“Laugh and the world laughs with you. Snore and you sleep alone” is a famous quote from the author Anthony Burgess.

Sleep Apnea affects 425 million adults over the age of 40. Yet, good treatments are unavailable. In this episode we address how Bioelectronic Medicines helps to alleviate the problem.

Links as promised:

  1. Inspire Medical – the first hypoglossal nerve stimulation product on the market.
  2. Kingman Strohl’s lecture
  3. A Ted Talk on Didgeridoo

SKRAPS is your podcast, where we on your behalf explores unsaid, underappreciated and sometimes, untold stories of sparks of brilliance in science, technology and innovation.

Show Credits

  • Created & Produced by: Arun Sridhar & JoJo Platt
  • Editing: Arun Sridhar
  • Sound design: Arun Sridhar & Swaminathan ThiruGnanaSambandam
  • Sound mixing and mastering: Swaminathan ThiruGnanaSambandam

Social Media:

You can help us fund the production costs by donating as little as $5 or £5 or in any currency of your choice as a one time or a recurring payment HERE


Laugh, and the word laughs with you. Snore and you sleep alone.  – Anthony Burgess 

Hey everyone, this is Arun,

JoJo  00:34

and JoJo,

Arun Sridhar  00:35

and you’re listening to SKRAPS bioelectronic medicines. If you really want to know what the sound that was playing at the beginning of the episode, you need to stay patient right up until the very end.

JoJo  00:49

Before we get started, we want to let you know that you should head over to our Twitter and LinkedIn profiles, both for a ruin and for myself. And then also check into the scraps podcast profile. Go ahead and support us by liking us on your favourite podcast app. If you haven’t already done it. And trust me, my daughter did it. You should do it too.

Arun Sridhar  01:11

So JoJo, how are you doing?

JoJo  01:12

I’m doing okay. It’s been crazy, crazy travel and work and work and travel and fun. And work. And work is fun. So it’s been fun. But in I feel like we’ve we’ve needed to work a little harder and keeping the podcast going.

Arun Sridhar  01:30

Well, yeah, you’ve really hit the road since April have, haven’t you so but I’m actually glad that both of us had a chance to meet face to face last month at one of the conferences in Minneapolis. And more importantly, before you hit the road again, I’m glad that we have some time to record this episode. So I know that it’s normally you asking what are we talking about today? But for a change. Let me ask what do you think we should talk about today, JoJo?

JoJo  02:00

Well, I think I think this whole season has been pretty special. And I don’t want to interrupt that flow. And it’s been a fun journey. And after doing our fully narrative podcasts on psychedelics, and we got back to our sort of a hybrid version of what we’ve done in the past, yeah,

Arun Sridhar  02:17

Purely as an experiment..!

JoJo  02:18

Well, that’s what this is science, right? We should experiment. And I think people seem to kind of like this approach, one where we mix discussion and narration and interviews. Do

Arun Sridhar  02:27

you have any favourite ones that people should check out? Any special recommendations from JoJo now?

JoJo  02:33

All of them? I love all my children equally

Arun Sridhar  02:37

Spoken like a true mother.

JoJo  02:40

Don’t….Don’t tell my kids. I don’t know that they would agree with that. But okay. I’ll be honest, I think one of my favourites has to be the patient pioneers. I think that there are so many instances where people get into this field of work and study and research for altruistic reasons. And so many people, especially the younger ones, don’t get that first hand experience with the patients themselves. So that’s one of my favourites. How about you?

Arun Sridhar  03:07

I personally love the episode two, purely because the fact that a modality. And I think Imran EBA also mentioned that to a certain extent where you actually have a non invasive modality and the impact of an Integrated Database stimulation can actually be so profound. It strikes so many cards with me, both philosophically as well as scientifically. So for me, that one is an absolute favourite of mine. Look, I know you asked for one, but I’m also going to give you another one, which is the fifth episode, titled the killing. I think the type of soundscapes that we created for that episode is something that took me so much time, but it was the most fulfilling of any episode production that I’ve done. This series. That’s that is a great one, one must check out this season of scraps and for what it’s worth, listen to the episodes in with your headphones on, or in a car stereo with no distraction, to fully understand the production value. And sorry, JoJo, I had to make that pitch. But now coming back to the episode and reversing the roles. What are we going to talk about today?

JoJo  04:25

Well, I kind of had an idea that I really, really wanted to put the screws to you. So it’s it’s gonna be some heavy lifting for you today.

Arun Sridhar  04:33

Wow. How’s that? All right, well,

JoJo  04:35

you’re the person who apparently knows everything in anything about by electronic medicine off the top of your head. And for some things that you always thought about the field of bioelectronic medicine space. There’s room for novel therapies beyond the traditional hammer looking for a nail brain computer interfaces, et cetera, et cetera. So, here I am to grill you on this. Oh,

Arun Sridhar  04:59

well What can I do apart from just accepting the challenge through this? Oh, let us actually see if I stand up to the inquisition. So what topics specifically are we going to talk about today?

JoJo  05:11

I kind of thought for the next three episodes, we’ll take three disease conditions, and go soup to nuts on each topic, so that everyone can understand the area well, be it a scientist or an engineer, or an investor, or a patient or a member of the general public. Hopefully, there should be something for everyone. Okay,

Arun Sridhar  05:32

so what specific disease condition are we going to talk about today? JoJo.

JoJo  05:36

Okay, so I have one for you. It’s something that impacts a huge chunk of the population that people don’t even realise they have it. And it’s usually somebody else that tells you that you have a problem. It’s not alcohol. They tell them that they’re loud, and they can’t sleep. What? Well,

Arun Sridhar  05:56

if anyone has naughty thoughts, please leave them at the door before you go any further. This is not that kind of a podcast. For that you can check out other episodes from other podcasts. And we will throw in a link in the episode description. But just kidding. Just kidding. You know, I think you’re referring to something less naughty. Like, I mean, let me ask you one more time. What did you have in mind?

JoJo  06:28

So will ruin you have a slightly perverted brain? And I’m talking about a disease condition, not a fantasy or fetish that keeps your partner up all night? Because of how loud you Oh, yes,

Arun Sridhar  06:38

that one?

JoJo  06:40

Yes, that one. The one that causes more new onset diabetes, more new onset of hypertension, atrial fibrillation, stroke, and sudden death. And for folks in the bioelectronic medicine field, this has the highest valuation today for a single asset class.

Arun Sridhar  07:00

So do you want to tell everyone what that is JoJo?

JoJo  07:04

Absolutely. I think it’s about time or only about 10 minutes into the podcast before I finally tell you that we’re talking about sleep apnea. Yes, you and your dirty mind. Can’t believe you changed a science podcast in a soft porn. I’ll never forgive you for this.

Arun Sridhar  07:21

But by the way, that category does exist too. This is not a paid promotion by any means. But just saying. But jokes aside, I think we want to tell you some important facts. Knowledge about sleep apnea goes back in history to about to about the period, even before Christ around 360 BC. And if I just list out some of the names in history, who have had sleep apnea or sleep disordered breathing, you’d be very surprised. Some of the names include Napoleon Bonaparte, a Queen Victoria, your answer brams. Winston Churchill. If you are a fan of Charles Dickens like me, if you’ve ever read his novel, Pickwick Papers, Joe, one of the supporting characters in the novel had excessive daytime sleepiness, and he fell asleep standing up while knocking on a door. And then, for the longest time in the 19th century, people with sleep disordered breathing in the 19th century, were referred to have a quickened syndrome, as a tribute to Charles Dickens is Pickwick Papers normal,

JoJo  08:35

I was startled by just how prevalent Sleep apnea is. Globally, its prevalence is roughly 425 million of all adults between the ages of 30 and 69. So just to put that into context, that’s roughly 5% of the entire world’s adult population.

Arun Sridhar  08:54

Yeah. And what’s worse than that, is the fact that most patients don’t even know that they have it.

JoJo  09:01

And so how do people know that they were

Arun Sridhar  09:04

exactly as how you pointed out Jojo, the partner who usually sleeps in the same room, has a very disturbed sleep due to how loud and noisy the other partner snores. So as a result of this, initially, this becomes a frustration when someone has woken up from sleep, and it changes to anger or not being able to sleep any further. And then to realise as the disease gets worse, where the awake partner with a disturbed sleep is seeing their partner lying down, and having loud snores, extremely loud snores snorts and then suddenly, the partner stops breathing. And this happens over and over again.

JoJo  10:06

I can tell you I have first hand experience with this. And it is maddening. And it’s, it’s hard to watch somebody else sleeping peacefully while you’re not sleeping. And so whatever you do have a light tap can overtime turn into a pretty brutal shove or nudge? Yeah. So there must be some deep science as to why this happens. And should we talk about that part first?

Arun Sridhar  10:33

Yeah, if that’s what we want to do first, because I think talking about that will help. A great deal.

JoJo  10:40

Yeah, I think it’s important for people to understand why this condition can be such a huge burden. And there’s more to it behind just angry non sleeping and disturbed sleep for, for the sufferer? Well, they’re both suffering, trust me.

Arun Sridhar  10:56

Okay, so think about how people breathe in a normal situation. They, they take a deep breath in, and the breath out. Inspiration or inhalation is an active process. While exhalation is a passive process. Does that

JoJo  11:15

mean I’m passive aggressive? Is that what you’re saying? Oh,

Arun Sridhar  11:18

that’s not what I’m saying.

JoJo  11:22

So aside from you, calling me passive aggressive, would you please explain this inhalation exhalation process

Arun Sridhar  11:29

when a person inhales air they have to recruit many muscles, the muscles of the nose, the oral cavity, the palate, the back of the throat, all contract for the nasal and pharyngeal cavity to dilate to hold more air when the skeletal muscles of the ribcage and the diaphragm have to contract in completely different directions to move. In fact, the ribs actually move out almost radially from the centre, and the diaphragm contracts, and it’s pushed down. And as a result, what happens, this creates a suction like effect in the chest, and that pulls air through the nose and the mouth. But imagine, for some reason, if the negative pressure that is caused by the chest moving out, and something that the person can actually control both the chest cavity and the diaphragm moving down is met with an obstructed oral nasal cavity. Then what happens?

JoJo  12:37

Sounds to me like that’s a recipe for not getting enough air with each breath, almost like a vacuum expansion and a cavity with nothing actually flowing into the chest.

Arun Sridhar  12:48

Yes, exactly. So although it is not as dramatic when it happens the first time, but you can imagine how the body gets conditioned to react when the oral nasal passage is obstructed, over and over. Although initially it might be abstracted to a very small degree, let’s just put a number to it, let’s say 20%. And then as the disease gets worse, it gets obstructed to slightly more around 50% And then over to 80%. And then over time with repeated breaths at a particular breath, a complete closure of the oral nasal cavity happens. This slow and sustained obstruction over time builds up carbon dioxide levels in the lungs.

JoJo  13:42

So is this why snoring gets worse? Over a period long periods of time, like days, weeks and months? Or is this? Is this happening in one night session that you’re talking about this repetition and things getting worse and devolving. So

Arun Sridhar  14:00

I’m talking about the evolution of the obstructed airway over many days to months and years. Initially, when it actually happens, it’s always milder, because nobody actually goes from a small obstruction or, or a snore to eventually to a very long and a loud snore. But it always happens hand over time, and especially over months, two years.

JoJo  14:28

So back to the buildup of the carbon dioxide and that’s because we take oxygen from the air and then exhale carbon dioxide

Arun Sridhar  14:36

Exactly. So while this problem slowly starts building up over time, it starts off as one that actually initially blocks inhalation of air into the lungs. But what it’s actually causing over time is a carbon dioxide buildup in the lungs.

JoJo  14:55

And what is that increased carbon dioxide do? Doesn’t sound good,

Arun Sridhar  14:59

well, carbon Under oxide, interestingly, apart from causing global warming, especially outside the body, and in the atmosphere within the body, it’s a very important molecule that our body senses. So how does that work for people who actually have studied physiology, or most of the medical students would actually really understand that carbon dioxide controls the acid base balance in the body. And I will explain that a bit more, our body has some remarkable structures, one in the periphery and one in the brain. And both of them sends carbon dioxide levels in the body. The one in the periphery that I just mentioned, is just a single grain of rice size structure that senses many things in the body, like pH of the blood, co2 levels, etc. To just name a few, and signals to the brainstem constantly about changes that will impact the body, and specifically the bloods acid base balance.

JoJo  16:01

Where is this race shaped structure of which you speak? It is

Arun Sridhar  16:05

bang in the middle of the carotid artery bifurcation in the neck. So if one wants to feel the pulse in the neck, and be careful before you actually do that, do not find your pulse in the neck on both sides simultaneously.

JoJo  16:20

Why is it kind of like me no rhythm and it’s out of sync? No, that’s

Arun Sridhar  16:24

not the reason. The reason for that is because most unskilled people could press hard on both sides trying to feel for the carotid artery pulsations. And compressing the carotid artery on both sides will reduce the blood flow to the brain. So you don’t want to be doing that

JoJo  16:40

as well. So now you just ruined my defence strategy within go to choke somebody, sir. Officer, I promise I was just trying to feel for a pulse on both sides. But alright, let’s come back to that single rice side structure.

Arun Sridhar  16:55

Yeah, I did say unskilled people Jojo, so you could almost pass as an unskilled person in the yard, because you’re not a healthcare professional.

JoJo  17:03

I know. But we’ve discussed it. Oh. precedents press precedence. We’ve discussed it now on tape, which makes that premeditated. So I’m taking that one off the table.

Arun Sridhar  17:15

Yes, it does.

JoJo  17:18

So let’s get back to this race around the structure.

Arun Sridhar  17:21

Yes. So this single grain of rice size structure is called as a carotid body. You have one on each side. And this signals constantly to the brainstem regarding the carbon dioxide and pH levels. For example, the signalling to the brainstem is mediated via a small nerve, which ultimately goes and joins the nine cranial nerve in the neck. And the electrical information that the carotid body sends to the brainstem appears in form of an increased firing upon detection of a higher carbon dioxide levels. And this tells the brainstem that something is wrong.

JoJo  18:05

And since this is a series about bio electronic medicines, it’s perfectly clear that this is all electric. Yep, it definitely is. So what is the brainstem do do and all this well, the

Arun Sridhar  18:18

brainstem is both intelligent and dumb at the same time,

JoJo  18:22

so yeah, no. See, I’m tempted to compare this intelligent and at the same time to certain classes of people. But let’s maybe back that off and say it’s maybe more like most dogs.

Arun Sridhar  18:40

Well, my wife will tend to disagree, and she will actually say that I’m both intelligent and dumb at the same time. Anyway.

JoJo  18:53

Okay, stay on topic rune. brainstem.

Arun Sridhar  18:55

Yeah, the brainstem, as I said, is sensing all the information that the carotid body is sending in the form of electrical impulses. And it is a fantastic integrator of information. It receives this barrage of electrical activity. This is interpreted by the brainstem nod as an activity that it must perform to reduce the carbon dioxide level directly. But to act impulsively in a completely different way,

JoJo  19:22

I identify with impulsivity. But that’s not what we’re talking about. So tell me more about this carbon dioxide reaction. The brainstem

Arun Sridhar  19:31

in this situation, integrates this information that it gets and talks to itself and says, Oh, normally, it’s my kidneys who are supposed to be doing the work to filter out all the bad things from the blood that the body doesn’t need. So if the carbon dioxide level is raising of us do something quickly to neutralise it. So it does two things. It cranks up signalling down to the heart and the blood vessels to reroute the blood to The brain. Because remember, increased carbon dioxide means that the brain is not getting enough blood or so the brainstem actually thinks, then it goes as a result into a self preservation mode and starts dumping more adrenaline into the system.

JoJo  20:17

Hmm. I think this is what is referred to as increased sympathetic signalling.

Arun Sridhar  20:24

Yeah, it is called sympathetic for a reason. So, this increased sympathetic signalling that is caused by sensing of a higher carbon dioxide level that is then integrated into the brainstem. And as a result is sent to the rest of the body through the many sympathetic nerves, increases blood pressure, causing hypotension. It also changes the way glucose or insulin acts on the various cells, and potentially long in the long term could cause diabetes.

JoJo  20:59

Well, okay, so that’s one thing. What about the second thing?

Arun Sridhar  21:03

Yeah, the first thing that I’ve just told you about is more like an instantaneous reaction. Like when someone whacks you on the head, in this case, I’m equating obstruction to the airway, and an increase in carbon dioxide buildup as that whack on the head, then your immediate reaction is to slap that person back. So the sympathetic signalling increase is much like Newton’s third law on steroids, where the response is conditioned to a greater level every time the obstruction happens, and the carbon dioxide level increases. And the second thing that I’m about to tell you is a little bit slow. But if the carbon dioxide levels keep rising over multiple days, even within a single day, due to multiple episodes of obstruction, and the person who has this obstruction is getting worse and worse over time. And when this gets worse, it leads to more carbon dioxide accumulation in the body.

JoJo  22:02

Yeah, I know, it takes me a long time to not feel breathless when I ran all four flights of stairs to my apartment when the phone’s ringing.

Arun Sridhar  22:09

Yeah, exactly. The oxygen and the carbon dioxide balance. And it’s equilibration happens very slowly. And this is where the kidneys get normally involved. But imagine if the obstruction happens with every breath. And this doesn’t allow time for equilibration because the rate of breathing is much faster. And this increased co2 levels as a result starts impacting the brainstem sensor over time. And this causes the brain to say, stop breathing. Why, really? Yeah, it’s almost like a vicious cycle, the person literally stops breathing. And when no breathing happens, and enough negative pressure from the ribs moving out, and the diaphragm moving down, somehow drives to activate respiration. The patients who stopped breathing will wake up with a gasp, and go back to sleep again. But over time, and over years, when the obstruction gets worse, this drive to breathe from the brainstem is also impacted negatively. That’s one of the reasons why patients can actually not breathe for a longer and longer time as the disease gets worse. So essentially,

JoJo  23:24

a loud snore is nothing but an obstructed airway, which in some cases, can lead to further obstruction and cause cessation of breathing.

Arun Sridhar  23:35

And that’s why it’s called an apnea. And as it happens during sleep, it’s called sleep apnea. And there are two kinds, obstructive and central sleep apnea. And today we’ll only speak extensively of obstructive sleep apnea. The reason for that is because the total commercial opportunity is much bigger in obstructive sleep apnea than central sleep apnea. But having said that, it’s not as if the impact of what the central sleep apnea causes in patients is any less. We’re not going to completely ignore central sleep apnea either. We’re just going to address it to a much smaller degree. Obstructive sleep apnea, as the name suggests, is due to a mechanical obstruction to the airflow. But central sleep apnea is caused by central respiratory activation gone awry. You remember just a few minutes ago, we said, we said that the accumulation of carbon dioxide in the body creates a vicious cycle that leads brain and the brainstem to not send any signals down to the chest to activate breathing. This carbon dioxide accumulation leads to a shutdown of respiratory centres and this precipitates more apnea and patients. That’s what we said right? But imagine if this buildup of co2 in the brain is not due to Mechanical obstruction to the airway, but more due to the hearts inability to pump blood. As it frequently happens with heart failure. The heart cannot keep up with the demands of the body, sometimes even baseline demands. So in the most severe cases of heart failure, as it happens in elderly patients, or patients who have severe heart failure due to other reasons, even under resting conditions, the buildup of co2 leads to the brain shutting down breathing. And the way it actually happens, was described by two physiologists. And the phenomenon is called his chain Stokes breathing. In patients with severe heart failure, who experienced this type of a phenomenon that chain Stokes breathing, the airway is not obstructed. But the brainstem fires less and less to activate breathing. So the breathing starts off as normal, but keeps winning down breath after breath, before completely stopping. So one can differentiate central versus obstructive sleep apnea by various tests that people will perform by monitoring pressure, an airway in the mouth, as it might happen in a sleep study using polysomnography. And we’ll come to that in just a bit. A notable person in history who had central sleep apnea and died as a result of that was Joseph Stalin.

JoJo  26:36

Okay, but I have a basic question. Why does it happen in sleep, and not while at work?

Arun Sridhar  26:43

Think about it. When someone is awake, it is voluntary. So you can control the inspiration or the inhalation of air and the expiration or the exhalation of air. But when a person goes to sleep, they are fully under involuntary control. And the muscles of the body go limp. So the chances of muscles collapsing and causing an obstruction is higher. What we haven’t mentioned yet is the reason for the obstruction of the airway that causes sleep apnea. Remember, I said the patient muscles of the oral nasal cavity has a lower muscle tone when asleep, so that the muscles of the upper airway can prolapse or fall back, the entire airway can just relax completely, the tongue only collapses in a certain percentage of patients. And tongue as a result of gravity tends to collapse back into the airway at the back of the throat. But most patients, as we know today are obese might actually have a bigger neck size. And as a result of that there is too much water in the interstitial space between their muscle. And as a result of that, due to gravity, the entire weight of the fluid in the neck and actually compress on the airway. And that can narrow the opening. So that is a reason when we talk about obstructive sleep apnea, the obstruction can come from either the tongue or from the other 20 or muscle groups that forms part of the upper airway, which is part of the nasal and the oral cavity.

JoJo  28:23

Okay, so I have another question here. The old wives tale is that snoring is caused by things like weight gain, and your tongue sort of getting in the way of the back of your throat, how true is any of that

Arun Sridhar  28:36

all of that is very true. So snoring is mostly nasal obstruction. And that’s why most of the things when people actually have sinusitis, when they have other forms of inflammatory kind of disease, etc, of the nose and nasal mucosa. Actually, the snoring gets really worse even compared to people who normally snore to a certain extent their snoring increases in intensity when they actually have an infection. And the tongue prolapsing is actually part of what actually happens at the back of the throat. So therefore, remember, both the nose and the mouth is connected. So the air goes through both the nose and the mouth when people are sleeping, because most people let’s face it tend to have their mouth open. They breathe both through their nose and the mouth. But ultimately, both of them converge at the back of the throat, mouth breathers and that’s where the obstruction happens because when you’re lying down the tongue, every other part of the muscle in the upper airway is attached to each other except for the tongue. And the tongue is the one that can actually prolapse freely because it is under the influence of gravity. So it is true that the tongue can actually prolapse

JoJo  29:44

Yeah, it is an independent little buggers isn’t it? But then I’ve also heard and experienced that snoring can get worse if the sleeper is in a really deep sleep and or just exhausted at the end of a really long, you know, long tough day does exhaustion and and deep sleep affect it too?

Arun Sridhar  30:07

Yes, both of them do affect, let’s take the first one exhaustion is you’re much more under involuntary control. So therefore you are completely asleep. And you might have heard of people saying sleep stages. So you might be in a really deep sleep, at which point of time your body is entirely limp the muscles of the body is very loose. And, and remember I told you that the muscles of the airway actually has to contract to dilate. So it basically has to it’s almost kind of it’s a circular pathway, right? So it actually has to contract to open the airway. But everything is relaxed, you actually have a much smaller lumen, as they call it for the air to pass through. So that’s what causes the obstruction with alcohol. It’s very similar to exhaustion, as an example. So that’s why if somebody is diagnosed with sleep apnea, they will actually be saying you need to not have too much alcohol, or reduce your alcohol intake to a certain extent. Because all of that will actually impact your snoring, your obstruction, as well as eventually to how worse it can get when you’re really asleep.

JoJo  31:19

Great. That’s awesome for the explanation. Thank you. And as we normally do, we rely on more than just a runes, skillful scientific explanations. So we’re going to include an excerpt here from a lecture that Dr. Kingman stroll, he’s one of the preeminent sleep physicians in the US, as he describes a patient’s sleep apnea with a video running in the background.

Kingman Strohl  31:44

So if I started here, you’ll hear background noise is he’s looking like he’s trying to take a breath. And now he’s breathing one. One breath only takes one breath and goes right into the next app. Now while it looks like he’s trying to breathe, he’s making efforts against a closed airway, his mouth is kind of working hard, but there is no airflow. And these efforts get larger. Until he breaks it with a resuscitate of snore, one, two. And then obstructed breath actually stops breathing here for a minute or for a few seconds, and then starts up again. And this particular cycle of obstructive apnea is rescue breaths and snorts and re entering into another apnea is the hallmark of obstructive sleep apnea, sleep apnea.

JoJo  32:50

So how many times can a patient stop breathing, say in an hour or a minute, and how do we diagnose them?

Arun Sridhar  32:58

That’s a great question. A person with obstructive sleep apnea, like with any disease condition, is graded as mild, moderate severe, so that the physicians can actually identify the severity of the disease and treat them. And the grading is based on the number of apnea hours or the time that they stopped breathing. And this is counted. So the cessation of breathing, or the pauses in the breath, or the half breaths, or the snorts, or the gasps, are all calculated by a healthcare professional, who is skilled at performing the sleep tests, when they are watching a person undergo a test called as polysomnography, where they measure multiple parameters like airflow pressures of the air moving in and out pressures of the oral cavity and the pharyngeal cavity before and after the obstruction, while also looking at the video of the person sleeping, so that they can clearly grade the episodes that are happening. And the total count of these complete and incomplete obstructive episodes,

JoJo  34:02

even breaths, pauses or lack of breaths, right?

Arun Sridhar  34:06

Correct. So these patients can actually stop breathing for anywhere up to 30 to 60 times in an hour. The total count of these episodes is expressed as a value called ahi. AhI refers to the apnea hypopnea index. And this number is used, along with the blood saturation levels that is also measured in the study as an indicator of how severe the co2 accumulation is in the body to provide an index of severity of the disease.

JoJo  34:37

Alright, so the next question, and I think it’s logical. You can check me on that for a problem this severe, where it affects so many people and it can be really scary for a person to stop breathing for several seconds and multiple times in an hour during one’s sleep session. Pharmaceutical therapies must have tried to attack this right now. Must be something out there over the counter prescription. What do they have?

Arun Sridhar  35:03

What is the problem and sleep apnea, it is the fact that patients actually stopped breathing. So you need a stimulant to make the person to start breathing again. And most respiratory stimulants as we know of wakes up the patient. So really, if you’re trying to treat sleep apnea and make the quality of sleep better, if you’re making a drug that is stimulating the brainstem to wake up the patient, you’re not really treating sleep apnea. And that’s why pharmaceutical therapies have not been available for this condition.

JoJo  35:38

So I think you’re telling me that the pharmaceutical solution is basically doing speed to keep you from sleeping, which stops the sleep apnea because you’re not sleeping because you’re on speed.

Arun Sridhar  35:50

Yeah, what I’m trying to tell you is that there is no pharmaceutical therapies for obstructive sleep apnea. The reason for that is because when you’re trying to develop a drug for obstructive sleep apnea, you need to ensure that you’re stimulating respiration without waking up the patient. And there is no drug that has ever been developed to to relieve an obstruction while continuing to provide sleep to the patient.

JoJo  36:14

Makes perfect sense. But then back to this obesity issue. In in a person who has a thicker neck, and I think you said it, or I’ve read it somewhere that it’s usually over somewhere around 60 centimetres in circumference, that patient, these obstructions are more common in those patients. And that sleep apnea is only it’s not only common and people who are obese is that what’s your take on that

Arun Sridhar  36:39

that’s that’s entirely true. I can see where the thought of obesity being associated with obstructive sleep apnea came from. In fact, it was made famous by Charles Dickens in his Pickwick Papers. But the real scientific and the clinical evidence came from a London physician called his wh Broadbent, who provided one of the early scientific descriptions of obstructive sleep apnea, characterising it as we described as a failure of inspiration to overcome the resistance in the fairings with Audible signs of snoring and periods of perfect silence with ineffectual chest movements. And he was the one who actually called it Pickwick Insert Row. And another physician called begelman reported that patients actually have alveolar hypoventilation associated with obesity. So this means that patients had lower blood oxygen saturations, and as a result presented with signs of bluish discoloration of their skin and mucous membranes. While obesity or increased BMI is a major risk factor for developing obstructive sleep apnea. There is emerging evidence to show that it is not just entirely an obese patient who is at risk of developing OSA or obstructive sleep apnea, but also the shape of the neck and the anatomy of the neck that predisposes people to obstructive sleep apnea.

JoJo  38:16

Yeah, cuz I have heard some skinny people saw logs. So pharmaceuticals obviously have a huge hurdle to overcome, and they haven’t done it yet. And so what does that leave as a treatment for patients asking for a friend

Arun Sridhar  38:29

so since the problem and obstructive sleep apnea is one of a mechanical obstruction to the airway, where in some patients it might be the tongue in some patients, it might be the entire rest of the airway, it must be treated with a mechanical solution. And obstructive sleep apnea is a respiratory issue. And blood oxygen levels, as I said, goes down due to a reduction in normal breathing. So the solution and the most widespread solution is a type of a pneumatic splint. So now that we’ve all been through COVID, I think most people will be aware of continuous positive airway pressure, or CPAP, or even BiPAP devices, the principle is all one of the same. It acts as a pneumatic splint for the airway to keep it open, carry on the CPAP and BiPAP devices, blow air at positive pressure, and force the air to act as a fluids plan to keep the airway open. The CPAP devices work as long as the patients use it. You will see that older patients tend to use it more frequently. And these devices and their businesses are a big market. Like for example, there are companies like Philips and ResNet, which actually make CPAP devices and they thrive and the bulk of their business is on making and marketing the CPAP devices because they get reimbursed year on year because the patients have To change their CPAP devices.

JoJo  40:02

So I know reimbursement especially in bioelectronic medicine is a big issue. That’s something that everybody wrestles with. What does reimbursement look like for a device like a CPAP? machine, or for makers of these devices?

Arun Sridhar  40:15

Yeah, the continuous positive airway pressure devices or CPAP devices are relatively well reimbursed. They are, in fact, the first line treatments for obstructive sleep apnea. It works as well as it does when it’s used, though. So

JoJo  40:31

why, what do you mean, when it’s used? Why would you say that, it seems like if you have a solution,

Arun Sridhar  40:37

the CPAP devices, as I told you, inherently blows air at positive pressure. So by nature, so by nature, when you’re forcing air at positive pressure, they tend to dry out the oral nasal mucosal layer, this can be very uncomfortable for the patient upon chronic use. Second, as I said, the more older the patient is, the more compliant they are. But OSA is not just a geriatric disease, it is seen more in the younger population, more in more fit a population, especially as far as I know, a remarkable number of NFL athletes, as an example, have obstructive sleep apnea. So if you have someone who travels a lot, or is of a younger age group, who is much more mobile, who doesn’t have a good sleeping pattern, having a device that has to be plugged in all the time through the night, and you got to be connected to the device through these tubes that come to your nose, and having a positive air being pushed into your nose, and your mouth can all be a bit problematic. So patients tend to use it less and less. So the average compliance rate for CPAP is between 40 and 60%. And I’m not coming up with this number. This is from a review that was commissioned by the American Association of Sleep Medicine. And the numbers that is found in the US is also very similar to what is found in the other countries.

JoJo  42:06

That actually I’ve I’ve done some other research in this area, and that 40 to 60% actually sounds high. And and here’s kind of one of the tricky things that I I know they they looked at to determine compliance for CPAP users, is they get the machine and they maybe turn it on, maybe use it a couple of times. But the indicator for how often they’re using it is actually how frequently they reorder the cleaning products that are also reimbursed for the machines and the tubing and all of that. Have you have you heard anything about that part? I mean, it’s, it’s, that’s a, that’s a pretty good use. It’s like if you’re not cleaning your machine, it’s because you’re not using it.

Arun Sridhar  42:46

Yeah, that is very true. That is that is absolutely true. And the and the reason for that is because when you’re blowing air, the air actually condenses the tubing, so which means you get mould and you need to clean the tubing or change the tubing, etc. But remember that these CPAP devices,

JoJo  43:06

yeah, so you stop snoring, but you get an infection.

Arun Sridhar  43:09

Yeah. And airway infections are not usually that great. And you don’t feel that well if you if you do have them,

JoJo  43:16

which probably leads to more snoring, right? Yes.

Arun Sridhar  43:19

So I think for coming to reimbursement, the point that you raised before, I think the guideline for reimbursement in the US, at least and US and Europe, is the fact that patients will actually have to use the CPAP device for at least four hours at the bare minimum for them to be provided with the next CPAP device. Because these CPAP devices tend to have a monitor for everyday use and for how long they’re being used on a given night. So this provides the information for the payer to actually monitor how much this

JoJo  43:52

welcome to the 21st century. Yeah,

Arun Sridhar  43:55

this provides the information back to the payer for how much these devices are being used. And if they’re used any less, these devices will not be provided, or reimburse for by the insurance company.

JoJo  44:08

And I’m guessing we have a third factorial in in compliance incompliance of use, and that would be the sleep partner if there is one. Because my understanding is that these machines can be a little bit loud, not just for the sleeper, but for the partner too. Yeah, that’s Is that true?

Arun Sridhar  44:25

That’s very true. Because these devices, to be honest, they’ve actually gotten quieter over the years, but it is still generating a certain amount of decibel noise and when you’re sleeping and if you’re very disturbed by the tick of the clock, or some of the sounds around you, just having a CPAP device and the constant hum is going to be a problem specifically for the partner. So that is also another reason why partners of patients with sleep apnea might actually tend to sleep in a different room purely because they don’t want to affect the sleep quote. Let the for the person but also the partner wants to remove themselves from the same room while they’re asleep. So it makes for not so great marital relationship,

JoJo  45:11

not to mention that the Darth Vader mask and the breathing and hum of the machine isn’t exactly sexy. So as a hypothetical, again, asking for a friend, what does a patient journey look like? Let’s say we’ve established through a sleep partner that asleep or has possibly OSA or, or, or sleep apnea in general, how does how do you go about diagnosing it? What’s the process

Arun Sridhar  45:42

usually when a when a person is actually referred to a physician, the physician will usually check for what is referred to in the field as a stop band criteria. So stop refers to snores the patient will be tired as a result of not sleeping well. O stands for observed apnea is most commonly referred by a partner or via study. P stands for pressure, which in this case refers to hypotension. And that’s a stop. And in the bank, it refers to B for BMI greater than 35. You do an assessment of the age whether it’s a paediatric population or an adult population and what the age of the patient really is, and refers to the size of the neck. And g refers to the gender, each specific letter of the acronym has an associated risk with it. So based on this score is assigned. And if it’s a case of a mechanical obstruction, and a paediatric population, like, say, an enlarged tonsils, which usually is a cause for obstructive sleep apnea and children, they would perform a tonsillectomy and those children, this procedure will usually take care of relieving the obstructive sleep apnea symptoms. But in the case of an adult population after examining and ensuring that the person is snoring is tired the next morning has a certain degree of reduction in cognitive function the next morning, has observed apnea is by the partner potentially has hypertension also is obese, and is has a thicker neck, and potentially is of a male gender, they will usually prescribe CPAP as we just discussed as the first line of therapy after CPAP. And patients will usually be monitored for compliance to CPAP, which we did discuss is anywhere between 40 to 60%. At best, if the patient is not compliant on CPAP, they actually have two options Most commonly, the first one is surgery. And this is usually only done in a very small subgroup of patients by end surgeons who will usually go ahead and change the shape of the pile. Remember, I told you that in some patients that could be an anatomical kind of obstruction because of how narrow the the oral cavity could actually be, they actually perform a very invasive and also what seems like a very painful procedure, when I say the name, they actually perform a procedure called as HPP, which is referred to as hypopharyngeal ovilla plasti. So they basically literally split your palate into half and then they re stitch it to make the the lumen of the cavity bigger than what it was before. So as you can imagine, that is a very invasive and also something that is not done widely. The next option is usually another non invasive modality which is referred to as a dental or a denture devices, patients will usually have a sub mandibular device. And that is usually provided to patients much like how a denture device is actually born. And this again is very painful, because it literally can be adjusted with screws to push the lower jaw out, so that the obstruction is actually very less, while I did tell you about CPAP devices that the compliance rate is around 40 to 60% at best, but in patients who actually comply. The efficacy can be as high as up to 95 to 100%. But with submandibular devices, it is a device that you actually get fixed by a doctor and you probably have to put that in before you go to sleep. All the patients are compliant because they are wearing it for the whole night. But the efficacy of it is almost close to 50%. So really, it’s a toss of a coin. So what I’m trying to tell you as a result of that is if you get diagnosed with sleep apnea, and if you don’t use CPAP well, then you have a big problem. And that’s where neuromodulation or by electronic medicines come to the park

JoJo  50:00

Dude, I knew you weren’t gonna leave us hanging without you weren’t gonna have us go through this whole discussion of a massive population of people that can’t be helped by drugs aren’t candidates for surgery. Nobody wants to wear a denture guard at night. And then additionally, you’re impacting asleep partner. So there has to be something that you’re holding in your back pocket. And I know you’re gonna tell us a lot about some of the companies that are looking at this because it’s a huge market, it’s relatively not well addressed, in what is out there in terms of options. And I, I smell opportunity. Yeah,

Arun Sridhar  50:41

there is a huge, huge opportunity. And as you said before Jojo, I think the the treatment for obstructive sleep apnea is the most valued asset in the field of electronic medicines, even bigger than deep brain stimulation or spinal cord stimulation in terms of market cap. But let’s actually talk about what exactly this option is, as I told you, obstruction to the airway can actually be a result of, of the, of the tongue, which is the most independent muscle group prolapsing back into the airway. And this tongue or the tongue is actually innervated by nerves. And this is what helps you to move your tongue when you speak, when you eat, etc. So therefore, stimulating the nerve to the tongue, can actually be very beneficial in moving the tongue out of the way such that air can enter and the symptoms of obstructive sleep apnea can be reduced. So that’s what the hypoglossal nerve stimulation companies do.

JoJo  51:50

Is, is that the only is that the only nerve target where bioelectronic medicine approach to OSA

Arun Sridhar  51:57

The answer is, at this point of time, they are the ones that are commercially approved. In fact, there is one device that is commercially approved, but the upper airway, which is a combination of the oral pharyngeal cavity, or the nasal oral pharyngeal cavity, which includes the nose as well as to the to the, to the back of the throat, as well as the pharynx. The lower throat is composed of 20 different muscle groups on either side. So there are great many nerve target options that could be available, because hypoglossal nerve stimulation only impacts 15% of the population. So let’s actually take 100 patients, you have 100 patients who are diagnosed with obstructive sleep apnea. So 40% are compliant with CPAP device 60% or 60. Patients Out of 100 are not compliant with CPAP device. So they’re looking for new options. hypoglossal nerve stimulation, at least the one that is approved back in 2014, by a company called as inspire medical systems that stimulates the hypoglossal nerve. And this only treats according to the pivotal trial 15% of the 60 patients, so which is approximately nine out of the 60 patients. The reason for that is because the Inspire medical systems device only stimulates on one side, because when they develop the system, they actually the FDA was very cognizant that you have two nerves, one on each side that is integrating the tongue. And the tongue doesn’t just contract, it also kind of moves in every other direction. So you have to be very specific to that specific branch of the nerve that innervates that causes a protrusion of the tongue. So therefore, the idea was really cognizant of making sure that the therapy was safe. So they only approved the device as a unilateral stimulation. And this unilateral stimulation device from inspire medical uses a stimulation device that is implanted under a dissection by an end surgeon. And another lead is actually tunnelled to the chest. And the lead that is tailored to the chest X is a sensor to see if the patient is breathing or not. So when a patient breathes, the chest moves, so diagnosis that as a breath, when the patient is actually not breathing, the chest doesn’t move, so the sensor actually knows that the patient is not breathing. But interestingly, you don’t want to wait until until the patient stops breathing to stimulate them. So what the hypoglossal nerve stimulation does is it senses the breathing, it senses the chest wall moving out, and it stimulates the hypoglossal nerve at the peak of inspiration. And the inspiration is only provided during the peak of the inspiration and then the stimulation of the nerve stops because that’s when you’re drawing in air. And that’s when you Want the tongue to be out, because when you’re forcing the the air out of the lungs, because it’s a passive process, the tongue with the air will automatically come out because the body has those defensive mechanisms to push those air out, because it’s a passive process. And you want to kind of accelerate the, the inhalation process and really the obstruction during during inhalation of air. So that’s what the Inspire medical systems do. It’s a unilateral stimulation, it stimulates at the peak of inspiration. And it has a sensing lead.

JoJo  55:29

So I want to I want to step back for a second. And first give kudos for the marketing department at Inspire, because it’s not just a play on a spark of, of genius and motivation as an inspiration, but in the actual act of inhaling, to inspire. And, yeah, that’s pretty clever. But if they’re only treating 15% of that original 100 people, potentially, I mean, you could argue that the 40% that are compliant with CPAP, may want something better, and could potentially be candidates there. But if inspires only treating 15% of this population, what other companies are going after this target? Yeah, where this first is indications to

Arun Sridhar  56:17

fall, I think the field is not without failures. So there had there was a company around the same time that inspira medical was developing its therapy, called his app next medical, that was also in the Twin Cities area. And it was interesting that both inspire and APMEX ran their their early efficacy studies in patient group with all types of of collapses. So let me explain that further. As I said, the tongue prolapse and the Inspire medical device currently, as it was done in the pivotal trial only works for 15%. And I also did say that the upper airway is composed of more than 20 different muscle groups on either side. So when you think about an opening, you can actually have a collapse on in the front and back, which is what the tongue does, because the tongue actually moves forward and backwards, that is called as anterior posterior collapse, there is a collapse that actually happens on the side, which is from left to right, that is called as lateral lateral collapse. And then there is something called as concentric collapse, which basically is the entire airway kind of blocking as one go. And most patients, and they did a study of drug induced sleep endoscopy. So one of both, I inspire an app next actually ran into trials in all patients who are not compliant with CPAP. And what they found was that it was only efficacious in the patients who actually had a tongue prolapse, but not in the other group. So therefore, inspire had to rerun its pivotal trials in the specific patient group to get FDA approval. Up next investors decided that they wouldn’t invest in the company and they killed it. So now, coming back to the dragon do sleep endoscopy studies. So the reason why, and how can you identify that a specific patient is a candidate for inspire medical device, the way it’s done in clinical practice is that after you fail CPAP or you don’t adhere to CPAP, these patients actually undergo what is called as a sleep endoscopy die study. They give you a small amount of medication to put you into sleeps. And they insert an endoscopy through your mouth, and they literally image what your muscles in the neck are doing when you’re falling asleep. And they will actually observe and quantify what type of a collapse the patient actually has, whether it’s anterior or posterior collapse, which means they might be a candidate for hypoglossal nerve stimulation, or whether the patient actually has a combination of other muscle groups, which might be the tongue, the palate, the hyper fairings, etc, etc. And they would grade the clinician would actually grade them. And the patient actually has anything but the tongue prolapse, which is the remaining 85%, who have a mixture of multiple muscle groups causing the collapse, there wouldn’t be a cloud a patient group for hypoglossal nerve stimulation. So therefore, inspired device currently requires patients to undergo a dye study to present themselves as candidates for the implant, which means that adds another layer of reimbursement hurdle, which means the payers will actually have to shell out another testing before the patients can actually get an inspired implant. So that was the big hindrance in the early days of Inspire medicals commercialization. And also there was an issue with the CMS coding etc. So it’s taken a while for them to actually ramp up their commercialization efforts and get to the stage where they are at this point of time. So that raises a very interesting point. And the opportunity, as you were, as you were alluding to, there is a big opportunity to treat the other patients. And remember, I told you that inspired device is only unilateral. There are other companies like Integra, which actually used whose differentiation point was that you didn’t have to put a cuff on the distal branch of where the Inspire was putting its device, you can actually put it on the bigger branch, and then use this intelligent kind of multi electrode, kind of concentric way of elucidating, which branch you would want to stimulate selectively, etc. without actually having a sensing lead. Because they felt that they will be able to predict which specific fascicle in the hypoglossal nerve could actually be stimulated to treat it. That completely did its patient trials in around 30 to 40 patients, if I’m, if I understand correctly, and was sold to leave a nova for close to 250 million. So leaving Nova is redoing its pivotal trials at this point of time. Because there were issues with both the IPG as well as the design of the pivotal trials, design of the trials that M that actually ran. So they’re redoing all of the effort. So even though in theory, this acquisition was five years ago, there is no product on the market at this point of time to compete with inspire medical. Then let’s come to the second point, which is alluding to what happens to the other forms of collapse the remaining 85% of the population who still don’t have a treatment because inspires device is actually relatively safe. And it’s been on the market for such a long time. There are other companies there are many different companies. At this point of time, there was even a company last week that actually raised 30 million for a series a financing called 12. Medical which refers to the hypoglossal nerve as a cranial nerve 12 or nerve x, which is another company that is that was out of UT Dallas. And there are and there are other companies which also use cryo ablation of the tongue muscles, etc, called cryo, sir. And there are also multiple other companies which also use ultrasound kind of modulation of to titrate, the CPAP, etc, as well. But purely from a pronouncing, yeah, they’re called Spinoza.

JoJo  1:02:30

Soon I think Sonos is doing that and Excella.

Arun Sridhar  1:02:33

Correct. So Nixa is actually going after the 85% population that they inspire, according to its pivotal trial is not able to was not able to treat by stimulating the hypoglossal nerve on both sides. So and the reason for that is because they believe that instead of having a very invasive surgery to dissect out the nerve, and then putting a lead in the chest and putting a hockey puck size IPG similar to what Inspire is doing, can they actually make the invasiveness of the implant to be smaller, so it’s a small incision in the chin to implant the calf with no battery, nothing and everything is powered from outside. So the patient in the case or the product in the case of Nixa is a small implant, which is wirelessly powered from outside using a little kind of adhesive strip. And a little kind of pouch that is that sticks to the chin. And that would actually stimulate the device. And that particular stimulator or the external actuator of the of the cuff, or the external actuator of the device, can actually be recharged during the day. So that’s the treatment that they are going after. And based on some early studies that they have put out, not published but put out. They’ve actually shown apparently, so or at least the claim is that they are efficacious in other patient groups or patients with concentric collapse because which is very different from the inspires anteroposterior collapse, widening the market group. So this is a reason why they actually, even after the early 20 patient study that they did called as a better sleep study. They went and IPO and the value of the company, despite just around 60 million of investment to the company has actually reached 800 million in the IPO. All based purely on inspires success, and them trying to push the boundaries on stimulating the hypoglossal nerve bilaterally and hoping that the tongue would move out of the way. And by because everything is attached, it would actually move some of the muscles out. But the jury’s still out. It still remains to be seen whether they will be successful in the pivotal studies or not. The studies that I quoted that they have actually claimed in that is not yet published was all done in Australia and New Zealand. him. And it all has to be peer reviewed. And


well, I was gonna go into I mean, this all sounds like

JoJo  1:05:08

really good news for snores and their long suffering sleep partners. And it sounds like if this inspires valuation is in the multiple billions of dollars range and you’ve got other companies like Spinoza using ultrasound, and Nick so and in spot and nerve x, this is a massive market size. I think because of the problems that that are caused by lack of sleep both for the sufferer and the sleep partner for the comorbidities that we’ve covered here. What do you see is being a potential cap on this market? Or where can they all survive? Can they all thrive,

Arun Sridhar  1:05:49

it can all survive capturing a subset of the market targeting the same across the various population. So inspire will continue to target it’s 15% The each device will continue to be used for a wider population. The reason for that is because FDA even though the pivotal trial trial was done in a narrower population, because the device was safe FDA granted them a wider label because there was no treatment available that market or that device numbers that was implanted in the non anteroposterior collapse. If Nixa was successful, will probably disappear, because Nixa we will capture that share of the market, there is an even kind of greater problem. Remember, I told you that the hypoglossal nerve stimulation purely acts to relieve the obstruction and makes the patient breathe. But there is another aspect of adaptation, a vicious adaptation, the brainstem is actually performing with it driving the patients to act completely stopped breathing. That is something if there was a nerve target that would add to relieve the obstruction, and also to provide that additional drive to breathe. without waking up the patient using neuro stimulation, that would be a great therapy. And there is no potentially new information or clinical trials on that area at this point of time. But that will be a huge opportunity.

JoJo  1:07:14

It sounds like not to be punny. But it does sound like an inspirational space to be working in huge opportunities for bioelectronic medicine. And I think there’s one of the worst things in the world is poor sleep, because it does affect everything else in your life. And I mean, they’re the reason that militaries all around the world look at sleep manipulation as a form of, of questioning, I mean, that’s the tactic that they use to get people to talk. So that’s how powerful it is. And I’m, I’m glad to see so much focus and attention being placed on on Osa and and hopefully it’s coming to a theatre near me very, very quickly.

Arun Sridhar  1:08:01

But I want to say one more thing about the type of of patients who are actually being treated, or who were treated both in the pivotal trials by both inspire as well as by next over. So the Inspire pivotal trial, as well as all of the NixOS clinical trial is all done in patients who are not as obese, whose obstructive sleep apnea is not so severe. And as a result of that they are cherry picking the patients or cherry picking the mind the moderate patients. And potentially as a result of that, if they show to be safe and efficacious in that patient population, the idea is that they will get a wider label, because the device is actually safe. And devices can actually be turned off. So therefore, if there is any problem, you can actually monitor the safety aspects of that. That’s the biggest pitfall of this area. And most of the market valuations or market valuations at this point of time and the market cap valuations are all based on the fact completely ignoring the fact that the existing devices only capture a selective subset within the eligible population, not just in terms of the collapses, but also in terms of severity of the disease. And that’s a huge pitfall that very few people are actually talking about.

JoJo  1:09:17

I wouldn’t. Okay, so I’m gonna, I know you’ll give me an honest answer to this. But isn’t that cherry picking? Actually, potentially? I mean, there, in my mind, it could be defensible, because cherry picking the least severe patients means that you are potentially helping a greater number of people. And I would imagine, and I this is the part I really don’t know, is can improvement be made incrementally. So if you have a moderate case of Osa and you’re helped by one of these devices, versus somebody with severe OSA who gets one of the newer devices, can they then be downgraded to moderate as opposed was too severe. If it’s not fully cured, can it be mitigated? And I would see that as a win for all the populations, especially the sleep partners,

Arun Sridhar  1:10:09

it is it is a bit of a trick, it’s a bit of a sticky question. The the reason for that is the following. There are patients who have moderate disease, which is a subset of the entire disease population. But most patient groups and most patients with OCD, the bulk of the patient groups actually have higher BMI is in excess of 35 in excess of 40. If you’re going to restrict your pivotal trials to patient subgroups with BMI of less than 32, then you have a problem in ensuring that you can convince a payer or potentially a patient in saying that it’s been successful and a BMI of 32. So therefore, we will actually have to put this into you and see if it’s going to work. Even though your BMI is 41, or 42, or whatever, right? Or your disease is actually more severe than what it is. I think this is exactly what Imran was actually talking about in the last episode when he said, companies should not just focus on generating the data that is required for approval. But it should also be high quality, high impact data that ultimately warrants expansion of the markets. At this point of time, I don’t see that happening. I might sound like I can actually criticise anybody in this field. But that’s not the point. The point is that we actually need to move the patient population in a clinical trial for obstructive sleep apnea from not just focusing on the narrow window, but also running additional trials to focus on on more severe populations, more obese patients, etc. Because that’s where the bulk of the patient population is.

JoJo  1:11:51

I don’t disagree with it. But if you can help one segment, and with with that inspire only hitting 15%, one could argue that they’ve only had a small percentage, or they’re losing a small percentage of patients is still meaningful to so many people.

Arun Sridhar  1:12:09

Absolutely, then their valuation should be entirely based on No, I can actually yeah, it is basically 15% of the eligible population, but their valuation of 6.5 billion cap is based on 100% of all eligible eligible patients that they can treat. And NixOS IPO is based is piggybacking on on on inspires kind of data. It’s all a bit kind of I find it a bit funny. And this is just their

JoJo  1:12:36

IPO but they’re coding and coding. Exactly. Yeah. And it’s not just the IPO valuation, it’s the coding and the reimbursement pathways correct inspire really did lay the groundwork for a lot of these other companies to follow on right, so not just not just the dollar amounts, but hey, more power to him, the more people that get a better night’s sleep, maybe the less road rage, the less, you know, poorly written emails, the less cranky people in the world. I’m all for it. So that

Arun Sridhar  1:13:07

was the gist on obstructive sleep apnea. But if you want to understand a bit more, as we promised initially, at the beginning of the episode about central sleep apnea, I just want to take you back to the thinking that when the carbon dioxide level accumulates in a normal person’s blood, the brainstem activates the breathing through firing nerve impulses in a nerve that innervates the diaphragm, called as phrenic nerve. And this protective cycle goes awry in a patient with central sleep apnea. A company called his raspy cardio, founded by an incubator called Korea developed a device which could stimulate the phrenic nerve, the nerve that innervates the diaphragm, through one of the ways that lies very close to the phrenic nerve, and a lead implanted in this Wayne could face the diaphragm by activating the phrenic nerve. If you need a bit more information, we interviewed Howard Levin, the founder of this company in our second season of the podcast, and you can go and check it out in the archive. We’ll post a link to that episode in the episode description. Recipe cardio, the company that developed a treatment for central sleep apnea targeting the phrenic nerve, completed its pivotal trial and was acquired by Zola medical for an undisclosed amount. This device is now FDA approved. So now we are going to leave you with something fun after an episode full of information, amazing amount of facts and also information pertaining to emerging treatments of both Central and obstructive sleep apnea. If you’re sick out there wondering that if the only way to treat sleep apnea is by stimulating nerves, because we said that the pharmaceutical treatments are non existent. I have a surprise for you. I want to take you back to that sound of an instrument that started this episode. This instrument is the oldest wind instrument ever known to man. It’s called didgeridoo and it is produced. It was identified by the Aboriginal people of Australia. And we have them to thank the Aboriginal people of Australia observed that the eucalyptus plants when attacked by termites was made hollow in its core, and this left a central cavity. Sometimes the central cavities would actually be blocked. So they would cut parts of the plant, which ended up giving a long to and use fire to drive out any remaining termites and played music with them. What is remarkable is the manner in which you play the instrument with a whiteboard is by practising a pattern of breathing, called a circular breathing. And guess what this type of breathing exercises your airway muscles. And just like how lifting dumbbells in the gym, causes someone to be rip. It ensures that the upper airway muscles are toned as a result of learning, circular breathing, and to play the didgeridoo. So some people even today learn to play the didgeridoo and it has been shown that playing didgeridoo reduces the severity of sleep apnea. Making these instruments however at scale, and learning to play them would mean destroying nature or messing with nature to create these instruments. So nerve stimulation remains a viable option for ones who do not have the time to learn to play didgeridoo. We leave you with the sound of the didgeridoo and how the overtones and the undertones can be modulated with various patterns of breathing. Finally, we like to thank our sponsors, core tech neuro and certified medical because without their help, we wouldn’t be able to pay for the production costs. Jojo and I however come free because we do this in our spare time. Mr. Swaminathan Telangana Simon them was their sound engineer and sound designer. And that’s it from us here at scraps. As we promised, we’re leaving you with the sound of the didgeridoo