Effect of Oral JZP-110 (ADX-N05) on Wakefulness and Sleepiness in Adults with Narcolepsy: A Phase 2b Study

Abstract

Study objectives: To evaluate the efficacy and safety of oral JZP-110, a second-generation wake-promoting agent with dopaminergic and noradrenergic activity, for treatment of impaired wakefulness and excessive sleepiness in adults with narcolepsy.

Methods: This was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial conducted at 28 centers in the United States. Patients were adults with narcolepsy who had baseline scores ≥ 10 on the Epworth Sleepiness Scale (ESS) and baseline sleep latency ≤ 10 min on the Maintenance of Wakefulness Test (MWT). Patients received a daily placebo (n = 49) or JZP-110 (n = 44) 150 mg/day weeks 1-4 and 300 mg/day weeks 5-12. Primary efficacy endpoints were change from baseline in average MWT sleep latency, and the Clinical Global Impression-Change (CGI-C); secondary endpoints were change from baseline in ESS score and Patient Global Impression-Change.

Results: Improvements were significantly greater with JZP-110 versus placebo on mean MWT sleep latency (4 w, 9.5 versus 1.4 min, P < 0.0001; 12 w, 12.8 versus 2.1 min, P < 0.0001), percentage of patients with CGI-C improvement (4 w, 80% versus 51%, P = 0.0066; 12 w, 86% versus 38%, P < 0.0001), and mean change in ESS (4 w, -5.6 versus -2.4, P = 0.0038; 12 w, -8.5 versus -2.5, P < 0.0001). Three JZP-110-treated patients (6.8%) discontinued due to adverse events (AEs). The most common AEs with JZP-110 versus placebo were insomnia (23% versus 8%), headache (16% versus 10%), nausea (14% versus 6%), diarrhea (11% versus 6%), decreased appetite (14% versus 0%), and anxiety (11% versus 0%).

Conclusions: At doses of 150-300 mg/day, JZP-110 was well tolerated and significantly improved the ability to stay awake and subjective symptoms of excessive sleepiness in adults with narcolepsy.

Clinical trials registration: Clinicaltrials.gov identifier NCT01681121.

Keywords: JZP-110; excessive sleepiness; narcolepsy; wakefulness.

© 2016 Associated Professional Sleep Societies, LLC.

Figures

Figure 1

Study design.

Figure 2

Patient disposition.

Figure 3

Results of the two primary efficacy endpoints at 12 w. (A) Change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT; average of first four periods). (B) Percentage of patients who were improved on the Clinical Global Impression of Change (CGI-C), defined as scores of “very much improved,” “much improved,” or “minimally improved.” aWeek 12 is an endpoint analysis representing last postbaseline observation carried forward; baseline and week 12: JZP-110 (n = 43); placebo (n = 47). SE, standard error.

Figure 4

Mean change from baseline in sleep latency on each of the individual periods in the Maintenance of Wakefulness Test (MWT) at weeks 4 (A) and 12 (B), and mean difference in change from baseline between JZP-110 and placebo (C). SE, standard error.

Figure 5

Change in Epworth Sleepiness Scale (ESS) scores. (A) Absolute ESS scores at weeks 4 and 12 relative to baseline. The horizontal broken line in A represents the threshold for normal ESS score. (B) Change in score over study duration. SE, standard error.

Figure 6

Percentages of patients who achieved improvement on global impression of change measures at weeks 1, 4, and 12. (A) Patient Global Impression of Change (PGI-C). (B) Clinician Global Impression of Change (CGI-C).