A new data analysis from a phase 1, randomized, double-blind, placebo-controlled, 3-period cross-over study (NCT05687903) showed both high and low doses ofTAK-861 (Takeda) had significant and dose-dependent improvements in wakefulness compared with placebo among healthy adult men, with no serious or severe adverse events.1 These findings suggest that TAK-861, an oral highly selective OX2R agonist, may potentially be a safe and effective therapy for patients with narcolepsy who experience excessive daytime sleepiness.
In the analysis, both high (30mg; 10mg) and low doses (15mg; 5mg) of the regimen significantly improved measures of sleepiness in participants. The least square (LS) mean differences from placebo in maintenance of wakefulness test (MWT) 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.
"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. The primary efficacy endpoint was mean sleep latency on the MWT, a test which asks participants to try to stay awake while reclined in a dimly lit room with nothing to do," lead author Melissa Naylor, MD, PhD, medical director of neuroscience at Takeda Development Center Americas, told NeurologyLive®.
- TAK-861, an investigational orexin agonist for narcolepsy, significantly improved wakefulness in healthy adult men, offering promise as a potential treatment for the sleep disorder.
- The study reported no severe adverse events, highlighting the safety and tolerability of TAK-861 in the tested doses, both high and low, among the participants.
- These findings suggest that TAK-861 may offer a new avenue for addressing excessive daytime sleepiness, a characteristic of narcolepsy, and potentially improve quality of life.
Presented at the 2023 World Sleep Congress, held October 20-25, in Rio De Janeiro, Brazil, Naylor and colleagues assessed TAK-861 in healthy adult men, aged between 18 and 40 years. The high-dose TAK-861 group received 30 mg dose followed by 10 mg, while the low-dose group received 15 mg followed by 5 mg. The unequal doses of the therapy were given 4 hours apart at 11pm and 3am, and patients stayed awake during each treatment period starting before dosing on day 1 until completion of the assessments, approximately 10 hours after the first dosage. Investigators had a minimum of 7 days between treatment period for an appropriate washout of study drug and normalization of sleep-wake cycles.
"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. We are encouraged by these results, which have demonstrated the efficacy and safety of TAK-861 in the tested doses, both high and low, among the participants," Naylor told.
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Throughout the study, investigators assessed safety as well as pharmacokinetic and pharmacodynamic parameters, assessed up to approximately 10 hours after the first dose in each treatment period. The measurements for sleepiness were analyzed with the MWT, at predose and 2, 4, 6, and 8 hours post-first dose, and KSS, at predose and after each MWT session. In the study, 11 patients were randomized to 1 of 3 treatment sequences either low dose-placebo-high dose (n = 4), high dose-low dose-placebo (n = 4) or placebo-high dose-low dose (n = 3).
Among the total number of patients, 10 (90.9%) of them completed all planned doses and only 1 participant in the high dose-low dose-placebo group withdrew consent from the study following the first treatment period. The groups that received both TAK-861 high and lose dose regimens had mean plasma concentrations that peaked between 3 and 5.5 hours after the first dose and then steadily reduced thereafter. Investigators noted that systemic drug exposures increased approximately proportionally with dose and most participants achieved the maximum MWT sleep latency of 40 minutes with TAK-861.
"These results suggest the potential wake-promoting effects of orexin agonists, such as TAK-861, are not limited to narcolepsy type 1, which is associated with orexin deficiency. These findings indicate TAK-861 could offer a promising new approach for addressing excessive daytime sleepiness in a wide range of disorders in which orexin levels are presumed to be normal," Naylor told.
As for safety measures in the study, 6 (54.5%) patients reported 10 treatment-emergent adverse events (TEAEs) with TAK-861, 9 of which were mild in severity and 1 moderate, as considered by the investigators. The 1 moderate TEAE was noted as increased blood creatine phosphokinase in a patient given a low dose of TAK-861 but was deemed unrelated to the study drug. Overall, investigators had no reports of deaths, serious TEAEs, TEAEs leading to discontinuation, or severe TEAEs in the study with TAK-861. Of note, 3 (27.3%) patients on TAK‑861 high dose reported micturition urgency, the most common TEAE.
"We are already working on the next steps! We currently have 2 placebo-controlled phase 2 ongoing trials to further investigate TAK-861 in sleep disorders: one study on narcolepsy type 1 and one on narcolepsy type 2. We also have an extension study for participants who complete these trials to start or continue taking TAK-861 if they want to; this extension study will help us to understand the safety of TAK-861 over a longer period of time," Naylor told. "The data from these phase 2 trials will teach us more about how TAK-861 impacts the symptoms of patients with narcolepsy. We look forward to sharing the results of these studies at a later date and to the continuous progress toward larger and longer clinical trials in patients with sleep-wake disorders and other populations."
1. 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.