Actigraphy-Based Nap Detection Algorithm Highlights Increased Napping in Narcolepsy Type 1, Reduced Napping With TAK-861

Raúl Torres

(Credit: LinkedIn)

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 narcolepsy type 1 (NT1) untreated and treated with TAK-861 (Takeda Pharmaceuticals), an investigational orexin receptor 2-selective agonist. Presented at the 2025 SLEEP Annual Meeting, held June 8 to 11, in Seattle, Washington, these findings support the algorithm’s utility in objectively assessing treatment-related changes in daytime sleepiness and napping behavior in NT1.¹

In the 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 a phase 2 interventional trial (NCT05687903) 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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At the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, data from the phase 2b trial of TAK-861 showed that treatment with the agent resulted in statistically significant and clinically meaningful improvements in primary and secondary end points among patients with NT1. Over the 8-week treatment period, TAK-861 demonstrated statistically significant increased sleep latency on the Maintenance of Wakefulness Test (MWT), the primary end point, relative to placebo. Of note, all doses approached or were in the normative range, with the most pronounced effects observed in the TAK-861 2 mg/5 mg cohort.

All doses of TAK-861 significantly and clinically meaningfully improved subjective wakefulness as measured by Epworth Sleepiness Scale (ESS), a secondary end point. At week 8, the percentage of participants reaching the normative range of ESS less than 10 was 19.0% in placebo, 66.7% in the 0.5 mg/0.5 mg TAK-861 arm, 95.2% in the 2 mg/2 mg arm, 81.8% in the 2 mg/5 mg arm, and 73.9% in the 7 mg QD arm. All improvements were sustained over time.

Treatment with TAK-861 also resulted in significant effects on cataplexy, a common problem for patients with NT1. Over the 8-week period, median weekly cataplexy rate (WRC) was 4.1 in placebo vs 1.4 in the 0.5 mg/0.5 mg group, 0.7 in the 2 mg/2 mg group, 0.7 in the 2 mg/5 mg group, and 4.3 in the 7 mg QD group. In addition, some patients reported insomnia symptoms; however, the majority of these cases were mild or moderate and resolved within 5 days. There were no participants who discontinued because of adverse events (AEs), including insomnia, as well as no insomnia events that required medical intervention.

Throughout the study, TAK-861 was shown to be generally safe, with the most common treatment-emergent adverse events (TEAEs) being insomnia, urinary urgency and frequency, and salivary hypersecretion. There were no cases of hepatotoxicity or visual disturbances reported during the double-blind period or ongoing long-term extension (LTE). Additionally, investigators found no treatment-related serious TEAEs or discontinuations because of TEAEs during the study.

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REFERENCES
1. 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.
2. Takeda’s TAK-861 phase 2b late-breaking data presentations at SLEEP 2024 demonstrate clinically meaningful impact of oral orexin agonist in narcolepsy type 1 compared to placebo. News release. June 3, 2024. Accessed June 14, 2024. https://www.takeda.com/newsroom/newsreleases/2024/tak-861-data-at-sleep-2024-on-narcolepsy-type-1/