Investigational Therapy TAK-861 Reduces Microsleeps in Phase 2 Trial of Narcolepsy Type 1

Yishu Gong, PhD, MPH

(Credit: LinkedIn)

According to newly presented findings from a phase 2 randomized, placebo-controlled trial (NCT05687903), treatment with TAK-861 (Takeda Pharmaceuticals), an investigational oral orexin receptor 2-selective agonist, led to significant reductions in microsleep rates and delayed the first occurrence of microsleep in patients with narcolepsy type 1 (NT1).¹ Presented at the 2025 SLEEP Annual Meeting, held June 8 to 11, in Seattle, Washington, these results demonstrate the potential of TAK-861 as an effective treatment for daytime sleepiness in NT1.¹

In the study (n = 122), participants with NT1 were randomized to receive TAK-861 in varying dosing regimens (0.5 mg twice 3 hours apart, n = 23;2 mg twice 3 hours apart, n = 21; 2 mg then 5 mg 3 hours later, n = 23; 7 mg once daily, n = 23) or placebo (n = 22). Across all TAK-861 treatment groups, microsleep rates prior to sleep onset decreased significantly from 6 microsleeps per 10 minutes at baseline to fewer than 2 per 10 minutes by 4 and 8 weeks.

Presented by lead author Yishu Gong, PhD, MPH, senior manager of statistics at Takeda, Maintenance of Wakefulness Tests (MWTs) were conducted at baseline, and after 28 and 56 days of treatment, with 4 MWT 40-minute sessions per day at 10AM, 12PM, 2PM, and 4PM. Researchers had microsleeps manually scored and analyzed using zero-inflated negative binomial mixed-effects models and mixed-effects survival analysis. Pairwise contrasts with baseline in each treatment were also conducted by researchers, averaging over MWT sessions.

Additional findings revealed that all treatment groups experienced a statistically significant prolongation in time-to-first microsleep compared with baseline (P <.005). Researchers reported that the average microsleep duration, excluding participants who experienced no microsleeps, did not show significant change in any treatment arm. Furthermore, participants in the placebo group exhibited minimal changes in microsleep frequency and timing across sessions and study visits.

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In another presentation at SLEEP 2025, a newly developed wrist-worn actigraphy-based nap-detection algorithm demonstrated high accuracy in identifying daytime naps and revealed key differences in nap patterns between patients with NT1 untreated and treated with TAK-861. These findings supported the algorithm’s utility in objectively assessing treatment-related changes in daytime sleepiness and napping behavior in NT1.²

For this study, investigators first validated the nap-detection algorithm using manually annotated nap data from 2237 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), achieving 86.5% sensitivity and an F1 area of 84.6% across 7 days. Presented by lead author Raúl Torres, associate director of data science at Takeda, statistically significant correlations were observed between napping behavior and self-reported sleepiness via the Epworth Sleepiness Scale (ESS), with nominal correlations among participants from the MESA validation cohort (R = -0.16, P <.001; R = 0.15, P <.001, respectively).

Researchers then had the algorithm be applied in a noninterventional study (NCT04445129) of 16 participants with NT1 and 16 matched healthy controls, as well as in the aforementioned phase 2 interventional trial of TAK-861 involving 112 participants with NT1. Across these studies, the algorithm measured the proportion of nap-free days and total daytime sleep minutes on days with more than 1 nap. In the noninterventional study, participants with NT1 demonstrated 11.5 fewer nap-free days (P <.001) and 37.5 more minutes of daytime sleep (P <.001) over a 4-week period compared with healthy controls.

In the phase 2 interventional study of TAK-861, participants with NT1 experienced statistically significant increases in nap-free days and reductions in daily daytime sleep minutes across all TAK-861 dose groups (0.5mg/0.5mg, n = 23; 2mg/2mg, n = 21; 2mg/5mg, n = 23; 7mg, n = 23; all P <.001) compared with baseline. Notably, authors reported no significant changes observed in the placebo group of the study (n = 22). Thus, the results showed an increase in napping among untreated participants with NT1 and a substantially reduced daytime napping in TAK-861-treated participants with NT1.

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REFERENCES
1. Gong Y, Tracey B, Olsen M, et al. Treatment with an Orexin Agonist Reduces Microsleeps and Improves Wakefulness During MWT in People with NT1. Presented at: 2025 SLEEP Annual Meeting; June 8-11; Seattle, WA. ABSTRACT 0847.
2. Torres R, Onorati F, Naylor M, et al. Actigraphy-Based Assessment of the Impact of TAK-861 on Daytime Napping in People with Narcolepsy Type 1. Presented at: 2024 SLEEP Annual Meeting; June 8-11; Seattle, WA. ABSTRACT 0846.