AAN 2026 | Orexin agonists and the future of narcolepsy treatment

I think it’s a very exciting time for narcolepsy because of this orexin agonist. As you know, it was discovered that the cause of narcolepsy is a lack of orexin, which is due to an autoimmune process, which is very likely triggered by specific flu strains. And it’s a lifelong disorder and people lack the orexin. And for a very long time, the treatment of this disorder was really symptomatic. We would use drugs that will knock out the patients at night, like oxybate, sodium oxybate, which makes them sleep very deeply. And then that helps them be more awake during the day, or stimulants or antidepressants to suppress REM sleep symptoms. However, recently, to my delight, there has been a development of orexin agonist, which can replace what is really missing, which is the orexin peptide, which the cells are missing as a result of the autoimmune process. And of course, as you can expect, these drugs are spectacular in this form of narcolepsy where the orexin is missing. It’s a little bit like insulin for type 1 diabetes. And we’re seeing now the results of many of the trials. One of the drugs, oveporexton, is going to be probably coming out in six months to a year or nine months, so it’s relatively soon. If the FDA approves it, then I’m not, of course, I can’t define what’s going to happen. And then the other one that’s following up from Alkermes is probably about a year or so, but maybe a year and a half behind. And both of these drugs, one of them just completed Phase III, the Takeda drug. And the results are really amazing. What you see is you see a reversal of the symptoms of narcolepsy in a way that we have not seen before. With all the current drugs, I like to say to my patients, you know, we often can bring you back 80%, 80% of the time. That’s sometimes I say that, but it’s not that good if you think about it. First, there are some patients that don’t do well. I mean, we can never really guarantee anything that don’t tolerate medications that we have currently. And then there are also some patients, even when they do well, optimally, they don’t have any more cataplexy. They nap only a few times. But still, I would say that their life is diminished. They just have to take their medication very regularly. They still have to nap. They have diminished ambition. Their life is not full as it used to be. And in fact, we see it because we can use a classic test that we use during this clinical trial. That’s called the maintenance of wakefulness test. It’s a horrible test for a narcoleptic. We put you in a dark room and we tell the patients, try to stay awake as long as you can. Fight it. I can tell you, patients with narcolepsy after two minutes untreated, already gone. I mean, they cannot do anything. They cannot watch TV. They cannot read. They cannot talk to anyone. They just have to stay awake. It’s impossible when there’s nothing to do. A patient with narcolepsy is already asleep. Just thinking about it. And with the current treatment, we raise the sleep latency, you know, to this nap from like a few minutes to maybe like, you know, seven minutes. And that’s really the best. And a normal person can stay awake like 30 minutes or 40 minutes, which is the total length of the test. So you see that they’re still very abnormal. And with this drug, I mean, it’s just amazing. I mean, they can stay awake 30 minutes or 40 minutes. It’s a completely different ballgame.

This is the area that’s very exciting, is this cognitive area. I mean, we know that they were able to stay awake, but as I said, they were not normal still. And, you know, they still had difficulties in cognition. They didn’t feel like they used to be, bright. And often they really decreased a lot of their ambition. You know, a lot of them would not be able to do their hobbies and things like that. And with this new drug, we see this restoration of functions that goes really beyond, you know, the sleepiness.

Now I should say it’s not perfect, okay? First, we don’t have, you know, long-term data, you know, and there are interesting ways, the way the drug effects are evolving, which are still under study. For example, initially, it’s extremely strong. You can imagine that these patients have never seen orexin for decades. So their receptors are very upregulated and you give them a tiny dose and boom, it’s like a light switch. Wow. They are really awake for like sometimes almost too awake initially and then it kind of settles, so we have to see a little bit how things are going to work on the long term, but it’s definitely going to be a game changer. We just have to find the right medications, the right administration, and also clinical trials results that are, you know, like way beyond anything that we have seen with the old drugs.

And one of the side effects that’s very odd is the patients have to go more to the bathroom for peeing. It’s not like unbearable, but it’s just that they have to go to the bathroom more often. That also kind of settles, but it’s still present. And I think that’s one issue that is with a drug, but it’s totally tolerable. I would say that sometimes their sleep is not completely restored at night. They don’t have as much of the hallucination and all the bad dreaming. All this improves because that’s abnormal REM sleep and that’s very much treated with this medication. But maybe they still have a little bit of insomnia. And that’s another thing that is clearly maybe not perfect. And then again, I want to stress, I have patients for one and two years and, you know, we don’t really know what’s happening in the long term. We really need a bit more information.

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