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Takeda plans to move TAK-861 into phase 3 in the first half of its 2024 financial year. Takeda’s narcolepsy work has finally yielded a phase 2b win, albeit with a blemish. After axing one asset over liver toxicity, the Japanese drugmaker’s continued faith in the mechanism has been rewarded with a primary endpoint hit—but the midphase program only supports progression in one form of the disease. The phase 2b program featured two trials, one in narcolepsy type 1 (NT1) and another in narcolepsy type 2 (NT2). Both studies tested TAK-861, an oral orexin receptor 2 agonist. The potential of the mechanism is clearer in NT1, a condition characterized by deficiency of the neuropeptide orexin, but Takeda saw an opportunity to move the needle in NT2, too. Orexin levels are normal in patients with NT2. Takeda’s bet on NT2, a rarer, normally milder form of narcolepsy, has failed to make the case for further development of TAK-861 in the indication. But the drugmaker is more encouraged by the results in NT1, leading it to outline plans to start phase 3 trials in that form of the condition this year. The NT1 clinical trial randomized 112 patients to receive one of four oral doses of TAK-861 or placebo. After eight weeks, Takeda saw “statistically significant and clinically meaningful improvement in objective and subjective measures of wakefulness compared to placebo.” The measures included the maintenance of wakefulness test, the primary endpoint. Takeda hit the endpoint with a p-value of less than 0.001.  An earlier trial of TAK-994, another oral orexin receptor 2 agonist, suggested the mechanism could “take a type 1 narcolepsy patient and make them look like a healthy individual,” Andy Plump, M.D., Ph.D., the president of R&D at Takeda, told investors in July. Liver toxicity forced Takeda to dump that candidate, but it identified the more potent TAK-861 as a molecule that could better balance the benefits and risks. Takeda is yet to share full safety data from the TAK-861 studies but said the treatment was generally safe and well tolerated in both trials, with no treatment-related serious adverse events, hepatotoxicity cases or visual disturbances. Buoyed by the data, Takeda plans to move into phase 3 in the first half of its 2024 financial year, which starts in April. The timing keeps Takeda tucked in behind NLS Pharmaceutics, which planned to start a phase 3 trial last month, in the race to bring an orexin 2 receptor agonist to market in NT1. Another rival, Jazz Pharmaceuticals, paused a phase 1 trial last year over visual disturbances and cardiovascular effects. Takeda retains an interest in NT2 and other conditions with normal levels of orexin. The company is still analyzing its data to inform the next steps in those settings and is “progressing multiple orexin agonists.” Plump previously laid out several paths that Takeda could take after seeing the phase 2b data, noting the potential to advance in NT1, NT1 plus NT2 or both settings plus additional indications.

Takeda announced plans to initiate Phase III studies for its oral orexin receptor 2 (OX2R) agonist TAK-861 in narcolepsy type 1 (NT1), following positive findings from a Phase IIb trial. Sarah Sheikh, head of global development, said the “clear and compelling results” enable the company to commence late-stage testing as early as the first half of fiscal year 2024.  The Phase IIb study, involving 112 patients with NT1, demonstrated statistically significant and clinically meaningful improvements in both objective and subjective measures of wakefulness for TAK-861 versus placebo at week 8. The primary endpoint, a maintenance of wakefulness test, was consistent with key secondary outcome measures, including the Epworth Sleepiness Scale and Weekly Cataplexy Rate. The drug was well tolerated, with no treatment-related serious adverse events.Takeda, which also ran a Phase IIb trial of TAK-861 in narcolepsy type 2 (NT2), stated it had no intentions of advancing the candidate in this indication. Findings from both studies will be presented at an upcoming scientific conference.Not all rosesTakeda’s orexin franchise encountered troubled waters in late 2021, when the Phase II programme for another oral OX2R agonist TAK-994 in NT1 and NT2 was axed after the emergence of a safety signal. The franchise also includes an investigational intravenous OX2R agonist TAK-925.Sheikh remarked that the drugmaker will continue to leverage its “deep and growing understanding of orexin biology” to investigate multiple orexin agonists across a wide range of indications, including conditions with normal orexin levels such as NT2.