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).

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.

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.