Narcolepsy Agent TAK-861 Moves to Phase 3 Studies Following Positive Phase 2b Data

Sarah Sheikh, MRCP, MSc, BCh

According to a recent announcement from Takeda Pharmaceutical, TAK-861, an investigational oral orexin receptor 2 agonist, performed well in a phase 2b trial (NCT05687903) of patients with narcolepsy type 1 (NT1). Based on these results, and in consultation with global health authorities, the company plans to initiate multiple phase 3 trials of the therapy in NT1 rapidly in the first half of its fiscal year 2024.¹

The TAK-861-2001 trial, a multicenter study, featured 112 patients with NT1 who were randomly assigned to either 1 of 4 dosed groups of TAK-861 or placebo, for either an 8- or 12-week period. All told, patients on the investigational agent demonstrated statistically significant and clinically meaningful improvement in change in mean sleep latency, the primary outcome, after 8 weeks of treatment (P <.001). These changes were measured through the Maintenance of Wakefulness Test, an assessment of a person’s ability to remain awake under soporific conditions for a defined period of time.

Patients treated with TAK-861 also showed statistically significant and clinically meaningful improvements in Epworth Sleepiness Scale and Weekly Cataplexy Rate, 2 secondary outcomes assessed. The therapy was considered safe and well-tolerated, with no treatment-related serious adverse events reported. Investigators also noted no cases of hepatotoxicity or visual disturbances in in the phase 2b trials or in the ongoing long-term extension.

"We are thrilled to announce these clear and compelling results from the TAK-861 trial in narcolepsy type 1 that allows us to rapidly initiate Phase 3 trials this year as we work to deliver a medicine to patients that could address the underlying pathophysiology of the disease," Sarah Sheikh, MRCP, MSc, BCh, head of the Neuroscience Therapeutic Area Unit and head of Global Development at Takeda, said in a statement.¹ "Takeda thanks the patients, caregivers and investigators who participated in our orexin agonist trials. We will continue to apply our deep and growing understanding of orexin biology as we work to develop and deliver transformative treatments to people across a range of indications who could benefit from this mechanism."

Most patients who completed the trial entered the long-term extension, which follows patients for a total of 23 weeks. Takeda plans to present results from both the NT1 trial of TAK-861 and the other trial (NCT05687916) assessing the agent in patients with narcolepsy type 2, at an upcoming meeting. In its announcement, the company noted that it does not plan to advance the therapy in NT2, and will continue to evaluate the data to determine next steps in orexin normal populations.

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The second study, a trial featuring 60 patients with NT2, assessed the efficacy, safety, and tolerability of 2 oral doses of TAK-861. Similar to the first trial, the double-blind portion of the study lasted 8 weeks, assessing change from baseline in mean sleep latency, in addition to change in ESS and overall safety. The company noted that it is "processing multiple orexin agonists in patient populations with normal levels of orexin neuropeptides such as NT2 and other indications where orexin biology is implicated."

In a previously completed phase 1 analysis of a healthy adult men, published findings showed both high and low doses of TAK-861 had significant and dose-dependent improvements in wakefulness. The least square (LS) mean differences from placebo in maintenance of wakefulness test mean sleep latency were 17.8 (95% CI, 12.2-23.5) minutes and 19.1 (95% CI, 13.6-24.6) minutes for TAK‑861 low and high doses, respectively (both, P <.0001). At the same time, the LS mean differences from placebo in change in Karolinska sleepiness scale (KSS) score were -2.65 (95% CI, -4.58 to -0.72; P = .0088) and ‑4.40 (95% CI, ‑6.29 to ‑2.52; P <.0001) for TAK‑861 low and high doses, respectively.2

"This study was the first instance in which we were able to demonstrate the efficacy of TAK-861. When healthy volunteers were given TAK-861 while staying awake overnight, the results showed increases in subjective and objective measurements of wakefulness when compared with placebo," Melissa Naylor, MD, PhD, medical director of neuroscience at Takeda, told NeurologyLive^® at the time. "The magnitude of the effects was quite striking with most subjects on each of the TAK-861 doses staying awake during all 4 of the 40-minute MWT sleep trials performed throughout the night; whereas only 1 participant did this while on placebo. TAK-861 also showed a favorable safety profile, with no instances of severe adverse events, fatalities, or treatment discontinuations because of adverse events reported."

REFERENCES
1. Takeda intends to rapidly initiate the first global phase 3 trials of TAK-861, an oral orexin agonist, in narcolepsy type 1 in the first half of fiscal year 2024. News release. Takeda Pharmaceutical. February 8, 2024. Accessed February 12, 2024. https://www.businesswire.com/news/home/20240208344780/en/Takeda-Intends-to-Rapidly-Initiate-the-First-Global-Phase-3-Trials-of-TAK-861-an-Oral-Orexin-Agonist-in-Narcolepsy-Type-1-in-First-Half-of-Fiscal-Year-2024
2. Naylor M, Neuwirth R, Abraham A, Olsson T. Safety, tolerability, pharmacodynamics, and pharmacokinetics of oral TAK-861 in an acute sleep phase delay paradigm in healthy male subjects. Presented at World Sleep Congress; October 20-25, 2023; Rio De Janeiro, Brazil.