The Future Role of Orexin Agonists for the Treatment of Narcolepsy, EDS, and Beyond

In this video, Greg Mattingly, MD, president, Midwest Research Group, explains the neurobiological processes by which sleep can become disrupted. Dr Mattingly also introduces innovative sleep disorder solutions made possible through the orexin receptor and its ability to modulate disordered sleep.

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Read the Transcript: 

Greg Mattingly, MD: Welcome, I'm Dr. Greg Mattingly, a psychiatrist from St. Louis, Missouri, where I'm an associate clinical professor at the Washington University School of Medicine and president of the Midwest Research Group.

Today we're going talk about a fascinating topic that involves something we all deal with every single day of our lives, and that is sleep. The important nature of sleep, the restorative nature of sleep, and how sleep can be disrupted when the neurobiology which governs circadian rhythm and sleep becomes disrupted.

We're going to talk about some new innovations, some innovations that I'm excited to talk about. I've been part of research looking at the orexin receptor and how it can modulate disordered sleep and how we can help to push that to normalize sleep and circadian rhythm for our patients. patients.

Neurology Learning Network: What are the implications of the positive results for TAK-861, an orexin agonist, in narcolepsy treatment compared to previous medications?

Dr Mattingly: Takeda just had a breakthrough finding with their compound, Takeda-861. It's a selective orexin 2 agonist that helps to stimulate the orexin pathway to increase arousal during the daytime. That compound was studied in people that had narcolepsy and the type of narcolepsy we see that we know is due to orexin deficiencies.

The people that fall asleep, they have cataplexy, they have disorganized sleep and disorganized wakefulness. This breakthrough study showed replicated findings, where it not only helped with wakefulness as measured in sleep labs, it helped people in their daily function to be less sleepy and more functional.

So, on the Epworth sleepiness scale, people said, "I'm alert, I'm awake, I'm engaged." So, significant findings with a very selective compound that hits the orexuin-2 receptor to help normalize sleep physiology in people that are troubled by narcolepsy.

Neurology Learning Network: What lessons can be learned from the success of TAK-861 and the challenges encountered with prior orexin 2 agonists, in terms of drug development and safety assessment?

Dr Mattingly: One of the challenges when it comes to modulating orexin is we have 2 different types of orexin receptors. We have orexin 1 and orexin 2.

Orexin 1 is found not just in the brain, but it's also found throughout the body. So we have orexin 1 receptors in the thyroid gland. We have orexin 1 receptors in the cardiovascular system.

Orexin 2 is localized specifically in the brain. It modulates sleep, cognition, circadian rhythm, probably also modulates eating behaviors. Takeda-861 is the most selective orexin 2 agonist we've had to date.

By doing being more selective they were able to keep the dose lower, which minimized off-target receptors and minimized any potential hepatic side effects that have been seen with prior orexin 2 agonists.

Neurology Learning Network: How do you envision the future of research on orexin agonists for narcolepsy, excessive daytime sleepiness, and ADHD treatment?

Dr Mattingly: The future of research when it comes to orexin agonists is really exciting. It’s exciting because it's transdiagnostic.

We know that orexin 2 modulation tends to help with arousal and sleep. We can normalize people that are having abnormal sleep cycles throughout the day. We can help with alertness and people that have fatigue from other associated mental health conditions.

You can think about those patients that are struggling with depression, chronic fatigue syndrome, other physical conditions where they have fatigue. This may be a way to help normalize wakefulness.

Finally, I'm really excited about the possibilities when it comes to cognition. I do a lot of work in the ADHD field and we know cognition is ubiquitous in mental health disorders. This may be a pathway to help with alertness and to promote cognition over and above our current pathways that we're using when it comes to helping with cognition.

Neurology Learning Network: What are the future potential benefits and challenges of using orexin agonists to enhance alertness and concentration, considering the current use for insomnia?

So, currently when we think about orexin, we mainly think about a orexin antagonists.

Too much orexin will keep you awake when you're trying to sleep. So, we have several different compounds that have been developed to help you sleep.

Now we're looking at the other pathway. If we push orexin, and people that don't have enough orexin, can we increase arousal? Can we help with energy? Can we help with cognition? Can we possible even help restore disordered eating and impulsive eating behaviors?

So it's an exciting area. We know like any other chemical in the brain, not having enough is bad. You develop narcolepsy, you develop problems with sedation. Having too much keeps you awake, keeps you alert, you can't sleep at night.

So restoring a normal balance through the orexin pathway is going to be the challenge as we develop these exciting new group of compounds.

Neurology Learning Network: What key research questions or clinical considerations need to be addressed as orexin agonists expand beyond sleep disorders into areas such as ADHD, alertness, and concentration?

Dr Mattingly: I think as we expand beyond just wakefulness with orexin agonists, we always have to keep in mind safety. Some of the original compounds had difficulties with hepatic safety.

The new Takeda compound looks very promising with regards to both efficacy and safety in their pilot studies so far. Beyond that, we want to look at duration of action. We know we want to push orexin to help with alertness, energy, cognition, to decrease impulsive behavior, but if we push erection too far into the evening, we're likely to get insomnia.

So it's not too hot, not too cold, finding that sweet spot right in the middle as we modulate the orexin pathway.

Let me just say that right now, the brain has never been more exciting. We're developing novel compounds to look at energy, wakefulness, concentration, to look at how we modulate our eating behaviors and beyond. So this is an exciting time to be in mental health and it's an exciting time to be in research. It's an exciting time to be a clinician. So, thank you for joining us for these episodes.

Greg Mattingly, MD, is a physician and principal investigator in clinical trials for Midwest Research Group. He is also a founding partner of St. Charles Psychiatric Associates where he treats children, adolescents, and adults. A St. Louis native, he earned his medical degree and received a Fulbright scholarship while attending Washington University. Dr. Mattingly is board certified in adult and adolescent psychiatry and is a Diplomat of the National Board of Medical Examiners. He is an Associate Clinical Professor at Washington University where he teaches psychopharmacology courses for the 3rd year medical students. Dr. Mattingly has been a principal investigator in over 400 clinical trials focusing on ADHD, anxiety disorders, major depression, bipolar disorder and schizophrenia.