Once-Daily Alixorexton Improves Cognition, Fatigue, and Disease Severity in Phase 2 Narcolepsy Type 1 Study

New results from the phase 2 Vibrance-1 study (NCT06358950) showed that alixorexton (Alkermes), an investigational oral and highly selective orexin 2 receptor agonist, was associated with improvements in patient-reported disease severity, cognition, and fatigue in patients with narcolepsy type 1 (NT1).¹

Presented at the 2026 American Academy of Neurology (AAN) Annual Meeting, held April 18–22 in Chicago, the randomized placebo-controlled Vibrance-1 study enrolled 92 adult patients with NT1 who were randomized to receive placebo (n = 23) or alixorexton at doses of 4 mg (n = 23), 6 mg (n = 22), or 8 mg (n = 24) once daily for 6 weeks of double-blind treatment. This was followed by an optional 7-week open-label extension (OLE), during which 88 patients completed treatment and received alixorexton 6 mg daily, with dose adjustments permitted during the first 2 weeks of the extension period.

Previously reported efficacy data from VIBRANCE-1 study demonstrated that alixorexton produced statistically significant, dose-dependent improvements in wakefulness as measured by the Maintenance of Wakefulness Test after 6 weeks of treatment across all doses. These improvements were accompanied by significant reductions in excessive daytime sleepiness, with Epworth Sleepiness Scale scores improving at all doses (P <.0001).²

In the current analyses, presented by Yves Dauvilliers, MD, PhD, director, Sleep Disorders Centre at Gui de Chauliac Hospital in France, improvements from baseline in Narcolepsy Severity Scale–Clinical Trials (NSS-CT) scores were observed across all alixorexton dose groups at week 6, with mean changes of −9.1 (4 mg), −12.4 (6 mg), and −11.0 (8 mg). All comparisons versus placebo at week 6 were nominally significant (P <.001), with improvements also observed at weeks 8 and 12 across groups.

READ MORE: Updated Meta-Analysis Reinforces Short-Term Efficacy of Modafinil for Excessive Daytime Sleepiness in Narcolepsy

“Results from the Vibrance-1 phase 2 study of alixorexton provide a rich and comprehensive dataset that allows us to better understand its treatment effects on core symptoms of narcolepsy type 1. Improvements observed at week 6 across patient-reported measures of disease severity, cognitive functioning and fatigue were sustained through the seven-week open-label extension, supporting the durability of alixorexton’s effects,” Giuseppe Plazzi, MD, PhD, director of the Narcolepsy Center at the IRCCS of the Neurological Sciences of Bologna at the University of Modena and Reggio Emilia, said in a statement.³ “These patient-reported outcomes highlight clinically relevant dimensions of narcolepsy that are often underrecognized, yet central to patients’ daily functioning, and demonstrate alixorexton’s potential to make a meaningful impact for people living with narcolepsy type 1.”

Exploratory patient-reported outcomes suggested improvements in cognition and fatigue. On the British Columbia Cognitive Complaints Inventory (BC-CCI), improvements from baseline were observed as early as week 2 and continued through week 6, with all alixorexton groups showing nominally significant differences versus placebo at week 6 (P <.0001). These improvements were maintained throughout the OLE. A similar pattern was observed for the Patient Global Impression of Severity (PGI-S) for cognition.

Fatigue-related outcomes followed a comparable trajectory. Scores on the PROMIS Fatigue Short Form 6a improved in all alixorexton dose groups by week 2 and were sustained through week 6, with all groups demonstrating nominal statistical significance versus placebo (P <.01). These improvements were also maintained during the OLE. The PGI-S for fatigue showed a similar trend, consistent with reductions in patient-reported fatigue severity over time.

“The breadth and depth of the data generated in the Vibrance-1 study provide strong evidence of alixorexton’s potential to meaningfully impact the lives of patients by addressing multiple elements across the spectrum of disease burden of narcolepsy type 1. Importantly, the differentiated profile observed across patient-reported symptom severity, cognition and fatigue highlights alixorexton’s potential to offer a distinct and clinically relevant approach for patients with narcolepsy,” Craig Hopkinson, MD, chief medical officer and executive vice president, Research & Development at Alkermes, said in a statement.³ “These data provide a strong foundation for our phase 3 program and reinforce our confidence as we enroll the recently initiated Brilliance Studies in narcolepsy type 1 and type 2. We look forward to further characterizing alixorexton’s efficacy and safety profile in these pivotal trials.”

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REFERENCES
1. Dauvilliers Y, Grunstein R, Mignot E, et al. Improvement in Patient-reported Disease Severity, Cognitive Functioning, and Fatigue in Patients With Narcolepsy Type One Treated With Alixorexton, an Orexin Two Receptor Agonist, in the Vibrance-1 Phase Two Study. Presented at: 2026 AAN Annual Meeting; April 18-22; Chicago, Illinois.
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 April 20, 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 to Present Additional Data From Vibrance-1 Phase 2 Study of Alixorexton in Patients with Narcolepsy Type 1 at the American Academy of Neurology (AAN) 2026 Annual Meeting. News release. Alkermes. April 16, 2026. Accessed April 20, 2026. https://investor.alkermes.com/news-releases/news-release-details/alkermes-present-additional-data-vibrance-1-phase-2-study