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

According to a recent announcement, the FDA has 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 2026.¹

“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.”

Findings from the VIBRANCE-1 study, a double-blind, placebo-controlled phase 2 trial, showed that treatment with alixorexton resulted in statistically significant, clinically meaningful, and dose-dependent improvements in the Maintenance of Wakefulness Test (MWT) after 6 weeks of treatment at all doses tested (4-mg, 6-mg, and 8-mg).² In addition, the data revealed statistically significant enhancements in excessive daytime sleepiness via the Epworth Sleepiness Scale (P <.0001 at all doses), a key secondary end point.

In this dose-range-finding trial, 92 patients were randomly assigned to alixorexton at 3 different doses of placebo, once daily for 6 weeks, with an optional 7-week, open-label study to follow once completed. Throughout study, all doses of alixorexton led to improvements in weekly cataplexy rates, with the 6-mg group demonstrating statistical significance (P = .005). On exploratory patient-reported outcome measures, the investigational agent demonstrated clinically meaningful improvements on the Narcolepsy Severity Scale (NSS; P <.001 at all doses), as well as in the British Columbia Cognitive Complaints Inventory (P <.0001 at all doses), a measure of cognitive complaints.

READ MORE: Secondary Analysis Finds Oveporexton Improves Cognitive Function in Adults With Narcolepsy Type 1

Although the reported P values were nominal in significance, the company believes they still demonstrated the potential therapeutic effect of alixorexton in treating NT1. Over the study period, all dosed groups had clinically meaningful improvements in fatigue, evaluated through Patient Reported Outcomes Measurement Information System-Fatigue, compared with placebo (P <.01 at all doses). In terms of safety, the investigational agent continued to show a consistent profile, with no serious treatment-emergent adverse events (AEs) and no treatment-related safety signals in hepatic and renal parameters, vital signs, or ophthalmic exams.

In the proof-of-concept phase 1 study, results showed that alixorexton was safe among healthy volunteers and patients with narcolepsy, with observed dose-dependent improvements in sleep latency.³ The data, released in 2023, was from single- and multiple-ascending dose evaluations in healthy participants and the first cohort of 4 patients with NT1.³ Following treatment with alixorexton, investigators observed mean improvements of 18, 30, and 37 minutes, in the 1-, 3-, and 8-mg dosed groups, respectively. The between-group differences for all 3 doses (1 mg; P <.01; 3 mg; P <.001, and 8 mg; P <.001) were all statistically significant, as those on placebo demonstrated a 1-minute reduction in mean sleep latency.

The study’s main goal was to assess safety and tolerability of the agent. At the conclusion of the treatment period, drug-related AEs were documented only at the 8-mg dose and were mild in severity. Insomnia (n = 3), pollakiuria (n = 2), and salivary hypersecretion (n = 2) were the only treatment-emergent AEs, observed in at least 1 treated participant. Notably, investigators observed no serious AEs or AEs that led to discontinuation, as well as no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.

“Despite available treatment options, people with NT1 continue to face profound unmet needs, particularly around persistent excessive daytime sleepiness and its impact on daily functioning. We look forward to working closely with the FDA as we progress alixorexton into phase 3 development,” Hopkinson said to NeurologyLive.

REFERENCES
1. 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
2. Alkermes Announces Positive Topline Results From Vibrance-1 Phase 2 Study of Once-Daily Alixorexton in Patients With Narcolepsy Type 1. News release. Alkermes. July 21, 2025. Accessed January 22, 2026. https://www.prnewswire.com/news-releases/alkermes-announces-positive-topline-results-from-vibrance-1-phase-2-study-of-once-daily-alixorexton-in-patients-with-narcolepsy-type-1-302509211.html
3. Alkermes Presents First Clinical Data for Orexin 2 Receptor Agonist ALKS 2680 at World Sleep Congress. News release. Alkermes. October 23, 2023. Accessed January 22, 2026. https://www.prnewswire.com/news-releases/alkermes-presents-first-clinical-data-for-orexin-2-receptor-agonist-alks-2680-at-world-sleep-congress-301963945.html