Development of JZP-258, a Low-Sodium Formulation of Oxybate for the Treatment of Cataplexy and Excessive Daytime Sleepiness in Narcolepsy

Narcolepsy is a lifelong neurologic disorder characterized by excessive daytime sleepiness (EDS), cataplexy, disrupted nighttime sleep (DNS), sleep-related hallucinations, and sleep paralysis. Narcolepsy pathophysiology may increase risk of cardiovascular disease (CVD) and cardiometabolic disorders, even among young, apparently healthy patients. Sodium oxybate (SXB) is an AASM standard of care for treatment of cataplexy, EDS, and DNS in narcolepsy. At recommended doses in adults (6–9 g/night), SXB contributes 1100–1640 mg sodium to daily intake. Recommended daily intake (RDI) of sodium is  < 2300 mg/day (ideally  < 1500 mg/day). Reduction in sodium intake is associated with decreased blood pressure and decreased risk of hypertension, CVD, and stroke. In response to the need for oxybate treatment with lower sodium, a new formulation was pursued. Considerations for the new formulation included the same active moiety at the same concentration as SXB, cation concentrations well within RDI guidelines, and appropriate levels to minimize potential adverse effects. Formulations including sodium, potassium, calcium, and magnesium cations were selected. Two formulations of interest were identified, one bioequivalent to SXB with 50% sodium reduction (JZP-507) and one non-bioequivalent (lower Cmax) with 92% sodium reduction (JZP-258). To better address patients’ needs, JZP-258 was selected as the product candidate for development. Efficacy and safety of JZP-258 for the treatment of cataplexy and EDS in patients with narcolepsy were demonstrated in a phase 3 clinical trial (NCT03030599). A New Drug Application has been accepted by FDA for priority review. JZP-258 may represent a new treatment option for patients with narcolepsy.