PHILADELPHIA – An orexin receptor antagonist – the first drug to affect a neural system that promotes wakefulness – has proven safe and effective for up to 1 year in a pooled analysis of three phase III studies of patients with insomnia.
The drug (suvorexant) significantly improved both subjective and objective measures of sleep, including sleep onset, total sleep time, and wakefulness after sleep, Dr. W. Joseph Herring said at the annual meeting of the American Academy of Neurology.
Based on these data, the manufacturer, Merck, proceeded last year to preliminary talks with the Food and Drug Administration. The committee considering suvorexant recommended that Merck focus on the smaller of two proposed dose ranges – 20 mg for people up to 64 years of age, and 15 mg for those aged 65 years and older.
Although the proposed higher doses of 40 mg for younger patients and 30 mg for older patients, were deemed safe and effective, the lower dose recommendation by the FDA is consistent with its "usual recommendations to go with lower doses of sleep medications," said Dr. Herring, Merck’s executive director of neuroscience clinical research. "So this 15/20-mg regimen is the most likely to be clinically relevant to prescribers."
The orexin neural system was discovered in the late 1990s, Dr. Herring noted. Orexin neurons release two neuropeptides that interact with downstream receptors that promote wakefulness. Secretion follows a circadian rhythm. Suvorexant orexin antagonists block the activity of this wake-signaling system, allowing sleep to occur.
So far, studies have investigated the drug in almost 3,000 patients; 160 of these were treated for at least a year. The three phase III trials comprised more than 275,000 exposure nights. Most of the patients were women; 46% of the patients were aged 65 years or older.
Sleep was measured by subjective assessment and objective scales, including polysomnography.
In the two efficacy studies, the higher doses decreased time to persistent sleep by 15 minutes on the first night; the lower doses did so by 10 minutes. By 3 months, the high-dose group’s decreased time to persistent sleep was 5 minutes; the low dose group’s time was lowered to 4 minutes.
On the first night, the high-dose drug reduced wakefulness after sleep by 40 minutes; the low-dose drug did so by 35 minutes. After 3 months, the reductions were similar (about 25 minutes).
When the night was divided into thirds, both doses decreased wakefulness significantly and about equally, especially in the second and third fractions of the night.
In the subgroup of 160 patients who were treated for at least 12 months, the drugs showed persistent efficacy overall, although the high doses were somewhat more effective, Dr. Herring said.
A multivariate regression analysis found that, compared with placebo, patients who took the high dose were 2.4 times more likely to be considered responders at 1 month and 1.8 times more likely to be responders at 3 months. Those who took the low dose were 1.8 times more likely to respond at 1 and 3 months.
"The drugs really proved about equal in the chances of a good response," said Dr. Herring.
Although there were more adverse events in the active groups than in the placebo groups – and more in the high-dose groups, compared with the low-dose groups – suvorexant was considered safe, he said. The discontinuation rates for drug-related adverse events in the high-dose, low-dose, and placebo groups were 4%, 3%, and 2%, respectively.
The most common issues were next-day somnolence (3% for placebo, 7% with the low dose, and 11% for the high dose, respectively); headache (6%, 7%, and 7%, respectively); and fatigue (2%, 2%, and 4%, respectively).
Few serious adverse events were reported. These included one case of suicidal ideation each in the placebo and low-dose groups, and eight cases in the high-dose group. Dr. Herring said these were mild to moderate and of short duration.
There were no cases of falls or cataplexy, although two patients taking the high dose showed complex sleep behaviors.
Neither of the doses was associated with withdrawal symptoms or clinically significant insomnia rebound during the washout periods. "The drug appears to have a low potential for abuse," Dr. Herring noted.
Merck sponsored the studies. Dr. Herring is a full-time employee of the company.
On Twitter @alz_gal