Takeda announced Thursday that it will launch global Phase III trials of its investigational oral orexin receptor 2 (ORX2) agonist TAK-861 in narcolepsy type 1 in the first half of fiscal year 2024, following positive topline data from a Phase IIb trial. The company simultaneously discontinued development of the candidate for narcolepsy type 2.
Phase IIb Trial Results Show Significant Efficacy
The randomized, double-blind, placebo-controlled, multiple dose TAK-861-2001 trial enrolled 112 patients with narcolepsy type 1 (NT1), a condition mainly characterized by the loss of orexin neurons. After eight weeks of treatment, TAK-861 induced "statistically significant and clinically meaningful" improvements in both objective and subjective metrics of wakefulness versus placebo.
Patients treated with TAK-861 saw significantly better outcomes in the Maintenance of Wakefulness Test—the trial's primary endpoint—with a p-value of less than 0.001. The drug also outperformed placebo in key secondary endpoints, including the Epworth Sleepiness Scale and Weekly Cataplexy Rate, with findings deemed statistically significant and clinically meaningful.
Safety Profile Supports Advancement
The Phase IIb trial documented no treatment-related serious adverse events. There were also no instances of hepatotoxicity or visual disturbances both in the mid-stage study and in the ongoing long-term extension trial. Most of the study's participants opted to enter into the long-term extension phase, indicating patient acceptance of the treatment.
"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 III trials this year as we work to deliver a medicine to patients that could address the underlying pathophysiology of the disease," said Sarah Sheikh, head of global development at Takeda.
Strategic Pipeline Decision for NT2
While advancing TAK-861 in narcolepsy type 1, Takeda conducted a separate Phase II trial of TAK-861 in patients with narcolepsy type 2 but announced it "does not plan to advance TAK-861 in [narcolepsy type 2]." The company did not explicitly reveal the reasoning behind discontinuing development in this indication.
Narcolepsy type 1 is diagnosed based on patients showing low levels of the brain hormone hypocretin or experiencing cataplexy and excessive daytime sleepiness. In contrast, narcolepsy type 2 involves excessive daytime sleepiness without experiencing muscle weakness triggered by emotions, with patients typically having less severe symptoms and normal levels of hypocretin.
Recovery from Previous Setback
TAK-861 represents Takeda's potential recovery from a previously stalled narcolepsy program. In October 2021, the company had to discontinue its previous Phase II oral narcolepsy candidate TAK-994 due to undisclosed safety concerns. The candidate has since been removed from Takeda's pipeline.
Elena Koundourakis, who leads the company's orexin program, noted that when TAK-994 was discontinued, "everybody working on 994 started working on TAK-861." She explained that the company maintained backup programs to ensure continuity in their narcolepsy research efforts.
Next Steps and Data Presentation
Takeda will continue to analyze data from both trials to determine next steps for its narcolepsy programs, particularly in populations with normal orexin levels. The company 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.
The findings from both trials of TAK-861 will be presented at an upcoming scientific meeting. Takeda stated that these trials will not impact its full year consolidated reported forecast for the fiscal year ending March 31, 2024.
