Improvement in Patient-reported Disease Severity, Cognitive Functioning, and Fatigue in Patients With Narcolepsy Type One Treated With Alixorexton, an Orexin Two Receptor Agonist, in the Vibrance-1 Phase Two Study
Yves Dauvilliers1, Ronald Grunstein2, Emmanuel Mignot3, Gerrit Lammers4, David Plante5, Erik Buntinx6, Rafael del Rio Villegas7, Hailu Chen8, Craig Hopkinson8, Bhaskar Rege8, Julie Himes8, Michael Doane8, Giuseppe Plazzi9
1Hopital Gui De Chaulliac, 2Woolcock Institute of Medical Research, Macquarie University, 3Stanford University School of Medicine, 4Leiden University Medical Center, 5University of Wisconsin-Madison, School of Medicine and Public Health, 6ANIMA Research, 7Neurophysiology and Sleep Disorders Unit, Vithas Madrid Hospitals, 8Alkermes, Inc., 9IRCCS Istituto delle Scienze Neurologiche di Bologna
Objective:
Describe the effect of once-daily alixorexton, an investigational, oral, highly selective orexin 2 receptor agonist, versus placebo on disease severity, cognition, and fatigue in patients with narcolepsy type 1 (NT1).
Background:
Beyond excessive daytime sleepiness (EDS), cataplexy, sleep-related hallucinations, sleep paralysis, and disturbed nighttime sleep, symptoms of NT1 include cognitive impairment and fatigue, which collectively are not adequately addressed by available therapies.
Design/Methods:
Efficacy, including patient-reported outcomes (PROs), and safety of alixorexton were assessed in a randomized, placebo-controlled phase 2 study called Vibrance-1 (NCT06358950). Adult patients with NT1 received placebo or once-daily alixorexton (4, 6, or 8mg) for 6 weeks of double-blind treatment. An optional 7-week open-label extension (OLE) followed, in which patients received 6mg alixorexton (dose adjustments were permitted during the first 2 weeks). Exploratory PROs included Narcolepsy Severity Scale-Clinical Trials (NSS-CT), British Columbia Cognitive Complaints Inventory (BC-CCI), Patient Global Impression of Severity (PGI-S) for Cognition, PROMIS-Fatigue Short-form 6a (PROMIS-Fatigue), and PGI-S for Fatigue.
Results:
Patients were randomized to placebo (n=23) or alixorexton (4mg, n=23; 6mg, n=22; 8mg, n=24); 88 completed OLE treatment. For all alixorexton groups, improvements from baseline on NSS-CT were seen at Week (Wk) 6 (4mg, −9.1; 6mg, −12.4; 8mg, −11.0; all nominal p<0.001 versus placebo), Wk8, and Wk12. Improvements on BC-CCI from baseline were seen at Wk2, Wk6 (all nominal p<0.0001 versus placebo at Wk6) and through the OLE for all alixorexton groups. A similar trend was seen on PGI-S Cognition. All alixorexton groups reported improved scores on PROMIS-Fatigue at Wk2 that were sustained through Wk6 (all nominal p<0.01 versus placebo) and the OLE. A similar trend was seen on PGI-S Fatigue.
Conclusions:
In patients with NT1, once-daily alixorexton demonstrated nominally significant, clinically meaningful improvements in patient-reported disease severity, cognitive impairment and fatigue, with improvements sustained through 12-13 weeks.
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