Therapeutic Potential of Orexin Agonist ALKS 2680 on Display at SLEEP 2024

Ron Grunstein, MD, PhD

Narcolepsy is a persistent sleep disorder that has a particular onset in teenagers and is marked by the aid of immoderate daytime sleepiness, which could have excessive effects on the patient. Type 1 narcolepsy is distinguished by cataplexy, which is muscle feebleness caused by intense emotional responses. Pharmacological intervention is typically needed in these patients. Drugs such as modafinil, armodafinil, methylphenidate, pitolisant, solriamfetol, and amphetamines, have been proven to be useful in treating narcolepsy but have certain adverse effects and cannot be given to a patient with a history of cardiovascular diseases.

Orexin receptor agonist bind to orexin receptors in the brain. which are activated by neuropeptides called orexins. As the master regulator of wakefulness systems in the brain, orexin keeps us awake. There are a handful of orexin agonists in development for the treatment of narcolepsy, including ALKS 2680. ALKS 2680 is a novel, oral, selective orexin 2 receptor agonist designed to address the underling pathology of narcolepsy with the goal of improving duration of wakefulness and providing cataplexy control.

At the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, data from a phase 1 study highlighted the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALKS 2680 in a cohort of patients with narcolepsy type 1. resulted in statistically significant and clinically meaningful improvements in mean sleep latency on the Maintenance of Wakefulness Test (MWT), with a mean change from baseline versus placebo of 18.4 minutes at the 1 mg dose (P = 0.0002), 22.6 minutes at the 3 mg dose (P = 0.0001), and 34.0 minutes at the 8 mg dose (P ≤ 0.0001)(least squares mean difference). At the 3 mg and 8 mg doses, the observed mean MWT scores over an 8-hour period post-dose were within the reported normal range for healthy individuals.

During the meeting, principal investigator Ron Grunstein, MD, PhD, head of Sleep and Circadian Research at the Woolcock Institute of Medical Research, sat down to give thoughts on the data, including some of the top findings. He spoke about the promising mechanism of action of ALKS 2680, the safety profile observed, and its ongoing phase 2 trial, where it will be further assessed for efficacy and safety.

NeurologyLive: Can you overview some of the major takeaways from this phase 1b study?

Ron Grunstein, MD, PhD: This was a phase 1b study, a first-in-patient study, and it involved a single dose of the orexin agonist, but we were testing different doses and placebo. So, dose 1 day off, dose 2 day off, dose 3 etc. I think the take home message was that it was a very successful study so that at all doses of the active drug, there was an improvement in sleepiness, but it depended on the dose. When we got to 8 milligram dose, we had basically a normal level of wakefulness in the participants in the study, all of whom had type 1 narcolepsy.

Regarding the mechanism of action of ALKS 2680, why do we believe it can be successful in narcolepsy?

Basically, orexin is a neurotransmitter that exists in the lateral hypothalamus with widespread connections to areas of the brain that are involved with wakefulness. People with narcolepsy type 1 are deficient in orexin, so if you have a receptor agonist, you're going to replace what's missing. What that means is that you're also going to get this widespread effect on wakefulness. Based on the studies, it’s been a success in the phase 1b portion, showing that it works. It means that we can bring it to a phase 2 trial, and if that [is successful], then phase 3, etc. So it's promising.

What does the phase 2 trial ential?

The phase 2 trial is already ramping up for narcolepsy type 1. There's a poster here at the conference which outlines the design of the study. Basically, it will involve 6 weeks of exposure to one of three doses, plus placebo. People are randomized to one of those, and then there's a phase where doses can be varied as well as an extension for another seven weeks [of treatment]. That should provide information that would be suitable for a phase 3 study, and also look at any adverse events and things like that. Again, it's in narcolepsy type 1, which means the patients need to have cataplexy. They need to have either positive HLA or low orexin levels in their cerebrospinal fluid, similar to the patients we used in the phase 1b study. It's going to be done in in the United States and Australia, and includes about 80 patients.

From a safety standpoint, are there any early concerns with this medication?

We haven't seen anything that would make you nervous about doing a phase two study. That’s the overarching sort of point. Occasionally, there were patients in the higher dose groups that had pollakiuria (increased urination). How much that's going to be a problem will be clear from the phase two study. But as far as I'm aware, it’s a common problem regarding the class of orexin agonists. Otherwise, things were transient. One patient had transient nausea, which settled very quickly. The report in our poster says insomnia, and that was my interpretation, because patients were suddenly awake and they wanted to do things. They wanted either phone up their family and say, “I'm so awake, I've never felt like this since I was a kid,” and that sort of stuff, or they were doing work. We had university students who had exams coming up, and so insomnia is usually a complaint. These people weren't complaining about insomnia. The reality about insomnia will only be worked out with later phase studies.

You can see it's certainly shown a fairly consistent profile on the maintenance of wakefulness test. Every patient that we asked had interest in the phase two study. In that sense, it was a very exciting study, but it's early days.

Transcript edited for clarity.