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Management of Narcolepsy and Excessive Daytime Sleepiness - Episode 15

Drugs in Development for Treatment of Narcolepsy

Michael J. Thorpy, MD: Well, we’ve certainly discussed a lot about narcolepsy today. We talked about its causes and symptoms. We discussed behavioral and nonpharmacological treatments. We’ve discussed all the current therapies available for narcolepsy. But now the question is, where do we go next? What’s happening? Are there new drugs on the horizon? What have you found, Russ?

Russell Rosenberg, PhD, DABSM: I’m very optimistic about what we’ve seen in the last 2 years. We went a long time without anything new—between the time that the modafinils were FDA approved to the more recent approvals for pitolisant and solriamfetol, and the use of sodium oxybate in younger patients. I think that physicians need to understand that it’s not stopping here. We still need more tools. There are other good things coming, such as a longer-acting sodium oxybate that is administered as once-a-night dosing. The currently available dosing is twice a night, typically.

Michael J. Thorpy, MD: So people have to wake up in the middle of the night to take a second dose?

Russell Rosenberg, PhD, DABSM: Correct. I think it does give the physician a chance to sort of regulate the total dose a little easier. When it’s a once-a-night dose, there’s no more. You just take whatever you’re prescribed and go forward from there.

Michael J. Thorpy, MD: There are some people who have difficulty waking up for that middle-of-the-night dose. Maybe this once-a-night formulation, when it becomes available, could be helpful?

Russell Rosenberg, PhD, DABSM: Yeah. It will first become available for adults and maybe later for children. I’m sure you’ve heard parents say, “You mean I have to disturb my sleep?” Parents are very willing to do most anything for their children, but this is one of the things they wish would go away. There’s also a lower-sodium oxybate formulation in development. The salt load is found to be too high for patients who have certain cardiovascular diseases. I think this will be a benefit to many patients. I think especially for patients with narcolepsy, we’re all trying to reduce salt intake. This will be a big help. And then sort of going more upstream pharmacologically, there are orexin agonists in development. These are in development not just for narcolepsy but for other disorders of excessive sleepiness. But that’s more years away compared to the low-salt and the longer-acting sodium oxybate. Those could be available to patients in the next 2 years.

Michael J. Thorpy, MD: This orexin agonist is replacing this neuropeptide that Kiran was talking about earlier. It’s also known as hypocretin.

Russell Rosenberg, PhD, DABSM: Correct.

Michael J. Thorpy, MD: But the drugs are actually under the name orexin agonists. They sound very exciting. Since we discovered in 1999 that low orexin was responsible for many cases of narcolepsy, we’ve waited for some way to be able to replace it. So the thought that there may be drugs coming out to help replace that lost orexin.

Russell Rosenberg, PhD, DABSM: It’s very promising. I think with the initial attempts at orexin agonists, the trouble was that it crossed the blood-brain barrier. And now, with better technology, there are ways to overcome that. I think these advancements will help many, many patients.

Michael J. Thorpy, MD: Yes. But it’s still going to be a few years before those are available, right?

Russell Rosenberg, PhD, DABSM: Yes. The orexin agonists could be 5 or more years away. The others might be more like 2 years away.

Michael J. Thorpy, MD: If low-sodium oxybate is available in the future, Alon, do you think that’s going to be useful for patients? How do you see that sort of interacting with the standard sodium oxybate that we have now? Do you think it will replace it, or will it be used sort of equally?

Alon Y. Avidan, MD, MPH: I have not prescribed sodium oxybate because I was concerned that someone’s salt load was too high to make the justification that the risk of the sodium load was overwhelming the need to control daytime sleepiness. The 1 scenario where it did happen was a gentleman who had secondary narcolepsy with destruction of the hypothalamus and SIADH [syndrome of inappropriate antidiuretic hormone secretion], who had difficulty with his salt balance. But by and large, I think it’s healthy. It’s nice not to give patients a high sodium load, but it’s not one of those reasons that we, as clinicians, do not prescribe sodium oxybate.

Michael J. Thorpy, MD: But in the elderly patients who have potential for hypertension, renal disease, cardiovascular problems…

Russell Rosenberg, PhD, DABSM: Definitely.

Michael J. Thorpy, MD: It should be an advantage when it becomes available. There are other medications also being investigated. There’s a drug called reboxetine that’s just gone through some initial studies. This is a norepinephrine reuptake inhibitor, and it’s like other antidepressants. But the interesting thing about the studies done with this drug is—whereas traditional antidepressants and norepinephrine reuptake inhibitors solely affect cataplexy—this drug was shown in these latest studies to improve sleepiness as well as cataplexy. And it didn’t disturb nighttime sleep. So that’s something that we need to look for.

Again, it’s going to be a number of years before that drug, if it ever gets approved, becomes available. But it’s exciting to think that we’ve got more options on the horizon. As you were saying earlier, Alon, we’re entering the phase of polypharmacy for patients with narcolepsy. It’s very hard to really cure these patients. You can’t cure them. However, to optimize their functions, we really need to have quite a number of options available.

Alon Y. Avidan, MD, MPH: Absolutely. I just read a recent study highlighting that folks with narcolepsy type 1 run a higher diastolic blood pressure than folks who are not on stimulants. Being on this older-generation medication, someone with an underlying condition can end up with conditions that we don’t want them to have—hypertension and cardiovascular disease. So, certainly, we’re aiming for and we’re reaching the precision medicine realm fairly quickly with more disease-modifying agents and agents that are more specific to the disease pathology, which is, in my opinion, very exciting.