Combination Therapy Expected in Narcolepsy: David T. Plante, MD, PhD

Durable treatment responses in narcolepsy and idiopathic hypersomnia depend on factors that can erode them over time, and patients will likely need more than 1 agent, according to David T. Plante, MD, PhD, who also discussed how dosing, psychiatric history, sodium load, and emerging orexin-2 receptor agonists shape treatment decisions.

In part 2 of the interview with The American Journal of Managed Care^® (AJMC^®), Plante, associate professor of psychiatry and medical director of the Wisconsin Institute for Sleep and Consciousness at the University of Wisconsin–Madison School of Medicine and Public Health, described how he chooses between once- and twice-nightly oxybate dosing, manages patients with a psychiatric history, and weighs sodium load when selecting therapy. He also explained how orexin-2 receptor agonists could change narcolepsy care and what managed care decision makers should keep in mind.

In part 1 of the interview, Plante explained that separating mood-related sleepiness from primary hypersomnia relies on the course of illness and sleep testing, and he described how he sequences oxybate and wake-promoting therapies in narcolepsy and idiopathic hypersomnia.

This interview has been edited for clarity.

AJMC: How durable is a response to these therapies in your experience, and how long do you tell patients to give a regimen before they decide whether it's working?

Plante: The durability of response depends a little bit on the person, the course of the illness, and the particular medication that's used. We hope that the response is very durable, that people can stay on a stable dose of medication and things don't really change or get worse, and if they're doing better, they stay better for a long time. Sometimes that may not be the case, but in my experience, people on oxybates, modafinil, or those types of medications can often be pretty stable for significant periods of time, at least several months, if not years. But there may be other things that come up that cause them to feel sleepier.

One thing we always keep in mind, if people have been stable for a while, is whether they have developed some other sleep disorder as they get older. Patients with narcolepsy especially are at increased risk for developing sleep apnea¹ and several other conditions. Sometimes the medication isn't less effective; something else has crept in to cause symptom worsening.

One of the challenges with using traditional stimulants is the potential to develop tolerance over time. In my experience, people may do well initially on stimulants, but over time they can develop some tolerance where the drugs become less and less effective, and that can be a real clinical challenge. Sometimes you can combat that by using things like drug holidays, but I think it's also very important to set expectations around stimulants and let people know about that particular risk with those medications.

AJMC: Patients with idiopathic hypersomnia (IH) have been managed with either a once nightly or a twice nightly dose. How do you choose between the 2 approaches, and how do you help set patients' expectations during titration?

Plante: We don't really have a good sense of how to pick once versus twice nightly dosing of oxybate, and if you ask different practitioners, you will get different responses. In general, this is how I tend to think about it in IH. I try not to wake people up with an alarm in the middle of the night if I can avoid it. What I will often do is start people on once nightly dosing and begin titrating, and what will often happen is people will declare whether they're going to wake up spontaneously in the middle of the night because usually with oxybates that are not sustained-release preparations, people will wake up on their own after a few hours.

If people do start to wake up in the middle of the night, that's an opportunity to potentially add a second dose and keep titrating that way. If people never wake up spontaneously during the night for the potential of a second dose, I will usually titrate to maximize the first dose first and, depending on how people are doing, potentially think about setting an alarm to have them take a second dose so we can increase the total dose further. Oftentimes I don't necessarily need to get to that, or, again, people declare themselves as someone who might benefit from twice nightly dosing just by naturally waking up in the middle of the night once they start once nightly.

AJMC: Depression is common in both conditions, and oxybates carry warnings around depression, suicidality, central nervous system depression, and misuse.² How do you manage patients who have an active or past psychiatric illness, who do you consider not the right candidate for these drugs, and how do you coordinate with a patient's psychiatrist or primary care physician?

Plante: This is something we always think about. I have a little bit of a bias because I trained in psychiatry originally, so I probably feel more comfortable with suicidality than many of my peers who may not have had that experience. I think it's important to be mindful of the warnings on the label, and if people have a significant psychiatric history, to be mindful of that and warn people about the potential risks of these medications.

That said, I don't think we should not use them in people who have a history of depression just because they have a history of depression. Obviously, if somebody's actively depressed, it may not be the first agent I reach for, but the reality is that people can often get better, and I've also seen mood improve with these medications in people who have pretty profound sleepiness and functional impairment without them. There are certainly higher risks but also potentially higher benefits.

What I do is walk people through the different risks and benefits of the medication and help them decide if they think it's worthwhile pursuing. I also develop a basic safety plan. If someone's actively suicidal, just to be clear, I wouldn't put them on an oxybate. But if they were to develop suicidal thoughts or have other safety concerns while on the medication under my care, I'd want them to contact me, and we would probably withdraw the drug and make sure things were safe. Letting people know about it as a possibility, and then helping them through the titration phase, is how I tend to manage these situations.

AJMC: Sodium is also a concern with these medications. About 74% of patients with IH and 69% of patients with narcolepsy have at least 1 sodium-related risk factor.³ How does sodium load factor into your choice of therapy, and what do you monitor once a patient is on treatment?

Plante: Here we're talking about oxybates pretty specifically, because the sodium issue centers around the fact that oxybate has to be bound to a positive cation. Historically, that has been sodium, and thus sodium oxybate. The more sodium oxybate you take, the more sodium you are ingesting. It's pretty well established that too much sodium isn't good for you. It can increase the risk of high blood pressure and a number of other things.

There are options if the clinician is concerned about the sodium load. For example, Xywav is the lower-sodium version of oxybate. If there are particular concerns around renal function, heart failure, hypertension, those kinds of things, that is a very good option in those cases. That said, sodium oxybate certainly has a place, especially [because it] comes in a once nightly formulation, that is currently approved for narcolepsy, so this convenience can be quite helpful for some patients. Many people who are otherwise generally healthy are better able to excrete excess sodium, so sodium oxybate may be less problematic for these patients compared to others with more medical comorbidities.

So in terms of oxybates and sodium, it’s a balancing act. We think about what's the overall risk, what medication we can get access to, and what the patient's preference is as well. Those are the things that go into the choice around managing sodium intake with oxybates.

AJMC: Orexin-2 receptor agonists are moving through late-stage development and the regulatory review process. How might they change treatment sequencing for narcolepsy and potentially for IH as well, looking ahead 3 to 5 years? And what is the most underappreciated issue for managed care decision makers in these conditions?

Plante: Starting with orexin agonists, these are medications that directly act on the receptors where orexin would normally act. Orexin is a neuropeptide neurotransmitter made in the hypothalamus that is really key to stabilizing transitions between sleep and wake. In narcolepsy type 1, it's the orexin neurons that are lost, presumably due to an autoimmune reaction. For patients with narcolepsy type 1 who have orexin deficiency, the data suggest that these orexin-2 agonists, one of which, [oveporexton],⁴ was recently approved, so it'll be first in class, really have a lot of therapeutic potential, because they're acting directly on the pathophysiologic mechanism in that disease. The data are pretty convincing that it can have sizable effects in a number of different domains for people with narcolepsy type 1.

Looking out 3 to 5 years, I would anticipate that agents from this class will ultimately be first-line choices for patients with narcolepsy type 1. I think that's somewhat common sense based on the mechanistic treatment.

It's unclear exactly how these agents will be involved in the treatment of NT2 [narcolepsy type 2] and IH. I think there's great potential that these medications may also be effective for those disorders. We do know that as a class, to see clinical effect, you tend to need a higher dose than what's used in narcolepsy type 1,⁵ so I think the challenge will be finding well-tolerated medications that you can get to a high enough dose that you don't have problematic [adverse] effects. That's what people are trying to figure out now. So orexin receptor agonists have a lot of potential for use in these other hypersomnolence disorders outside of narcolepsy type 1 and potentially other brain disorders as well, but it is very hard know exactly how this story is going to play out in the future. I would anticipate there will be options for people with NT2 and IH in the future as well, that hopefully they'll be able to choose from one of several different options that are most effective for them.

Managed care is always challenging in these disorders, especially in a space where many different medications are becoming available or getting approval right around the same time, and they are all very different. The important thing from the managed care perspective is to realize that these disorders are quite disabling and quite challenging for people to manage, and these medications can help people lead much more normal lives and be functioning members of society. It's important to keep in mind that polypharmacy is often needed in these patients, because although these medications can be effective singularly in some patients, oftentimes they are not.

It is not unusual, and it should be expected, that some patients may need multiple agents in order to function, and that needs to be kept in mind from a managed care perspective. It's certainly reasonable to ask people to have tried and failed different medications and to try to limit very expensive medications from a managed care standpoint, but at the same time, if it were your spouse, your sibling, your child with these types of problems, you would probably want them to be adequately and optimally treated as well. That's how I tend to think about it.

REFERENCES

Miano S, Kheirandish-Gozal L, De Pieri M. Comorbidity of obstructive sleep apnea and narcolepsy: A challenging diagnosis and complex management. Sleep Med X. 2024;8:100126. Published 2024 Sep 18. doi:10.1016/j.sleepx.2024.100126

Sodium oxybate (Lumryz). Package insert. Alkermes Inc; 2002. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=10e5e40c-52f3-4c73-8a34-2c29c690a934&type=display

Markt SC, Drachenberg C, Kovacs RJ, et al. Sodium-relevant comorbidity risk factors are highly prevalent in individuals with narcolepsy or idiopathic hypersomnia. Sleep Med. 2026;145:109023. doi:10.1016/j.sleep.2026.109023

Dauvilliers Y, Mignot E, Antczak J, et al. Oveporexton for Narcolepsy Type 1 - Results from Two Phase 3 Trials. N Engl J Med. 2026;395(12):1166-1179. doi:10.1056/NEJMoa2601598

Grunstein RR, Yee BJ, Chapman JL, et al. Targeting Orexin 2 Receptors in Idiopathic Hypersomnia and Narcolepsy: A Randomised Phase 1b Proof-Of-Concept Study of Alixorexton. J Sleep Res. Published online August 4, 2026. doi:10.1111/jsr.70429