Small Molecule · ALKS 2680

Alixorexton

Phase 3Alkermes plc (ALKS)
  • Breakthrough Therapy
  • Orphan Drug

Alixorexton (ALKS 2680) is an oral, once-daily, highly selective orexin receptor 2 (OX2R/HCRTR2) agonist developed by Alkermes to address the orexin (hypocretin) deficiency underlying narcolepsy. By selectively activating OX2R on wake-promoting neurons it enhances wakefulness and reduces excessive daytime sleepiness. It is the lead asset in Alkermes' orexin franchise and is being developed across hypersomnolence disorders: narcolepsy type 1 (NT1, lead indication; Phase 3), narcolepsy type 2 (NT2; Phase 3) and idiopathic hypersomnia (IH; Phase 2).

Also known as: ALKS 2680, Alixorexton, 2648347-56-0

Data current as of

Modality
Small molecule
Chemical class
macrocycle, sulfonamide
Chemistry
Single enantiomer
Mechanism
OX2R agonist
Highest phase
Phase 3
Lead indication
Narcolepsy
Developer
Alkermes plc (ALKS)
Designations
Breakthrough Therapy, Orphan Drug
Trials
4 tracked · 2 recruiting · 114 sites
Next catalyst
2H 2026 — Topline data (Narcolepsy)

Mechanism of action

Alixorexton is a potent, orally bioavailable, blood-brain-barrier-permeable, highly selective orexin receptor 2 (OX2R/HCRTR2) agonist with minimal activity at OX1R. By selectively activating OX2R on wake-promoting hypothalamic and brainstem neurons, it restores deficient orexin signaling in narcolepsy, augmenting downstream monoaminergic and cholinergic wake-promoting pathways to increase wakefulness and reduce excessive daytime sleepiness.

TargetActionAffinity
OX2RprimaryHCRTR2Agonist—ⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
Alixorexton oral tablet
Once-daily oral doses of 4 mg, 6 mg, and 8 mg evaluated in the Vibrance-1 Phase 2 study (1 mg, 3 mg, 8 mg in Phase 1b)
OralOnce daily—

Development timeline

Phase 3Apr 2026 – May 2027
  1. UpcomingPhase 3 Brilliance NT1 (Study 302) topline anticipated, evaluating the primary MWT endpoint at Week 12 in narcolepsy type 1.Narcolepsy
  2. UpcomingVibrance-3 Phase 2 topline results anticipated in idiopathic hypersomnia (primary endpoint ESS at Week 8).Narcolepsy
  3. Alkermes initiated the Phase 3 Brilliance program evaluating alixorexton in narcolepsy type 1 and type 2: three 12-week, randomized, double-blind, placebo-controlled studies (Brilliance NT1 Study 302 NCT07455383 and Study 304 NCT07540897; Brilliance NT2 Study 303 NCT07502443).Narcolepsy↗
Phase 2May 2025 – Dec 2026
  1. UpcomingVibrance-3 Phase 2 topline results anticipated in idiopathic hypersomnia (primary endpoint: change in Epworth Sleepiness Scale at Week 8).Idiopathic Hypersomnia
  2. U.S. FDA granted orphan drug designation to alixorexton for the treatment of idiopathic hypersomnia (the European Commission separately granted orphan designation for narcolepsy).Idiopathic Hypersomnia↗
  3. FDA granted Breakthrough Therapy designation to alixorexton for the treatment of narcolepsy type 1, based on Phase 1 and Phase 2 data including the positive Vibrance-1 study.Narcolepsy↗
  4. metVibrance-2 Phase 2 study in narcolepsy type 2 met the primary MWT endpoint at 14 mg and 18 mg, with ESS significant at 18 mg (p<0.05 adjusted).Narcolepsy↗
  5. metVibrance-1 Phase 2 study in narcolepsy type 1 met the primary MWT endpoint across all doses (4, 6, 8 mg) with statistically significant, dose-dependent improvements in wakefulness vs placebo.Narcolepsy↗
  6. Vibrance-3 Phase 2 study in idiopathic hypersomnia (NCT06843590) initiated (study start 22 May 2025): a randomized, double-blind, parallel-group, dose-range-finding study of once-daily alixorexton (10, 14, 18 mg) vs placebo over 8 weeks, primary endpoint change in ESS at Week 8.Idiopathic Hypersomnia

Alixorexton for Narcolepsy

Phase 3ActiveNarcolepsy indication →

Alixorexton (ALKS 2680) is in Phase 3 development for narcolepsy type 1 (lead indication). Following positive Phase 2 results from the Vibrance-1 study in NT1 (NCT06358950; all doses met the primary MWT endpoint), the FDA granted Breakthrough Therapy designation for NT1 on 2026-01-06. Alkermes initiated the global Phase 3 Brilliance program (three 12-week studies across NT1 and NT2) on 2026-04-06. The positive Vibrance-2 Phase 2 study in NT2 (NCT06555783) supports the NT2 Phase 3 study, and Vibrance-3 in idiopathic hypersomnia (NCT06843590) is ongoing in Phase 2. Alixorexton also holds U.S. orphan drug designation for idiopathic hypersomnia and EU orphan drug designation for narcolepsy.

Readouts

  • May 2027AnticipatedTopline dataNCT07455383

    Phase 3 Brilliance NT1 (Study 302) topline anticipated, evaluating the primary MWT endpoint at Week 12 in narcolepsy type 1.

  • 2H 2026AnticipatedTopline dataNCT06843590

    Vibrance-3 Phase 2 topline results anticipated in idiopathic hypersomnia (primary endpoint ESS at Week 8).

  • 2025-11-12ReportedTopline datametNCT06555783

    Vibrance-2 Phase 2 study in narcolepsy type 2 met the primary MWT endpoint at 14 mg and 18 mg, with ESS significant at 18 mg (p<0.05 adjusted). ↗

  • 2025-07-09ReportedTopline datametNCT06358950

    Vibrance-1 Phase 2 study in narcolepsy type 1 met the primary MWT endpoint across all doses (4, 6, 8 mg) with statistically significant, dose-dependent improvements in wakefulness vs placebo. ↗

Alixorexton for Idiopathic Hypersomnia

Phase 2RecruitingIdiopathic Hypersomnia indication →

Alixorexton (ALKS 2680), an oral, once-daily, selective OX2R agonist, is in Phase 2 development for idiopathic hypersomnia (IH) via the Vibrance-3 study (NCT06843590), a randomized, double-blind, parallel-group, dose-range-finding trial. Approximately 96 adults with IH (diagnosed per ICSD-3-TR) are randomized 1:1:1:1 to placebo or alixorexton 10, 14, or 18 mg once daily for 8 weeks following a 2-week washout; the primary endpoint is change in Epworth Sleepiness Scale (ESS) from baseline to Week 8 and the key secondary is change in the Idiopathic Hypersomnia Severity Scale (IHSS). The study started 22 May 2025 and is recruiting, with estimated primary completion in November 2026. The U.S. FDA granted alixorexton orphan drug designation for IH (announced 15 June 2026). IH is a non-lead indication within Alkermes' orexin franchise (narcolepsy type 1 is the lead, now in Phase 3).

Readouts

  • 2H 2026AnticipatedTopline dataNCT06843590

    Vibrance-3 Phase 2 topline results anticipated in idiopathic hypersomnia (primary endpoint: change in Epworth Sleepiness Scale at Week 8).

Clinical trials

NCT07455383ALKS 2680-302Phase 3Recruitingn=150

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ALKS 2680 in Adults With Narcolepsy Type 1 (Brilliance NT1 - 302)

Started Apr 2026· Primary completion May 2027· 📍 17 sites across 2 countries (United States, Canada)

NCT06843590ALKS 2680-203Phase 2Recruitingn=126

A Phase 2, Randomized, Parallel-Group, Double-Blind, Dose-Range-Finding Study to Evaluate the Safety and Efficacy of ALKS 2680 in Subjects With Idiopathic Hypersomnia (Vibrance-3)

Started May 2025· Primary completion Nov 2026· 📍 50 sites across 8 countries (United States, Spain, Australia, France)

NCT06555783ALKS 2680-202Phase 2Completedn=93

A Phase 2, Parallel-Group, Dose-Range-Finding Study With Randomized Double-Blind Treatment and Open-Label Periods to Evaluate the Safety and Efficacy of ALKS 2680 in Subjects With Narcolepsy Type 2 (Vibrance-2)

Started Jul 2024· Primary completion Nov 2025· 📍 47 sites across 8 countries (United States, Italy, Spain, Belgium)

metsecondaryChange in Epworth Sleepiness Scale (ESS) from baseline to Week 8 — Clinically meaningful reductions in excessive daytime sleepiness across all doses; statistical significance reached at 18 mg. (18 mg P<0.05 (adjusted for multiplicity))

ESS achieved statistical significance at the 18 mg dose (p<0.05 adjusted), with clinically meaningful improvements in daytime sleepiness across all doses vs placebo.

metprimaryChange in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT) from baseline to Week 8 — Clinically meaningful improvements in MSL vs placebo across all doses (10, 14, 18 mg); statistical significance reached at 14 mg and 18 mg. (14 mg and 18 mg P<0.05 (adjusted for multiplicity))

Met the primary MWT endpoint at the 14 mg and 18 mg doses (p<0.05 adjusted), with clinically meaningful improvements in wakefulness across all doses vs placebo over 8 weeks.

NCT06358950ALKS 2680-201Phase 2Completedn=92

A Phase 2, Parallel-Group, Dose-Range-Finding Study With Randomized Double-Blind Treatment and Open-Label Periods to Evaluate the Safety and Efficacy of ALKS 2680 in Subjects With Narcolepsy Type 1 (Vibrance-1)

Started Mar 2024· Primary completion Jun 2025

metprimaryChange in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT) from baseline to Week 6 — LSM difference from placebo: 4 mg +22.2 min; 6 mg +24.1 min; 8 mg +26.0 min. All active dose groups reached normative wakefulness (observed MSL ~24, 26, and 28 min vs ~3 min at baseline). (4 mg P=0.01; 6 mg P<0.0001; 8 mg P<0.0001)

Met the primary endpoint across all doses with statistically significant, clinically meaningful, dose-dependent improvements in wakefulness on MWT vs placebo, sustained over 6 weeks.

metsecondaryChange in Epworth Sleepiness Scale (ESS) at Week 6 — LSM difference from placebo: 4 mg -6.4; 6 mg -8.7; 8 mg -8.3 (4 mg P=0.01; 6 mg P<0.0001; 8 mg P<0.0001)

Clinically meaningful reductions in excessive daytime sleepiness on the ESS across all doses vs placebo at Week 6.

Conference coverage

ALKS 2680 appears in 4 CNS Pulse conference abstracts:

Related compounds

Other OX2R compounds

More from Alkermes plc

Identifiers

Sources

  1. A Study to Evaluate the Efficacy and Safety of ALKS 2680 in Adults With Narcolepsy Type 1 (Brilliance NT1 - 302) — ClinicalTrials.gov
  2. A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Idiopathic Hypersomnia (Vibrance-3, ALKS 2680-203) — ClinicalTrials.gov
  3. A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Narcolepsy Type 1 (Vibrance-1, ALKS 2680-201) — ClinicalTrials.gov
  4. A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Narcolepsy Type 2 (Vibrance-2, ALKS 2680-202) — ClinicalTrials.gov
  5. Alixorexton for Narcolepsy Type 1: New Detailed Positive Phase 2 Results From Vibrance-1 Study — Psychiatric Times
  6. Alixorexton Granted Breakthrough Therapy Designation by U.S. FDA for the Treatment of Narcolepsy Type 1 — Alkermes plc / Business Wire
  7. Alkermes Announces Initiation of Phase 3 Brilliance Studies Evaluating Alixorexton for the Treatment of Narcolepsy Type 1 and Type 2 — Alkermes plc
  8. Alkermes Announces Orphan Drug Designations for Alixorexton in the U.S. and Europe — Alkermes plc / BioSpace
  9. Alkermes Announces Positive Topline Results From Vibrance-1 Phase 2 Study of Once-Daily Alixorexton in Patients With Narcolepsy Type 1 — Alkermes plc
  10. Alkermes Announces Positive Topline Results From Vibrance-2 Phase 2 Study of Once-Daily Alixorexton in Patients With Narcolepsy Type 2 — Alkermes plc / PR Newswire
  11. Alkermes Presents First Clinical Data for Orexin 2 Receptor Agonist ALKS 2680 at World Sleep Congress — Alkermes plc (via PR Newswire)