Dr Ron Grunstein Discusses Outcomes, Future Direction of ALKS 2680 Trial for Narcolepsy Type 1

Ron Grunstein, MD, PhD, head of sleep and circadian research, Woolcock Institute of Medical Research, provided insights into the objectives and design of the phase 1 ALKS 2680 study in part 1 of his interview with The American Journal of Managed Care^® (AJMC^®). This research investigated the safety and efficacy of a novel orexin agonist, which had observable benefits for patients managing narcolepsy type 1.

In part 2 of his interview, Grunstein discussed in detail the safety considerations during their trail, outcomes, and ensuing steps in this research. These findings and more developments in sleep research were presented at the 2024 SLEEP: American Academy of Sleep Medicine and Sleep Research Society Annual Meeting.

This transcript has been lightly edited for clarity.

AJMC: Can you discuss the safety assessments conducted throughout the study and any adverse events observed?

Grunstein: From a safety point of view, we looked at regular ECGs [electrocardiograms], blood pressure, or vital signs. We monitored symptoms, subjective feelings, checked out for any symptoms like nausea or what has been observed previously in studies of orexin agonists in healthy volunteers, which is a symptom called pollakiuria, where people essentially urinate more frequently. But from that point of view, we didn't see any sort of effects. There was one case of fairly transient pollakiuria.

We had people who reported insomnia, but it wasn't as a complaint, because these are people who can never stay awake at night and suddenly they were able to do so. I'm not sure I would call it insomnia, but from an adverse event reporting perspective, it was. Participants in the study, when they were awake, even if at 1 am or sometimes 2am, they felt it was great. Sometimes they ring friends or family just to show them that they're awake or they did sort of university work or other work that they had to do. It was not really a complaint of insomnia.

AJMC: What were the key pharmacodynamic effects observed with ALKS 2680 in this study, and how do these effects correlate with improvements in narcolepsy symptoms?

Grunstein: The primary variable of interest was the ability to stay awake on a maintenance of wakefulness test, which is basically when you sit in a comfortable chair, the room is darkened, and we make things conducive to sleep. You're not allowed to do anything to keep yourself awake, like bang your head against something or that sort of thing. You just try and stay awake.

What we found was that people were able to stay awake—certainly not on the placebo, because they'd been withdrawn from their usual medication some weeks earlier—but in the 3 different doses. From the 1-mg dose to the 8-mg dose, there was an increasing level of wakefulness, so much so that on the 8-mg dose, the level of wakefulness was deemed normal. It was a remarkable finding, in my view. We also did pharmacokinetics and blood collection for pharmacokinetic samples. The important thing about this medication is it's once a day. People were concerned about getting a sustained effect with once-a-day dose, and they certainly did. So, there was no plan to change that to a twice a day. In the phase 2 studies, it will be once a day.

AJMC: What are the next steps for the clinical development of ALKS 2680, and how do you envision its potential role in the treatment landscape for narcolepsy type 1?

Grunstein: The next plan is to do a study, which is called Vibrance-1, which is starting to get organized; we are getting ethics approval and so forth. Vibrance-1 will be phase 2 study, which will involve 6 weeks on medication or placebo. There will be 3 different doses of medication and a placebo arm, so people will be randomized to 1 of those 4 arms. And then there's a 7-week follow-up period where everyone gets medication, but it will be able to be titrated. So that should allow us to see efficacy of the medication, follow up on any potential adverse effects, and get some idea of the performance of the medication and subjective symptoms.