The FDA just approved a new oxybate formulation for the treatment of excessive daytime sleepiness or cataplexy in patients 7 years and older with narcolepsy. Should your patients switch?
By Sree Roy
For more than a decade and a half, Xyrem (sodium oxybate) has been prescribed to patients with narcolepsy who experience cataplexy or excessive daytime sleepiness. It was the only US Food and Drug Administration (FDA)-approved therapy for the treatment of cataplexy (though sleep physicians also prescribe other drugs off-label to alleviate the symptom of muscle weakness).
Marketed by Jazz Pharmaceuticals plc, Xyrem has demonstrated efficacy for narcolepsy management. But each milliliter of the oral solution contains 91 mg of sodium. To put that into context, the American Heart Association recommends a maximum intake of 2,300 mg of sodium a day for adults and says an ideal limit is closer to about 1,500 mg. So at the common sodium oxybate doses of 6 g, 7.5 g, and 9 g, patients consume 1,092 mg, 1,365 mg, and 1,638 mg of sodium, respectively—or almost the maximum recommended intake for their entire day, even before any food or drink consumption.
“A low-sodium diet is an important part of the health of everyone, but especially for patients with narcolepsy, who are known to have increased cardiovascular risk factors,” says Rob Iannone, MD, executive vice president, research and development at Jazz Pharmaceuticals. “It’s critically important that sleep physicians are as informed as possible about cardiovascular risks that narcolepsy patients have and the potential negative effects of a high-sodium intake.” It’s particularly relevant because narcolepsy is a lifelong disorder with lifelong therapy needs, he adds.
For nearly a decade, scientists have been working to create a lower-sodium narcolepsy therapy that would be as efficacious as Xyrem. With Jazz Pharmaceutical’s newly FDA approved Xywav (calcium, magnesium, potassium, and sodium oxybates), the company reports that it has finally been successful. Xywav leverages other positively charged ions that “don’t have the negative effects of sodium” with oxybate, Iannone says, resulting in an oral solution with 92% less sodium than Xyrem.
“There are high proportions of patients with narcolepsy who are already facing cardiovascular issues that require medication treatment,” he says. “There were also patients not given Xyrem due to underlying cardiovascular issues, so those patients will have a new treatment option.”
Why did it take so long? Pharmacokinetic differences between Xywav and Xyrem— Xywav has a lower Cmax (peak serum concentration) than Xyrem—meant Xywav couldn’t be developed through simple bioequivalency studies, but rather it required efficacy trials. The slightly different pharmacokinetics might be favorable, according to lead investigator of the phase 3 study Richard K. Bogan, MD, FCCP, FAASM, who also notes that Xywav’s phase 3 trial results show it to be equivalent to Xyrem in terms of efficacy and safety.
Xywav Dosing & Safety Data
When patients start Xywav after sodium oxybate, it should start at a dose-by-dose equivalent, then be titrated based on efficacy and tolerability. “Most patients were transitioned to equivalent dose” in the phase 3 trial, Bogan says. “As a group, probably only one adjustment was made. Clinicians will tweak our patients over time.”
Both Xyrem and Xywav require two doses to be swallowed several hours apart. But Xywav has more flexibility: Unlike Xyrem, it can be dosed asymmetrically (due to Xywav’s lower Cmax). Bogan likens the pharmacokinetics to “the shampoo effect,” explaining that it’s as though “the first time, you get the oil out; the second time, you get a lot of suds.”
“We found clinically that asymmetric dosing sometimes helps with improvement in terms of adverse events and outcomes,” says Bogan, who is associate clinical professor at the University of South Carolina School of Medicine and a medical officer at SleepMed in Columbia, SC.
Like Xyrem, Xywav is FDA approved for children as young as 7 years. There were no children in the clinical trials for Xywav, but “the FDA was willing to consider the efficacy data in children in Xyrem, in addition to the safety, efficacy, and pharmacokinetic data in Xywav,” Iannone says.
The safety profile for Xywav is equivalent to that of Xyrem, Bogan says. It has a boxed warning as a central nervous system (CNS) depressant and for its potential for abuse and misuse. Because of these risks, Xywav will be available only through a restricted program under a risk evaluation and mitigation strategy (REMS), the “Xywav and Xyrem REMS Program.”
Adverse reactions that impacted 5% or more of adults in the phase 3 trial were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting. “The side effects profile in the patients already on sodium oxybate was lower in that cohort group than the other cohorts. So if patients have taken sodium oxybate before, they were more easily able to transition over to Xywav than the naive patients,” Bogan says.
In his opinion, “it’s sort of a no-brainer to put everyone on Xywav, assuming it’s a comparable expense,” Bogan says.
Transitioning from Xyrem to Xywav
Abstracts about the phase 3 trial were published at World Sleep 2019 and Virtual SLEEP 2020, and the data suggests patients can transition smoothly from Xyrem to Xywav without efficacy- or safety-related problems.
The phase 3 clinical trial was designed in part to study transitions of patients from their current therapies (if any) to Xywav. For patients on off-label anticataplectics, the trial allowed them to stay on their current therapy for two weeks while starting Xywav—to blunt potential rebound cataplexy.
The trial was designed so patients could switch “in a way that minimizes any symptoms they might have with narcolepsy,” Iannone says. “Some patients were on Xyrem; some were on other anticataplectics….The study not only demonstrated the expected level of efficacy as one would expect from Xyrem but also that the transition can be made seamlessly, so patients don’t experience unwanted symptoms.”
Bogan adds, “We learned a lot about rebound cataplexy. When you wean [off off-label therapies], we could see the cataplexy increase quickly and maybe even above the baseline.”
The phase 3 trial was a good representation of real-life type 1 narcolepsy patients, Bogan says, in terms of severity and current narcolepsy medications. Compared to patients in a typical sleep practice, “if anything, they might have been more severe or more defined,” he says.
Bogan expects to publish the complete phase 3 study results in a peer-reviewed journal. “We’re going to see a lot of literature coming out of it, in terms of experience with other anticatapletic therapies and with the ability to transition patients over,” he says.
What’s Next for Xywav?
Jazz Pharmaceuticals plans to launch Xywav by the end of 2020, following REMS implementation.
Bogan says he considers Xywav to be a firstline drug for patients with narcolepsy, though he historically starts patients on a wakefulness medication before introducing them to Xyrem (and presumably Xywav, once available). He thinks most patients who are on Xywav or Xyrem are also going to be on stimulants for narcolepsy management. “I usually start on stimulants, see how they do, and then start the [oxybate formulation],” Bogan says, adding that if a patient has cataplexy, many times he’ll put them on Xyrem at the same time as the stimulant.
Bogan has seen narcolepsy have a negative impact on patients’ quality of life—but has also seen drug therapies make their lives much better. So, in his view, “The important message is our patients with narcolepsy deserve to know about this new drug.”
Sree Roy is editor of Sleep Review.