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New Sleeping Pills (2015): Orexin Receptor Antagonists

Some sources estimate that nearly 60 million Americans have difficulties falling asleep a.k.a. a condition known as insomnia.  There are many causes of insomnia, including circadian rhythm disturbances, poor diet, inadequate or excessive exercise, high stress, drugs, overworking, and mental illness.  In many cases, insomnia can lead to deficiencies in both sleep quality and quantity.

When a person isn’t getting enough sleep as a result of insomnia, they may experience impaired mental performance, mood disturbances, and even physical health problems.  Lack of sleep is known to slow metabolism, and ultimately cause weight gain.  The myriad of adverse physiological cascade effects stemming from insomnia can be damaging to an individual’s overall health and ability to function.

While some individuals have managed to address the root cause of their insomnia and rid themselves of this condition via conscious lifestyle changes, society is always looking for the latest and greatest “quick fix” in the form of pharmaceutical sleeping pills.  Most sleeping pills on the market function as nonbenzodiazepines, affecting the neurotransmission of GABA similar to benzodiazepines.

New Sleeping Pills: Orexin Receptor Antagonists (2015)

A serious concern is evidence suggesting nonbenzodiazepine sleeping pills are linked to dementia, early mortality, and increased risk of cancer; they are dangerous psychiatric drugs.  As a result, many people with severe insomnia are hoping for development of a new, safer sleep aid.  Fortunately there is a newer class of (potentially safer) sleeping pills under development dubbed the “orexin receptor antagonists.”

Many companies have hopped on the bandwagon of orexin receptor antagonist development. One company (Merck) already has an orexin receptor antagonist called “Belsomra” (Suvorexant) approved by the FDA for the treatment of insomnia.  Despite the fact that one drug from this class is on the market, it remains unknown whether this new class of sleeping pills will be safe over the long-term.

  • Source: http://bmjopen.bmj.com/content/2/1/e000850.full

Approved Agents

Belsomra (Suvorexant)

This drug functions as a dual orexin receptor antagonist (DORA) and was developed by Merck & Co.  It is regarded as a clinically effective intervention for insomnia for up to 4 weeks compared to a placebo.  It had received FDA approval as of August 2014 and is considered a “Schedule IV” controlled-substance.

The drug didn’t actually hit the United States market until February 2015.  Due to the fact that it is a new sleeping pill, and relatively expensive compared to other options, not many people have tested it.  It remains unknown whether this drug will be preferred over nonbenzodiazepine GABAergic options in regards to long-term safety.

Clinical Trials

1. Lemborexant (E-2006)

This drug functions as a dual orexin receptor antagonist (DORA); specifically on the OX1 and OX2 receptors.  Should the drug be granted approval by the FDA, it would fall under the same classification as Belsomra and have a very similar mechanism of action.  It is being developed by the pharmaceutical company Eisai and as of 2014 it has been in Phase II clinical trials.

In part of Phase II trials, 291 participants were involved in determining the efficacy of Lemborexant; 64% were female and 36% were male.  Reports from June 2015 indicate that after 15 days of treatment with Lemborexant, participants experienced a 50% decrease in latency to persistent sleep (LPS) and wake after sleep onset (WASO), plus an 86% increase in sleep efficiency (SE).

Though there is a long way to go before this drug gets approval for the treatment of insomnia, preliminary evidence suggesting its efficacy is promising.

2. MIN-202 (JNJ-42847922)

MIN-202 is a drug currently in “Phase I” clinical trials for the treatment of both major depressive disorder and insomnia.  It functions specifically as a selective antagonist of the OX2 orexin receptor.  In other words, it differs from the already-approved Belsomra in that it has no action on OX1 receptors.

The drug entered Phase I trials in 2014, and initial data has been reported as of 2015.  A neuroscientist commented suggesting that selective inhibition of OX2R is sufficient to induce sleep and prolong sleep.  She elaborated by suggesting that the specificity of action on OX2 receptors may be preserve physiological sleep.

Based on evidence from rodent tests, this drug elicited dose-dependent effects on NREM latency and increased NREM sleep duration; REM wasn’t affected.  Most OX1 and OX2 “dual orexin receptor antagonists” (DORA) are thought to alter REM more by comparison. As of now, it is considered to have a favorable safety profile.

Significantly more testing needs to be conducted with this drug, but it may be favorable in that it is more selective than “DORA” agents.  Development of this drug is being done by Minerva Neurosciences in conjunction with Janssen Pharmaceuticals.

3. SB-649868

This is another DORA (dual orexin receptor antagonist) in clinical trials for the treatment of insomnia.  In Phase I of clinical trials, the drug showed significant efficacy in sleep latency without any major adverse reactions.  It is currently in Phase II clinical trials and has shown early promise in reducing symptoms of insomnia.

A study published in 2012 analyzed the effects of this drug on 52 male participants diagnosed with primary insomnia (as confirmed by polysomnography).  SB-649868 was administered after dinner approximately 90 minutes before bedtime at varying doses (10 mg, 30 mg, or 60 mg).  The drug was shown to significantly reduce latency to persistent sleep, wake after sleep onset (WASO), and increased total sleep time (TST).

Researchers noted that the drug produces a dose-dependent response.  The dosage influences the degree of REM sleep and REM latency.  Currently, the drug is regarded as being well-tolerated and having minimal “next day” effects (e.g. drowsiness upon waking).  Significantly more trials need to be completed before this drug hits the market.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22851805

4. ACT-462206

As of 2014, the drug “ACT-462206” was investigated in a double-blind, placebo-controlled, randomized study.  This drug functions as a novel DORA (dual orexin receptor antagonist).  The goal for researchers was to investigate its safety, pharmacokinetics, and pharmacodynamics.

Researchers discovered that the drug was well-tolerated and drug-induced sleepiness was dependent upon the dosage.  It was noted to reduce vigilance, attention, alertness, and motor coordination.  Currently it is unknown whether this will remain a research chemical or if it will be formulated into a potential drug.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24691844


Almorexant (ACT-078573)

This drug was developed by the company Actelion and GlaxoSmithKline (GSK).  In 2007 it was hyped as being a potentially groundbreaking sleeping pill, mostly due to the fact that it was among the first orexin receptor antagonists in development.  Its mechanism of action was classified as a competitive OX1 and OX2 receptor antagonist.

Initially, it was thought that the drug would produce better sleep and have less side effects than standard “Z-drugs” (nonbenzodiazepines).  In 2008, Actelion sold the development and marketing rights of Almorexant to GlaxoSmithKline for $147 million.  Though the drug eventually managed to complete Phase III clinical trials in November 2009, the drug was scrapped from development due to speculative adverse side effects.

Filorexant (MK-6096)

This is a drug that functions as a dual OX1 and OX2 receptor antagonist.  It was developed by Merck & Co. and had finished Phase II clinical trials for the treatment of insomnia.  The company was also investigating its potential as a treatment for migraine prophylaxis, major depression, and diabetic neuropathy, but wasn’t considered effective.

Merck discontinued development of the drug as of May 2015, possibly due to the fact that the drug didn’t show as much promise is the company had hoped.  Others speculate that it may have been too costly to develop and/or may have caused unwanted side effects.  Perhaps the approval of Belsomra (a drug created by Merck) was reason for its discontinuation.

Other Orexin Receptor Antagonists Used in Research

Some other orexin receptor antagonists are utilized for research purposes in animals and humans.  These research chemicals may help with the development of new drugs as well as helping scientists get a better understanding of the orexin system, including receptors and orexinergic neurons.

  • EMPA: This functions as an OX2 receptor selective antagonist. It is regarded as having a 900-fold affinity for the OX2 receptor compared to the OX1 receptor.
  • SB-334867: This is regarded as the very first non-peptide antagonist with selective properties for OX1 receptors compared to OX2 receptors. It is estimated that it has a 50-fold affinity for the OX1 receptor by comparison.  The compound has been studied in animals and produces a sedative effect.  It also has allowed researchers to characterize regulation of brain systems responsible for regulation of orexin.
  • SB-408124: This is considered a non-peptide antagonist, with a high affinity for the OX1 receptor compared to the OX2 receptor. It is estimated to have nearly a 70-fold greater affinity for OX1 than OX2.  It is currently utilized as a scientific compound in research to identify orexin-producing neurons.
  • TCS-OX2-29: This is regarded as the very first non-peptide antagonist that was selective for the OX2 receptors over OX1 receptors. Specifically, it is thought to be nearly 250-fold more selective for the OX2 receptor compared to the OX1 receptor.

Frequently Asked Questions (FAQs): Orexin Receptor Antagonists

Below are some frequently asked questions and additional information regarding Orexin (hypocretin) and orexin receptor antagonists.

What is orexin (hypocretin)?

Orexin (hypocretin) is a neurotransmitter discovered in 1998 that is responsible for promoting wakefulness, vigilance, arousal, and appetite.  The term “orexin” is derived from the Greek term “orexis” which roughly translates to appetite.  Other scientists refer to it as hypocretin due to the fact that it is produced by the “hypothalamus” and vaguely resembles the hormone “secretin.”

Individuals diagnosed with narcolepsy lack these 10,000 to 20,000 orexin-producing neurons, and as a result, are prone to frequent bouts of fatigue and excessive sleepiness.  As a result, they are often prescribed wakefulness-promoting agents called “eugeroics” like Provigil (Modafinil) which in part functions by stimulating orexin receptors to promote wakefulness.

How Orexin Receptor Antagonists work…

The new sleeping pills in development function as orexin receptor antagonists.  This means they act by binding to orexin receptors and inhibiting normative stimulation from orexin (hypocretin).  Without sufficient orexin stimulation, a person begins to feel similar to individuals with narcolepsy – fatigued and prone to excessive sleepiness.

Unlike standard hypnotic agents, the orexin receptor antagonists will not affect GABA, histamine, or melatonin.  The newer drug Belsomra is technically classified as a DORA (dual orexin receptor antagonist) via its selective effects on the OX1 receptor and OX2 receptor.  In other words, these drugs strictly target orexin receptors and don’t act on other neurotransmission.

Potential Advantages of Orexin Receptor Antagonists

The major potential advantage associated with orexin receptor antagonists is that they may not increase mortality risk, cancer risk, and risk of neurodegeneration.  Still, this is only speculative as most of these agents haven’t been well-researched.  Heck, nobody knew what orexin was until 1998 – and drugs targeting this neurotransmitter are just hitting the market.

It should be emphasized that favorable long-term effects compared to most current-market options is not a guarantee.  In fact, for all we know, the long-term effects of orexin receptor antagonists could be even worse than the drugs that target GABA.  Perhaps one favorable aspect of orexin receptor antagonists is that we know they’re specifically targeting orexin rather than GABA.

This may result in less potential for addiction, abuse, and potentially less adverse reactions.  By eliciting selective effects on orexin receptors, side effects may be less severe. Currently there aren’t any studies comparing the efficacy, tolerability, and treatment outcomes associated with nonbenzodiazepine “Z-Drugs” to the new orexin receptor antagonists.  It’ll take years before we get an accurate idea of outcomes associated with treatment from these new medications.

Are orexin receptor antagonists better than other hypnotics?

These drugs should not be considered utopian hypnotics.  Just like other sleep drugs, they have side effects that include things like: sleepiness, headaches, weird dreams, dry mouth, sleep paralysis, cataplexy, and hypnagogic hallucinations. Furthermore, it is known that several investigative orexin receptor antagonists have been discontinued from development as a result of either poor efficacy or tolerability (e.g. adverse reactions).

The hypnotics currently available probably shouldn’t be viewed as any less safe than the new class of orexin receptor antagonists.  In regards to “next day” functioning after orexin receptor antagonists, Belsomra has shown to impair motor functioning as evidenced by next-day driving tests.  Just like other hypnotics, these drugs could have dangerous effects when mixed with other CNS depressants.

As of now, there isn’t enough data to determine whether these drugs will be associated with rapid-onset tolerance, dependence, addiction, and/or discontinuation symptoms.  As more orexin receptor antagonists hit the market in future years, we should get a better understanding of any benefits and/or drawbacks associated with their usage.

Why you probably shouldn’t take sleeping pills…

It is known that there are many different types of insomnia – some of which happen to be more severe than others.  If your insomnia isn’t very severe, you may want to make healthy lifestyle changes rather than opt for a “quick-fix” pill with potentially adverse effects and long-term effects. Although new hypnotics like the orexin receptor antagonists may be perceived as safer than older nonbenzodiazepine “Z-drugs” – there is no evidence to justify these claims.

A majority of sleeping pills work well short-term, but are not a great long-term fix.  It is known that they may cause neurodegeneration and increase your risk of early-morning vehicle accidents.  Plus people have reported significant amnesia and cognitive impairment following usage of these sleep aids.

You may want to pursue natural treatments like melatonin before using a pharmaceutical sleeping pill.  For most people, proper diet, exercise, stress reduction, and following a predetermined “fixed” sleep-wake schedule will alleviate symptoms of insomnia.  Should you decide to take a sleeping pill, recognize that there’s no biological free lunch; there may be unfavorable consequences associated with ingestion of an exogenous chemical – even if it’s a “new” drug.

What do you think of orexin receptor antagonists?

I think there is significant potential of orexin receptor antagonists to uproot the older hypnotics in regards to having favorable safety and tolerability.  Unfortunately it is difficult to suggest that any new class of drug is automatically superior than the last.  The orexin receptor antagonists cannot yet be considered a superior option to older hypnotics, but they can be considered “different.”  Feel free to share any thoughts you have regarding orexin receptor antagonists in the comments section below.

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