Phenotyping as a Rational for Drug Development in Obstructive Sleep Apnea

Danny Eckert, PhD, Neuroscience Research Australia, and Professor of Medicine at the University of New South Wales

Danny Eckert, PhD

While continuous positive airways pressure (CPAP) is first-line treatment for obstructive sleep apnea (OSA), its long-term compliance is poorly tolerated with adherence rates of 50% or less. Second-line therapies like mandibular advancement splints and upper airway surgery often result in unpredictable efficacy, and needless to say, there’s been quite a shortcoming of existing therapies. Recent advances in OSA pathogenesis using upper airway and respiratory phenotyping techniques have identified 4 key causes for OSA—with an impaired anatomy or narrow or collapsible upper airway as the primary cause—unlocking new approaches for targeted treatment.

OSA has been recognized as a heterogenous disorder with both anatomical and non-anatomical factors. In addition to the varying degrees of impairment in upper airway anatomy, researchers have identified 3 key non-anatomical contributors to OSA: impaired upper airway dilator muscle function; a low respiratory arousal threshold; and an unstable respiratory control [high loop gain].

Despite the recent advances, there’s still a great need for additional tools such to identify and estimate the 4 phenotypic causes of sleep apnea in individual patients in the clinical setting, however, this framework offers promise. As each phenotype is a potential therapeutic target, these new prospective pharmacotherapies will be a major advance for the field.

To provide more insight into the latest knowledge in sleep apnea phenotyping and the role it’s playing to develop targeted pharmacotherapies, NeurologyLive sat down with Danny Eckert, PhD, Neuroscience Research Australia, and Professor of Medicine at the University of New South Wales, at the 24th Congress of the European Sleep Research Society in Basel, Switzerland.

NeurologyLive: Can you discuss OSA pathophysiology?

Danny Eckert, PhD: For a long time, we've been trying to come up with a pharmacotherapy to treat this very common disorder, but unfortunately, despite multiple attempts we have not yet succeeded. It's an exciting time in the field because we've now not only identified new therapeutic targets for the reasons why people get their sleep apnea, but this has also unlocked new therapeutic targets including pharmacotherapies. There's 4 main causes of sleep apnea, your anatomy or how collapsible your upper airway is, so from the back your throat to the back of the nose, as well as 3 non-anatomical causes and these include how well the muscles around the throat are able to open the airway during sleep, a muscle trait, the next one is how easily you sleep or what we call arousal threshold, and the fourth point is what we call respiratory control or loop gain. Now the latter 3, the non-anatomical ones, are quite recent in terms of our knowledge and these are all novel therapeutic targets.

We've now identified these 4 main reasons of why people get sleep apnea. We've always known that it's an anatomical issue, so people with crowded or narrow airways whether it be due obesity or skeletal issues can be a main driver of sleep apnea, but now we know about these other 3 causes and how the muscles respond and that third of people are not able to activate their muscles during sleep which furthers people with sleep apnea, a third of people also have problems with how easily they wake up, so they're light sleepers if you like, or have what we call a low arousal threshold, and the remaining 1 is respiratory control so some people are just too sensitive to carbon dioxide during sleep and that causes all sorts of problems in terms of cyclic albeit breathing and feeds into sleep apnea. Those latter 3 non-anatomical causes really have opened new targets for pharmacological therapy for this common disorder.

What treatment options are available for reducing OSA severity?

DE: If I start with the control of breathing trait, something which is not pharmacological, but is a drug intervention is oxygen therapy, which can reduce the unstable control of breathing in people that have that issue. Another one is a drug called acetazolamide, which is a common generic agent that people take when they go to altitude to reduce mountain sickness, which can also half sleep apnea in the right people. Then there are other drugs that can stabilize sleep or promote sleep, if you like, so common hypnotics, sleeping pills, things like zolpidem, zopiclone, trazadone, temazepam, these agents can actually promote sleep and we used to think that was really bad for those with sleep apnea and it would actually make them worse, but a lot of work that we and others have done in the last 10 years or so, have shown that certain sleeping pills can actually promote breathing stability and in fact reduce sleep apnea in certain people that have that problem of waking up too easily that's contributing to their sleep apnea; others however, this can actually make them worse, so it really does have to be this targeted approach of giving it to be to the right patients.

In addition, the other main trait that we've been trying to target for a long time is the muscles, and we used to think that serotonin was a really important driver of pharyngeal muscle control and it turned out a lot of that knowledge was based on really reduced preparations in animal models where there were a lot of anesthetic agents onboard and when we did those human studies it turned out the endogenous serotonin was really playing a minor role. We now know from more detailed animal studies and freely behaving animals that of Richard Horner's lab and others in Toronto, that these cholinergic and muscarinic processes are really important in mediating pharyngeal muscle control. There’s now a body of work that's going on to try and use agents that target those particular targets and is showing some exciting results in the proof-of-concept work in terms of reducing sleep apnea severity.

What role does phenotyping play in sleep apnea?

DE: What we're trying to do unlike the main therapy for sleep apnea, continuous positive airway pressure (CPAP) therapy that opens up the airway, it really doesn't matter why you get your sleep apnea and if you can tolerate the therapy that will keep your airway open and stabilize breathing during sleep, the problem is that half or more of patients that try that therapy are unable to tolerate it and others are unwilling to even try it. What we hope that phenotyping can do, and by phenotyping, I mean understanding those specific 4 causes on a per patient basis, if we knew exactly why each individual was getting their sleep apnea, we could then target individualized therapies based on each of the individual specific problems. We've developed quite complex techniques to measure those in the research lab and now our next challenge is to roll those out into the clinic and simplify them down, and, again, we're having some progress in in obtaining that goal which will really be necessary in terms of rolling out targeted or precision medicine for sleep apnea.

What’s the clinical impact that phenotyping can have on this patient population?

DE: Recognition and awareness that most patients have 1 or more non-anatomical contributors to their sleep apnea is changing the way clinicians evaluate their patients and is beginning to inform treatment decisions. This is especially true for those who do not respond to traditional therapies. For example, there is greater recognition that a key reason that many patients do not respond to second-line therapies that target the anatomical problem such as mandibular advancement therapy and upper airway surgery is residual issues with unstable control of breathing (high loop gain) which these therapies do not address.

Transcript edited for clarity.