Transcript
[00:00:00] Host: Dr. Strollo, thank you so much for joining us. Could I ask you to please introduce yourself and tell us about your clinical and research work in sleep medicine?
[00:00:08] Dr. Strollo: I'm currently a professor of medicine in clinical and translational science at the University of Pittsburgh in the Division of Pulmonary Allergy, Critical Care and Sleep Medicine.
[00:00:17] I've had substantial experience in this field, um, over 35 years, and have really focused on clinical trials in two particular areas, bringing new treatments to the management of obstructive sleep apnea primarily, and also for new diagnostic procedures. So today, I'm excited about having a conversation about our newest trial, which is the SynAIRgy trial.
[00:00:46] And the SynAIRgy trial is the one of the largest pharmacologic trials in the area of sleep medicine that involves a first-in-class drug that you take on a nightly [00:01:00] basis to really target neuromuscular activation of the airway during sleep.
[00:01:07] Host: And so obviously our understanding of obstructive sleep apnea has evolved considerably over the past decade. And what do you see as the biggest shifts in, in how we think about the pathophysiology of OSA and, and how have these changes affected clinical practice?
[00:01:21] Dr. Strollo: So treatment of, uh, obstructive sleep apnea historically has really been related to the targeting the upper airway closure using positive airway pressure via pneumatic splint.
[00:01:35] So initially it was CPAP, and that's evolved in terms of different ways to apply positive pressure to the upper airway. Bi-level pressure, which tends to decrease the pressure during exhalation, which frequently is more comfortable for patients. And then more recently, people have designed auto titrating CPAP and auto titrating [00:02:00] bi-level pressure.
[00:02:01] But unfortunately, many patients can't tolerate this approach, so this leaves many, many patients untreated. For example, in the United States, about 80 million people have risk factors for obstructive sleep apnea. But frequently 80% of individuals re- remain undiagnosed and untreated. And in the individuals that we do diagnose, those individuals, many accept and adhere to positive airway pressure, and that's generally where we start.
[00:02:37] But roughly it's been modeled that about 37% of people that we treat with positive airway pressure cannot tolerate positive pressure. So it leaves, uh, a, a group of individuals that, that we really struggle to treat with. So this has really caused us to look at other treatment options.
[00:02:57] Historically, we've looked at, [00:03:00] uh- Oral appliance therapy, which is beneficial in some individuals. And more recently, I was involved with the STAR trial, which what we did was we actually used upper airway stimulation of the hypoglossal nerve, a device, a impulse generator that's implanted much like a pacemaker to pace the upper airway primarily by stimulating the hypoglossal nerve unilaterally.
[00:03:26] However, that requires surgery. It, it's rather expensive for, for many individuals. And so more recently, really, there, there's been a, a push to identify a approach pharmacologically to treat obstructive sleep apnea. And as you, as you know, the SURMONT-OSA trial using tirzepatide has been approved for obstructive sleep apnea.
[00:03:50] That targets a phenotype, which is the obesity phenotype, and what the current study that we're gonna talk about today, SynAIRgy, [00:04:00] is really targeting neuromuscular activation, which is a completely different approach. So that's why this is exciting to, to the field. It offers a, another tool in the toolbox that we can effectively treat individuals, uh, who are at risk for obstructive sleep apnea and complications.
[00:04:22] Host: So you Recently published the results from this phase 3 SynAIRgy trial. Could you tell us about how AD109, um, the drug in this trial, how it works, how it's different from existing treatments? I think you touched on that briefly just, just now, but how AD109 works, what it's targeting, and what do you consider to be the most important findings from the study?
[00:04:41] Dr. Strollo: Yeah. No, that's a very good question, and, um, the, the new approach using AD109 is, is the fact that it, it targets the, the hypoglossal motor nucleus. And, and we kind of described this in two papers that were [00:05:00] simultaneously published at the time in the American Thoracic Society meeting. So our phase three trial, which i- is generally a, a safety and efficacy trial, was published in the American Journal of Respiratory and Critical Care Medicine.
[00:05:14] And a mechanisms paper that was simultaneously published in the red journal, which is the American Journal of Respiratory and Cellular Biology for the American Thoracic Society. So what makes the mechanism differ from- Targeting just weight loss is the fact that there are two drugs that are combined to address neuromuscular function.
[00:05:42] And, and so atomoxetine, which was a fixed dose in this particular study of 75 milligrams, and R-oxybutynin, which is the enantiomer of oxybutynin, the R enantiomer, which tends to have more favorable side effects, that was dosed at [00:06:00] 2.3 milligrams. And what atomoxetine does is it, it's a serotonin reuptake inhibitor, so it increases norepinephrine stores, and that tends to increase upper airway muscle tone during sleep.
[00:06:17] And R-oxybutynin is a anti-muscarinic, so it decreases acetylcholine signaling during sleep. So the combination of these two drugs really affect upper airway muscle tone during sleep by modulating signaling through the hypoglossal motor nucleus. And th- this work was really informed by very basic work that was, uh, in- initially, uh, addressed by Dr.
[00:06:44] Horner, who's one of the co-authors of the, of the paper in the Reg journal. And like everything else in medicine, it took 20 years to really find, you know, how we were gonna deploy this clinically. But it's, it's one of those success stories that, [00:07:00] you know, with persistence and understanding mechanisms of drug signaling, that we can now target the hypoglossal motor nu- nucleus and improve upper airway muscle tone during both non-REM and REM sleep.
[00:07:14] Host: Wow. Yeah, so that's-- So it's like targeting the muscles rather than targeting specifically weight loss. What were the findings from the study? What, what were the most important sort of takeaways did you find? Yeah, so, so the important thing to keep in mind in this particular study, we, we really studied a very broad population that was reflective of the North American population.
[00:07:35] Dr. Strollo: So it was half men, half women, people across all weight classes. So a third of the population was not obese, and approximately one-third was obese, and a third was significantly overweight. Also, the severity of sleep apnea, unlike many of our other trials that we've done in sleep apnea, we looked at, at mild, moderate, and severe obstructive sleep [00:08:00] apnea to really understand how the drug may affect from a, both a safety and efficacy standpoint. The primary endpoint in this particular trial was, which was a reduction in the apnea-hypopnea index. That's sort of the standard metric that we use to identify severity of disease.
[00:08:20] We also looked at secondary outcomes, which involved measures of hypoxemia. So we looked at the decrease in hypoxic burden, the decrease in the oxygen desaturation index, and also the time below 90%.
[00:08:40] In addition to that, we, we looked at patient-reported outcomes, which obviously is important when we manage patients with obstructive sleep apnea. So, you know, there, there were three real targets. The first being a reduction in the apnea-hypopnea index, which was the primary target. And then the secondary endpoints [00:09:00] involved both improvement in oxygenation parameters, which we know have been informed by a number of epidemiologic studies that those frequently are associated with cardiovascular and cerebrovascular risk.
[00:09:14] But we also looked at, at additional secondary endpoints, which were patient-reported outcomes, decreases primarily in, in the PROMIS fatigue and the PROMIS sleep improvement score, as well as snoring. And the remarkable findings from this particular study was that we saw a fairly substantial reduction in the, in the hypoxic burden measure, which tends to be a much better measure of sleep apnea-specific hypoxemia.
[00:09:50] So we, as opposed to just looking at the apnea-hypopnea index or the oxygen desaturation frequency, which are just [00:10:00] frequency counters, what hypoxic burden takes into account is sleep apnea-specific Hypoxic burden. So it's the time under the curve that's associated with a drop in the oxygen saturation that's related to either an apnea or a hypopnea event.
[00:10:20] So we also saw in this study that there was a significant improvement in a change of apneas to hypopneas and a decrease in hypopneas, which was an important observation. The, the other thing that was, was really remarkable in this study was we saw a very significant reduction in, in snoring And so a- approximately 70% of the individuals who were treated with AD109 had a, a statistically significant improvement in snoring, and that's one of the key clinical parameters that [00:11:00] bring patients to the office, and, and also tends to impact, you know, intimacy from a bed partner's perspective.
[00:11:07] So the bottom line here is that, you know, we have a large population of patients in the United States, and even worldwide, that, are at risk for obstructive sleep apnea. While PAP therapy is effective in the laboratory, many patients struggle with PAP therapy as a sole therapy, and much like a- any other treatment in medicine, you know, not every treatment is accepted or adhered to.
[00:11:34] So, so AD109, uh, represents a, a new tool in the toolbox, and the surprising findings primarily were the reduction in the hypoxic burden that we observed, as well as a substantial reduction in snoring. Hypoxic burden is also important from the standpoint that our colleagues at the Brigham and Women's Hospital have done some secondary [00:12:00] analysis of large epidemiologic cohorts, and shown that this was a better measure than the apnea-hypopnea index in predicting cardiovascular and cerebral vascular complications long term.
[00:12:15] So we were very comforted by that study. The other thing is that in terms of the safety signal, there were no deaths in the treatment arm of the study. This was a randomized, placebo-controlled parallel design study that did not demonstrate any significant safety signal, no deaths. There were some side effects, as one would expect in any study.
[00:12:38] These side effects were primarily individuals who had dry mouth, an insomniac, and then some GI symptoms, which would be expected with this combination medication. And, and just to remind you that atomoxetine has a long history of being used primarily for attention deficit disorder, so this is [00:13:00] sort of repurposing the drug that, you know, we have a long understanding of.
[00:13:05] The R-oxybutynin is a novel clinical entity that was designed and it was informed by our prior work in terms of the phase one and phase two studies, the phase two study being a, a one-month study called the Mariposa study. So this seems to, to really mitigate some of the symptoms that would be associated with, with atomoxetine and, and also address sleep, not only in non-REM sleep, but apnea related to REM sleep as well.
[00:13:38] So Fairly exciting and a positive study overall.
[00:13:43] Host: So we talked about how PAP and CPAP They- they've been kind of seen as, like, the standard of care for sleep apnea. And let's say a drug like AD109 was approved. How do you e- envision that would fit into the treatment landscape? What kind of patients might be referred to for this? Um, who would benefit the [00:14:00] most?
[00:14:00] Dr. Strollo: You know, a- as I mentioned previously, of, of the patients that we offer PAP therapy to, you know, what, what the modeling seems to support is about 37% accept and adhere to PAP therapy, and that's the only thing you have to do. But that leaves, you know, a substantial number of individuals that cannot accept PAP therapy, and that really, uh, mandates, you know, alternative treatments.
[00:14:26] And as I mentioned, there are other treatments that are available, but AD109 may serve individuals who we really can't, uh, treat properly with PAP. Remember, in this particular study, the way it was designed, we enrolled individuals who could not accept or adhere to treatment with PAP therapy. So it was really w- what we look at as almost salvage therapy.
[00:14:53] We've done this also in the upper airway stimulation space, the, you know, using the Inspire [00:15:00] device. So how, this will be labeled by the FDA, that's out of my lane. That will be a conversation with the FDA and the company. But it is going to be something that will be talked about, obviously, you know, because it's, uh, once-a-night dosing of medication, and it stands to improve a number of patients' quality of life as well as the manifestations of obstructive sleep apnea that are generally related to hypoxemia, as well as snoring.
[00:15:33] So this, as I mentioned before, is something that I, I think is, is going to be discussed in, in the medical community, and neurologists as well as pulmonologists and general internal medicine people, as well as family practitioners, who all participate in care of, of patients with obstructive sleep apnea, will, uh, be interested.
[00:15:57] And, you know, how, how it fits into [00:16:00] our rubric of, of treating patients, I, I think that still needs to be, you know, defined, and it will probably be informed by FDA labeling.
[00:16:10] Host: And, you know, neurologists are frequently working with patients who not only have sleep apnea, but also may have Parkinson's or Alzheimer's disease or, or headache or epilepsy, and we know that sleep apnea has, has some connection to cognitive outcomes sometimes.
[00:16:24] Do you think there's any future where you might investigate other comorbidities with this drug? And also, do you think any of these patients who have comorbidities might, um, benefit from a drug like AD109?
[00:16:37] Dr. Strollo: Yeah. So, so it's a very good question. In this particular study, the SynAIRgy trial, and then also the Lunero trial, which wa- the SynAIRgy trial was conducted for, for six months, and, you know, with the primary outcome of safety and efficacy.
[00:16:53] We, we excluded individuals with significant cardiovascular and, and cerebrovascular disease in [00:17:00] this particular trial, and also in the Lunero trial, there were similar inclusion and exclusion criteria. However, in, in data that we presented at the SLEEP meeting just recently, we, we looked at pool data, and we also reported that at the ATS meeting.
[00:17:18] We didn't report the impact on cognition with treatment with this drug. However, we have collected information looking at PVT, which is response times, as well as digital substitution time in the VULT test, and we'll be analyzing that a little more completely. The preliminary information looks favorable, but it needs to be fully analyzed, and will be recorded subsequently.
[00:17:49] Host: And, um, lastly, you know, there's been some recent research talking about how OSA might not be a single disease, but sort of a collection of, of phenotypes. Do you think we're moving [00:18:00] towards a more personalized approach to treatment of sleep disorders, and, and how might that affect, uh, therapeutic decision-making in the future?
[00:18:08] Dr. Strollo: Excellent point, and the whole notion across all of medicine is to hopefully try to provide a more precision-based approach. And in the sleep apnea space, historically, we really only looked at one phenotype, the apnea-hypopnea index, in an individual who have socially unacceptable snoring. More recently, we've really tried to focus on phenotypes and endotypes.
[00:18:33] And so again, the team at the Brigham, which the Apnea Med team is working with as well, were able to endotype individuals as a result of, of the polysomnogram. So in the SynAIRgy trial in particular, we did a baseline in-lab polysomnogram, we did a polysomnogram at four weeks, and then we did a polysomnogram at six months.
[00:18:57] And what that allows us to do is to look at [00:19:00] the endotype, the specific endotype of the individual with obstructive sleep apnea. And so we defined, in this field, really three additional endotypes as opposed to just critical closing pressure of the airway, which is usually associated with obesity. But there's also insufficient upper airway activation, neuromuscular activation, which is what AD109 would target.
[00:19:29] There is an endotype of high loop gain, which is an exaggerated response to an apnea that, that causes hyperventilation, and then an endotype of what we call low arousal index. So if someone is, is very easily stimulated by an event which causes sleep fragmentation, obviously is associated with daytime sequelae of usually sleepiness.
[00:19:56] So understanding these different [00:20:00] pheno-endotypes helps us identify what treatment may be more effective, and in particular, AD109 may have a greater effect on inadequate neuromuscular activation during the sleep period. So it's important to remember that, you know, during, during wakefulness, we really operate under behavioral control of respiration, so the upper airway muscles are activated behaviorally.
[00:20:29] But as we fall asleep, muscles tend to relax, and, and individuals that are at risk for obstructive sleep apnea, those are the ones that, that tend to have airway obstruction.
[00:20:40] Host: Well, Dr. Strollo, thank you so much for your time and your excellent insights. Um, we really appreciate you joining us today for this episode of Neuro Frontiers.
[00:20:48] Dr. Strollo: All right. Well, it's been my pleasure, and have a great day
