FDA kicks off review of Takeda's narcolepsy hopeful

The FDA has started a priority review of Takeda's oveporexton for sleep disorder narcolepsy, setting up a decision in the third quarter of the year.

The acceptance of the new drug application (NDA) puts oveporexton in pole position to become the first orexin agonist to be approved for narcolepsy type 1 (NT1), a form where the sleep symptoms are accompanied by a sudden loss of voluntary control tone known as cataplexy.

The drug is a selective orexin receptor 2 (OX2R) agonist that is designed to tackle a deficiency in orexin-producing neurons and compromised orexin signalling in the sleep disorder, according to Takeda. If approved, it will be the first drug to reach the market that addresses the underlying cause of NT1, rather than simply treating symptoms.

The start of the review is a major achievement for Takeda, given that its orexin agonist programme looked in jeopardy in 2021 when lead asset TAK-994 was abandoned after a liver toxicity signal emerged in phase 2 trials in type 1 and type 2 narcolepsy (NT2), another form characterised by sleep symptoms only.

Pivoting to focus on oveporexton (TAK-861) in type 1 narcolepsy only, Takeda was able to gather positive phase 3 results in two studies – FirstLight (TAK-861-3001) and RadiantLight (TAK-861-3002) – which revealed improvements in wakefulness, excessive daytime sleepiness, cataplexy, ability to maintain attention, overall quality of life and daily life functions with the drug compared to placebo.

It has high expectations for oveporexton, despite the narrower development focus, and has previously suggested peak sales could come in between $2 billion and $5 billion a year.

There are an estimated 100,000 people with NT1 in the US alone, but the challenge for Takeda will be accessing the eligible patient population if oveporexton reaches the market, as many of them are either undiagnosed or misdiagnosed.

"The FDA's acceptance of our NDA is a milestone for people living with narcolepsy type 1," said Andy Plump, president of R&D at Takeda.

"Considering the high unmet need, this community deserves a new and different treatment approach that aims to address the underlying orexin deficiency that causes NT1 by restoring orexin signalling," he added. "We are one step closer to potentially transforming the current treatment paradigm and intend to deliver through our leading work in orexin science."

Oveporexton has also been filed in China with a rolling marketing application also underway in Japan, according to Takeda's latest pipeline update. It is also developing other orexin agonists, including TAK-360, which is in clinical trials for NT2 and idiopathic hypersomnia, a chronic neurological disorder characterised by excessive daytime sleepiness even when well rested.

Other companies working on orexin agonists for narcolepsy include Alkermes, which has alixorexton (formerly ALKS 2680) in phase 2 trials for NT1, NT2, and idiopathic hypersomnia, as well as Eisai, which has E2086 in phase 1b testing.

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