Abstract Introduction Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness, cataplexy, sleep-related hallucinations, sleep paralysis, and disturbed nighttime sleep. Patients also often report cognitive impairment and fatigue, which remain inadequately addressed by current therapies. We describe the effects of alixorexton, an investigational, oral, highly selective orexin 2 receptor agonist on disease severity, cognition, and fatigue in patients with NT1. Methods Vibrance-1 (NCT06358950) was a randomized, placebo-controlled phase 2 study that assessed the efficacy, including patient-reported outcomes (PROs), and safety of alixorexton in adult patients with NT1. Patients were randomized 1:1:1:1 to placebo or once-daily alixorexton (4, 6, or 8mg) in the 6-week double-blind treatment period, followed by treatment with alixorexton in an optional 7-week open-label extension (OLE). PROs, including Narcolepsy Severity Scale-Clinical Trials (NSS-CT), British Columbia Cognitive Complaints Inventory (BC-CCI), PROMIS-Fatigue Short-form 6a (PROMIS-Fatigue), and Patient Global Impression of Severity (PGI-S) Cognition and Fatigue items were exploratory outcomes. Statistical testing for PRO endpoints was not adjusted for multiplicity; all p-values were nominal. Results Patients received placebo (n=23) or alixorexton (4mg, n=23; 6mg, n=22; 8mg, n=24); 88 completed OLE treatment. For all alixorexton-treated groups, improvements from baseline on NSS-CT score were observed at Week (Wk) 6 (4mg, −9.1; 6mg, −12.4; 8mg, −11.0; all p 0.001 versus placebo), Wk8, and Wk12. Improvements from baseline on BC-CCI were seen for all alixorexton-treated groups at Wk2, Wk6 (least squares mean LSM change from baseline at Wk6: 4mg, −3.5; 6mg, −3.7; 8mg, −4.8; all p 0.0001 versus placebo) and through Wk13. Similarly, most alixorexton-treated patients reported mild/no cognitive impairments at Wk6 on PGI-S Cognition. All alixorexton groups reported improved scores on PROMIS-Fatigue at Wk2, which sustained through Wk6 (LSM change from baseline at Wk6: 4mg, −8.7; 6mg, −12.4; 8mg, −12.9; all p 0.01 versus placebo) and through Wk13. A similar trend was seen on PGI-S Fatigue, with most alixorexton-treated patients reporting reduced fatigue severity from baseline at Wk6, and through Wk13. Conclusion In the phase 2 Vibrance-1 trial, alixorexton demonstrated nominally significant, clinically meaningful improvements in PROs assessing disease severity, cognitive impairment and fatigue in patients with NT1 at Wk6 that were sustained through 12-13 weeks. Support (if any) Alkermes, Inc.
Dauvilliers et al. (Fri,) studied this question.