Alixorexton for Narcolepsy Type 1: New Detailed Positive Phase 2 Results From Vibrance-1 Study

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Alkermes announced positive results from the Vibrance-1 phase 2 study evaluating alixorexton in participants with narcolepsy type 1 (NT1). According to these results, alixorexton is the first orexin 2 receptor agonist to demonstrate clinically meaningful and statistically significant impact on wakefulness, cognition, and fatigue with once-daily dosing across a range of doses.^1,2

Alixorexton, formerly ALKS 2680, is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in phase 2 development as a once-daily treatment for NT1, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).

The randomized, placebo-controlled, 6-week, double-blind phase 2 study conducted in 92 participants with NT1 demonstrated clinically meaningful and statistically significant improvements in wakefulness, cognition, and fatigue. These effects were sustained over the 6-week treatment period. Additionally, alixorexton was generally well tolerated at all doses tested: 4 mg, 6 mg, and 8 mg. The data were presented in 3 oral presentations at World Sleep Congress on September 5-10, 2025, in Singapore.

"The detailed Vibrance-1 dataset presented at World Sleep highlights the robust efficacy of once-daily alixorexton in improving wakefulness and reducing excessive daytime sleepiness in patients with NT1, along with its generally well tolerated safety profile. The improvements in patient-reported outcomes, especially those related to fatigue and cognitive function, suggest that alixorexton may offer meaningful relief across a spectrum of symptoms that impact patients," said Giuseppe Plazzi, MD, PhD, a neurologist, director of the Narcolepsy Center at the IRCCS of the Neurological Sciences of Bologna, and professor of childhood neuropsychiatry at the University of Modena and Reggio Emilia. "These data underscore alixorexton's potential to be an important new treatment option for NT1 and to reduce the broader disease burden of this complex neurological disorder."

Once-daily alixorexton met the primary endpoint across all doses tested, demonstrating statistically significant, clinically meaningful, and dose-dependent improvements from baseline compared with placebo in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT) at week 6. Participants had a mean sleep latency of approximately 3 minutes at baseline. All alixorexton dose groups achieved normative wakefulness on the MWT (mean sleep latency ≥20 minutes), with observed mean sleep latency of approximately 24 minutes, 26 minutes, and 28 minutes for the 4, 6, and 8 mg doses, respectively.

Alixorexton also demonstrated robust and clinically meaningful improvements on the key secondary endpoint, which was evaluating change from baseline vs placebo on the Epworth Sleepiness Scale (ESS) at week 6. Participants had a mean ESS score of 18.5 at baseline. Improvements in ESS were sustained in the normal range (a score of ≤10) for all doses tested across all timepoints during the 6-week double-blind treatment period and the subsequent open-label extension period through week 13. On the key secondary endpoint evaluating mean weekly cataplexy rates, alixorexton demonstrated numerical and clinically meaningful improvements across all doses compared with placebo at weeks 5 and 6. Additionally, on the prespecified analysis, alixorexton achieved statistical significance at the 6 mg dose. More than 40% of participants receiving the 6 mg and 8 mg doses achieved 100% reduction in cataplexy during week 6 of the study.

Investigators of Vibrance-1 also included a range of exploratory patient-reported outcome measures. Alixorexton drove statistically significant and clinically meaningful improvements from baseline compared with placebo in disease severity, fatigue, and cognitive impairment. At week 6, most patients receiving alixorexton reported mild narcolepsy severity. Across all timepoints and all dose groups, mean cognitive impairment scores fell within the lowest severity category of "none or minimal" impairment and mean fatigue scores fell into the "normal" range—meaning alixorexton effectively achieved normalization across both cognition and fatigue.

As to safety and tolerability, alixorexton was generally well tolerated across all doses tested throughout the 6-week, randomized, double-blind treatment period. No serious treatment-emergent adverse events were reported. There were no clinically meaningful changes in hepatic and renal parameters, vital signs, ECGs, or ophthalmic exams in the group treated with alixorexton. Most treatment-emergent adverse events were mild to moderate in severity, with the most common being pollakiuria, insomnia, salivary hypersecretion, urinary urgency, and blurred vision. Events of insomnia largely occurred and resolved within the first week of dosing. Events of blurred vision were mostly mild and intermittent and largely occurred and resolved within the first 3 days of treatment.

More than 95% of participants from the 6-week double-blind portion of the trial entered into the 7-week open-label extension.

"As we seek to unlock a new era of innovation in neuroscience, the compelling results from Vibrance-1 underscore the strength of Alkermes' orexin program. These data represent a significant new contribution to the evidence base supporting the utility of orexin 2 receptor agonists in central disorders of hypersomnolence and support exploration of the broader therapeutic potential of the class across a range of psychiatric and neurological conditions," said Richard Pops, chief executive officer of Alkermes. "We believe orexin-targeted therapeutics represent a significant opportunity for growth. We look forward to advancing alixorexton into phase 3 as soon as possible, and ALKS 4510 and ALKS 7290 into first-in-human studies this year, with the goal of delivering novel and differentiated new treatments across a broad range of disorders."

Based on these results, Alkermes intends to initiate a global phase 3 program for alixorexton in Q1 of 2026. Vibrance-2, a phase 2 study evaluating the safety and efficacy of alixorexton in adults with NT2 (NCT06555783), recently completed enrollment. Vibrance-3, a phase 2 study evaluating the safety and efficacy of alixorexton in adults with IH (NCT06843590), is currently enrolling.

References

1. Alkermes presents detailed positive results from Vibrance-1 phase 2 study of alixorexton in patients with narcolepsy type 1 at World Sleep Congress 2025. News release. September 8, 2025. Accessed September 9, 2025. https://investor.alkermes.com/news-releases/news-release-details/alkermes-presents-detailed-positive-results-vibrance-1-phase-2

2. Dennis M. Alkermes, Takeda detail results underpinning orexin drugs for narcolepsy. First Word Pharma. September 8, 2025. Accessed September 9, 2025. https://firstwordpharma.com/story/5995609