The Role of Orexin Receptor 2 Agonists in Sleep and Narcolepsy Type 1

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CLINICAL CONVERSATIONS

Recently, Takeda shared positive topline results from a phase 2 trial evaluating TAK-861, an oral orexin receptor 2 agonist, in patients with narcolepsy type 1. Based on these results, Takeda plans to initiate global phase 3 trials of TAK-861 in narcolepsy type 1. To learn more about this development, Psychiatric Times sat down with Elena Koundourakis, the head of the Orexin Franchise Development and Portfolio Strategy at Takeda.

PT: What is narcolepsy and what role do orexin receptor agonists play in sleep and narcolepsy?

Elena Koundourakis: Narcolepsy is a chronic, rare neurological disorder of central hypersomnolence. It is currently classified into 2 different types. Narcolepsy type 1 (NT1) is caused by significant loss of orexin neurons with resulting lack of orexin and also involves cataplexy. The other type is narcolepsy type 2 (NT2) where orexin levels are generally normal and does not involve cataplexy. Orexin receptor 2 agonists, such as TAK-861, are designed to target the underlying pathophysiology of NT1 to restore orexin receptor 2 signaling.

PT: Takeda just released positive topline results from a randomized, double-blind, placebo-controlled, multiple dose phase 2b trial evaluating TAK-861, an oral orexin receptor 2 agonist, in patients with narcolepsy type 1. Can you speak to the importance of the trial’s findings?

Koundourakis: Narcolepsy significantly impacts everyday life. Patients with NT1 experience excessive daytime sleepiness, cataplexy, disturbed nighttime sleep, sleep paralysis, and hypnagogic or hypnopompic hallucinations.

The clear and compelling results from the phase 2b study of TAK-861 in NT1 demonstrated statistically significant and clinically meaningful improvement in objective and subjective measures of wakefulness compared with placebo including on the primary endpoint Maintenance of Wakefulness Test (MWT) (P < 0.001). Improvements in key secondary endpoints including Epworth Sleepiness Scale and Weekly Cataplexy Rate were also found to be statistically significant and clinically meaningful, consistent with the primary endpoint. TAK-861 was generally safe and no treatment related serious adverse events were reported. In addition, no cases of hepatotoxicity or visual disturbances were reported.

Based on these results, and in consultation with global health authorities, Takeda plans to initiate the first global phase 3 trials of TAK-861 in NT1 rapidly in the first half of its fiscal year 2024.

PT: Why should clinicians and patients be excited about these findings and the potential treatment of narcolepsy?

Koundourakis: Currently, individuals living with NT1 must take several different therapies to address the multitude of symptoms they experience daily. TAK-861 is designed to address the underlying pathophysiology of NT1, and the topline data from the phase 2b trial demonstrated statistically significant and clinically meaningful improvement in objective and subjective measures of wakefulness compared with placebo including on the primary endpoint Maintenance of Wakefulness Test. This marks an important milestone in bringing this potential treatment to patients where there remains considerable unmet need despite available therapies.

PT: What makes TAK-861 different from current narcolepsy treatments?

Koundourakis: Unlike current treatments, which are designed to address certain symptoms of the disease, TAK-861 is designed to target the underlying pathophysiology of the disease by stimulating the orexin receptor 2 and restoring signaling in individuals with NT1.

PT: You plan to initiate phase 3 trials for TAK-861 in narcolepsy type 1 this year. Tell us about the first steps as we move forward.

Koundourakis: We are evaluating the data and discussing the phase 3 study design for NT1 with regulatory authorities and intend to rapidly initiate global phase 3 trials of TAK-861 in NT1 in the first half of Takeda’s fiscal year 2024.

PT: Takeda does not plan to advance TAK-861 for narcolepsy type 2. Can you describe what next steps will be taken to address the need in patients with narcolepsy type 2, who generally have normal orexin levels?

Koundourakis: At this time, Takeda does not plan to advance TAK-861 in NT2. Data are being further analyzed to determine next steps to find treatments for patients with normal orexin levels. Takeda is progressing multiple orexin agonists in patient populations with normal levels of orexin neuropeptides such as NT2 and other indications where orexin biology is implicated.

PT: Thank you!

Ms Koundourakis is head of the Orexin Franchise Development and Portfolio Strategy at Takeda.