▎WuXi AppTec Content Team Report

Screenshot source: CDE official website

NT1 is a chronic, rare central nervous system hypersomnia disorder,Due toOrexinMassive loss of neurons leads to low levels of orexin neuropeptides in the brain and cerebrospinal fluid.Patients with NT1 experience symptoms such as excessive daytime sleepiness (EDS), cataplexy, disrupted nighttime sleep, and hallucinations upon falling asleep and waking up. These debilitating symptoms significantly reduce quality of life and severely impact the patient's work, daily life, and interpersonal relationships.

TAK-861 is designed toSelective Stimulation of Orexin ReceptorsTo address the orexin deficiency in NT1。Agonists that activate orexin 2 receptors may substitute for endogenous orexins, activating signaling pathways that promote wakefulness.

In June this year, Takeda announced positive results from the Phase 2b clinical trial of TAK-861 in treating type 1 narcolepsy. This randomized, double-blind, placebo-controlled clinical trial (n=112) met its primary and secondary endpoints. The primary endpoint of the Phase 2b trial showed,In the Maintenance of Wakefulness Test (MWT), all dose groups showed statistically significant and clinically meaningful improvements in sleep latency compared to the placebo group (p≤0.001). The improvements were sustained over 8 weeks.。

The study also achieved consistent results in key secondary endpoints, including the Epworth Sleepiness Scale (ESS) and weekly cataplexy rate (WCR), showing significant improvements in subjective sleepiness and cataplexy frequency compared to the placebo group, with sustained efficacy over 8 weeks. At the end of the 8-week treatment period, the MWT and ESS results for the majority of NT1 patients were within the normal range.

According to a previous press release from Takeda, the Phase 2b data also supported the recent grant by the U.S. FDA of TAK-861 for the treatment of NT1.Excessive Daytime SleepinessBreakthrough Therapy Designation.

Orexin is a key regulator of the sleep-wake cycle and is involved in other fundamental functions such as respiration and metabolism. TAK-861 is the leading project in Takeda's orexin series. The company is also developing a variety of orexin products for other indications involving orexin biology.TAK-360, an Oral OX2R Agonist, is studying the treatment of type 2 narcolepsy and idiopathic hypersomnia, recently initiated a phase 1 trial, and received FDA Fast Track designation; andDanavorexton (TAK-925), an intravenous OX2R agonist, a Phase 2 trial is being conducted for patients with moderate to severe obstructive sleep apnea who are undergoing general anesthesia.

Globally, orexin receptor agonists (including OX1R and OX2R) are also expected to be used in the treatment of neurological and psychiatric disorders such as insomnia, sleep disorders, circadian rhythm sleep disorders, Alzheimer's disease, and depression. Public data shows that dozens of products targeting orexin receptors are currently under development worldwide.。

References:

[1] Official website of the Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Sep 6, 2024, from https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c

[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. Retrieved June 3, 2024, from https://www.takeda.com/newsroom/newsreleases/2024/tak-861-data-at-sleep-2024-on-narcolepsy-type-1/