0585 A four-week randomized, double-blind, placebo-controlled, phase 2 study of mazindol ER in the treatment of narcolepsy

Abstract

Abstract Introduction Mazindol is the first partial orexin 2 receptor agonist and triple monoamine reuptake inhibitor in development for the treatment of narcolepsy. A novel extended release (ER) formulation was developed to allow once-daily dosing and may provide a differentiated treatment option. (ClinicalTrials.gov Identifier: NCT04923594). Methods Study NLS-1021 was a Phase 2, four-week, double-blind, randomized, placebo-controlled study of mazindol ER (NLS-2) for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy type 1 (NT1) or type 2 (NT2). Efficacy, safety, tolerability, and pharmacokinetics were assessed. Adult subjects diagnosed with NT1 or NT2 and washed out of narcolepsy medications at baseline were randomized 1:1 to receive placebo or 2 mg mazindol ER once-daily for one week followed by 3 mg once-daily for three weeks. The primary efficacy endpoint was the change from baseline at Week 4 in excessive daytime sleepiness using the Epworth Sleepiness Scale (ESS). Secondary efficacy endpoints included improvement in weekly cataplexy attacks and overall disease severity as rated by the investigators (Clinician Global Impression of Severity; CGI-S) and patients (Patient Global Impression of Severity; PGI-S). Results Sixty-seven subjects were randomized (n = 33 NLS-2; 34 placebo). The baseline mean [SD] ESS score was 17.9 [2.97] in subjects receiving NLS-2 and 18.0 [3.05] in placebo. NLS-2 met the pre-specified primary endpoint, demonstrating a statistically significant improvement in EDS with a least-squares mean [SE] difference (NLS-2-placebo) of –3.6 [1.33] in the ESS total score at Week 4 (p = 0.0081). Observed mean change from baseline in ESS total score was –7.1 [5.6] for NLS-2 and –3.2 [5.3] for placebo. In NT1 subjects, baseline weekly number of cataplexy episodes was 14.1 [10.8] in subjects receiving NLS-2 (n=11) and 15.0 [10.2] in placebo (n=12). At Week 4, the weekly number of cataplexy episodes was reduced to 4.1 with NLS-2 and to 8.5 with placebo. NLS-2 was generally safe and well-tolerated with no severe or serious adverse events or discontinuations due to adverse events. Conclusion In subjects with narcolepsy, NLS-2 significantly improved EDS and the number of cataplexy attacks compared with placebo. Support (if any) NLS Pharmaceutics