Advances in Orexin-Based Therapies: Key Updates From the Past 6 Months

World Sleep Day is an annual global awareness campaign held on the Friday before the March equinox to promote the importance of healthy sleep and the prevention and management of sleep disorders. Organized by the World Sleep Society, the initiative was first launched in 2008 and brings together clinicians, researchers, and public health advocates to raise awareness of sleep health and the growing burden of sleep-related conditions worldwide. Each year features a dedicated theme, such as the 2026 theme, “Sleep Well, Live Better”, to emphasize the role of restorative sleep in supporting physical, cognitive, and emotional health.¹

In parallel with awareness efforts such as World Sleep Day, research in sleep medicine continues to advance novel therapeutic strategies for sleep disorders. One emerging area involves orexin receptor agonists, investigational agents that activate the brain’s orexin (hypocretin) system, which regulates wakefulness and arousal. Loss of orexin-producing neurons is a hallmark of narcolepsy type 1, contributing to excessive daytime sleepiness and disrupted sleep–wake regulation. By stimulating orexin receptors, these therapies aim to restore wake-promoting signaling and improve daytime alertness, representing a promising disease-targeted approach for narcolepsy and related hypersomnolence disorders.²

This feature highlights the most notable news surrounding orexin receptor agonists from the past 6 months, including FDA drug application acceptances, new clinical trial data, and other emerging research shaping this evolving therapeutic class. Below is a roundup of key updates clinicians and researchers should know.

FDA Grants Orexin Agonist Alixorexton Breakthrough Therapy Designation for Narcolepsy Type 1

In recent news, the FDA granted breakthrough therapy designation to Alkermes’ alixorexton, an investigational oral, selective orexin 2 receptor (OX2R) agonist, for the treatment of narcolepsy type 1 (NT1), using positive phase 1 and phase 2 data, including the phase 2 VIBRANCE-1 trial (NCT06358950), to support the decision. The company noted that it plans to initiate a global phase 3 narcolepsy program for the agent in the first quarter of 2026.³

“Our team was encouraged by the FDA’s Breakthrough Therapy designation for alixorexton in patients with NT1, which recognizes the strength of our early clinical data and the potential of alixorexton to meaningfully improve care for people living with this complex condition,” Craig Hopkinson, MD, chief medical officer and executive vice president of Research & Development at Alkermes, told NeurologyLive^®. “Results from the Vibrance-1 phase 2, multiweek study in 92 patients with NT1 demonstrated clinically meaningful improvements in wakefulness and a generally well tolerated safety profile. These data support continued development of alixorexton and underscore the potential of orexin 2 receptor agonists for the treatment of NT1.”

FDA Accepts New Drug Application for Oveporexton in Narcolepsy Type 1, Grants Priority Review

The FDA accepted Takeda’s new drug application (NDA) and granted priority review to oveporexton, investigational OX2R–selective agonist, for the treatment of patients with NT1. The agent, designed to address the underlying orexin deficiency that causes NT1 by restoring orexin signaling, has a Prescription Drug User Fee Act action date set for the third quarter of 2026.⁴

“Narcolepsy type 1 is a relentless disease that can have a debilitating impact on a person’s everyday life from work and school to social interactions. The currently available treatments offer symptom relief, but don’t address the underlying cause of the disease,” Andrew Plump, MD, PhD, president of research and development at Takeda, told NeurologyLive^®. “Our investigational therapy oveporexton is designed to do just that by restoring orexin signaling. If approved, it would offer people living with narcolepsy type 1 and their health care providers a new approach to the way we treat this disease."

Orexin Agents ORX750 and ORX142 Show Promising Early Phase 1 and 2 Data

Centessa Pharmaceuticals shared positive early-stage data for its investigational OX2R agonist agents, including ORX750 in various neurologic sleep disorders and ORX142 in healthy volunteers. ORX750, which showed treatment potential in both narcolepsy subtypes as well as idiopathic hypersomnia (IH), is expected to enter a registrational program early next year.

OXR750 is currently being tested in the CRYSTAL-1 trial (NCT06752668), a phase 2a, adaptive, double-blind, placebo-controlled study featuring independent cohorts of NT1, narcolepsy type 2 (NT2), and IH. After the initial dose cohorts, the study transitioned to a 4-week parallel design enrolling at least 8 participants with NT1 and 12 with NT2 or IH per cohort, in which participants are randomized to one of two blinded sequences to receive 4 weeks of ORX750 or placebo followed by a 2-week crossover.⁵

Daridorexant Provides Relief for Insomnia in Women During Menopausal Transition

A subgroup analysis from a large-scale, phase 3 study (NCT03545191) revealed that daridorexant (Quvivq; Idorsia) at 50-mg doses may provide benefits in sleep onset, sleep maintenance, and daytime functioning in women with insomnia disorder in menopausal transition age.^6,7

The findings, presented at the World Sleep Congress, held September 5 to 10, 2025, in Singapore, represent the first evaluation of daridorexant in women with insomnia disorder during the menopausal transition age. Approved in 2022, daridorexant is among the dual orexin receptor antagonist class, working by blocking the binding of orexin-A and orexin-B neuropeptides to their receptors.

Dual Orexin Receptor Agonists Show Lower Real-World Abuse Potential Than Traditional Insomnia Treatments

A real-world study using data from the FDA Adverse Event Reporting System (FAERS) database revealed that among several different classes of medications for insomnia, dual orexin receptor agonists (DORA) had the lowest reported cases of abuse, misuse, overdose, and other safety risks. Overall, the case reports for abuse related features were far less than approved benzodiazepine (BZ) and z-drugs as well as the non-approved and unscheduled drug, tradozone.^8,9

Presented at the World Sleep Congress (WSC), the rates of abuse, dependence, and withdrawal were highest for BZs approved for any indication (27.7%), followed by BZs approved for insomnia (23.0%), trazodone (22.7%), doxepin (22.3%), z-drugs (15.3%), ramelteon (8.0%), and DORAs (2.6%). The analysis included the 3 approved DORAs–suvorexant, Lemborexant, and daridorexant–which came into the market in 2014, 2019, and 2022, respectively.

References
1. World Sleep Day. World Sleep Society global awareness initiative observed annually on the Friday before the March equinox to promote healthy sleep and address sleep disorders. Accessed March 18, 2026.
2. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662. doi:10.1056/NEJMra1500587
3. Alixorexton Granted Breakthrough Therapy Designation by U.S. FDA for the Treatment of Narcolepsy Type 1. News release. January 6, 2026. Accessed January 22, 2026. https://investor.alkermes.com/news-releases/news-release-details/alixorexton-granted-breakthrough-therapy-designation-us-fda
4. U.S. Food and Drug Administration accepts new drug application and grants priority review for Takeda’s oveporexton (TAK-861) as a potential first-in-class therapy for narcolepsy type 1. News release. Takeda. February 10, 2026. Accessed February 11, 2026. https://www.takeda.com/newsroom/newsreleases/2026/fda-accepts-nda-priority-review-oveporexton-narcolepsy-type-1/
5. Centessa Pharmaceuticals Reports Financial Results for the Third Quarter of 2025 and Provides Update on Potential Best-in-Class Orexin Receptor 2 (OX2R) Agonist Program. News release. November 5, 2025. Accessed November 13, 2025. https://www.globenewswire.com/news-release/2025/11/05/3181265/0/en/Centessa-Pharmaceuticals-Reports-Financial-Results-for-the-Third-Quarter-of-2025-and-Provides-Update-on-Potential-Best-in-Class-Orexin-Receptor-2-OX2R-Agonist-Program.html
6. Idorsia shares new analyses of daridorexant for patients with insomnia at World Sleep 2025. News release. Idorsia. September 10, 2025. Accessed September 15, 2025. https://www.globenewswire.com/news-release/2025/09/10/3148005/0/en/Idorsia-shares-new-analyses-of-daridorexant-for-patients-with-insomnia-at-World-Sleep-2025.html
7. Schaedel Z, Bakker T, Bassetti C, et al. Efficacy and safety of daridorexant in women with insomnia disorder during menopausal transition: a subgroup analysis. Presented at: World Sleep Congress; September 5-10, 2025; Singapore.
8. Idorsia highlights very low real-world abuse potential of DORA class for insomnia treatment at WSC 2025. News release. Idorsia. September 8, 2025. Accessed September 10, 2025. https://www.globenewswire.com/news-release/2025/09/08/3146311/0/en/Idorsia-highlights-very-low-real-world-abuse-potential-of-DORA-class-for-insomnia-treatment-at-WSC-2025.html
9. Saskin P, McCall WV, Neubauer D, et al. Real-world data on the abuse potential of medications for the treatment of insomnia. Presented at: World Sleep Congress 2025; Abstract 167.