Medical Technology

First FDA-Approved Hypersomnia Drug Data Published

Lower-sodium oxybate (Xywav, Jazz Pharmaceuticals) results in clinically significant improvement of the symptoms of idiopathic hypersomnia in adults, according to new research.

The results of the phase 3 study that led to US Food and Drug Administration (FDA) approval of the drug in August were published in the January issue of Lancet Neurology.

A total of 37,000 people in the United States have idiopathic hypersomnia, a neurologic sleep disorder characterized by chronic excessive daytime sleepiness.

Other signs include severe sleep inertia and sleep drunkenness. This is defined as persistent difficulty awakening with frequent reentries to sleep, irritability, and confusion along with long, unrefreshing naps and extended, non-restorative nights.

Novel Drug

Lower-sodium oxybate is an innovative product of oxybate that has a unique composition of cations. It contains 92% less sodium than sodium-oxybate(Xyrem).

Phase 3 of the study enrolled the 154 adults who had met the criteria for idiopathic hyposomnia . They were from 50 centers across six European countries, as well as the United States.

Participants received lower-sodium-oxybate treatment (oral solution once or twice a night) in an open-label titration period lasting between 10 and 14 weeks. Then, they were followed by a 2-week open-label stable-dose period. The ideal dose was between 2.5 and 9.0 grams per day.

After the open-label periods the 115 patients were randomly assigned to continue the optimized stable dose of lower-sodium oxybate or switch to placebo during a double-blind withdrawal phase.

Through open-label titration as well as optimization using oxybate with lower sodium, Epworth Sleepiness Scale (ESS) scores decreased, which indicates the existence of a “substantial” treatment effect, which was maintained throughout the stable-dose timeframe, report Yves Dauvilliers, MD, working with the Sleep and Wake Disorders Center, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France, and colleagues.

During the double-blind and randomized withdrawal period, the mean ESS scores increased (worsened) in the placebo group (from 5.8 to 13.3 points) but remained stable in the lower sodium oxybate groups (from 6.3 to 7.0).

The statistically significant difference in ESS scores between the two groups was statistically significant (least squares difference, -6.5; 95% CCI; -8.0 to –5.0; .0001).

The results also showed statistically significant and clinically relevant differences in favor of lower-sodium oxybate over placebo on the secondary endpoints of Patient Global Impression of Change ( P< .0001) and the Idiopathic Hypersomnia Severity Scale ( P< .0001).

Treatment-emergent adverse events (TEAEs) reported (> 10%) included nausea (22%), headache (18 percent) dizziness (12%) anxiety (11%), and vomiting (11 percent). Most TEAEs were mild or moderate. Nine serious TEAEs were experienced by four participants, however none of them was related to the drug being tested. No deaths occurred during the trial.

Xywav comes with a boxed warning because it is a central nerve system depressant. There is also the potential for abuse or misuse. Only a risk assessment and mitigation strategy program can make the drug available.

“The results strongly suggest lower-sodium oxybate may be a good first-line treatment, either as an individual therapy or in conjunction with alerting agents, to treat of idiopathic hypersomnia, which is a disease state that has no other approved treatments,” Dauvilliers and colleagues conclude.

Cautionary Notes , Caveats

The author of a connected commentary cautions that the FDA’s approval of the first and only medication to treat Idiopathic Hypersomnia does not suggest that it should be considered an initial treatment.

Lynn Marie Trotti MD, Department of Neurology and Sleep Center Emory University School of Medicine in Atlanta, Georgia notes that there was no head-to-head comparison for any active medication like modafinil.

Another caveat is the fact that the study cohort did not include only patients who were not taking treatment. Trotti points out that more than half of the participants in the study were taking drugs to promote wakefulness and lower-sodium oxygenate for an adjunct treatment.

She writes that the trial of Dauvilliers and her colleagues, has many strengths, which include assessing important clinical outcomes that go beyond sleepiness, as well as the recognition of a condition that’s been long ignored and likely not recognized.

However, more research is needed to “examine how lower-sodium Oxbate compares with other treatments” and how to tailor treatment for patients suffering from Idiopathic Hypersomnia.

The study was funded by Jazz Pharmaceuticals. Dauvilliers has served as consultant to and has served on advisory boards for Jazz Pharmaceuticals and UCB Pharma, Avadel and Idorsia as and Bioprojet and Theranexus. Trotti is a member of the American Academy of Sleep Medicine’s Board of Directors.

Lancet Neurol. 2022;21:53-65, 25-26. Abstract, Editorial

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