SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel agreed that suvorexant, a drug for insomnia with a novel mechanism of action, was effective in improving the time it took to get to sleep, and for maintenance of sleep in elderly and younger adults. The panel also agreed that its safety profile was acceptable at the lower starting doses.
But at the May 22 meeting, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee was divided on whether the higher doses recommended for people with inadequate responses on the starting doses were safe, because serious adverse events such as evidence of impaired driving and excessive daytime somnolence were increased at those doses.
The panel was not asked to vote on whether to recommend approval of the drug, which is being reviewed for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance. If approved, suvorexant, an orexin receptor antagonist, would be the first drug in this class to be approved for insomnia. The FDA usually follows the recommendations of its advisory panels.
The manufacturer, Merck Research Laboratories, studied the drug in almost 3,000 patients, including 1,784 in phase III studies, and has recommended doses of 20 mg (starting dose) up to 40 mg taken at bedtime for adults aged under 65 years, and 15 mg (starting dose) up to 30 mg for people aged 65 and older.
Suvorexant blocks the binding of orexin A and B neuropeptides to orexin receptors, "presumably inhibiting activation of neurons to the arousal system," according to the FDA.
Testing of suvorexant involved three phase III studies – two studies that compared the effects of higher and lower doses against placebo on the onset and maintenance of sleep over 3 months, and a 1-year safety study in a total of 2,809 patients, including 1,784 treated with suvorexant. The drug was effective in improving the onset of and maintenance of sleep, and was sustained for a year, according to the company. In the phase III studies, next-day somnolence was reported by 3% of those on placebo, compared with 7% and 11% of those on low and high doses of suvorexant, respectively. Excessive daytime sleepiness was reported by 0.2% of those on placebo, compared with 0.6% and 1.1%, of those on low and high doses, respectively.
The FDA raised concerns about next-day somnolence, suicidal ideation, impaired driving, and other potentially serious side effects of the drug that appeared to be dose related, and concluded that a dose below 15 mg would be preferable. "Suvorexant is effective but not safe at the higher doses mainly studied," said Dr. Ronald Farkas, clinical team leader in the division of neurology products at the FDA’s Center for Drug Evaluation and Research. The risk-benefit profile may be more favorable at lower doses, since lower doses have similar efficacy, and phase II data suggested that the 10-mg dose may be effective, he told the panel.
In a 16-0 vote with 1 abstention, the panel agreed that based on the clinical trial results, suvorexant was effective for sleep maintenance, and voted 12-4 with 1 abstention, that the drug was effective for improving sleep onset, reflecting less robust effects on this endpoint.
The panel voted 13-3 with 1 abstention that the starting doses were acceptably safe. But they voted 8-7 with 2 abstentions that the safety of the higher doses – 40 mg among those under age 65 and 30 mg among those aged 65 and older – were not acceptable.
"Even though I think the lower doses are probably safe, I have to assume that many patients are going to graduate up to the higher doses," said Dr. Robert Clancy, professor of neurology and pediatrics at the University of Pennsylvania, Philadelphia. Dr. Clancy voted that the safety of the higher doses was not acceptable. He cited the 1.1% rate of excessive daytime sleepiness associated with the higher dose as a particular concern, which he predicted would result in fatalities, although none occurred in trials.
Dr. Ronald Chervin, professor of neurology and director of the sleep disorders center at the University of Michigan, Ann Arbor, was among those who agreed that the higher doses were acceptable. "My gut feeling overall is that we’re not seeing anything different in terms of a dose response on the safety side ... than what we would see for any of the hypnotics that we are currently using," he said.
The company expects the FDA to take action on the drug by mid-year, and if approved, the drug will have to go through the drug scheduling process, the company said in a statement after the meeting.