The Role of Orexin Agonists in Idiopathic Hypersomnia: Dr Michael Thorpy

In an interview with The American Journal of Managed Care^®, Michael Thorpy, MD, professor of neurology, Albert Einstein College of Medicine, discussed the use of orexin agonists to combat idiopathic hypersomnia. This topic was explored further at this year’s 2024 SLEEP: American Academy of Sleep Medicine and Sleep Research Society (APSS) Annual Meeting.

This transcript was lightly edited for clarity and length.

Transcript

Can you discuss the mechanism of action of orexin agonists and how they target the underlying causes of hypersomnia?

One of the problems that we have with idiopathic hypersomnia is we really don't understand the pathophysiology of it. We think that some forms of idiopathic hypersomnia might be related to a loss of orexin, and that's one of the reasons why the newer orexin agonists are being used to help idiopathic hypersomnia. But there are also other theories as to why people have idiopathic hypersomnia and one is because of an effect of the gamma aminobutyric acid (GABA-A), which is a depressant in the brain. And, hence, clarithromycin is a GABA-A antagonist and it's counteracting that GABA mechanism.

There are the other medications being studied. Ones like serdexmethylphenidate, which is a sympathomimetic agent. And it tends to affect the reuptake of a lot of the alerting medication. So, it increases the alerting medications in the blood during the daytime.

And then we have pitolisant, which also affects alerting neurotransmitters, but is very specific for the histamine. It's a histamine H3 receptor inverse agonist, which means it blocks a H3 receptor for histamine and causes more histamine to be produced in the brain. And that histamine in the brain increases alertness—and that's why that's being applied to idiopathic hypersomnia.

And then finally, the other drug that's being studied is the once-nightly oxybate, which is a GABA-B agonist, the xywav as a GABA-B agonist—its long acting—or the low sodium oxybate; and that's a GABA-B agonists and that has an effect of stimulating wake-promoting neurons in the brainstem, and so helping with the idiopathic hypersomnia. And so, now the once- nightly formulation, which does the same thing, is being studied for idiopathic hypersomnia.