Dr Jed BlackJed Black, MD
Positive data from a phase 3 study of JZP-258, an investigational treatment for cataplexy and excessive daytime sleepiness (EDS) in adults with narcolepsy developed by Jazz Pharmaceuticals, have been presented at World Sleep 2019 in Vancouver, Canada.

The study, which featured a randomized-withdrawal design aimed to measure the maintenance of effect for participants who continued on active treatment, as well as worsening for those randomized to placebo. The data revealed a significant increase in the weekly number of cataplexy attacks in those randomized to placebo compared to JZP-258, equally a difference of 2.35 attacks per week (P <.0001).

"We are pleased with the positive results from the Phase 3 study of JZP-258, which demonstrate the efficacy of JZP-258 for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy," said Jed Black, MD, senior vice president, Sleep and Neuroscience, Jazz Pharmaceuticals, and adjunct professor, Stanford University Medical Center, Stanford Center for Sleep Sciences and Medicine, in a statement.

Overall, the study enrolled 201 subjects, of which 134 were randomized to either JZP-258 or placebo. The cohort included patients who were both naïve to and had been treated with sodium oxybate, with or without other antinarcoleptic therapy. Patients went through an up to 12-week optimization and titration period followed by a 2-week stable dose period with JZP-258, and then a 2-week randomization period to treatment or placebo.

During the double-blind withdrawal period, participants randomized to placebo experienced 2.35 (interquartile range [IQR], 0.00 to 11.61) weekly cataplexy attacks compared to 0 (IQR, –0.49 to 1.75) in the JZP-258 group. Additionally, significant increases in median Epworth Sleepiness Scale (ESS) scores were observed in the placebo group (median, 2.0 [IQR, 0.0 to 5.0]) compared to the treatment group (median, 0 [IQR, –1.0 to 1.0]; P <.0001).

Safety was deemed consistent with prior clinical trials of sodium oxybate, with the most common adverse events (AEs), occurring in ≥5% of patients, were headache, nausea and dizziness. Serious AEs were reported by 2 patients—a state of confusion and a visual hallucination after accidental JZP-258 overdose—which were deemed treatment-related.

"These data support the efficacy and overall safety profile of a lower-sodium oxybate formulation for people living with narcolepsy, a chronic condition that may require lifelong therapy,” Black said. “There is broad consensus among health care organizations, like the National Academy of Sciences and American Heart Association, that lowering sodium intake lowers the risk of cardiovascular disease. We believe that JZP-258, if approved, will provide a clinically meaningful benefit to patients prescribed oxybate."

Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change (CGI-C) indicated a greater worsening—measured by the percentage of patients deemed “much worse” or “very much worse”—in those randomized to placebo (PGI-C, 44.6%; CGI-C, 60%) compared to those treated with JZP-258 (PGI-C, 4.3%; CGI-C, 5.9%; P <.0001).

In those who were on a sodium oxybate regimen at entry, cataplexy was held stable with JZP-258 treatment in the open-label treatment titration and optimization period as well as the stable dose period. For those also taking an antidepressant/anticataplectic at study entry, cataplexy was stable during the initial titration, then increased during discontinuation and tapering, and re-stabilized during the stable dose period.

In the patients on an anticataplectic other than sodium oxybate at study entry, cataplexy decreased during initial titration of JZP-258, then increased during taper and discontinuation of the other anticataplectic, and stabilized again during the stable dose period. Those who were treatment-naïve experienced consistent decreases from week 1 through study end.

"It's encouraging to see these positive results from the phase 3 study, as JZP-258 may represent an important and novel product candidate for people with narcolepsy with the benefit of a 92% reduction in sodium compared to sodium oxybate," said lead investigator Richard K. Bogan, MD, FCCP, FAASM, associate clinical professor, University of South Carolina School of Medicine, and chief medical officer, SleepMed, in a statement. "This is important for people living with narcolepsy because narcolepsy is a chronic condition that may require lifelong treatment, and is associated with increased risk of comorbid conditions, including hypertension and cardiovascular disease."
REFERENCE
1. Jazz Pharmaceuticals Presents Positive JZP-258 Phase 3 Study Data at World Sleep 2019 [press release]. Dublin, Ireland: Jazz Pharmaceuticals; Published September 25, 2019. prnewswire.com/news-releases/jazz-pharmaceuticals-presents-positive-jzp-258-phase-3-study-data-at-world-sleep-2019-300925650.html. Accessed September 27, 2019.