Sodium Oxybate Oral Solution Proves Positive in Topline Hypersomnia Data

Robert Iannone, MD, MSCE

Positive topline data from a phase 3 study (NCT03533114) of the investigational use of calcium, magnesium, potassium, and sodium oxybates (Xywav; Jazz Pharmaceuticals) oral solution have been announced that suggest the agent is effective and safe for adult patients with idiopathic hypersomnia.¹

The double-blind, multicenter, randomized clinical trial featured patients who had excessive daytime sleepiness associated with their idiopathic hypersomnia. All of those who were treated with the agent, formerly known as JZP-258, experienced clinically meaningful improvements in Epworth Sleepiness Scale (ESS) scores during the open-label titration period.

Jazz noted that it plans to submit the data for presentation at an upcoming medical meeting and will use them to support its upcoming submission of a supplemental New Drug Application (sNDA) to the FDA, which is expected to be filed as early as the first quarter of 2021. The FDA granted a fast track designation to the therapy in September 2020.

"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 Robert Iannone, MD, MSCE, executive vice president, research and development, Jazz Pharmaceuticals, in a statement.

The primary end point of the study—ESS score—and the key secondary end points—Patient Global Impression of Change (PGIC) and Idiopathic Hypersomnia Severity Scale (IHSS)—were measured during the randomized withdrawal portion of the study. That section included 115 patients, and those given the oxybates combination reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations.

Additionally, highly statistically significant worsening was observed for those administered placebo in comparison with the Jazz agent for ESS (P <.0001), PGIC (P <.0001), and IHSS (P <.0001).

"There is a significant need for greater awareness of idiopathic hypersomnia, which can severely impact a person's daily life, and can often be misdiagnosed or undiagnosed over a substantial period of time," said lead investigator Yves Dauvilliers, MD, director, Sleep Disorders Centre, Gui de Chauliac Hospital, in Montpellier, France. "Currently, there are no approved treatment options for idiopathic hypersomnia, and these data are a welcome advance for patients.”

This study in idiopathic hypersomnia included a titration and optimization period lasting up to 14 weeks, followed by a 2-week stable-dose period and a 1:1 randomization to either the study treatment or placebo for 2 weeks. After the completion of the double-blind, placebo-controlled treatment period, patients entered a 24-week open-label safety extension period.

"For more than 15 years, Jazz has been at the forefront of sleep medicine,” Iannone added. “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."

READ MORE: ​​FDA Approves Pitolisant for Cataplexy in Narcolepsy

The oxybate product contains a unique composition of cations resulting in 92% less sodium, or approximately 1000 to 1500 mg/night, than sodium oxybate (Xyrem; Jazz), the only other approved agent for this indication. The treatment does not carry warnings about sodium content but does include safety risks for those under the drug. Designated as a Schedule III medicine, JZP-258 also contains a boxed warning as a central nervous system depressant and for its potential for abuse and misuse. Therefore, the treatment is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Xywav and Xyrem REMS Program.

Jazz has noted previously that taking the therapy along with other central nervous system (CNS) depressants such as medicines used to make a patient or their child fall asleep, including opioid analgesics, benzodiazepines, sedating antidepressants, antipsychotics, sedating anti-epileptic medicines, general anesthetics, muscle relaxants, alcohol, or street drugs, may cause serious medical problems, including respiratory depression, hypotension, drowsiness, syncope, and death. Gamma hydroxybutyrate (GHB) is the active ingredient of Xywav and abuse of illegal GHB alone or with other drugs can cause serious side effects. Among them include seizures, trouble breathing, changes in alertness, coma, and death.^2,3

The oral solution was recently approved in July 2020 for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age or older with narcolepsy. The basis of that approval came from data displaying that the drug demonstrated statistically significant differences (P <.0001) in the weekly number of cataplexy attacks and ESS scores compared to placebo in a phase 3 study. During the double-blind withdrawal period, participants randomized to placebo experienced 2.35 (interquartile range [IQR], 0.00 to 11.61) weekly cataplexy attacks compared to 0 (IQR, –0.49 to 1.75) in the JZP-258 group. Additionally, significant increases in median ESS scores were observed in the placebo group (median, 2.0 [IQR, 0.0 to 5.0]) compared to the treatment group (median, 0 [IQR, –1.0 to 1.0]; P <.0001).²

REFERENCES
1. Jazz Pharmaceuticals Announces Positive Top-line Results from Phase 3 Study of Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution in Adult Patients with Idiopathic Hypersomnia. News release. Dublin, Ireland. Jazz Pharmaceuticals. Published October 8, 2020. Accessed October 15, 2020. prnewswire.com/news-releases/jazz-pharmaceuticals-announces-positive-top-line-results-from-phase-3-study-of-xywav-calcium-magnesium-potassium-and-sodium-oxybates-oral-solution-in-adult-patients-with-idiopathic-hypersomnia-301148512.html
2. Jazz Pharmaceuticals announces US FDA approval of Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution for cataplexy or excessive daytime sleepiness associated with narcolepsy. News release. Dublin, Ireland. Jazz Pharmaceuticals. Published July 22, 2020. Accessed October 15, 2020. jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavtm-calcium
3. Jazz Pharmaceuticals Announces FDA Acceptance of New Drug Application for JZP-258 for Cataplexy and Excessive Daytime Sleepiness Associated with Narcolepsy. News release. Dublin, Ireland. Jazz Pharmaceuticals. Published March 25, 2020. Accessed October 15, 2020. investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-fda-acceptance-new-drug