Insomnia: an interview with Dr Darryle Schoepp

Published on July 26, 2012 at 8:19 AM · No Comments

Interview conducted by , BA Hons (Cantab)

INSIGHTS Schoepp ARTICLE IMAGE

Please could you tell us a little bit about insomnia, what it involves and who it affects?

Insomnia is a very common disorder. In medical terms it can affect a third of people. It affects elderly as well as non-elderly people, and is more common in women.

People can have trouble falling asleep and also maintaining sleep. The classic problem with sleep is that people wake a number of times during the night and that does not lead to a very restful sleep.

Insomnia is really about being awake when you’re trying to be asleep.

People, like nearly all mammals, need sleep for health. If you don’t get enough sleep then it can make you more vulnerable to other illnesses. It can even shorten your lifespan.

What causes insomnia?

There has been a lot of new research in the area of sleep. A lot of people think that when you are sleeping your brain is asleep. It turns out that it is much more complicated than that.

The real breakthrough in sleep research has been to elucidate the orexin system.

The orexin neurons in the hypothalamus collect information and let you know whether it is ok for you to go to sleep or whether you need to stay awake. The brain then uses the orexin system to promote wakefulness.

Insomnia does not occur because your brain can’t fall asleep, but because your brain can’t stop staying awake.

By keeping the orexin neurons quiet it helps you fall asleep and stay asleep.

Lots of things cause insomnia. There are genetic factors which mean that some people are more susceptible than others to insomnia. As I mentioned before, women seem to have more susceptibility to insomnia than men. Also, any condition that disturbs your body, for example neuropathic pain, can also disturb sleep.

There are many psychiatric or neurological conditions that make it harder for people to get a good night’ sleep. For example, patients with Parkinson’s disease often have problems with sleep. Alzheimer’s patients tend to have a lot of trouble with sleep too.

Depression is another condition where people have deregulated sleep.

Merck has been testing a new drug to treat insomnia, please could you tell us a little bit about this?

Suvorexant is an orexin receptor antagonist. The orexin neurons have two different receptors, called receptor 1 and receptor 2, and they secrete two orexin peptides which act on these receptors. These receptors are the chemical messenger receiving points that promote wakefulness.

When your neurons fire, they release orexin peptides and the peptides act on these receptors.

Suvorexant is a competitor, so it competes with the orexin peptides. This means that the orexin peptides are less effective at promoting wakefulness. They would have to fire faster and release a lot more orexin to try to overcome the effects of the drug.

We did studies with people with insomnia and gave them our compound at night. We found that people who were given suvorexant went to sleep faster than those who were given a placebo. They also stayed asleep for longer – they had fewer awakenings. They had what is called a better sleep efficiency, which is to do with how long you spend in bed compared with out of bed during the night. This was quite an exciting finding.

The drug has been described as one that targets insomnia in a different way to other medicines. Please could you explain to us how it works and how it differs from traditional therapies?

All the other drugs that help sleep work through what is called the GABA system. About half the neurons in your brain have a neurotransmitter called GABA. This is in billions of neurons. In comparison, there are only around 100,000 neurons with orexin. Yet, if you block their effects, you still get the same effect of aiding sleep.

In the 1970’s it became recognised that hypnotics worked by turning off GABA neurotransmitters throughout the brain. GABA drugs were used for many different things. They were used to stop convulsions; to make you forget things; to treat anxiety and so forth. Essentially, their ability to aid sleep was discovered by accident.

What is exciting about suvorexant is that it comes out of elegant science. We have learnt about how the sleep system works and now we have discovered how we can tap into the system. The drug is rationally designed.

How have the trials for this new medicine been going?

We have completed our trials and we have stated publically that we are filing New Drug Application (NDA) for suvorexant with the U.S. Food and Drug Administration (FDA) this year.

We have completed a one year safety study, which has never been done for a sleep drug before. Many of the other sleep drugs that are out there do not have the same level of safety data that we have.

We studied our drug for a year, and we showed that our drug maintained good efficacy. Even after a year the drug was still working. We had very good tolerability with very low adverse side effects. About 90% of patients who took the drug had no next-day somnolence.

The efficacy studies were two very large, well-designed, pivotal studies in both elderly and non-elderly. There were two types of measures in them: subjective and objective measures. Those were made at 1 night, 1 month and 3 months. This is the first time anyone has ever studied a drug like this.

The trials were very comprehensive. There were 15 primary endpoints in each of the two trials. We had very significant effects in 29 out of 30 of those endpoints. In the studies, suvorexant significantly reduced the time it took patients to fall asleep and increased the time that patients stayed asleep as early as the first night and at the three-month time point compared to placebo. The one endpoint that didn’t quite make it was an onset endpoint at 3 months. However, this is still demonstrates a remarkably effective drug.

When you combine this with the efficacy studies in the chronic safety study, it is quite a good profile for efficacy.

Has the drug been shown to work on all patients or only some?

We measured multiple doses in these studies. We had a high dose and a low dose. It was more effective at a high dose than a low dose. It was effective in both elderly and non-elderly populations. You can’t really segregate patients beyond that.

Were there any side effects of the drug?

There were some reports of next day somnolence. This occurred in a small proportion of patients and at a rate which is quite acceptable for sleep drugs.

Ninety percent or more had no problem with next day somnolence.

Beyond that there really was nothing else in our data that suggested any other side effects.

If the trials are successful, how soon will it be before the drug is available to patients?

Our next step is to file an NDA with the FDA for the drug. This will happen this year. The drug then has to be reviewed by the FDA. We can’t really speculate on how long this will take.

What are Merck’s future plans for insomnia medication?

We have plans to do other studies. We have a second molecule that we are studying for other conditions, such as depression, migraines, neuropathic pain.

How do you see the future of insomnia medication progressing as a whole?

I think that suvorexant, the orexin antagonist, is a real break-through. It is the first new thing, if you look at it mechanistically, that has happened in decades. It teaches you a lot about the brain and what might be happening in insomnia. It actually opens up a new avenue for sleep research.

There have been times in the past when this looked like it was going to happen, but these things have never come to fruition. For example, there were serotonin drugs which people were previously excited about, but they never translated in the clinic. They never had any efficacy. They never helped people sleep. There was also the melatonin system, but this also did not seem to be very effective.

This is the first time you have an effective new treatment which takes you away from the old treatments.

Where can readers find more information?

More information can be found at:

About Dr Darryle Schoepp

Darryle D. Schoepp joined Merck Research Laboratories in 2007 as Senior Vice President and Franchise Head for Neuroscience.  He has global responsibility for neuroscience and ophthalmology from discovery through late clinical development, and is a member of the Merck Global Scientific Strategy group responsible for therapeutic area strategies and prioritization of the Merck pipeline. 

Darryle Schoepp2

Merck Neuroscience has focused its research directions in neurology, psychiatry, and ophthalmology research towards important medical needs where the science and the clinical path are the most promising, and have built industry leading drug discovery platforms and target engagement biomarkers to enable better translation into the clinic. 

Merck has established an innovative late and early stage Neuroscience pipeline with highly promising programs for insomnia, migraine/pain, schizophrenia, Parkinson's disease, and Alzheimer's disease.

Prior to joining Merck, Dr. Schoepp was a drug discovery scientist at Eli Lilly for 20 years, where from 2004 – 2007 he served as vice president of neuroscience research responsible for the company's neuroscience strategy and pipeline.

As a scientist, he is recognized for having made major contributions in the investigation of the excitatory amino acid neurotransmitter glutamate in disease pathophysiology, pharmacology and therapeutics.

Dr. Schoepp's honors include the 2002 Pharmacia / ASPET Award for Experimental Therapeutics for his research on the experimental therapeutics of metabotropic glutamate receptors in psychiatry, and 2007 Ray Fuller / ASPET Lecturer in Neurosciences in recognition of translational pharmacology work in the glutamate field. 

He has organized and/or participated in numerous international meetings and symposium, published over 200 papers and reviews, and is an inventor of 14 US patents. 

Dr. Schoepp's professional activities include Basic Pharmacology Executive Committee member of the Pharmaceutical Manufacturers Foundation, member of the American College of Neuropsychopharmacology (ACNP), and editorial board for Neuropharmacology

Dr. Schoepp received his bachelor's degree in Pharmacy from North Dakota State University and his doctoral degree in Pharmacology and Toxicology from West Virginia University.

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