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SAFETY AND EFFICACY RESULTS FROM THE PHASE 2 VIBRANCE-1 STUDY OF THE OREXIN 2 RECEPTOR AGONIST ALIXOREXTON IN PATIENTS WITH NARCOLEPSY TYPE 1

Giuseppe Plazzi — Ronald Grunstein2, Emmanuel Mignot3, Gert Lammers4, David Plante5, Erik Buntinx6, Rafael del Río Villegas7, Hailu Chen8, Alexandra Lovett8, Craig Hopkinson8, Bhaskar Rege8, Julie Himes8, Yves Dauvilliers9 1IRCCS Istituto delle Scienze Neurologiche di Bologna; University of Modena and ReggioEmilia, 2Woolcock Institute of Medical Research, Macquarie University; Sydney Health Partners, The University of Sydney, 3Stanford Center for Sleep Sciences and Medicine, Stanford University School of Medicine, 4Leiden University Medical Center; Stichting Epilepsie Instellingen Nederland, Sleep-Wake Centre, 5University of Wisconsin School of Medicine and Public Health, 6ANIMA Research, 7Neurophysiology and Sleep Disorders Unit, Vithas Madrid Hospitals, Universidad CEU San Pablo, CEU Universities, 8Alkermes, Inc., 9Sleep–Wake Disorders Centre, , Hopital Gui de Chauliac; University of Montpellier, INSERM Institute for Neurosciences of Montpellier

2026 ASCP Annual Meeting

Background

Narcolepsy type 1 (NT1), a central disorder of hypersomnolence, is characterized by excessive daytime sleepiness, cataplexy, and orexin deficiency. Alixorexton is a potent, oral, selective orexin 2 receptor agonist being investigated as a treatment for narcolepsy. The randomized, phase 2 Vibrance-1 study (NCT06358950) examined the safety and efficacy of alixorexton in patients with NT1. Methodology: In Vibrance-1, adults with NT1 were randomized (1:1:1:1) to receive placebo or once-daily alixorexton (4, 6, or 8 mg) for 6 weeks in the double-blind treatment period, which was followed by 7 weeks of alixorexton treatment in an optional open-label extension (OLE) period. The primary endpoint was change from baseline to Week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Key secondary endpoints were change from baseline to Week 6 in Epworth Sleepiness Scale (ESS) score and mean weekly cataplexy rate (WCR) at Week 6. Safety was assessed via treatment-emergent adverse events (TEAEs), which were collected as a secondary endpoint. P values were adjusted for multiplicity.

Results

A total of 92 patients were randomized to placebo (n=23) or alixorexton (4 mg, n=23; 6 mg, n=22; 8 mg, n=24); 88 (96%) patients completed OLE treatment. Least squares mean [LSM; 95%CI] changes from baseline to Week 6 in MSL versus placebo for the 4, 6, and 8 mg groups were 22.2 (17.2, 27.2), 24.1 (19.0, 29.1), and 26.0 (21.0, 31.0) min, respectively (all p≤0.01); all alixorexton doses achieved normative levels of wakefulness. At Week 6 mean ESS score was improved for all alixorexton doses (LSM change from baseline versus placebo [95% CI]: 4 mg, −6.4 [−9.6, −3.3]; 6 mg, −8.7 [−11.9, −5.5]; 8 mg, −8.3 [−11.4, −5.2]; p≤0.01 for all doses). Additionally, all doses of alixorexton reduced WCR at Week 6, with statistically significant improvement observed at the 6 mg dose (p=0.01 versus placebo). Improvements in ESS and WCR were sustained through Week 13. Most TEAEs were mild to moderate in severity and there were no serious TEAEs. Through Week 6, TEAEs reported in ≥10% of patients who received alixorexton were pollakiuria, insomnia, salivary hypersecretion, micturition urgency, and blurred vision. In the OLE, these TEAEs occurred primarily in patients who switched from placebo to alixorexton.

Conclusions

Alixorexton achieved clinically meaningful and statistically significant improvements in the MWT and ESS, and resulted in clinically meaningful reductions in WCR at Week 6. Improvements observed in ESS and WCR were sustained through Week 13. Alixorexton was generally well tolerated. Funding: Alkermes, Inc.