Jazz Submits NDA for JZP-258 for Cataplexy, Excessive Daytime Sleepiness

Robert Iannone, MD, MSCE

Jazz Pharmaceuticals has submitted a new drug application (NDA) to the FDA for JZP-258, its novel oxybate agent, as an investigational treatment for cataplexy and excessive daytime sleepiness (EDS) in those ages 7 years and older with narcolepsy.¹

The candidate product is supported by a phase 3 global, double-blind, placebo-controlled study, from which the data compiled have shown that JZP-258 demonstrated highly significant differences compared to placebo as measured by the change in the weekly number of cataplexy attacks and the change in Epworth Sleepiness Scale (ESS) score, the primary and secondary end points, respectively.²

Additionally, patients who were randomized to JZP-258 showed clinically meaningful conservation of efficacy, while those randomized to placebo experienced a statistically significant worsening for both ESS and cataplexy end points.

"Narcolepsy is a chronic disorder, for which lifelong therapy may be clinically indicated, and is associated with an increased risk of comorbid conditions, including hypertension and cardiovascular disease," Robert Iannone, MD, MSCE, executive vice president, research and development, Jazz Pharmaceuticals, said in a statement. "Jazz is committed to addressing unmet needs in sleep medicine, which includes working for nearly a decade to develop a novel oxybate formulation with a significant reduction in sodium."

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Jed Black, MD, senior vice president, Sleep and CNS Medicine, Jazz Pharmaceuticals, and adjunct professor, Center for Sleep Sciences and Medicine, Stanford University Medical Center, previously detailed that the company’s novel oxybate product candidate has “92% less sodium than sodium oxybate.” This, Jazz stated, “could allow patients to achieve a daily sodium intake target of 2300 mg, and ideally 1500 mg, as set by the American Heart Association.”

The treatment has been shown, in data presented at World Sleep 2019, to be efficacious and safe in treating patients with narcolepsy who have cataplexy. 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. Data suggested 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).³

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 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).

Lead investigator Richard K. Bogan, MD, FCCP, FAASM, associate clinical professor, University of South Carolina School of Medicine, and chief medical officer, SleepMed, said in a statement in September 2019 that "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.”

"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," he said.

REFERENCES

1. Jazz Pharmaceuticals Submits New Drug Application for JZP-258 for Cataplexy and Excessive Daytime Sleepiness Associated with Narcolepsy [press release]. Dublin, Ireland: Jazz Pharmaceuticals; Published January 22, 2020. investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-submits-new-drug-application-jzp-258. Accessed January 22, 2020.

2. Jazz Pharmaceuticals Announces Positive Top-line Results from Phase 3 Study of JZP-258 in Adult Narcolepsy Patients with Cataplexy and Excessive Daytime Sleepiness [press release]. Dublin, Ireland: Jazz Pharmaceuticals; Published March 26, 2019. prnmedia.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-positive-top-line-results-from-phase-3-study-of-jzp-258-in-adult-narcolepsy-patients-with-cataplexy-and-excessive-daytime-sleepiness-300819008.html. Accessed January 22, 2020.