Belsomra: Weighing Benefits and Risks

Belsomra, Merck’s new sleeping pill, is now the hottest topic on this blog. Insomnia sufferers who write in with comments are wondering about dosage, effectiveness, side effects, and how it compares with other sleeping pills.

Reviews of Belsomra, or suvorexant, have been lukewarm so far. Since I haven’t tried it myself, I can’t weigh in based on personal experience. But my search for information turned up more than I shared in my blog last August. Here’s a bit of context and more details.

insomnia sufferers should weigh benefits & risks of new sleeping pillBelsomra, Merck’s new sleeping pill, is now the hottest topic on this blog. Insomnia sufferers who write in with comments are wondering about dosage, effectiveness, side effects, and how it compares with other sleeping pills.

Reviews of Belsomra, or suvorexant, have been lukewarm so far. Since I haven’t tried it myself, I can’t weigh in based on personal experience. But my search for information turned up more than I shared in my blog last August. Here’s a bit of context and more details.

How to Put the Brain to Sleep

There are two ways to induce sleep chemically: by (1) facilitating the action of neurons that promote sleep and (2) deactivating neurons associated with arousal. Z-drugs like zolpidem (Ambien) and eszopiclone (Lunesta) do the former. They enhance the ability of GABA neurons to shut the brain down.

Belsomra, on the other hand, works by disabling the orexin neurons that fire continuously when we’re awake. These orexin neurons—70,000 in all–reside in a part of the brain called the hypothalamus. They’re connected to GABA neurons there, and when the orexin neurons are firing, they hold GABA neurons in check.

Mice that lack orexin neurons are constantly falling asleep. In mice that have orexin neurons, temporarily disabling the neurons also puts the mice to sleep. Blocking the action of the orexins in humans should have a similar effect.

Why Shouldn’t We Stick with Drugs That Act on GABA?

The problem with these drugs is that in some users they have negative side effects: sleep walking, sleep eating, and sleep driving, not to mention interfering with memory formation and possibly increasing mortality. For several years the z-drugs were touted as safe for long-term use, but post-marketing tests have given rise to skepticism among some healthcare providers.

Besides, although sleep scientists are still unclear about the causes of insomnia, the prevailing theory is not that insomnia is the result of a flawed sleep system but rather that it stems from excessive arousal, which is conditioned and/or genetically predisposed. The word often used to describe our predicament is hyperarousal. So it makes sense drug developers are working on insomnia drugs that will tamp the arousal down.

Safety and Efficacy of Belsomra

The safety and efficacy of the drug apparently depend on the dose. The FDA approved Belsomra in doses of 5, 10, 15, and 20 mg based on the results of 3 double-blind, placebo-controlled trials that showed it to be better than placebo at putting subjects to sleep and keeping them asleep.

Merck also conducted a one-year safety study in which investigators also looked at the efficacy of 30 and 40 mg of the drug. By the end of the first month, patients taking suvorexant were falling asleep 10 minutes faster than patients taking a placebo and sleeping about 23 minutes longer.

But the main purpose of this study was to assess the drug’s safety. In this respect, suvorexant performed well enough. Subjects who took suvorexant maintained their sleep improvements throughout the year. When they stopped taking the drug at the end of the study, they experienced no more rebound insomnia or withdrawal symptoms than the placebo group. This suggests the drug’s potential to foster the build-up of tolerance and dependency is low.

The one prominent safety issue that did come up was daytime grogginess, unsurprising in a drug whose half-life is about 12 hours. Of the patients on Belsomra, 13 percent experienced next-day sleepiness, sometimes severe, compared to 3 percent on placebo. In studies where patients were taking lower doses of Belsomra—15 and 20 mg—fewer patients experienced next-day sleepiness (7 percent vs. 3 percent on placebo).

The tradeoff, though, was reduced efficacy, especially in doses under 20 mg. Subjects who took a 10-mg dose did not get to sleep significantly sooner than patients on placebo (although they did sleep about 22 minutes longer). So it looks like business as usual here: higher doses are more efficacious but they may also leave you feeling groggy and impair your driving ability the next day.

How Does Belsomra Compare with Other Sleeping Pills?

Merck did not conduct any toe-to-toe comparison studies. The FDA does not require that new drugs be tested against existing drugs. Comparison studies, if they’re done at all, are typically conducted after a new drug comes out.

But results of a Phase-2 study showed that in healthy subjects, suvorexant altered the overall electrical activity in the brain less than 3 other medications—gaboxadol, zolpidem, and trazodone–used for sleep. These findings, say investigators, suggest that drugs like suvorexant “might lead to improvements in sleep without major changes in the patient’s neurophysiology as assessed by electroencephalography.”

Orexin Drugs Coming Our Way in the Future

Our bodies actually produce 2 different orexin neuropeptides and have 2 different orexin receptors. Belsomra is a “dual orexin receptor antagonist,” or DORA. It promotes sleep by blocking both orexins from binding to their receptors.

In the laboratory, writes Cormac Sheridan in the October 2014 issue of Nature Biotechnology, Belsomra over time shows a greater binding affinity for the orexin-1 receptor. Yet animal knockout studies suggest that of the 2 receptors, the orexin-2 receptor may actually be more important to sleep regulation. So the activity profile of Belsomra may not be ideal.

At least 2 drug companies–GlaxoSmithKline and Minerva Neurosciences—have orexin receptor antagonists in the works. Drugs that more strongly target the orexin-2 receptors may prove to be more effective as hypnotics than Belsomra. The race is on to see.

If you have tried Belsomra, what do you think of it?

 

Merck's New Sleeping Pill to Come Out Soon

Roll over, Ambien! After much debate, the FDA has finally approved Merck’s new drug for insomnia. Expect to see Belsomra (a.k.a. suvorexant) on the market early next year.

So what can we hope for from this new sleeping pill and how does it differ from hypnotics available now?

Belsomra, a new sleeping pill approved for insomnia, will enter the market early next yearRoll over, Ambien! After much debate, the FDA has finally approved Merck’s new drug for insomnia. Expect to see Belsomra (a.k.a. suvorexant) on the market early next year.

So what can we hope for from this new sleeping pill and how does it differ from hypnotics available now?

 

A Different Path to Sleep

Older sleeping pills—from barbiturates and benzodiazepines to Ambien and Lunesta—induce sleep via the GABA system. GABA is the main neurotransmitter responsible for calming the brain and putting us to sleep. GABA-producing neurons are found throughout the brain, and when they start firing, other brain activity grinds to a halt. Most sleeping pills speed this process up, thus helping put us to sleep and keep us asleep.

Belsomra does not achieve its soporific effect through the GABA system. Instead, it works on the orexin system—on a much smaller group of neurons in the hypothalamus. These orexin-producing neurons are normally quiet during periods of sleep. But in the daytime they fire continuously, keeping us awake and alert. People who lack orexin neurons are narcoleptic, succumbing to irresistible sleep attacks during the day.

Insomnia sufferers may have the opposite problem, researchers have suggested. The orexin neurons in our brains may be overactive, keeping us awake at night. Orexin receptor antagonists such as Belsomra are being developed based on experiments that show that suppressing activity of the orexin neurons induces sleep.

How Effective Will Belsomra Be?

The FDA does not require new drugs to be more effective than older drugs before gaining approval. How Belsomra stacks up against Ambien, America’s most popular sleeping pill, is anybody’s guess.

But new drugs do have to work better than placebo. Here, Belsomra apparently passes muster. Compared with placebo, it has helped insomnia sufferers fall asleep faster and experience fewer middle-of-the-night awakenings. A year-long trial published in the May 2014 Lancet Neurology showed that after one month, insomniacs who took Belsomra got to sleep about 10 minutes faster than insomniacs taking a placebo and slept about 23 minutes longer. No great shakes! But we’re talking averages here.

Is the New Drug Safe?

A year ago there was quite a bit of concern that suvorexant in doses higher than 10 mg left a significant number of test subjects feeling groggy in the morning, impaired their driving, and led to other “narcolepsy-like” symptoms. But, based on documentation subsequently submitted by Merck, the FDA has decided to approve Belsomra for use in doses of 5, 10, 15, and 20 mg. Higher doses of the drug are said to be more effective—but they also tend to come with more side effects.

The US Drug Enforcement Agency will probably make Belsomra a scheduled drug. A Schedule IV classification would place it in the same category as Ambien and most other hypnotics on the market today. So if and when Belsomra comes on the market and you go on to try it, use it with care.

February 3, 2015: There seems to be a lot of interest in this new sleeping pill. Belsomra is now available here in the United States, and people are writing to me with questions about  effectiveness, side effects, and cost.

I have no plans to try it myself, so I can’t comment on it one way or another. But if you try Belsomra, I know others would appreciate hearing what you think about it.

You may also be interested in learning more about the safety and efficacy of Belsomra. You’ll find that information here.

A Better Sleeping Pill: Are We There Yet?

My hope springs eternal when it comes to the possibility of a better sleeping pill. Suvorexant, Merck’s new insomnia drug, is currently under review at the FDA, and I’m wondering whether this will be it.

Suvorexant is a different from sleeping pills like Ambien (a.k.a. zolpidem) and Lunesta. Here’s how.

AlchemyMy hope springs eternal when it comes to the possibility of a better sleeping pill. Suvorexant, Merck’s new insomnia drug, is currently under review at the FDA, and I’m wondering whether this will be it.

Suvorexant is a different from sleeping pills like Ambien (a.k.a. zolpidem) and Lunesta. These older pills work by enhancing the activity of GABA, the main neurotransmitter that shuts the brain down at night.

Suvorexant works on a different system—the orexin system. Neurons that produce orexin fire rapidly when we’re awake. The new sleeping pill works by temporarily blocking the action of orexin, thus facilitating sleep. So unlike like the Ambien clones approved in recent years (Edluar and Zolpimist, for example), suvorexant is a truly novel drug.

Efficacy and Safety

But my hopes for any new sleep med are never too high. Many sleeping pills go up for review by the FDA only to receive a thumbs-down, and not because they’re ineffective. To gain FDA approval on measures of efficacy, a new drug only has to work better than placebo.

It’s the safety standards that are so hard to meet, especially in a climate like this one, where Ambien has recently emerged as a culprit in traffic accidents and rising numbers of visits to the emergency room. To develop an insomnia drug that knocks people out at night but then wakes them up in the morning appears to be about as easy as winning a Pulitzer.

Expert Recommendations

So I wasn’t surprised to learn on Wednesday that, while a panel of experts voted to endorse the efficacy of suvorexant, they had serious reservations about its safety at higher doses. They deemed the 10 mg dose, the lowest dose tested by Merck (and also the least efficacious), safe. But enough subjects taking higher doses suffered grogginess in the morning, impaired driving, thoughts of suicide, and “narcolepsy-like” symptoms, that a majority of the experts voted against approving doses of 15 to 40 mg. (Read the full story by FierceBiotech here.)

The FDA is not bound by these expert recommendations. But it will consider them as it completes its review of suvorexant, which should, according to Merck, be issued by the middle of the year.

Me, I’m not going to predict how the FDA will decide this one, or whether, if approved, the 10 mg dose of suvorexant will be a balm for what ails me. Safe but ineffective, or effective but unsafe: new sleeping pill, same caveats.

Would you consider trying this drug if it comes on the market? Why or why not?