@biospace.com, tristan@tristanmanalac.com or on LinkedIn.