ARTICLE IN BRIEF
In a number of large clinical trials, the orexin antagonist suvorexant — the first of its class — was shown to reduce subjective and objective measures of insomnia, but higher doses have met with disapproval from the U.S. Food and Drug Administration.
PHILADELPHIA—The orexin antagonist suvorexant, the first drug of its class, reduces both objective and subjective aspects of insomnia, according to large clinical trials whose results were summarized at the AAN Annual Meeting here in April. But higher, more effective doses have met with disapproval from the United States Food and Drug Administration, meaning that only lower doses are likely to be approved for clinical use.
William Herring, MD, PhD, executive director of clinical neuroscience for the drug's manufacturer, Merck Research Laboratories in North Wales, PA, presented results and approval status for the drug in the Contemporary Clinical Issues plenary session.
Identification of the orexin system in the late 1990s set the stage for development of suvorexant, Dr. Herring explained. Originally discovered in the context of cataplexy, orexin-secreting neurons in the hypothalamus secrete two forms of orexin peptides, A and B, which interact with two downstream receptors, OX1R and OX2R, to promote wakefulness. At night orexin signaling falls, allowing the onset of sleep. While no elevation or overactivity of orexin has been found in those with insomnia, orexin blockade nonetheless emerged as a promising treatment.
Suvorexant is a highly selective antagonist of both the OX1 and OX2 receptors. “This transiently blocks wake signaling, allowing sleep to occur,” explained Dr. Herring. The drug is delivered orally, and has a plasma half-life of about 12 hours.
MULTIPLE CLINICAL STUDIES
The clinical development program was extensive, including 32 phase 1 studies in over 800 individuals, in order to make sure that blockade would not lead to cataplexy, as well as other central nervous system effects such as suicidal ideation, addiction, or respiratory depression. These were followed by a phase 2b study of over 200 patients with insomnia, and three phase 3 trials, one examining long-term safety and two confirming efficacy, conducted in almost 3000 patients.
The phase 3 trials included patients, mostly elderly, from two dozen countries. Most subjects were white, and women made up about two-thirds of the study population, in line with their higher representation among insomnia patients.
In the two efficacy trials, patients were randomized to one of three arms: placebo, low-dose suvorexant, or high-dose suvorexant. The low dose was 20 mg for non-elderly patients and 15 mg for the elderly, while the high dose was 40 mg for the non-elderly and 30 mg for the elderly. Polysomnography and subjective efficacy were recorded over the three months of treatment. At the end of that period, some patients on active treatment were randomly switched to placebo for 1 week, to look for symptoms of rebound or withdrawal. In the yearlong safety trial, patients received placebo or high-dose suvorexant, followed by a two-month randomized switch to placebo, again to look for rebound or withdrawal.
Suvorexant was superior to placebo at improving sleep on multiple measures. Subjective sleep onset was decreased on the high dose by about 10 minutes more than placebo throughout the three-month trials. Polysomnography confirmed this benefit on the first night and after one month, and after three months in one of the trials, though not in the other. An increase in total sleep time of about 25 minutes and a decrease in time awake after sleep onset of about 30 minutes were also seen with treatment.
Improvements for low-dose treatment were smaller, but remained statistically significant. At both doses, there was a trend over time for some decline in objective benefit compared with baseline in both latency to onset of persistent sleep and time awake after sleep onset. The magnitude of subjective measures also showed a dose response, but did not show the same trend of decline with time.
Insomnia patients often have little trouble remaining asleep during the first third of the night, Dr. Herring said, but are awake for as much as an hour during the final third. Among the most important effects from treatment was improvement in sleep maintenance during that final third, with a reduction in wake time of about 25 minutes for low dose and 30 minutes for high dose at the start of treatment, again with some diminishment over time.
In the yearlong safety study, high-dose treatment (the only active arm) remained superior to placebo throughout the study on each of three subjective measures, with roughly stable improvements of about 25 minutes in time to sleep onset, 35 minutes in awake time after sleep onset, and 60 minutes in total sleep time. “Suvorexant provides a consistent, long-term benefit in insomnia patients,” he concluded.
Discontinuation rates were low and similar among groups, indicating that the drug was well tolerated, Dr. Herring said.
The rates of adverse events, including serious adverse events, were similar among placebo, low-dose, and high-dose groups across the three trials. Drug-related adverse events were higher in those receiving active treatment. Somnolence affected 3 percent of those on placebo, 7 percent of those on the low dose, and 11 percent of those on the high dose of the drug. There was no evidence of rebound or withdrawal effects. There was no evidence of an increase in cataplexy, falls, or sleep paralysis. There was one report of suicidal ideation on placebo, one on low dose, and eight on high dose.
While Merck judged the high-dose regime to be generally safe and well tolerated, Dr. Herring said, the Food and Drug Administration “concluded that the totality of the safety and tolerability data across the development program do not support” the 40/30 mg dose for treatment of insomnia. “Consequently, the 20/15 mg data are likely to be most relevant for clinicians.” Merck and the FDA are currently determining the need for further trials to support an even lower dose for certain patients.
Suvorexant's novel mechanism of action “may provide benefit to patients whose insomnia is not well controlled on current medications,” according to Thomas Scammell, MD, sleep researcher and professor of neurology at Harvard Medical School, who was not involved in the study. It and other orexin antagonists “may be especially helpful for patients who wake during the night and have trouble getting back to sleep. This is a tough pharmacological problem” not addressed by most current drugs, he said.
“We haven't had any major innovations in new mechanisms of action for treatment of insomnia over the past decade,” said Phyllis C. Zee, MD, PhD, professor of neurology, neurobiology, and physiology, and director of the Sleep Disorders Center and the Sleep Medicine Fellowship at Northwestern University Medical School in Chicago, IL, who was not involved in the study. There is a major need for new agents, especially given the side effect profile of GABA drugs, and the fact that at least 10 percent of the population, and almost half the elderly, experience insomnia.
Suvorexant “clearly does improve both objective and subjective measures” of sleep, said Dr. Zee. Importantly, she said, effects were seen on both initiation and maintenance, both of which are troubling to patients. While the effect on initiation was “modest,” comparable with that provided by GABA drugs, the effect on maintenance was “more robust,” albeit at the higher dose.
She was encouraged that there was no cataplexy seen, “but we need to remember this is a relatively healthy population, without comorbid neurologic or psychiatric disorders,” which may raise the risk of cataplexy. Assessment of safety in these populations is crucial, she said. But Dr. Scammell noted that current drugs can be problematic in these populations, as well as in the elderly and patients with a history of substance abuse, and that orexin antagonists may therefore play an important role in such patients.
Dr. Zee noted that the commonly used insomnia medications don't bind to orexin receptors, suggesting there may be a role for adjunctive therapy in insomnia treatment, especially perhaps for antidepressants, which are sometimes prescribed for this condition.
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However, she noted, there is still much to be learned about the orexin system, whose receptors are widespread in the brain, including in the ventral tegmental area, involved in addiction. “It would not be surprising if they have more functions than sleep-wake promotion.”
That may represent an opportunity, she suggested. “We can think about stress modulation, pain modulation, feeding and metabolism,” and perhaps even cognition, being affected by the orexin system.
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