Alixorexton Shows Sustained Wakefulness and Daytime Sleepiness Benefits for Up to Nine Months in Narcolepsy

Alkermes has reported positive interim results from the ongoing long-term extension (LTE) study of alixorexton, showing sustained improvements in wakefulness, excessive daytime sleepiness, cognition, and fatigue in adults with narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). The investigational oral orexin 2 receptor agonist remained generally well tolerated across all evaluated dose levels, supporting its continued development in late-stage clinical trials.

Scientific and Clinical Context

Narcolepsy is a chronic neurological sleep disorder characterized by excessive daytime sleepiness, with many patients also experiencing cognitive impairment, fatigue, and, in NT1, cataplexy. Current treatment options primarily address symptoms rather than the underlying biology.

Alixorexton is an investigational, once-daily, oral, selective orexin 2 receptor (OX2R) agonist that restores wake-promoting signaling by activating the orexin pathway. Because orexin regulates multiple neural circuits involved in maintaining wakefulness, the therapy has the potential to improve symptoms in both orexin-deficient and non-deficient hypersomnolence disorders.

The U.S. Food and Drug Administration has granted alixorexton Breakthrough Therapy designation for NT1 and Orphan Drug Designation for idiopathic hypersomnia (IH), while the European Commission has granted orphan designation for narcolepsy.

Long-Term Extension Study Demonstrates Durable Clinical Benefit

The ongoing open-label LTE study (NCT06767683, ALKS 2680-301) evaluates the long-term safety, tolerability, and durability of alixorexton following completion of the randomized Phase 2 Vibrance-1 study in NT1 (NCT06358950) and Vibrance-2 study in NT2 (NCT06555783). This planned interim analysis included safety data through May 12, 2026, and efficacy assessments collected after 24 weeks in the extension study, representing approximately nine months of total treatment.

Among participants with NT1, approximately 85% of patients completing Vibrance-1 enrolled in the LTE, and nearly 90% remained on treatment at the data cutoff. Across all dose groups, participants achieved normative wakefulness on the Maintenance of Wakefulness Test (MWT), with a mean sleep latency of approximately 29 minutes at week 24. Epworth Sleepiness Scale (ESS) scores remained within the normal range, averaging 7.5, while weekly cataplexy rates continued to improve. Patient-reported outcomes also showed sustained normalization of cognitive function and fatigue scores.

In NT2, approximately 70% of eligible participants entered the LTE, and about 80% remained on treatment. Mean sleep latency improved further to approximately 18 minutes at week 24, while ESS scores remained within the normal range for participants receiving the 14 mg and 18 mg doses. Improvements in cognition and fatigue were also maintained throughout long-term follow-up.

Safety Findings

Alixorexton continued to demonstrate a favorable safety profile across both narcolepsy populations. No serious treatment-emergent adverse events (TEAEs) were reported during the interim analysis, and most adverse events were mild to moderate in severity. In NT1, the most common TEAEs included headache, micturition urgency, pollakiuria, and nasopharyngitis. Among NT2 participants, the most frequently reported adverse events were insomnia, headache, pollakiuria, and upper respiratory tract infection.

Clinical Implications

Yves Dauvilliers, M.D., Ph.D., Professor of Neurology and Physiology and Director of the Sleep-Wake Disorders Center at the University of Montpellier, said the sustained improvements in wakefulness, cognition, and fatigue highlight alixorexton’s potential to address multiple dimensions of narcolepsy beyond excessive daytime sleepiness. He added that the consistency of benefit across both NT1 and NT2 supports the therapy’s potential regardless of narcolepsy subtype.

Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes, said the long-term findings strengthen confidence in the durability of alixorexton’s clinical benefit and its favorable tolerability profile. He noted that the results also support flexible dosing to address the diverse needs of patients with different orexin biology.

Regulatory Path Forward

Alkermes plans to present the LTE findings at an upcoming medical meeting while continuing enrollment in the Phase 3 Brilliance studies evaluating alixorexton in adults with NT1 and NT2. The company is also advancing the Phase 2 Vibrance-3 study in idiopathic hypersomnia, with completion expected later this year. Together, these programs could support the development of a novel orexin-based treatment that offers durable improvements in wakefulness and other clinically important symptoms across central disorders of hypersomnolence.

What This Means for Patients

The long-term extension results suggest that alixorexton may provide sustained relief from excessive daytime sleepiness for people living with narcolepsy type 1 and type 2. Improvements in wakefulness, cognition, and fatigue were maintained for up to nine months, while the treatment remained generally well tolerated. Although these findings are encouraging, alixorexton is still an investigational medicine and must complete ongoing Phase 3 clinical trials before it can be considered for regulatory approval and routine clinical use.

Reference

Alkermes’ Alixorexton Demonstrated Sustained Improvement in Wakefulness in Adults With Narcolepsy Type 1 and Type 2 in Long-Term Extension Study Interim Analysis | Alkermes plc