Orexin

Thanks, Yaron.

We, we're never scared of a controversy, are we? Um, let's, uh, move on to, um, Matt to talk about Orexin.

I just want to remind, uh, everyone that Orexin initially, or targeting Orexin, was initially thought as a g-good way of trying to deal with, uh, obesity or weight loss.

And then, of course, it moved over to, um, um, treatment of, of, uh, insomnia.

I-I've actually personally tried Quviviq, find it quite a good, uh, drug for when you're traveling and you need your jet lag dealt with.

So we're gonna ask, um, Matt to talk us through this and, and what he thought of, of the data and the news.

Yeah.

So, so, um, this week, Alkermes, which is one of the, one of the furthest along players in the Orexin space, put out some data on ADHD, uh, which, um, yeah, I think most notably the Orexin study in ADHD succeeded.

Music Remember, NICE recommends sleep hygiene as a foundation, CBTI as first-line active treatment and hypnotics only as short courses at the lowest effective dose when CBTI isn't available, hasn't worked or isn't suitable.

More recently, NICE has approved a new class of hypnotics, daridorexant, a dual orexin receptor antagonist.

Orexin, also called hypocretin, is a brain chemical that promotes wakefulness and we'll be returning to it properly in our next episode on narcolepsy, where the story of its discovery is remarkable.

Dyridorexent works by blocking orexin's wake-promoting signal rather than by acting on the same GABA system as Z-drugs and benzodiazepines.

NICE recommends it specifically for adults with chronic insomnia.

Taper too fast and you get rebound insomnia, anxiety, potentially seizures if it's a high enough dose of a benzo.

If it's an orexin antagonist, which is the newer class, the suvorexant and lemborexant type drugs, the mechanism is different.

Orexin is a wake-promoting neuropeptide, and blocking it promotes sleep.

Tapering, that's less about seizure risk and more about the insomnia coming back as the receptors resensitize to orexin.

But the clinical problem is the same.

And interestingly, it has activity in other domains like pain, and seizures, and anxiety, for example.

But what are we looking to find? Given that I just said this could be the next Orexin or a PD1-like moment for the brain, we're trying to get as much early as possible as we can, as much insight, uh, much like we did with the epilepsy program.

So specifically in the phase one study, what we're looking for is the traditional metrics, but we're also conducting exploratory electrophysiology to try to show signs of neuroactivity consistent with the mechanism of action, so GABA or the braking system in our brain working more effectively.

But what this phase one will kick off is a really important translational study that I think could be quite meaningful for the world and the investment community as well.

Uh, we've guided that we'll start that challenge before the end of this year.

It's a short study, but what it will do is ask and answer potentially many important questions about neuroactivity, neuroactivity on mechanism, translational biomarkers that we've already established, and it uses biomarkers on electrophysiology that give us a read-in to the predictive clinical effect.

And that's a big deal because if we have an Orexin or PD1-like target of the brain where we have broad therapeutic activity and could work in a number of psychoses from Alzheimer's, to PD, to schizophrenia, to others-

Mm-hmm

Got it.

And what is it that they're inhibiting? They're orexin,

O-R-E-X-I-N, which is an important chemical that affects wakefulness.

So you take this and it inhibits the wakefulness.

Okay,

Hello and welcome to this episode of the VJ Neurology podcast.

In this episode, we're shining a spotlight on the evolving landscape of orexin agonists for the treatment of narcolepsy.

Orexin plays a critical role in regulating wakefulness and loss of orexin signaling is a key feature of narcolepsy type 1.

The development of orexin agonists therefore represents a novel approach to treatment aiming to restore the signaling pathway that is disrupted in the disease.

On August 5th, 2026, Obaparaxin was approved by the FDA for the treatment of narcolepsy type 1 in adults, making it the first orexin-targeted therapy to receive regulatory approval.