David Baxter PhD
Late Founder
Novel Insomnia Drug Safe, Effective in Phase 3 Trials
Megan Brooks, Medscape
June 13, 2012
The investigational dual orexin receptor antagonist suvorexant (Merck) improved sleep onset and maintenance over a 3-month treatment period in 2 pivotal phase 3 efficacy studies. The drug was generally safe and well tolerated in the 2 trials, as well as in a third phase 3 trial lasting 12 months.
The results were presented here today at SLEEP 2012: Associated Professional Sleep Societies 26th Annual Meeting.
Taken together, the data show that suvorexant "improves the ability to fall asleep, the ability to stay asleep and has a good residual effect profile in terms of next day effects and is safe for chronic use as well," study investigator W. Joseph Herring, MD, from Merck, Whitehouse Station, New Jersey, told Medscape Medical News.
In a safety study, patients took suvorexant nightly for a year, which is unusual for a placebo-controlled trial of sleep medications, he added.
Novel Mechanism of Action
Suvorexant has a novel mechanism of action; it targets the neuropeptides orexin receptor-1 and orexin receptor-2, which help to regulate the brain's sleep-wake process. "The orexin system is one that hasn't been [targeted] in the treatment of insomnia previously," Dr. Herring said. "It's a new integral part of the sleep-wake cycle that's been identified over the last decade or so."
"Orexin neurons live in the lateral hypothalamus of the brain and project down into important brain stem centers and through the cortex. Upon awakening, the orexin neurons firing trigger other centers responsible for ramping up wakefulness and maintaining wakefulness over the day. Orexin antagonists like suvorexant block that wakefulness function and facilitate sleep by doing so," Dr. Herring explained.
James Geyer, MD, from Alabama Neurology and Sleep Medicine, PC, in Tuscaloosa, who was not involved in the study, said he's been "following the development of this medication for some time. The availability of a new agent for insomnia which has a different mechanism of action and no evidence of dependence is especially important."
"This type of medication may serve as an excellent adjuvant treatment to cognitive behavioral therapy as well as monotherapy for both sleep onset and sleep maintenance insomnia," Dr. Geyer told Medscape Medical News.
Pivotal Efficacy Data
The 2 pivotal phase 3 efficacy studies of suvorexant were multicenter, randomized, double-blind, placebo-controlled trials in patients with primary insomnia (1021 patients in trial 1 and 1009 in trial 2). Over 3 months, the trials tested against placebo a high and a low dose of suvorexant against placebo: high dose, 40 mg in patients aged 18 to 64 years and 30 mg in patients aged 65 years and older; low dose, 20 mg in patients 18 to 64 years and 15 mg in patients 65 years and older.
At 3 months in trial 1, patients reported that suvorexant reduced the time it took them to fall asleep by 25.7 minutes vs 17.3 minutes with placebo and helped them to sleep 60.3 minutes longer (vs 40.6 minutes with placebo), relative to the time it took before taking suvorexant.
For the objective polysomnographic measures, patients taking suvorexant entered into continuous sleep 36.0 minutes faster (vs 26.6 minutes with placebo) and spent less time awake during the night by 47.9 minutes (vs 25.0 minutes with placebo) compared with the time it took before suvorexant treatment. All of these differences between suvorexant and placebo were statistically significant, the investigators say.
At 3 months in trial 2, patients reported that suvorexant reduced the time it took them to fall asleep by 33.7 minutes (vs 20.5 minutes with placebo) and helped them to sleep 62.8 minutes longer (vs 37.7 minutes with placebo), compared with before taking suvorexant.
For the objective measures at 3 months, suvorexant did not achieve statistical significance on the measure of patients falling into continuous sleep faster than with placebo (-32.2 minutes vs -28.6 minutes; P = .265). However, patients taking suvorexant spent significantly less time awake during the night by 54.2 minutes (vs 24.8 minutes with placebo) compared with before they started taking suvorexant.
"Good" Safety Profile
The researchers report that both dose regimens of suvorexant were generally well tolerated and without evidence of clinically important rebound or withdrawal on discontinuation. "The safety profile is very good," Dr. Herring told Medscape Medical News.
In the 3-month trials, there were no statistically significant next-day objective residual effects compared with placebo, as measured by the Digit Symbol Substitution Test. Roughly 10% of patients taking suvorexant (high or low dose) reported next-day sleepiness at 3 months, compared with roughly 3% of those taking placebo. Cataplexy was not reported in either study. Patients with narcolepsy or cataplexy were excluded from these trials.
No serious drug-related adverse effects were observed in either trial with the high dose of suvorexant.
Similar efficacy and safety data were achieved in the 12-month trial involving 522 patients randomly assigned to suvorexant (40 or 30 mg) and 259 assigned to placebo; 62% of patients in each group completed the trial, and 97% of these completed a discontinuation phase in which the researchers assessed possible rebound and withdrawal effects.
Merck plans to file a New Drug Application for suvorexant with the US Food and Drug Administration in 2012. If the drug is approved, it would be the first orexin receptor antagonist approved for use in patients with difficulty falling or staying asleep, the company says.
The studies were funded by Merck. Most of the authors are employees or have financial relationships with the company. Dr. Geyer has disclosed no relevant financial relationships.
Source: SLEEP 2012: Associated Professional Sleep Societies 26th Annual Meeting. Abstracts #LBA-4 and #0641. Presented June 13, 2012
Megan Brooks, Medscape
June 13, 2012
The investigational dual orexin receptor antagonist suvorexant (Merck) improved sleep onset and maintenance over a 3-month treatment period in 2 pivotal phase 3 efficacy studies. The drug was generally safe and well tolerated in the 2 trials, as well as in a third phase 3 trial lasting 12 months.
The results were presented here today at SLEEP 2012: Associated Professional Sleep Societies 26th Annual Meeting.
Taken together, the data show that suvorexant "improves the ability to fall asleep, the ability to stay asleep and has a good residual effect profile in terms of next day effects and is safe for chronic use as well," study investigator W. Joseph Herring, MD, from Merck, Whitehouse Station, New Jersey, told Medscape Medical News.
In a safety study, patients took suvorexant nightly for a year, which is unusual for a placebo-controlled trial of sleep medications, he added.
Novel Mechanism of Action
Suvorexant has a novel mechanism of action; it targets the neuropeptides orexin receptor-1 and orexin receptor-2, which help to regulate the brain's sleep-wake process. "The orexin system is one that hasn't been [targeted] in the treatment of insomnia previously," Dr. Herring said. "It's a new integral part of the sleep-wake cycle that's been identified over the last decade or so."
"Orexin neurons live in the lateral hypothalamus of the brain and project down into important brain stem centers and through the cortex. Upon awakening, the orexin neurons firing trigger other centers responsible for ramping up wakefulness and maintaining wakefulness over the day. Orexin antagonists like suvorexant block that wakefulness function and facilitate sleep by doing so," Dr. Herring explained.
James Geyer, MD, from Alabama Neurology and Sleep Medicine, PC, in Tuscaloosa, who was not involved in the study, said he's been "following the development of this medication for some time. The availability of a new agent for insomnia which has a different mechanism of action and no evidence of dependence is especially important."
"This type of medication may serve as an excellent adjuvant treatment to cognitive behavioral therapy as well as monotherapy for both sleep onset and sleep maintenance insomnia," Dr. Geyer told Medscape Medical News.
Pivotal Efficacy Data
The 2 pivotal phase 3 efficacy studies of suvorexant were multicenter, randomized, double-blind, placebo-controlled trials in patients with primary insomnia (1021 patients in trial 1 and 1009 in trial 2). Over 3 months, the trials tested against placebo a high and a low dose of suvorexant against placebo: high dose, 40 mg in patients aged 18 to 64 years and 30 mg in patients aged 65 years and older; low dose, 20 mg in patients 18 to 64 years and 15 mg in patients 65 years and older.
At 3 months in trial 1, patients reported that suvorexant reduced the time it took them to fall asleep by 25.7 minutes vs 17.3 minutes with placebo and helped them to sleep 60.3 minutes longer (vs 40.6 minutes with placebo), relative to the time it took before taking suvorexant.
For the objective polysomnographic measures, patients taking suvorexant entered into continuous sleep 36.0 minutes faster (vs 26.6 minutes with placebo) and spent less time awake during the night by 47.9 minutes (vs 25.0 minutes with placebo) compared with the time it took before suvorexant treatment. All of these differences between suvorexant and placebo were statistically significant, the investigators say.
At 3 months in trial 2, patients reported that suvorexant reduced the time it took them to fall asleep by 33.7 minutes (vs 20.5 minutes with placebo) and helped them to sleep 62.8 minutes longer (vs 37.7 minutes with placebo), compared with before taking suvorexant.
For the objective measures at 3 months, suvorexant did not achieve statistical significance on the measure of patients falling into continuous sleep faster than with placebo (-32.2 minutes vs -28.6 minutes; P = .265). However, patients taking suvorexant spent significantly less time awake during the night by 54.2 minutes (vs 24.8 minutes with placebo) compared with before they started taking suvorexant.
"Good" Safety Profile
The researchers report that both dose regimens of suvorexant were generally well tolerated and without evidence of clinically important rebound or withdrawal on discontinuation. "The safety profile is very good," Dr. Herring told Medscape Medical News.
In the 3-month trials, there were no statistically significant next-day objective residual effects compared with placebo, as measured by the Digit Symbol Substitution Test. Roughly 10% of patients taking suvorexant (high or low dose) reported next-day sleepiness at 3 months, compared with roughly 3% of those taking placebo. Cataplexy was not reported in either study. Patients with narcolepsy or cataplexy were excluded from these trials.
No serious drug-related adverse effects were observed in either trial with the high dose of suvorexant.
Similar efficacy and safety data were achieved in the 12-month trial involving 522 patients randomly assigned to suvorexant (40 or 30 mg) and 259 assigned to placebo; 62% of patients in each group completed the trial, and 97% of these completed a discontinuation phase in which the researchers assessed possible rebound and withdrawal effects.
Merck plans to file a New Drug Application for suvorexant with the US Food and Drug Administration in 2012. If the drug is approved, it would be the first orexin receptor antagonist approved for use in patients with difficulty falling or staying asleep, the company says.
The studies were funded by Merck. Most of the authors are employees or have financial relationships with the company. Dr. Geyer has disclosed no relevant financial relationships.
Source: SLEEP 2012: Associated Professional Sleep Societies 26th Annual Meeting. Abstracts #LBA-4 and #0641. Presented June 13, 2012
