With new narcolepsy drugs available—and more in the pipeline—sleep specialists face the challenge of selecting the most suitable therapies for their patients.

By Sree Roy

In the increasingly verdant landscape of narcolepsy pharmacotherapy, no two drugs fill the same space. 

The variety of narcolepsy drugs available in the United States work through different mechanisms—GABA, histamine, and perhaps soon orexin, as well as other systems. The drugs treat narcolepsy symptoms—such as excessive daytime sleepiness and cataplexy—to differing degrees, with none promising full resolution. They are taken at different times of day in different doses. So despite the seeming multitude of options approved by the US Food and Drug Administration (FDA) recently, the sleep medicine subspecialty should expect more narcolepsy-treating drugs to continue to surface. Sleep specialists must understand the sometimes subtle differences and how to weigh the pros and cons for each patient. 

“We’re entering the stage where we’re using drugs with different activities in a particular patient to try to get the maximum improvement in their functional ability,” says neurologist-sleep specialist Michael J. Thorpy, MD, an investigator in Avadel Pharmaceuticals’ REST-ON phase 3 trial for Lumryz, which is the most recent narcolepsy therapy to get FDA approval. “But it does make it more complicated for the average physician prescribing for a patient with narcolepsy because we do have so many different types of medications available. It’s not easy to work out what the best first drug or the best combination is for a particular patient.”

Avadel’s Lumryz, which was FDA cleared in May 2023 and became commercially available in June, is an extended-release formulation of sodium oxybate taken once at bedtime for the treatment of cataplexy or excessive daytime sleepiness in adults with narcolepsy. 

Sodium oxybate is a mainstay of narcolepsy therapy. The other available sodium oxybate formulation is Xyrem, which was FDA approved in 2002 and is marketed by Jazz Pharmaceuticals. Xyrem is taken twice nightly. A related option also marketed by Jazz Pharmaceuticals is Xywav, or calcium, magnesium, potassium, and sodium oxybates, which was FDA approved in 2020 and is an oxybate product with 92% less sodium than sodium oxybate. It too is dosed twice nightly.

For many patients, the once-nighty dosing of new entrant Lumryz is an advantage, says Thorpy, who is also director of the Sleep-Wake Disorders Center at Montefiore and professor of neurology at Albert Einstein College of Medicine. “Many patients don’t like the idea of having to wake up at night to take a second dose of the traditional or the low-sodium oxybate,” he says.

Maurice M. Ohayon, MD, DSc, PhD, a professor of psychiatry and behavioral sciences (sleep medicine) at Stanford University and a consultant for Tris Pharma, which is working on its own oxybate formulation for narcolepsy, says twice-nightly dosing may “might also entice some patients to use [over-the-counter] sleep aids to fall back asleep.”

But Kelvin Tan, MB BCh, MRCPCH, Jazz Pharmaceuticals senior vice president and chief medical officer, says any advantages of once-nightly dosing are outweighed by the negatives of the sodium content of sodium oxybate, in his opinion. (Both Xyrem and Lumryz contain 1,640 mg of sodium in a 9 g dose.) “Patients may base their treatment decisions on the inaccurate understanding that removing a single nighttime awakening will return them to normal sleep,” he says. “No existing oxybate therapy can restore normal sleep, normalize sleep architecture, or eliminate nighttime disruptions” for people with narcolepsy.

Xywav is the only approved oxybate therapy that does not carry a warning and precaution related to high sodium intake. Tan characterizes Xywav as “a safer treatment option for people living with narcolepsy, which is associated with an increased prevalence of comorbidities such as obesity, hypertension, diabetes, and cardiovascular disease.”

Thorpy thinks the choice is more individual. “Our general experience has shown us that younger patients tend to be less concerned about sodium and the potential for cardiovascular problems, and so in those patients, they may lean more toward the once-nightly as being preferable because younger patients also tend to have greater difficulty awakening at night to take the second dose if they’re on twice-nightly….Older patients may be concerned about the potential for the sodium load and cardiovascular risk going forward and may not see taking oxybate twice a night as being a problem because older patients tend to awaken more often at night.”

People who are newly diagnosed, Thorpy says, “will make a choice based on either the preference of taking the once-nightly or whether they feel that a low-sodium formulation is better for them in terms of the potential for reducing sodium and perhaps cardiovascular risk factors in the future. They will balance that out.”

It follows then that a low-sodium, once-nightly oxybate formulation could be an even better option, which is what Tris Pharma is currently working on. “Oxybate ER POS is currently being developed for patients diagnosed with narcolepsy suffering from cataplexy or excessive daytime sleepiness (in patients 7 years and older) as well as idiopathic hypersomnia,” says Joseph Grieco, PhD, head of clinical development at Tris. “Unlike currently approved products, Oxybate ER POS will combine the benefits of low sodium content with a single daily dose, thus providing a treatment for patients at risk for cardiovascular comorbidities (ie hypertension) while simultaneously avoiding disrupted sleep, a potential cause of excessive daytime sleepiness possibly associated with a twice-nightly treatment regimen.”

Oxybates are far from the only pharmacotherapy option for narcolepsy. 

Also available is WAKIX (pitolisant), marketed by Harmony Biosciences, which works through the histamine system. It is administered once daily in the morning upon wakening. Axsome Therapeutics Inc recently acquired Sunosi (solriamfetol), which is a dual-acting dopamine and norepinephrine reuptake inhibitor indicated to improve wakefulness in adult patients with excessive daytime sleepiness due to narcolepsy or obstructive sleep apnea. It too is administered once daily in the morning upon wakening. Stimulants and antidepressants (the latter prescribed off-label to potentially reduce cataplexy) are also commonly used.

Polypharmacy is common in narcolepsy management. 

“The big thing about narcolepsy is one-drug-doesn’t-suit-all patients,” Thorpy says. “There is always some residual impairment that’s there even with optimal treatment, so most patients do require more than one medication to be able to control those symptoms and improve their functional ability.”

Narcolepsy drug candidates with other mechanisms of action are in the pipeline too. NLS Pharmaceutics, for example, is “very excited about mazindol,” says George Apostol, MD, MS, chief medical officer and global head R&D at NLS Pharma. 

Mazindol, a sympathomimetic amine, was FDA approved in 1973 as a weight-loss drug but was later voluntarily withdrawn due to low sales. According to Apostol, the drug has advantages over currently available narcolepsy drugs. For example, Apostol says, studies suggest it does not interfere with the efficacy of other medications, such as oral contraceptives. Mazindol so far has shown high efficacy for both excessive daytime sleepiness and cataplexy. It was classified as Schedule IV by the Drug Enforcement Administration, meaning that it was considered to have a low potential for abuse and addiction. It is being investigated as a single morning tablet dose for narcolepsy. “I think it’s under-recognized,” Apostol says.

Apostol says a small pilot study conducted with orexin-knockout and regular mice suggests an orexin component to mazindol. “It’s a serendipitous finding that explained some of the peculiarities of the drug. Usually, if you give a stimulant, you don’t improve cataplexy,” he says. NLS Pharma is working on a bigger study on this that it plans to submit for peer review.

So how should sleep specialists address the plethora of new narcolepsy drug options? Consider opening discussions with new and established patients. “We will be advising patients about the availability of the once-nightly, and we’ll be discussing it with them. We expect that some patients who have difficulty with taking a second dose will eagerly want to use the once-nightly,” Thorpy says. “There are other patients who are well-controlled on twice-nightly who probably won’t want to change.”

Staying abreast of developments of the narcolepsy drug candidates in the pipeline is also worth consideration. The narcolepsy drug landscape is expected to continue to grow.

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