A Newly Available Drug for Insomnia Addresses Both Sleep Onset and Maintenance0

DAYVIGO targets orexin receptors to facilitate sleep. It’s been trialed in the elderly and in patients with common comorbidities.

By Sree Roy

Ivan Cheung was particularly affected by the story of a woman with insomnia who took naps in her car during lunch and other breaks just to function at her job. Cheung, chairman of Eisai Inc and president of its global neurology business group, watched this video as part of his engagement with patients during the development of Eisai’s insomnia drug DAYVIGO (lemborexant). In the video, it’s apparent that the woman has stashed blankets and other sleep accessories in her vehicle. “It’s tough to watch,” says Cheung, who holds an MBA from Harvard University.

Eisai’s DAYVIGO was FDA approved on December 20, 2019, to treat adults with insomnia. As a single agent that addresses both sleep onset and sleep maintenance, its developers say DAYVIGO is unique among hypnotics. DAYVIGO launched first in the United States (in 5 mg and 10 mg tablets), has since launched in Japan, and is expected to be available in select other countries soon.

Tushar Patel, PhD, vice president, global strategic marketing, neurology business group, at Eisai, says, “People don’t like the fact that they can’t fall asleep or stay asleep. But what patients really get emotional about…is the impact on their next day ability to function. They express anxiety, anger, and other strong emotions. For us as a team, this was very powerful.”

Russell Rosenberg, PhD, DABSM, was principal investigator in DAYVIGO’s clinical trials. He emphasizes that insomnia treatment should always involve cognitive behavioral therapy. But for patients who also use a prescription pharmaceutical, DAYVIGO is a “perfectly reasonable first choice for physicians,” he says, adding, “That’s up to them and their patients. In terms of its efficacy and safety, I see no reason why it couldn’t be a firstline treatment, whether for a hypnotic-naive patient or a patient who is more experienced with hypnotics.”

Rosenberg also emphasizes that DAYVIGO dosing is only once per night. “It’s not to be taken in the middle of the night,” he says, and the patient must have at least 7 hours of time in bed available.

Eisai Develops Orexin Receptor Antagonist In-House

In the late 1990s, the orexin signaling system (also known as the hypocretin system) was discovered and its role in sleep and wake characterized. Within a few years, Eisai initiated a program to look at the neuropeptide orexin as a therapeutic target for sleep and neurological disorders.

DAYVIGO is an orexin receptor antagonist. “It’s thought that it works by antagonizing the wakeup system,” Rosenberg says, essentially tamping it down so sleep can occur. It targets the orexin 1 and orexin 2 receptors, leaning preferentially toward the orexin 2 receptor. “The receptor kinetics become very important,” Patel says. “One of the things we got right in early discovery is the balance between orexin 1 and orexin 2 receptors and how quickly it’s on and off. So when endogenous orexin levels start to rise, you don’t have the antagonist there at a time of day when you want to start waking up.”

Sleep professionals are familiar with BELSOMRA (suvorexant), another orexin receptor antagonist indicated for insomnia. There are no head-to-head studies comparing suvorexant to lemborexant. But, Rosenberg says, “All orexin receptor antagonists are not the same.”

An Eisai-funded study published in JAMA Network Open found DAYVIGO to perform better than zolpidem tartrate extended release (AMBIEN CR) to treat insomnia disorder in patients 55 years and older. “We are very proud DAYVIGO is the first FDA-approved medication for insomnia with a direct head-to-head comparison,” Cheung says. “That is a bold stand that we’ve taken.”

[RELATED: Insomnia in the Elderly Is Often Eclipsed by Other Disorders But Recognizing It Can Help Resolve Comorbidities]

Clinical Trials Designed to Replicate Real-Life Scenarios

“In the past, most studies with hypnotics, especially the pivotal trials, excluded comorbidities,” Rosenberg says. “But now that we understand that insomnia is comorbid with so many psychiatric and medical disorders, this trial was designed to be more inclusive….It’s more generalizable to the kind of patients who walk into a physician’s door.”

As long as they were stable, comorbidities such as depression, hypertension, and diabetes were not used as a reason for exclusion in DAYVIGO’s pivotal trials. What’s more, older adults were included; indeed, the SUNRISE 1 trial focused on adults 55 years and older.

Patel says, “One of the places where we made a lot of effort was to study older and elderly patients. There’s tremendous unmet need from an efficacy and safety standpoint for that group.” The safety profile and dosing for DAYVIGO were determined to be the same for older patients as for younger ones. Patel adds, “We show that there is no difference in postural stability.”

The most frequent adverse event in the trials was somnolence, which occurred at twice the rate compared to the placebo group. “Somnolence is an issue with regard to the potential falls for older adults, especially at the higher 10 mg dose,” Rosenberg says, though falls were not captured in the study.

Via the self-report SUNRISE 2 trial (which included a mix of patient ages), DAYVIGO has been studied for safety out to 1 year. Patel says, “It’s the only insomnia agent that’s been studied for that long. It gives a lot of confidence when you’re prescribing this, particularly to vulnerable populations, that we’ve got a lot of long-term safety data.”

Due to using Bayesian adaptive design—a statistical method that allows trial design to be adapted to improve efficiency, Eisai figured out the dose window early in its phase 2 trials. The now-approved 5 mg and 10 mg doses need no adjustment for age, sex, or body mass index. This is important since the prevalence of insomnia increases with age and is also greater for women (compared to men), Patel says.

DAYVIGO’s vehicle driving study—which assesses how well a person stays in the middle of the road lane—did not find statistically significant differences between DAYVIGO and placebo. But some patients on the 10 mg dose experienced more drifting, and a warning cautions patients about the possibility of impaired mental alertness.

Don’t Prescribe to People with Narcolepsy

Though insomnia can be comorbid with the neurological sleep disorder, DAYVIGO is contraindicated in patients with narcolepsy. “We don’t want to reduce their orexin levels further,” Rosenberg says.

The prescription label includes warnings about the potential of narcolepsy-like symptoms, including cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations. “Orexin is primary neuropeptide/neurotransmitter implicated in narcolepsy, especially in narcolepsy type 1,” Rosenberg says. Though Rosenberg did not see narcolepsy-like symptoms manifest at his site during the clinical trials, narcolepsy-like symptoms can be “a factor of this class of medication,” he says.

Managing Patients on DAYVIGO

“I think insomnia can be managed well not only in a primary care setting but in a sleep clinic setting as well,” Rosenberg says. “I think within the first 30 days patients should be monitored relatively frequently. They should be encouraged to call into the nurse or physician about what potential adverse events they’re having or if they’re responding well. If they’re not responding well within the first week or two weeks, then the physician should thinking about comorbidities that could be playing a role in the insomnia.”

Once a patient is comfortable using the medication, Rosenberg says that following up every 2 to 3 months would be appropriate. There are no restrictions on the duration of utilization of DAYVIGO, he says.

Eisai also offers a tool, dubbed DAYVIGO Together, to help manage patients. The support program gives patients direct phone access to DAYVIGO nurse educators who can answer questions about the medicine.

Sree Roy is editor of Sleep Review.

Photo credit: ID 125352762 © Rido | Dreamstime.com

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