FDA Accepts Sodium Oxybate Application for Children With Narcolepsy

July 10, 2018

The FDA has accepted a supplemental new drug application for sodium oxybate as a treatment for cataplexy and excessive daytime sleepiness in children with narcolepsy.

Jed Black, MD

The FDA has granted a priority review to a supplemental new drug application for sodium oxybate (Xyrem) as a treatment for cataplexy and excessive daytime sleepiness (EDS) in children with narcolepsy, according to a statement from Jazz Pharmaceuticals, the company developing the drug. The agency will decide on the application by October 27, 2018.

Long-term findings from the phase II/III EXPRESS study for sodium oxybate in pediatric patients were recently presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies. In this study, there were few changes in cataplexy throughout the study, with a median change in weekly cataplexy attacks of 0.0 (range, -2.25 to 4.17). The same was observed for Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) for EDS, with a change from baseline of 0.0 (range, ‑3.0 to 3.0).

"There has been a great deal of interest from the narcolepsy community in understanding the safety and efficacy of Xyrem in pediatric patients. We look forward to the FDA review and the potential for a new Xyrem indication specific to cataplexy and EDS in children and adolescents," Jed Black, MD, senior vice president, Sleep and CNS Medicine at Jazz Pharmaceuticals and adjunct professor, Stanford Center for Sleep Sciences and Medicine, said in a statement. "Jazz continues to strive to address unmet needs within the sleep community."

The EXPRESS study included a 2-week double-blind, placebo controlled initial phase, after which participants entered an open-label safety period for up to 47 weeks. Overall, 96 patients completed the first phase of the study and 79 completed 6 months or more of treatment, with 46 completing the full year. Change in cataplexy was calculated form daily diaries and EDS was assessed at each visit.

Patients enrolled in the study were between the ages of 7 and 16 years. Participants may have been pretreated with off-label sodium oxybate or were sodium oxybate naive prior to study entry. Those who were treatment-naive had their doses titrated to an optimal level. Across pivotal trials in adults, the effective dose for sodium oxybate ranged from 6g to 9g per night in 2 equal divided doses. The dose is typically started at 4.5g per night and titrated up to a maximum of 9g per night. A similar strategy was taken for the pediatric and adolescent population.

At a preplanned interim analysis, a data safety monitoring board recommended discontinuation of the placebo arm, based on the level of efficacy seen with sodium oxybate. Those in the placebo group saw a median increase in cataplexy of 12.7 attacks per week. In the sodium oxybate group, there was an increase of just 0.3 attacks. In the placebo group, 65.6% of patients said their cataplexy was much worse or very much worse by the clinical global impression system. In the sodium oxybate arm, only 17.2% of patients met this criterion.

The safety profile of sodium oxybate was similar in children and adolescents as observed in adults. The most common treatment-emergent adverse events (TEAEs) were enuresis, nausea, vomiting, headache, decreased weight, decreased appetite, nasopharyngitis, and dizziness. There were 2 serious TEAEs in the study—acute psychosis and suicidal ideation. Both events occurred during the titration period and resolved with dose reduction.

"Although the symptoms of narcolepsy typically begin during childhood, there are no cataplexy treatments approved for patients under the age of eighteen," said Black. "Jazz has studied Xyrem extensively in the pediatric population as part of our commitment to addressing unmet needs in sleep medicine."

Sodium oxybate was initially approved by the FDA in 2002. The oral medication, which is a schedule III controlled substance, is indicated for cataplexy and EDS in nacrolepsy.

Plazzi G, Ruoff C, Lecendreux M, et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health. 2018;2(7):483-494.