Generic Name: Suvorexant (DORA-22, MK4305)
Brand Name: Not Assigned
Approval Status: Not Approved; NDA submitted to FDA; Complete Response Letter from FDA received by Merck on July 1, 2013; further approval status pending
Company: Merck & Co.
Proposed Indication: Treatment of insomnia (difficulty in falling or staying asleep).

The New Drug Application (NDA) for suvorexant was submitted in November 2012 and Merck received an FDA Complete Response Letter in July 2013; resubmittal of the NDA for approval of suvorexant is pending. In the Complete Response Letter, the FDA stated:

  • the efficacy of suvorexant has been established at doses of 10 mg to 40 milligram (mg) in elderly and nonelderly adult patients;
  • 10 mg should be the starting dose for most patients, and must be available before suvorexant can be approved;
  • 15 mg and 20 mg doses would be appropriate in patients in whom the 10 mg dose is well-tolerated but not effective; and,
  • for patients taking concomitant moderate CYP3A4 inhibitors, a 5 mg dose would be necessary.

In addition, the FDA determined that the safety data do not support the approval of the suvorexant 30 mg and 40 mg doses. Manufacturing studies will be required to advance the 10 mg dosage form, and Merck will discuss with the FDA whether additional clinical studies will be required to support the 5 mg dose. If approved, assignment of controlled status by the Drug Enforcement Agency (DEA) may further prolong the final launch date. Suvorexant has also been filed with regulators in Japan.

Market Potential

Originally, analysts predicted suvorexant could have sales close to $900 million per year if approved, although those numbers may be adjusted in response to the July 2013 FDA Complete Response Letter.  Many generic sleep agents, such as zolpidem and lorazepam, are already available at a low-cost in the U.S. market; however, they are controlled substances typically indicated for short-term use, with a potential for dependence, and with serious sleep-related behavioral side effects.

Insomnia is estimated to occur in roughly 10 percent of the U.S. population, and about 30 percent of these individuals take medications to help with sleep. Chronic insomnia is defined as persistent trouble sleeping more than three nights each week. Insomnia is more common in women and the elderly, and is common in patients who also have psychiatric comorbid conditions such as depression, anxiety, dementia, or substance abuse.

Possible future indications for dual orexin 1 and 2 receptor antagonists may include shift-work sleep disorders or other circadian rhythm disorders.

Strengths and Dosage Forms

In Phase III clinical trials published in December 2012, patients received suvorexant in 10, 20, 40, or 80 milligram strengths. Other studies have evaluated 15 and 30 milligram doses. Suvorexant was shown to improve sleep efficiency in a dose-related manner; however, side effects such as next-day drowsiness appear to be dose-related, as well. Dosage forms (i.e., tablet, capsule) were not reported. Lower 15 and 30 mg doses have been studied in patients 65 years of age and older.

Mechanism of Action

Suvorexant, known as a dual orexin 1 and 2 receptor antagonist (DORA) blocks orexin, a brain chemical that is associated with sleep disruption. Orexin-A and -B peptides are produced in the hypothalamus and are necessary for normal wakefulness. Loss of orexin neurons in humans is linked with narcolepsy, a sleep disorder which involves excessive daytime sleepiness and cataplexy, a sudden loss of muscle tone. Normally, orexin levels increase during the day and fall at night. The loss of orexin in narcolepsy points to the importance of orexin to maintain a wakeful state. Suvorexant would be the first in a new drug class called orexin receptor antagonists.

Other drugs that treat insomnia affect the brain on a larger scale, and occupy γ-aminobutyric acid type A and BZ receptors (GABA-A, GABA-BZ), but can lead to residual side effects like daytime drowsiness, forgetfulness (amnesia), or rebound insomnia. Unusual sleep-related behaviors such as sleep-driving, or sleep eating have also been reported. Sedating antidepressants, such as trazodone, doxepin, and amitriptyline have also been used to induce sleep. Antihistamines, like diphenhydramine (Benadryl), and melatonin are available over-the-counter for insomnia.

Suvorexant Phase III Clinical Trials

Suvorexant Effectiveness: Nine clinical trials have been completed for suvorexant as of May 2013. The NDA for suvorexant is based on data from a broad clinical development program looking at efficacy and safety in adult patients. Studies included:

  • Two pivotal, three-month effectiveness trials that evaluated the ability of suvorexant to help patients fall asleep and stay asleep.
  • A 12-month study, followed by a two-month discontinuation phase, that was designed to assess the safety of suvorexant, while also evaluating its longer term efficacy and the impact of stopping treatment.
  • Two next-day driving studies that provided an assessment of residual effects following evening use of suvorexant.

Animal studies in rhesus monkey and rats show suvorexant has less of an effect on cognitive abilities, such as attention or memory. When common sedative-hypnotics such as zolpidem (Ambien), eszopiclone (Lunesta), or diazepam (Valium) were administered to the animals, there was a comparatively greater effect on cognitive abilities. Human comparative trials with currently marketed insomnia medications are not available.

Placebo-controlled trials have shown that patients who took suvorexant reported that they fell asleep faster, remained asleep longer, and spent less time awake during the night compared with patients who received placebo (P < .001; all results significant during the first month). Results occurred as early as the first night of dosing.

Suvorexant met statistical significance for all primary endpoints except for one measurement at month three; the difference in time to fall into continuous sleep did not reach statistical significance compared to placebo (-32.2 minutes vs. -28.6 minutes, p=0.265). The objective data showed that patients taking suvorexant spent less time awake during the night by 54.2 minutes (vs. 24.8 minutes with placebo) compared to before they started taking suvorexant.

In the 12-month study, which was followed by a discontinuation phase, those who switched from suvorexant to placebo in the final two months had no clinically meaningful evidence of withdrawal or rebound insomnia.

In 2011, GlaxoSmithKline and Actelion halted Phase III clinical trials with almorexant, another orexin antagonist, due to its unfavorable side effect profile.

Suvorexant Safety

Official FDA labeling is not yet available for suvorexant; however, clinical trial reports have identified possible side effects. Reported suvorexant side effects (greater than or equal to 5 percent and more often than placebo):

  • headaches (roughly 7 percent vs. 6 percent with placebo)
  • next-day sleepiness (roughly 10 percent vs. 3 percent with placebo)

It does not appear that the FDA will approve the highest 30 and 40 mg doses of suvorexant based on safety data. Patients taking the highest dose of suvorexant demonstrated an eight-fold increase in next day drowsiness compared to the lowest dose; somnolence is obviously dose-related. Next-day driving was also impaired as noted by the FDA. Merck previously reported they had not seen any cases of narcolepsy, a sleep disorder marked by daytime sleepiness and daytime sleep attacks, or cataplexy; in addition, these patients were excluded from studies. However, in clinical trials there were more than 40 suspected cases of cataplexy; the FDA stated some cases may have been actual cataplexy.

An increased risk of suicidal behaviors has been reported with the active drug, as well; none were reported with placebo. It is important to note that the long-term side effects of using orexin antagonists are unknown.

Related Articles


Last Update: Feb 09, 2014 by Leigh Anderson, Pharm D.