Alkermes’ oral orexin 2 receptor agonist alixorexton met dual primary endpoints in the Phase 2 VIBRANCE‑2 study, showing significant improvements in wakefulness, daytime sleepiness, fatigue, and cognition in adults with narcolepsy type 2, with a favorable safety profile.
Written By: Farha Farheen, PharmD
Reviewed By: Pharmacally Editorial Team
Alkermes plc has reported positive Phase 2 results from the VIBRANCE-2 study evaluating alixorexton, an investigational oral orexin 2 receptor (OX2R) agonist, in adults with narcolepsy type 2 (NT2). Data presented at SLEEP 2026 showed statistically significant and clinically meaningful improvements in wakefulness and excessive daytime sleepiness compared with placebo, along with benefits in fatigue and cognition.
Narcolepsy Type 2 Remains an Area of Unmet Need
Narcolepsy type 2 is a chronic neurological sleep disorder characterized by excessive daytime sleepiness, fatigue, cognitive impairment, and reduced daily functioning. Unlike narcolepsy type 1, where orexin deficiency is well established, the role of orexin signaling in NT2 remains less clearly understood, making these findings particularly noteworthy.
Study Design
VIBRANCE-2 (NCT06555783) was a randomized, double-blind, placebo-controlled, dose-ranging study that enrolled 93 adults with NT2. Participants received once-daily alixorexton at doses of 10 mg, 14 mg, or 18 mg, or placebo for eight weeks, followed by an optional five-week open-label extension.
Dual Primary Endpoints Achieved
The study met both primary efficacy endpoints. Wakefulness was assessed using the Maintenance of Wakefulness Test (MWT), where alixorexton produced clinically meaningful improvements across all dose groups. The 14 mg dose achieved statistical significance versus placebo (p=0.049), as did the 18 mg dose (p=0.047).
Participants entered the study with a mean sleep latency of approximately six minutes. By week eight, observed mean sleep latency increased to approximately 16 minutes in the 10 mg group and approximately 14 minutes in the 14 mg and 18 mg groups, demonstrating improved ability to remain awake during testing.
Excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). Clinically meaningful reductions were observed across all dose groups, with statistical significance versus placebo achieved at the 18 mg dose (p=0.046). Baseline ESS scores averaged approximately 17, indicating severe daytime sleepiness, while most treated participants reported normal or mild sleepiness by week eight.
Improvements in Fatigue and Cognition
Alixorexton also demonstrated benefits across exploratory patient-reported outcomes. On the PROMIS-Fatigue scale, improvements compared with placebo were observed across all dose groups, with nominal statistical significance at the 14 mg dose (p=0.044) and 18 mg dose (p=0.001). Benefits emerged by week two and were sustained through treatment.
Cognitive symptoms measured using the British Columbia Cognitive Complaints Inventory (BC-CCI) also improved, with nominal statistical significance observed at the 18 mg dose (p=0.042).
Richard K. Bogan, M.D., Principal of Bogan Sleep Consultants and Associate Clinical Professor at the University of South Carolina School of Medicine, said the findings provide compelling evidence that alixorexton can improve wakefulness, fatigue, and cognition in adults with NT2.
Favorable Safety Profile
Alixorexton was generally well tolerated during both the randomized treatment period and open-label extension. No serious treatment-emergent adverse events were reported, and no clinically meaningful safety signals were observed involving hepatic or renal parameters, vital signs, electrocardiograms, or ophthalmologic assessments.
The most common adverse events were pollakiuria, insomnia, micturition urgency, dizziness, and headache. Most were mild to moderate in severity, and more than 95% of participants completed the eight-week treatment period.
Phase 3 Development Underway
According to Alkermes, alixorexton is the first OX2R agonist to demonstrate statistically significant improvements in both objective and subjective measures of wakefulness in a controlled study of NT2. While encouraging, the Phase 2 study was relatively small, and larger trials will be needed to confirm long-term efficacy and safety.
Alkermes has initiated the global Phase 3 BRILLIANCE studies evaluating once-daily and split-dose regimens of alixorexton in patients with narcolepsy types 1 and 2. Alixorexton has received FDA Breakthrough Therapy Designation for narcolepsy type 1, FDA Orphan Drug Designation for idiopathic hypersomnia, and European Commission Orphan Drug Designation for narcolepsy.
What This Means for Patients
People living with narcolepsy type 2 often experience persistent daytime sleepiness, fatigue, impaired concentration, and difficulty maintaining alertness during daily activities. The VIBRANCE-2 results suggest that alixorexton may improve several symptoms of the disorder while enhancing wakefulness. If confirmed in ongoing Phase 3 studies, the therapy could offer an important new treatment option for patients with limited disease-specific therapies currently available.
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About the Writer
Farha Farheen, PharmD (LinkedIn) is a pharmacy professional with a strong interest in pharmacovigilance and clinical research. She has completed her Doctor of Pharmacy (Pharm.D) along with her internship as a Clinical Pharmacist. She has hands-on experience in adverse drug reaction (ADR) reporting, safety data documentation, and pharmacovigilance workflows, and is proficient in using VigiFlow. She is also a patent holder for an antibacterial formulation enriched with bioactive substances, granted by the German Patent and Trademark Office.