JZP-258 Granted Orphan Designation in Narcolepsy

The calcium, magnesium, potassium, and sodium oxybates oral solution, marketed as Xywav, is currently also under review for the treatment of idiopathic hypersomnia, with an FDA decision expected by August 12, 2021.

Jazz Pharmaceuticals has announced that the FDA has granted orphan drug exclusivity to its calcium, magnesium, potassium, and sodium oxybates oral solution, marketed as Xywav, for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.1

The orphan drug designation program is intended to progress the development of drugs that treat a condition affecting 200,000 or fewer patients in the US annually. The 7-year market exclusivity for this agent, previously known as JZP-258, began on July 21, 2020, the date it received FDA approval.

The FDA published an accompanying summary of clinical superiority findings for the oral solution in the treatment of cataplexy or EDS associated with narcolepsy, specifically citing its performance compared to the company’s other agent, sodium oxybate (Xyrem), in providing a better safety profile.2 The FDA's summary also noted that "the differences in the sodium content of the 2 products at the recommended doses will be clinically meaningful in reducing cardiovascular morbidity in a substantial proportion of patients for whom the drug is indicated."

The agent, according to Jazz, is an oxybate product with a unique composition of cations that result in a significant reduction in sodium—approximately 1000 to 1500 mg/night, or 92%—than sodium oxybate at the recommended dosage range of 6 to 9 g.

"We are pleased that FDA has recognized the greater safety of Xywav by virtue of the greatly reduced chronic sodium burden. This action is consistent with FDA's long-established position on the benefits of reducing daily sodium intake," Robert Iannone, MD, MSCE, executive vice president, research and development, and chief medical officer, Jazz Pharmaceuticals, said in a statement. "As a long-time leader in sleep medicine, we are well-aware of the many challenges facing patients living with narcolepsy, including the greater risk of cardiometabolic comorbidities, including obesity, hypertension, diabetes, and hypercholesterolemia.”

“We are encouraged that FDA recognized the benefits of reducing sodium in a chronic medication for these patients. We advanced low-sodium Xywav from concept to commercial availability, demonstrating Jazz's maturing capabilities and delivering a much-needed medicine for patients in critical need,” Iannone added.

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In February 2021, Jazz announced that its supplemental new drug application (sNDA) for the combination agent in the treatment of idiopathic hypersomnia was accepted by the FDA for review.3 The therapy won a fast track designation from the FDA in September 2020 for this indication, and in December 2020 was granted a rolling submission, allowing for the submission of portions of the application as completed. Jazz stated that it plans to bring JZP-258 to patients in the fourth quarter of 2021, pending its potential approval. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of August 12, 2021.

Currently, there are no approved agents for the treatment of idiopathic hypersomnia, with the majority of physicians turning to off-label use of wake-promoting therapies with effectiveness in those with narcolepsy to help address the sleepiness issues.4 Jazz noted in its release at the time that data from insurance claims suggest that the prevalence of idiopathic hypersomnia includes more than 37,000 adults, but it is likely that many more remain undiagnosed.3

Positive topline data from a phase 3 study (NCT03533114) of the investigational use of the calcium, magnesium, potassium, and sodium oxybates oral solution were announced in October 2020, and suggest that Jazz product is effective and safe for adult patients with idiopathic hypersomnia. The double-blind, multicenter, randomized clinical trial featured patients who had EDS associated with their idiopathic hypersomnia, and all of those treated with the agent experienced clinically meaningful improvements in Epworth Sleepiness Scale (ESS) scores—the primary end point—during the open-label titration period. Both the primary and the key secondary end points—Patient Global Impression of Change (PGIC) and Idiopathic Hypersomnia Severity Scale (IHSS)—were measured during the randomized withdrawal portion of the study. That section included 115 patients, and those given the oxybates combination reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. As well, highly statistically significant worsening was observed for those administered placebo in comparison with the agent for ESS (P <.0001), PGIC (<.0001), and IHSS (P <.0001).3

REFERENCES
1. Jazz Pharmaceuticals Announces Orphan Drug Exclusivity for Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution. News release. Jazz Pharmaceuticals. June 25, 2021. Accessed June 25, 2021. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-orphan-drug-exclusivity-xywavtm
2. Clinical Superiority Findings. FDA. Updated June 24, 2021. Accessed June 25, 2021. https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/clinical-superiority-findings
3. Jazz Pharmaceuticals Completes Submission of Supplemental New Drug Application for Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution for Idiopathic Hypersomnia. News release. Jazz Pharmacueticals. February 16, 2021. Accessed June 25, 2021. https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-completes-submission-of-supplemental-new-drug-application-for-xywav-calcium-magnesium-potassium-and-sodium-oxybates-oral-solution-for-idiopathic-hypersomnia-301228862.html
4. About Treatment. Hypersomnia Foundation website. Revised February 2021. Accessed June 25, 2021. hypersomniafoundation.org/treatment.