Roughly one-fifth of adults in the US experience insomnia, and they'll try everything from counting sheep to popping pills to get some shuteye. Last year, US sleep seekers filled more than 60 million prescriptions for sleep medications and sales topped $1.6 billion, according to the Connecticut-based market research firm IMS Health. But sleeping pills can cause dependence, and their side effects—including falls, confusion and memory problems—can be a nightmare. In some cases, people taking the medications have even started driving cars or binge-eating in their sleep. But a new therapeutic drug class could overcome many of these problems, and the lead compound is now on the verge of regulatory filing.

Reporting at last month's Annual Meeting of the Associated Professional Sleep Societies in Boston, the US drug giant Merck presented data from two phase 3 clinical trials showing that an experimental drug called suvorexant helped people fall asleep faster and stay asleep longer on average than a placebo, without causing serious side effects. Merck plans to file a new drug application with the US Food and Drug Administration (FDA) later this year.

Sweet dreams: Looking beyond GABA drugs. Credit: Sepracor Inc./PRN/Newscom

If approved, suvorexant would be the first sleep medication that blocks a neurotransmitter called orexin, which is involved in controlling the body's sleep-wake cycles. In contrast, most popular sleeping pills, including Sanofi's Ambien (zolpidem) and Sunovion Pharmaceuticals' Lunesta (eszopiclone), work by enhancing signaling of a neurotransmitter called gamma-aminobutyric acid (GABA), which quiets activity throughout the brain, including the regions involved in sleep. However, because GABA plays a crucial part in a variety of brain functions, the drugs have a laundry list of potential side effects, which prompted the FDA to add stronger warning labels to some medications in 2007. Some antianxiety pills are also commonly prescribed off label to treat insomnia; however, they come with their own set of concerns, including a 36% increased risk of death, according to one recent estimate (Can. J. Psychiatry 55, 558–567, 2010).

Because orexin signaling happens primarily in the hypothalamus, a key region in regulating sleep, the hope is that blocking this protein will promote sleep without affecting other regions of the brain and causing unwanted effects. As John Renger, site lead of neurosymptomatic disorders at Merck in West Point, Pennsylvania, points out, the process mimics “what goes on naturally in your brain.”

“It's a very targeted approach,” says David Neubauer, a psychiatrist at the Johns Hopkins Sleep Disorders Center in Baltimore who was not involved in testing suvorexant. “It's not often that you have a compound come along that has a completely new mechanism of action,” adds orexin researcher Thomas Scammell, a neurologist in the Harvard Medical School's Division of Sleep Medicine in Boston.

Differentiation protocol

Suvorexant isn't the first orexin blocker to make it to phase 3 trials. A few years back, the Swiss company Actelion Pharmaceuticals collaborated with the UK's GlaxoSmithKline (GSK) to test a drug called almorexant at 90 clinical centers across Australia, Israel and Europe. Almorexant met its main target in the 700-person trial, outperforming placebo with “evidence for differentiation” from Ambien, the companies reported in December 2009. But a little over a year later, they announced plans to halt development of the drug, leaving Merck's suvorexant as the front-runner in the drug class.

Actelion and GSK have not released any details about why they decided to shelve almorexant, although onlookers suspect it was due to off-target effects that triggered a worrisome tolerability profile. According to Renger, Merck saw no major cause for concern among the 2,000 participants enrolled in the company's pivotal three-month trials. The most common complaints associated with suvorexant were headaches and sleepiness, but there were no signs of long-lasting side effects. GSK also has a similar compound called SB-649868 that recently completed phase 2 testing, the results of which have not been released.

Dreams of riches: The top-selling prescription sleeping pills in the US last year. Credit: IMS Health

According to Gustav Ando, a pharmaceutical analyst with the IHS Healthcare Group in London, Merck's latest results help alleviate some of the nervousness caused by almorexant's failure. Still, he says, “there are quite a lot of question marks out there.” In one of Merck's trials, suvorexant failed to reduce the amount of time it took individuals to fall into a continuous sleep. “Regulators are going to be asking why it missed such a critical endpoint,” Ando says, especially given that the drug was competing against a placebo rather than another medication.