Phase 3 Studies With Daridorexant for Insomnia Management

Nathaniel F. Watson, MD, highlights the use of daridorexant for treating patients with insomnia as seen from phase 3 trials and data presented at the World Sleep 2022 meeting and managing adverse events.

C. Michael Gibson, MD: Talk to us about daridorexant in terms of the development program, the trials, and the evidence supporting its use.

Nathaniel F. Watson, MD The trials were published earlier this year in Lancet Neurology. There’s a great paper that I encourage you to read by Emmanuel Mignot and colleagues. They included 2 pivotal studies, which each had about over 900 patients that were randomized to various dosages. The dosages that were tested were 50 milligrams, 25 milligrams, 10 milligrams, and were compared to placebo. The primary end points were ascertained objectively with polysomnographies. It was latent in C2 persistent sleep and then wake after sleep onset. Then, secondary outcomes were subjective total sleep time and the sleepiness component of the Insomnia Daytime Symptoms Impact Questionnaire [IDSIQ], which is a new patient reported outcome measure that was developed according to FDA guidelines to address daytime symptoms in patients with insomnia. At both the 50- and 25-milligram dosages, you found significant improvement over the placebo in study 1 and study 2. The positive effects were more robust in the 50-milligram dose, and importantly, when you talk about the IDSIQ, the Insomnia Daytime Symptoms Impact Questionnaire and the sleepiness domain of that did improve in patients that received the 50-milligram dose of daridorexant. That’s another distinguishing feature between all of these DORAS [dual orexin receptor antagonists], which is the fact that the daridorexant has data showing improvement in daytime sleepiness, where the others really don’t have that. If we looked at adverse effects, they’re fairly comparable between the various dosages. The adverse event that caused study discontinuation occurred in the placebo group. This is rigorously studied. They picked good outcomes and showed a dose response improvement as you went from the 25 to 50 milligram doses in both the primary end points. From the secondary end point standpoint, the 50 milligram-dose showed an improvement in daytime sleepiness.

C. Michael Gibson, MD: We’re always looking for 2 things. There is very objective information that the drug’s doing something. It sounds like they had a lot of good quantitative objective information. On the other hand, you have patients who want to feel better. It sounds like it has the patient-reported outcomes information supporting it as well. Any recent updates on DORAs, and what’s going on with them?

Nathaniel F. Watson, MD: For daridorexant, there was a 40-week extension study conducted by the World Sleep Society. When the patients finished these 2 pivotal trials, which lasted 3 months each, they either stayed on their medication, or those that were on placebo were randomized to placebo or 25 milligrams, and then, they were followed out to an additional 40 weeks. They were followed for a year for the totality of the original pivotal study plus the extension study. This was done to look at treatment, emergent adverse effects, assess safety, and assess the permanence of the positive impacts on the sleep outcomes. Nasopharyngitis was the most common emergent adverse event. They didn’t find any evidence for withdrawal or rebound symptoms after discontinuation. There’s no evidence of tolerance, or dependency for daridorexant. They did show that for the subjective total sleep time, the effects, which were essentially over 60 minutes of more sleep compared to baseline, were persistent for the whole year. Showing that when the medication is taken regularly, it does continue to have positive impacts and positive effects. We don’t have comparative effectiveness studies between all the various DORAs, so we can’t explore that much. From the World Sleep Society meeting, that extension study for daridorexant was very revealing about the efficacy of the medication.

C. Michael Gibson, MD: Are there any drug-drug interactions given some of the other common medications that people take? Are there interactions with the DORAs? How does it do with alcohol and some recreational drugs?

Nathaniel F. Watson, MD: There’s a contraindication with strong CYP3A4 inhibitors in patients taking daridorexant. That’s in the package insert and you have to take that into consideration. Also, there is severe hepatic impairment. A Child-Pugh score higher than 10 would be a contraindication to taking daridorexant. But certainly, you want to think about those CYP3A4 inhibitors like clarithromycin, diltiazem, and others. You’re going to want to be careful with those when co-prescribing that with daridorexant.

C. Michael Gibson, MD: Lastly, are these permanent treatments, or transient kind of situational treatments with DORAs?

Nathaniel F. Watson, MD: It’s interesting. It’s studied as a nightly medication, so the data that we have is only for if it’s taken every night. We see that the therapeutic benefits do seem to improve over time, so we have to think of it as a nightly medication. In fact, I like that because when you think about PRN treatments for insomnia, there’s some problems with that. Number 1 is that you force the patient to begin thinking earlier in the evening if they’re going to have a bad night’s sleep, or not sleep that night. You and I both know that just thinking about having a bad night’s sleep probably starts the ball in motion to having a bad night’s sleep. We want people thinking about a good night’s sleep, not bad night’s sleep. It gets that kind of negative thinking going. Then, if you take it in the middle of the night when you’re having problems sleeping, you’re already having a bad night of sleep and taking the medication then doesn’t necessarily get you back to an optimal night’s sleep. In fact, you may not have the full 7 hours to sleep when you take it and there’s a greater chance that you’d have some residual effects the next day. Those are just some thoughts about that. But really, it’s a bit of a different viewpoint, or a different thought about the management of insomnia that say, “Hey, this is a chronic disease, and we need to treat it with an every-night medication.” It’s perplexing why there’s so much reticence to do that for me. If you poll primary care doctors and ask them, they’ll say that prescription medications are most effective for insomnia, but 50% will only reach for it first. Even though they know it's the best therapy, they won’t go for it. You wonder why that is. Patients say that they are reluctant to discuss their sleep problems with primary care doctors for fear that they’ll get a sleeping pill. What is that all about? There seems to be some stigma around insomnia. There seems to be some stigma, or concern, around what it means to take insomnia medication chronically, whereas people don’t ask those questions if they’re taking a statin, or a beta blocker, or something for cardiovascular disease. As a sleep field, we must understand this phenomenon better.

Transcript edited for clarity

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