DUBLIN—While most people have heard of narcolepsy, idiopathic hypersomnia—a sleep disorder characterized by chronic and disabling daytime sleepiness—might be considered its less-popular sibling. Individuals with this disorder face difficulty staying awake during the day, unplanned lapses into sleep, prolonged nighttime sleep and sleep inertia (difficulty waking with frequent lapses back into sleep), and at present there are no approved treatments.
But that could be changing soon, thanks to progress by Jazz Pharmaceuticals plc. Near the end of 2020, the company shared positive top-line data from its Phase 3 study of Xywav oral solution in adult patients with idiopathic hypersomnia.
“Insurance claims data suggest diagnosed prevalence of idiopathic hypersomnia (IH) is approximately 37,000 patients; however, given known mis- and under-diagnoses of IH, in addition to lack of FDA-approved therapies, the unmet need may be significantly greater,” explains Philip Jochelson, Jazz’s vice president and therapeutic area head of Clinical Development, Neuroscience. “IH is a debilitating illness that can significantly affect social, school and occupational functioning ... We have long understood that sleep disorders can impact every facet of someone’s life; this positive data shows hope for Xywav to be the first FDA-approved treatment option for people living with IH.”
Current treatment options for individuals with idiopathic hypersomnia are largely focused on managing symptoms through the use of stimulants or approved therapies for narcolepsy. Jochelson notes that “Existing therapies are used off-label and have been reported to have limited impact on symptomatology and overall quality of life.”
The Phase 3 Xywav trial was a double-blind, multicenter, placebo-controlled, randomized withdrawal study to assess the safety and efficacy of Xywav for the treatment of idiopathic hypersomnia in adults. Xywav is currently approved for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy. The primary endpoint of the study was the change in Epworth Sleepiness Scale (ESS) from Xywav and placebo over the randomized-withdrawal period, with key secondary endpoints consisting of Patient Global Impression of Change (PGIc) and Idiopathic Hypersomnia Severity Scale (IHSS).
The study included a titration and optimization period of up to 14 weeks, a Xywav stable-dose period of two weeks, followed by a 1:1 randomization to either Xywav or placebo for two weeks. After the treatment period, patients entered a 24-week, open-label safety extension period.
The primary endpoint of ESS and the secondary endpoints of PGIc and IHSS were measured during the randomized withdrawal portion of the trial, which consisted of 115 patients. Participants who received Xywav showed clinically meaningful maintenance of efficacy for ESS, PGIc and IHSS, while patients who received placebo saw highly statistically significant worsenings compared to the Xywav arm for ESS (p-value <0.0001), PGIc (p-value <0.0001) and IHSS (p-value <0.0001).
Xywav’s safety profile in this study was consistent with previous results, with no new safety signals observed.
“We are excited by these compelling results and the magnitude of improvement observed in the study, in particular for people living with idiopathic hypersomnia who currently have no approved treatment option. We are deeply grateful to the patients and investigators who participated in the study, and look forward to working quickly with the FDA to make Xywav available to patients as soon as possible,” said Dr. Robert Iannone, executive vice president of research and development at Jazz Pharmaceuticals. “For more than 15 years, Jazz has been at the forefront of sleep medicine. Our purpose is to innovate to transform the lives of patients and we are committed to bringing new options for people living with serious sleep disorders where there are no or limited treatments available.”
Xywav’s exact mechanism of action is unknown, but it is believed that the drug’s effects are mediated through GABAB actions during sleep at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons. The drug received Fast Track designation from the FDA in September.
According to Jochelson, Jazz intends to submit a supplemental New Drug Application for Xywav in idiopathic hypersomnia as early as Q1 2021.
“We are excited by these compelling results and the magnitude of improvement observed in the study, and we look forward to evaluating the full data,” he adds.