0724 Safety and Efficacy of the Orexin 2 Receptor Agonist Alixorexton in Patients with Narcolepsy Type 1: The Phase 2 Vibrance-1 Study

Abstract Introduction Alixorexton is a potent, oral, selective orexin 2 receptor agonist being investigated as a treatment for narcolepsy. The phase 2 Vibrance-1 study (NCT06358950) evaluated alixorexton in patients with narcolepsy type 1 (NT1). Methods Adults with NT1 were randomized (1:1:1:1) to receive placebo or once-daily alixorexton (4, 6, or 8mg) in the double-blind period for 6 weeks, followed by alixorexton for 7 weeks in an optional open-label extension (OLE). The primary endpoint was change from baseline to Week (Wk) 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Change from baseline to Wk6 in Epworth Sleepiness Scale (ESS) score and mean weekly cataplexy rate (WCR) at Wk6 were key secondary endpoints. Treatment-emergent adverse events (TEAEs) were collected as a secondary endpoint. P values were adjusted for multiplicity. Results 92 patients were randomized to placebo (n=23) or alixorexton (4mg, n=23; 6mg, n=22; 8mg, n=24); 88 completed OLE treatment. Least squares mean [LSM; 95%CI] change from baseline to Wk6 in MSL versus placebo was 22.2 (17.2, 27.2), 24.1 (19.0, 29.1), and 26.0 (21.0, 31.0) min for 4, 6, and 8mg, respectively (all p≤0.01), with all doses reaching normative levels of wakefulness. Mean ESS score improved at Wk6 (LSM change from baseline versus placebo [95%CI]: 4mg, -6.4 [-9.6, -3.3]; 6mg, -8.7 [-11.9, -5.5]; 8mg, -8.3 [-11.4, -5.2]; p≤0.01 for all doses). Clinically meaningful numerical reductions in mean WCR were observed for all doses at Wk6 (p=0.01 for 6mg versus placebo). Reductions from baseline in ESS and WCR were sustained through Wk13. Most TEAEs were mild to moderate in severity and none were serious. Through Wk6, TEAEs observed in ≥10% of patients treated with alixorexton were pollakiuria, insomnia, salivary hypersecretion, micturition urgency, and blurred vision. Most of these TEAEs that occurred in the OLE were observed in patients transitioning from placebo to alixorexton. Conclusion Alixorexton achieved statistically significant improvements in MWT and ESS and resulted in clinically meaningful reductions in WCR at Wk6 in patients with NT1 at all doses tested. Improvements in ESS and WCR persisted through Wk13. Alixorexton was generally well tolerated. Support (if any) Alkermes, Inc.