SLEEP 2026 | Orexin agonists in narcolepsy: trial findings, subtype differences, and biomarker-guided therapy

So oveporexton is a highly potent oral receptor 2 selective agonist, and it demonstrated significant improvements in narcolepsy symptoms in two Phase III trials. So these were placebo-controlled clinical trials called the FirstLight and the RadiantLight studies. And so we had information about objective wakefulness on MWT and sleepiness on the Epworth Sleepiness Scale and also the cataplexy frequency, so these were the end points of the study. And the compound was safe and well tolerated, and it showed a lot of improvements in all the end points studied with a huge reduction in cataplexy frequency and a major improvement in wakefulness and subjective sleepiness in narcolepsy type 1 patients. Indeed, it was also presented at the SLEEP Congress, but it’s not yet published. So what I will say is very hypothetical, but we think that given the pathophysiology of narcolepsy type 2, probably the effectiveness will be different and maybe we’ll need different doses, but this needs to be proven. Narcolepsy type 2 is a disease where we have no biomarker, but we know that orexin is supposed to be normal. So if we perform a lumbar puncture, orexin is normal in narcolepsy type 2, whereas in narcolepsy type 1 patients are orexin deficient. So probably the orexin receptor 2 agonist will have an effect on wakefulness as they do in healthy controls, and it was in the Phase I and previous studies, but it will be slightly different because it will not act specifically on the pathophysiology of the disease. So this is really new and we have to wait for the published results, but it seems that it works. It’s a wake-promoting agent, but it works probably differently, with different side effects, etc. Now that we have these new drugs that are really a revolution in the sleep field, we do want to know the orexin status of the patients because the strategy will probably be different if we know the patient is orexin deficient, and for example, we have some narcolepsy type 1 patients with no cataplexy. It’s 20% of cases. So if you don’t do the lumbar puncture, you don’t know if they are orexin deficient or not, then probably it will guide the treatment choice. So we will give, for sure, we will try to give, when it will be available, orexin receptor 2 agonists to patients orexin deficient. For the others, maybe the strategy will be different. Maybe we will try other wake-promoting agents before this one. I don’t know yet. It’s a new field, but yes, orexin deficiency is more than ever a biomarker of major importance in hypersomnolent disorders.

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