Alkermes Reports Sustained Long-Term Benefits of Alixorexton in Narcolepsy Types 1 and 2
Alkermes plc has announced encouraging interim results from the ongoing long-term extension (LTE) study evaluating alixorexton, its investigational oral orexin 2 receptor (OX2R) agonist, in adults with narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). The latest findings demonstrate that patients receiving alixorexton continued to experience clinically meaningful improvements in excessive daytime sleepiness, wakefulness, cognition, and fatigue after up to nine months of treatment. The therapy also maintained a favorable safety and tolerability profile across all dose levels evaluated, reinforcing its potential as a promising treatment option for multiple forms of narcolepsy.
The results represent an important milestone in Alkermes’ sleep disorder development program, providing additional evidence that restoring orexin signaling may offer durable symptom control beyond the initial benefits observed in earlier phase 2 studies. Alixorexton is currently being investigated not only for NT1 and NT2 but also for idiopathic hypersomnia (IH), another debilitating neurological sleep disorder characterized by excessive daytime sleepiness.
Addressing the Unmet Needs of Narcolepsy Patients
Narcolepsy is a chronic neurological disorder caused by impaired regulation of the sleep-wake cycle. Patients often experience overwhelming daytime sleepiness that interferes with work, education, and daily life. Individuals with NT1 additionally suffer from cataplexy, a sudden loss of muscle tone triggered by strong emotions, while those with NT2 primarily experience excessive sleepiness without cataplexy.
Although currently available therapies can improve wakefulness or reduce cataplexy, many patients continue to struggle with persistent fatigue, impaired concentration, cognitive dysfunction, and reduced quality of life. These symptoms frequently remain inadequately controlled despite existing treatments.
Unlike conventional stimulants that indirectly promote wakefulness, alixorexton is designed to directly activate the orexin-2 receptor, targeting the biological pathway disrupted in narcolepsy. Orexin is a naturally occurring neuropeptide responsible for maintaining alertness and regulating the sleep-wake cycle. By stimulating orexin receptors, alixorexton aims to restore more natural wakefulness while potentially improving several aspects of the disease simultaneously.
Interim Analysis Demonstrates Durable Clinical Benefit
The ongoing open-label LTE study is evaluating the long-term safety, tolerability, and durability of alixorexton after completion of the Vibrance-1 and Vibrance-2 phase 2 studies. The interim analysis included safety information collected through May 12, 2026, along with efficacy outcomes measured after 24 weeks in the extension study.
For many participants, this represents approximately nine months of continuous treatment since receiving their first dose during the parent clinical trials.
Across both NT1 and NT2 populations, patients maintained clinically meaningful improvements on objective and subjective measures of daytime alertness.
Key assessments included:
- Maintenance of Wakefulness Test (MWT)
- Epworth Sleepiness Scale (ESS)
- Cognitive performance evaluations
- Fatigue assessments
- Cataplexy frequency (NT1 only)
Overall, the results indicate that treatment benefits remained stable over prolonged therapy without new safety concerns.
Strong Long-Term Results in Narcolepsy Type 1
The Vibrance-1 phase 2 study previously demonstrated statistically significant improvements in excessive daytime sleepiness and cataplexy among patients with NT1. Approximately 85% of participants from that trial chose to continue into the LTE study, reflecting strong patient retention and treatment acceptance.
Dose adjustments during the first month of the extension allowed investigators to individualize therapy, with most participants receiving either 6 mg or 8 mg daily.
At the interim analysis cutoff:
- Nearly 90% of enrolled NT1 patients remained on treatment.
- All dose groups achieved normal wakefulness on the Maintenance of Wakefulness Test.
- Mean sleep latency reached approximately 29 minutes after 24 weeks in the LTE.
- Improvements in daytime sleepiness remained within the normal range on the Epworth Sleepiness Scale.
- Mean ESS scores decreased to approximately 7.5 across participants.
- Reductions in weekly cataplexy frequency observed during the parent trial were maintained throughout long-term treatment.
These findings suggest that alixorexton can provide sustained control over both excessive daytime sleepiness and cataplexy, two defining symptoms of NT1.
Improvements Extend Beyond Sleepiness
An important aspect of the LTE analysis involved patient-reported outcomes measuring cognition and fatigue.
Many patients with narcolepsy report persistent “brain fog,” memory problems, difficulty concentrating, and overwhelming fatigue even when excessive sleepiness improves. These symptoms significantly affect workplace productivity, academic performance, and overall quality of life.
According to the interim analysis:
- Most NT1 participants achieved cognitive function scores within the normal range.
- Fatigue scores also improved into the normal range across treatment groups.
- Prior to therapy, participants generally reported moderate cognitive impairment and fatigue.
These sustained improvements suggest that alixorexton may positively influence broader aspects of neurological function beyond simply increasing wakefulness.
Continued Clinical Benefits in Narcolepsy Type 2
The Vibrance-2 study previously demonstrated significant improvements in wakefulness among patients with NT2. Approximately 70% of participants enrolled in the LTE study after completing the randomized trial.
Following dose optimization, most patients received either 14 mg or 18 mg during long-term treatment.
As of the interim analysis:
- Approximately 80% remained on therapy.
- Maintenance of Wakefulness Test performance continued improving through week 24.
- Mean sleep latency reached approximately 18 minutes.
- ESS scores remained within the normal range for the two higher-dose groups.
- Average ESS scores were approximately 8.9 after extended treatment.
The data suggest continued symptom improvement rather than a gradual loss of therapeutic benefit over time.
Cognitive and Fatigue Improvements Also Observed in NT2
Patients with NT2 demonstrated encouraging improvements in cognitive function and fatigue similar to those observed among NT1 participants.
According to patient-reported assessments:
- Cognitive performance improved into the normal or mild impairment range.
- Fatigue scores reached values considered within the normal range.
- Baseline evaluations had indicated moderate impairment before treatment.
These findings reinforce the possibility that orexin receptor activation may improve several dimensions of disease burden regardless of narcolepsy subtype.
Favorable Long-Term Safety Profile
Safety remains a critical consideration for chronic neurological therapies intended for long-term use.
Across both NT1 and NT2 populations, alixorexton continued to demonstrate a generally favorable safety profile.
Among NT1 participants:
- No serious treatment-emergent adverse events were reported.
- Most adverse events were mild or moderate.
- Frequently reported events included headache, urinary urgency, increased urinary frequency, and nasopharyngitis.
Among NT2 participants:
- No serious treatment-emergent adverse events occurred.
- Most side effects remained mild to moderate.
- Common adverse events included insomnia, headache, increased urinary frequency, and upper respiratory tract infections.
Importantly, investigators reported no new safety signals during prolonged exposure, supporting continued clinical development.
Expert Highlights Importance of Long-Term Findings
Professor Yves Dauvilliers, M.D., Ph.D., Professor of Neurology and Physiology at the University of Montpellier and Director of the Sleep-Wake Disorders Center, emphasized that narcolepsy affects far more than daytime sleepiness alone.
He noted that many patients experience persistent cognitive dysfunction and fatigue that significantly impair daily functioning. According to Dr. Dauvilliers, the sustained improvements observed across multiple clinical measures provide encouraging evidence that alixorexton may address several important aspects of narcolepsy while maintaining benefits over extended treatment.
He added that the consistency of the results across both NT1 and NT2 supports the therapy’s potential regardless of narcolepsy subtype.
Company Continues Advancing Late-Stage Development
Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes, described the interim results as an important step toward establishing alixorexton as a potential new standard treatment.
He highlighted the durability of improvements across wakefulness, cognition, fatigue, and patient-reported outcomes while noting the favorable long-term safety profile observed during the extension study.
Hopkinson also emphasized the importance of dose flexibility, allowing clinicians to tailor therapy to individual patient needs across different forms of narcolepsy.
Ongoing Phase 3 Program
Building on the encouraging phase 2 and LTE findings, Alkermes is advancing alixorexton through multiple late-stage clinical trials.
The development program currently includes:
- Phase 3 Brilliance studies in adults with narcolepsy type 1.
- Phase 3 Brilliance studies in adults with narcolepsy type 2.
- The ongoing Phase 2 Vibrance-3 study evaluating alixorexton in adults with idiopathic hypersomnia.
Enrollment in the Phase 3 Brilliance program continues, while Alkermes expects to complete the Vibrance-3 study later this year.
The company plans to present the latest LTE findings at an upcoming scientific conference, where additional analyses of long-term efficacy and safety will provide further insight into the potential role of alixorexton in treating narcolepsy and related sleep disorders. If future studies confirm these durable benefits, alixorexton could emerge as an important therapeutic advance by addressing not only excessive daytime sleepiness but also the cognitive and functional challenges that continue to affect many patients living with chronic sleep disorders.
About Alixorexton
Alixorexton (formerly referred to as ALKS 2680) is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in development for the treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH). Orexin, a neuropeptide produced in the lateral hypothalamus, is considered to be the master regulator of wakefulness due to its activation of multiple, downstream wake-promoting pathways that project widely throughout the brain.9
Targeting the orexin system may address excessive daytime sleepiness across hypersomnolence disorders, whether or not deficient orexin signaling is the underlying cause of disease.10 Alixorexton is currently being evaluated in the phase 3 Brilliance Studies in patients with NT1 and NT2, and in the phase 2 Vibrance-3 study in patients with IH.
The U.S. Food and Drug Administration (FDA) has granted alixorexton Breakthrough Therapy designation for the treatment of NT1 and Orphan Drug Designation (ODD) for the treatment of IH. The European Commission has granted ODD to alixorexton for the treatment of narcolepsy.
About Alkermes plc
Alkermes plc (Nasdaq: ALKS), a mid-cap growth and value equity, is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia, bipolar I disorder and narcolepsy.
Alkermes’ pipeline includes late-stage clinical candidates in development for narcolepsy and idiopathic hypersomnia, and orexin 2 receptor agonists in early clinical development for other neurological disorders, including attention-deficit hyperactivity disorder (ADHD) and fatigue associated with multiple sclerosis and Parkinson’s disease. Headquartered in Ireland, Alkermes also has a corporate office and research and development center in Massachusetts and a manufacturing facility in Ohio.