First-in-Class Insomnia Treatment Headed for Approval?

Pauline Anderson

November 29, 2012

A new study suggests that suvorexant (Merck & Co. Inc), the first agent of its kind that works on the orexin signaling pathway to selectively dampen unwanted wakefulness, could be a safe and effective alternative to current treatments for insomnia.

A newly published study shows that this investigational agent improves sleep efficiency, with dose-related effects.

"The trial was successful in that it allowed us to identify doses that both provided sleep onset and sleep maintenance efficacy but it also showed that it was well tolerated by patients," lead author W. Joseph Herring, MD, PhD, executive director of clinical research at Merck, told Medscape Medical News.

The randomized, double-blind, placebo-controlled crossover study was published online November 28 in Neurology. It was funded by Merck Research Laboratories.

Since completion of this phase 2b study, Merck released phase 3 studies characterizing the drug's safety and efficacy at 2 sleep meetings earlier this year, 1 of these reported by Medscape Medical News. The company also announced that the US Food and Drug Administration (FDA) has accepted its New Drug Application for suvorexant.

Transient Antagonism

First described in the late 1990s, the orexin system "is very focused and targeted towards sleep/wake" and represents "evolving science," said Dr. Herring. It's believed that antagonism of the orexinergic system temporarily reduces orexinergic tone, thereby reproducing symptoms consistent with narcolepsy.

But whereas patients with narcolepsy fall asleep excessively during the day, suvorexant transiently antagonizes downstream orexin receptors, not the neurons, allowing patients to sleep at night with no daytime symptoms, said Dr. Herring.

The newly published study was carried out at 29 sites in the United States and 12 sites in Japan. Prospective participants were entered into a 1-week run in during which polysomnography was performed. To quality for the study, patients had to have a latency to persistent sleep (LPS) of 20 minutes on 2 nights a week apart and a mean wake after sleep onset (WASO) of at least 60 minutes on both nights.

Dr. Joseph Herring

The study randomly assigned 254 patients aged 18 to 64 years with confirmed primary insomnia. They had an average total sleep time (TST) of 316 minutes, an average sleep efficiency or SE (TST divided by time in bed [fixed at 480 minutes] multiplied by 100) of 66%, an average WASO of 101 minutes, and an average LPS of 69 minutes. Their average Insomnia Severity Index score was 17, which corresponds to insomnia of moderate severity. The average Sheridan Disability Scale score was 9, indicating mild disruption of work/social/family life by disease symptoms.

The study compared 4 doses of the drug (10, 20, 40, and 80 mg) with placebo in a double-dummy design (with patients receiving 1 of 4 doses and placebo). Each of the 8 treatment sequences lasted 4 weeks. A total of 228 patients completed the study.

The study showed that all doses of suvorexant were more effective than placebo for SE (P < .01), with improvements, for example, ranging from 5% (10 mg) to 13% (80 mg) on night 1. All doses were also more effective than placebo in extending the WASO, from about 21 to 37 fewer minutes awake compared to placebo (P ≤ .001).

Sleep Architecture

As for sleep architecture, all suvorexant doses increased TST seemingly consistently across hours of the night. Compared with placebo, the TST increases ranged from 22 to 62 minutes depending on the dose and evaluation night. This increase was mainly attributable to greater time spent in REM and stage 2 sleep.

There were also increases in slow wave sleep, but these were "more or less proportional to effects seen with placebo," said Dr. Herring.

The positive effects of the drug appeared to be dose-related, with the 40-mg and 80-mg doses the most consistently effective, and the 10-mg dose the least effective.

Patients completed questionnaires of sleep assessment using an electronic patient diary. According to their reports, the 40- and 80-mg doses of suvorexant were superior to placebo for subjective time to sleep onset, subjective TST, and subjective quality of sleep. The 80-, 40-, and 20-mg doses showed greater improvement of insomnia at week 4 compared with placebo as assessed by the total score on the Insomnia Severity Index.

Generally, suvorexant had no effect on the number of wakenings, a measure of sleep fragmentation.

Well Tolerated

Suvorexant was well tolerated, with no reported serious adverse events and no patient deaths. The most common adverse event was somnolence, which showed a dose-related increase. Other adverse events included headache, dizziness, abnormal dreams, upper respiratory tract infection, urinary tract infection, and an increase in alanine aminotransferase that was mild and resolved spontaneously.

The authors noted that anterograde amnesia, an adverse effect associated with benzodiazepine receptor agonists, was not reported. No adverse events indicating potential for abuse occurred.

Although orexin is thought to possibly play a role in promoting weight gain, the study found no evidence that patients taking suvorexant had weight gain relative to placebo.

There was no significant evidence of insomnia rebound or withdrawal effects after the drug was stopped.

The total number of patients included in this study was relatively small. Other limitations were the somewhat brief treatment duration (4 weeks) and lack of elderly patients.

However, at SLEEP 2012, the 26th Annual Meeting of the Associated Professional Sleep Societies held in June, Merck released results of a 3-month phase 3 multicenter controlled trial of a 30-mg dose of the drug in older patients as well as the 40-mg dose in nonelderly patients. The research showed that suvorexant significantly reduced the time it took patients to fall asleep and increased the time they stayed asleep as early as the first night compared to placebo.

Another trial investigated lower doses: 20 mg in younger patients and 15 mg in older ones.

Best Profile

Dr. Herring believes the results point to the 40-mg dose as providing "the best benefit to risk profile," but that the 20-mg dose could be an option for patients who don't tolerate the higher dose. "The phase 3 program was set up to kind of look at those 2 doses and provide options for patients."

The positive reports continued at the 21st Congress of the European Sleep Research Society (ESRS) in September, where the company presented results of a 12-month study of 781 patients who were randomly assigned to receive a consistent dose of suvorexant (40 mg in patients 18 - 64 years of age or 30 mg in those 65 years and older) or placebo.

Again, patients who took suvorexant reported that they fell asleep significantly faster, stayed asleep significantly longer, and spent significantly less time awake during the night compared with patients who received placebo (P < .001 during the first month).

With this latest study, which included a large proportion of elderly patients, "we now have a robust elderly database," said Dr. Herring. This is important because this segment of the population makes up a large percentage of patients with insomnia.

Also at that meeting, the company reported on efficacy data from patients who continued to take suvorexant through 14 months. These patients experienced mean improvements in their ability to fall asleep and stay asleep that were consistent with those seen during the first 12 months compared with placebo.

Adverse experiences reported during this 2-month discontinuation phase were generally consistent with those reported during the 12-month study. Compared with patients who continued to take placebo, those who switched from suvorexant to placebo had no clinically meaningful evidence of withdrawal or rebound insomnia.

Earlier this month, Merck announced that the FDA has accepted its filing of a New Drug Application for suvorexant. If approved, suvorexant would be the first orexin receptor antagonist approved for patients with primary insomnia.

New Class of Drugs

Asked for comment on these findings, Pradeep Sahota, MD, professor and chair, Department of Neurology, director, Sleep Disorders Center, University of Missouri School of Medicine, Columbia, and a member of the American Academy of Neurology, said it's "exciting" to see a new class of drugs being investigated.

The current study and others suggest a significant benefit by way of improved sleep efficiency, Dr. Sahota told Medscape Medical News, adding that medication discontinuation is not accompanied by significant withdrawal symptoms or rebound insomnia and that the adverse effect profile seems "reasonable."

However, she said she has some concerns:

  • First, the long-term effects of using orexin agonists are unknown. "We don't know if the medication could potentially induce narcolepsy-like symptoms in some patients. And while there are no reports of cataplexy, there is a reported increase in excessive daytime sleepiness (EDS) especially on high doses (11.5% in this study and 13.2% vs. 2.7% for placebo in another study). In fact, 1 patient was reported to have extended EDS for 4 hours."

  • There were 2 reports each of sleep paralysis and visual hallucinations. "This raises concern re: the potential to see dissociated states in these patients," she said.

  • Because insomnia can be acute or chronic and even chronic insomnia can be multifactorial, the medication would not be the answer for every patient with insomnia. "While the medication will hopefully prove to be useful for some patients, others will need other pharmacological and behavioral interventions," said Dr. Sahota. She noted that current mainstays of insomnia treatment include benzodiazepines and, more recently, gamma-aminobutyric acid  receptor agonists ("the Z-drugs") as well as cognitive behavioral therapy. Antihistamines, melatonin, and melatonin receptor agonists are also used.

"Further research, including long-term studies and careful data collection, will be needed before we can announce a major advance in treatment of insomnia," she said.

The study was funded by Merck Research Laboratories. Dr. Herring is an employee of Merck and owns stock/stock options in Merck.

Neurology. 2012;79:2265-2274. Published online November 28, 2012. Abstract

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....