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EFFECTS OF ALIXOREXTON ON PATIENT-REPORTED DISEASE SEVERITY, COGNITIVE FUNCTIONING, AND FATIGUE IN PATIENTS WITH NARCOLEPSY TYPE 1: RESULTS FROM THE PHASE 2 VIBRANCE-1 STUDY

Yves Dauvilliers — Ronald Grunstein2, Emmanuel Mignot3, Gert Lammers4, David Plante5, Erik Buntinx6, Rafael del Río Villegas7, Hailu Chen8, Craig Hopkinson8, Bhaskar Rege8, Julie Himes8, Michael Doane8, Giuseppe Plazzi9 1Sleep–Wake Disorders Centre, Gui de Chauliac Hospital; University of Montpellier, INSERM Institute for Neurosciences of Montpellier, 2Woolcock Institute of Medical Research, Macquarie University; Sydney Health Partners, The University of Sydney, 3Stanford University School of Medicine, 4Leiden University Medical Center; Stichting Epilepsie Instellingen Nederland, Sleep-Wake Centre, 5University of Wisconsin-Madison, School of Medicine and Public Health, 6ANIMA Research, 7Neurophysiology and Sleep Disorders Unit, Vithas Madrid Hospitals; Universidad CEU San Pablo, CEU Universities, Vithas Madrid Hospitals, 8Alkermes, Inc., 9IRCCS Istituto delle Scienze Neurologiche di Bologna; University of Modena and Reggio-Emilia

2026 ASCP Annual Meeting

Background

Narcolepsy type 1 (NT1) is traditionally characterized by excessive daytime sleepiness, cataplexy, sleep-related hallucinations, sleep paralysis, and disturbed nighttime sleep. In addition, cognitive impairment and fatigue are often reported by patients, but these symptoms are not adequately treated with current therapies. The effects of alixorexton, an investigational, oral, highly selective orexin 2 receptor agonist, on disease severity, cognition, and fatigue in patients with NT1 were examined in the phase 2 Vibrance1 study. Methodology: Vibrance-1 (NCT06358950) was a randomized, placebo-controlled phase 2 study that evaluated the efficacy, including patient-reported outcomes (PROs), and safety of alixorexton in adults with NT1. Patients were randomized 1:1:1:1 to receive double-blinded treatment with placebo or once-daily alixorexton (4, 6, or 8 mg) for 6 weeks, followed by 7 weeks of treatment with alixorexton in an optional open-label extension (OLE) period. PROs evaluated as exploratory outcomes included the Narcolepsy Severity Scale-Clinical Trials (NSS-CT), the British Columbia Cognitive Complaints Inventory-Expanded Version (BCCCI-E, which includes items assessing both severity and impact of cognitive impairment), the PROMIS-Fatigue Short-form 6a (PROMIS-Fatigue), the Patient Global Impression of Severity (PGI-S) Cognition item, and the PGI-S Fatigue item. Statistical analyses of the PRO endpoints were not adjusted for multiplicity, thus all p-values are nominal.

Results

A total of 92 patients were randomized and treated with placebo (n=23) or alixorexton (4 mg, n=23; 6 mg, n=22; 8 mg, n=24) during the double-blind treatment period; 88 (96%) patients completed OLE treatment. All alixorexton-treated groups showed improvements from baseline in NSS-CT score at Week 6 (4 mg, −9.1; 6 mg, −12.4; 8 mg, −11.0; all p < 0.001 versus placebo), surpassing the 8-point minimum clinically important difference. Improvements on the NSS were sustained at Week 8 and Week 12. Improvements from baseline on the BC-CCI were observed for all alixorexton-treated groups at Week 2, Week 6 (least squares mean [LSM] change from baseline at Week 6: 4 mg, −3.5; 6 mg, −3.7; 8 mg, −4.8; all p < 0.0001 versus placebo) and through Week 13. Similarly, most patients treated with alixorexton reported mild or no cognitive impairments at Week 6 on PGI-S Cognition. All alixorexton-treated groups showed improved scores on PROMIS-Fatigue at Week 2; these improvements were sustained through Week 6 (LSM change from baseline at Week 6: 4 mg, −8.7; 6 mg, −12.4; 8 mg, −12.9; all p < 0.01 versus placebo) and through Week 13. Scores on PGI-S Fatigue demonstrated a similar trend with most patients treated with alixorexton reporting decreased fatigue severity from baseline at Week 6, and through Week 13.

Importance: Results of the phase 2 Vibrance-1 study showed that patients with NT1 treated with alixorexton achieved nominally significant, clinically meaningful improvements in PRO measures of disease severity, cognitive impairment and fatigue at Week 6. These improvements were sustained through OLE treatment. Funding: Alkermes, Inc.