Jazz Pharmaceuticals plc enrolled the first patient in a phase III trial of JZP-258, a follow-on to its banner drug for narcolepsy symptoms, Xyrem (sodium oxybate). With 90 percent less sodium than Xyrem, the candidate is just one piece of the Dublin-based company's multifaceted defense of its substantial share of the narcolepsy therapy market. Xyrem accounted for three-quarters of Jazz's 2016 sales.

Should its trial of '258 succeed, the company expects to file an FDA new drug application seeking approval to market it for the treatment for cataplexy and excessive daytime sleepiness (EDS) in adult narcolepsy patients in 2019.

JZP-258 is one of two candidates the company is evaluating for cataplexy and EDS. The other is JZP-507. Both candidates contain less sodium than Xyrem, with '258 cutting the sodium content by 90 percent and '507 cutting it by 50 percent.

"We believe that reducing sodium intake in narcolepsy patients is a clinically meaningful goal as patients with narcolepsy are at risk for high sodium intake-related consequences, including hypertension and other cardiovascular diseases," said Karen Smith, Jazz's global head of research and development and chief medical officer.

Xyrem is the only FDA-approved treatment for narcolepsy with cataplexy and EDS. At the highest approved dose of 9 grams per night, it contains 1,640 mg of sodium, exceeding the 1,500 mg of sodium per day that the American Heart Association recommends as part of an ideal diet for most adults. Nutritional guidelines released by the U.S. Office of Disease Prevention and Health Promotion in January 2016 are more permissive, recommending that people over the age of 14 years consume less than 2,300 mg of sodium per day. JZP-258 contains a mixture of oxybate salts, resulting in 90 percent less sodium content than Xyrem.

Jazz's double-blind, placebo-controlled, randomized-withdrawal study of '258 is expected to enroll about 185 patients at centers across the U.S. and the EU in order to randomize about 130 patients. Its primary endpoint is change in weekly number of cataplexy attacks. Change in patients' Epworth Sleepiness Scale score will also be measured as a secondary endpoint. According to ClinicalTrials.gov, its estimated completion date is in November 2018.

In a pilot study, JZP-507, the other lower-sodium candidate Jazz is investigating, has demonstrated bioequivalence to Xyrem with a 50 percent reduction in sodium content. The company anticipates submitting an NDA to the FDA for it by the first quarter of 2018.

FDA-approved in July 2002, with EMA approval following in October 2005, Xyrem's global net sales have continued to climb steadily, reaching about $1.1 billion in 2016. But creeping threats to that prosperity continue to advance. Seven companies have so far sent Jazz notices that they had filed abbreviated new drug applications, or ANDAs, with the FDA seeking approval to market generic versions of Xyrem, including West-Ward Pharmaceuticals Corp., formerly known as Roxane Laboratories Inc.

Provigil (modafinil) is also approved to improve EDS in narcolepsy and is dosed once daily, and other approved psychostimulants (dextroamphetamine and methylphenidate) and antidepressants, which are often prescribed off-label for cataplexy, have also created competition for the company.

In addition, Paris-based Bioprojet SCR's pitolisant, an orally active histamine H3 inverse agonist was approved by the EMA in March 2016 for the treatment of narcolepsy and associated EDS, with or without cataplexy. Avadel Pharmaceuticals plc, formerly Flamel Technologies SA, is another potential competitor. It is using its technology for delivery of a sodium oxybate formulation to eliminate second nighttime dosing for narcolepsy patients. It has an FDA-approved special protocol assessment. On March 7, it said it had begun enrolling and dosing patients in a phase III trial, called Rest-On.

Narcolepsy is rare, with a prevalence of 0.05 percent in the general population. It affects an estimated one in 2,000 people in the U.S., with symptoms typically appearing in early adulthood.

Shares of Jazz (NASDAQ:JAZZ) closed Thursday at $135.85, down $2.97.