Nyxoah SA (NYXH) Earnings Call Transcript & Summary

All right. I would like to welcome everyone to Nyxoah's inaugural investor announcement here in New York City. So forward-looking statements, which everyone here knows. We're really honored today to have 3 leading sleep clinicians here with us. So ladies first, Dr. Maria Suurna from the University of Miami. And then we have Dr. Maurits Boon from Thomas Jefferson University; and Dr. David Kent from Vanderbilt University. All right. So in terms of the agenda, we're going to start off with the Nyxoah journey. Opening will be Olivier Taelman, Chief Executive Officer. And then we'll move into hypoglossal nerve stimulation and the Genio solution from Professor Boon. Maria will touch on how we're looking to expand the OSA market or HGNS OSA market between complete concentric collapse patients. And then Dr. Kent is going to touch on ansa cervicalis and the ability to treat patients right now that are not responsive to HGNS. Then we'll have closing remarks, question and answers and a cocktail reception. And before I turn it over to Olivier, just one more person who's very important to Nyxoah and this is our Founder and Chairman, Robert Taub whom -- had the pleasure [ knowing him for 50 years ]. So Robert, thanks for joining. And off to Olivier.

Thank you, David. So first of all, welcome, everyone. It's the first time that we are doing this in New York. So it's a very special day for us. We're all very excited and I'm happy to have you. Also to the people that called in or dialed in also welcome to them because we have over 100 people asking -- the request as well, please see what we are presenting [indiscernible] okay, go to the middle. So my introduction will not be too long. But what I would like to say is -- start with that what we believe at Nyxoah that can be potentially - a potential blueprint for success. So when you are in the med tech business, everything is solved by having a market for that patients, of the patients in need for treatment options. So when we look at obstructive sleep apnea and I'm sure that you're all familiar with those data and the market and the need for patient is really huge. So when we look at the U.S. alone, we are talking about more than 0.5 million patients that are suffering from moderate-to-severe OSA who are really in need for treatment. So the first part of the blueprint is there a market? Is there a clear unmet need? I think the answer is definitely yes. Next to the U.S., we're also focused on Europe. And in Europe, if you look at the numbers, it's almost a comparable number. It's also roughly 0.5 million moderate-to-severe obstructive sleep apnea patients that are in need for a treatment. Now the second, and I think most important for a med tech company is when you want to help people, you need an innovative solution. And when we look at innovation, we are looking, in fact, can you come with a technology that can be disruptive and that can be breakthrough. Now if we look at what we are having at Nyxoah and what we truly believe in is the fact that we definitely have an innovative technology with the potential to disrupt the market, where there is currently one commercial player in the U.S. Next, when we look at breakthrough. And you will hear this later in the presentation more in detail. Breakthrough when we focus on a huge unmet need for patients suffering from complete concentric collapse, and Dr. Suurna will also walk us through her thoughts on this. Also there, we believe with the bilateral stimulation that we can offer, that this will make a significant difference, also helping this patient population where there is currently really a contraindication even for the existing hypoglossal nerve stimulation solution. And then last, somebody needs to pay for all this. So who wants to pay for a solution? So in the U.S., we have to give credits to competition of doing all the heavy lifting and convincing the U.S. payers that when a person is suffering from OSA, that he or she can benefit from a treatment option. In Europe, like most of the times, it's a little bit more complex because we have so many different and smaller countries. So you have to go one by one. You have to negotiate with the people in Switzerland, in Germany, in France and the U.K. and they all have a kind of different view on how they see things and what they use as criteria to reimburse the technology. But we can say, and you will see this later in our commercial approach in Europe, like the #1 country outside of the U.S., Germany, there we can benefit already from a full reimbursement. So coming back to the blueprint, quickly in summary, there is a market. We with Nyxoah, we are offering an innovative breakthrough and disruptive solution. And when it comes to reimbursement, we already have the first successes in Europe. And of course, we are working hard to the IDE pivotal study in the U.S. also there to enter the market commercially. Talking about Nyxoah, and David started already by saying we have today also the privilege of having the Founder, everything is stronger than 2009. And in 2009, Robert and the team of Israeli research and physicians were saying, how can we offer obstructive sleep apnea patients a solution that would be minimum as good as what is existing when it comes to hypoglossal nerve stim, but that would be putting the patient really at the center, really offering something that as a patient, you don't even realize. I have an implant, you don't need to worry. You don't need to push no buttons, if you allow me to say this, it will simply activate when you go to sleep and make sure that your airway remains open during the night. Then you go to a typical part, I think, it's something that you will all recognize for med tech. It starts with first-in-man proof of concept. But the first big milestone was 2019 because that was the date that we achieved or that we received CE Mark approval in Europe. And on the back of the CE Mark approval, we could start going and reaching out to health care authorities. And what we got was a full reimbursement in Germany, they call it the DRG, so that we could also commercially start promoting our product in Europe. So in Germany, the largest market today, we can compete. We are at the same price point. That is the same payment for physicians, also for hospital. And I'm really proud to say that we also invested heavily in building a German dedicated Nyxoah team today. We are 15 people. And for those who listened into the earnings call yesterday, I think they did great in the first year after having a full reimbursement, leaving or exiting the year with more than 30% market share, a clear illustration that physicians and patients are really embracing our technology. Now jumping from the CE Mark. Of course, the year after 2020, another great milestone, U.S. approval by FDA to start a pivotal study. A pivotal study that started or some people may be a little bit slow. But also here, I have to really compliment the team, starting in the days of COVID, making sure you have to train and educate all surgeons because it's a total different technique. In the beginning, some and we have 3 [ high ] of the leading surgeons with us. But I know and I remember we had discussions where people were thinking, "Oh, it's just like Inspire, you know how to implant and how to get access to the hypoglossal nerve." It's not. It is different. The access point, the entry point is different. There is the bilateral stimulation. It takes a little time. And when we say a little time, we see that on average, it's 3 to 4 implants that you do [indiscernible] and then the surgeons are feeling really comfortable implanting by themselves. But again, we have the experts with us, feel free to ask them their opinion. But it's a different technique, DREAM study today, it's done. I mean the implants are done and now the hard work will begin in having the patients follow up. I'm also extremely happy that we can also share the results already on the first 34 patients because every one of you that I interact with, everyone is asking me always the same question, how is DREAM, how are patients doing? What do you think? Will you make your primary endpoints? The only thing I can say today based on facts is that we really started very well and that for the entire Nyxoah team, when we see this data, we are not saying we are happy, we are saying, yes, it's a confirmation of what we've seen in the past. And in the past, it's commercial, but also in other studies. So this is what is making us really excited. So next to DREAM. Of course, patient-centric. When we say patient-centric from day 1, we talk what -- when you suffer from OSA, what do you want? You want to have a safe technology, 1.5, 3 tesla full-body MRI compatibility. We have it from the beginning because we really -- I think a confirmation illustration or we put patients at the center. Then the next thing was CCC, complete concentric collapse, a large patient population, roughly 30% of all moderate-to-severe OSA patients. Today, hypoglossal nerve contraindicated. We at Nyxoah based on a study conducted in Australia, we have today the label expansion in Europe. And in Germany, we started seeing also the first results. We are seeing results of the first implanted patients. And I'm a little bit selling all this, but when I see a patient with an AHI of 48, CCC. And 6 months later, the patient coming back, and the AHI is 9. We not only see happy patients, I also see happy physicians. And then people can say or think and say maybe it's already very early to make conclusions. This one patient, his life has changed. And I'm happy that we could offer this with our bilateral stimulation. I will not go too long, but the DREAM completion you all are aware. To do all this, you also need a little bit of money. So we were a private company, always supported by our Founder. And I always call it investment trends, and we were always putting us in a position that we could focus on the priority in getting our technology better. Then we went from private to public. We did a very successful IPO on Euronext. And when I say very successful, we were more than 7x oversubscribed. Somebody in the U.S. told me don't say this because it doesn't need anything in the U.S. I know it meant a lot to us because there was a lot of [ hard work ] behind, and it was illustrating that there were really solid institutional investors that want to put money in our company. One of them is the building where we are in today. So afterwards, we did a Nasdaq IPO, [indiscernible]. So also there, we saw the same interest. And I think the most important thing with all this is that we managed to secure the finance situation of the company, again, focusing on the essence, and that is developing a technology that can be minimum as good, preferable better and definitely much more patient-centric compared to what is out there because that is, in fact, our mission. So who are we? I will go pretty fast. I have to show and give it a little bit of time because I know [ Himi ] may put a lot of hard work in this -- in having a rotating globe. So that's why I'm showing this. Belgium, we are headquartered in Belgium. You can find Loic, our CFO and his team, finance, clinical and marketing. And I think more important, since this year, we have a fully validated manufacturing side. And that is also crucial. If you want to grow, if you want to scale, you need product. You need product and in order to have products, you need to be able to build this. We always did it historically in Israel, we continue doing it. But now in Belgium, it's done. It's fully validated, and the first products are coming out of this manufacturing site. Next, Germany. I touched on Germany, why it is important for us. That's where we want to do our commercial proof of concept. We started great. The United States, so here, it's Dan, Jey, the clinical team, regulatory, and we also made our first modest investment in market access. And when I say modest, I think that is also something that is in the Nyxoah DNA. We know that we have to reach our primary endpoints. We feel comfortable about this. And in the meantime, how can we prepare the landscape, how can we prepare anything in the U.S. And therefore, one of the key things is having a coding, a CPT code. So therefore, we hired an expert. We are working on this. We are working together with the Physician Association, AAO. We made a recommendation, or they made a recommendation to AMA and now we are waiting to get this result. So also there, we're already looking very proactive. Israel, I touched on this. It today -- it's our R&D unit. It's the hub -- R&D hub. I think Dr. Suurna is going in June -- no, end of May, he told me to Israel not only to look at our facility and to work with our engineers, also to see a little bit of the beautiful country there. But Israel is our R&D hub with still manufacturing and also where manufacturing is, there is quality. I mean, that's what you can find in Israel. And then definitely not last, Australia because in Australia, we conducted the first studies. There we still have a very small team, and I'm going to say very small, I mean, 7 people, all clinical people just focusing on doing a follow-up on patients that we have implanted because I think that's also crucial. You cannot just implant and then leave, no, you stay and you give the follow-up that patients are deserving. That being said, I would like to hand it over to Dr. -- in Europe, we say professor. They told me you say Dr. and not professor. So Professor Dr. Boon, please.

Can everybody hear me okay? I'm going to touch a little bit on some of the things that he just went over in terms of sort of the need for this therapy. And so I'm actually Mau, but you can call me Dr., Professor or whatever you want, but I prefer Mau. And disclosures and then I will start with the multiple choice question here. And so you'll have to indulge me. I recently spent a lot of time trying to figure out how to teach my kids to study and I ended up reading a book that basically is called Make it Stick. And one of the premises of this book is that basically, if you just talk to somebody, they don't usually remember much. If you ask questions and quiz, people tend to retent more. So I won't belabor too many questions, but one multiple choice question. So which of the following is true? Worldwide prevalence of at least mild OSA is greater than 900 million. Conventional treatment of CPAP is highly effective, but poorly tolerated. Hypoglossal nerve stimulation is ineffective, alternative to CPAP therapy, which is highly effective in select patients and of course, terrible trick question because all 3 are true, of course. And so what I'd like to try to do in the short time I have is a little bit about background of OSA and perhaps this is a review for many of you, but I just want to make sure you sort of understand some of what we talk about in the medical world here so that you can then kind of infer from that why we actually have such optimism about this therapy. I'm going to again touch base on the scope of the problem, how prevalent it is, why there is an incredible need for this therapy, how a therapy in general works and some of the unique features of the Genio system and again, why there's specifically a need for this worldwide and, of course, specifically in the United States. So again, forgive me if this is too basic, but all of you may be familiar, but obstructive sleep apnea is repetitive episodes of airway obstruction that occur in the context of sleep. And we know that basically, it has many, many ramifications for patients in addition to just quality-of-life issues with poor quality of sleep. We know that it impacts the cardiovascular system. It has major impact especially on things like atrial fibrillation, heart attacks, a big impact on stroke and this doesn't take into consideration all the impact on motor vehicle accidents, work-related accidents. And so we know that this is a huge burden on society and clearly is something that we have to address to help our patients, help the population. And so this is a slide from -- or a picture from the Lancet publication that basically looked at overall worldwide prevalence of sleep apnea. And again, it gets back to this concept of how prevalent disease is, 900 million in the world. If you compare that to diabetes, which, of course, is a hugely prevalent problem, it actually is more prevalent than diabetes, and you can imagine how impactful diabetes is. You just want to basically then look specifically at the United States, of course. We recognize that, again, huge, huge numbers of patients with this problem. And so clearly, there is a huge need for treatment for sleep apnea. And then basically, before I get into a little bit of more about the need, I presume many of you know this information, but I just want to make sure, again, the terms are familiar. And so we typically use a term called the AHI or the REI and that simply refers to the number of times any patient has a given respiratory event in the context of an hour during sleep. And so it's the primary metric by which we gauge sleep apnea severity. There's lots of argument about what's the best measure to use, but this is the primary one that we look at in the literature. And so normal, it's less than 5 episodes an hour, 5 to 15 is mild, 15 to 30 is moderate and greater than 30 is severe. And we really worry particularly in this range because this is where we know that health risks start to really surge. So all those things that we talked about before and many more really go up when we basically see the moderate-to-severe sleep apnea patients. We also recognize that we have a great treatment for sleep apnea, which is CPAP. And so if you look at efficacy of CPAP, so continuous positive airway pressure, which is basically a pneumatic splint, it works really well. It actually is effective in treating the vast majority of patients. But the unfortunate thing is that CPAP is not a question of effectiveness. It's really a question of adherence. And unfortunately, if you've seen this picture before, we have many, many, many patients who are like this guy here who cannot, will not tolerate CPAP. And so when you look at overall adherence, data varies depending on the study you look, but we generally think about it around 50% of patients are not going to be able to adapt to their CPAP. And if you look at it as a year out, actually, after they initiate CPAP, the numbers actually drop. And so now you take that into consideration, then you basically have, again, this disease state that is so prevalent, you have a therapy that unfortunately is the primary modality, which is not serving a huge number of our patients. We do have other alternatives. So be aware that there are things that exist on the markets, oral appliances, scale of framework surgery, we have actually surgery to address the pharyngeal airway. Many of these are limited by efficacy. Many of these are limited by tolerance, and many of these are limited by patient acceptance. So fast forward now to this concept of hypoglossal nerve stimulation. And again, I apologize if this is basics for you, but we have this wonderful, unique nerve that basically, first and foremost, is a motor nerve so we can stimulate it without causing discomfort for patients. And the other thing that's great is that by whatever means whoever created this nerve, it has an incredible unique anatomy and that basically is the nerve goes from the brain out to the periphery, it selectively is responsible for actually protruding and stiffening the tongue, and we exploit this because if we just unselectively stimulate the hypoglossal nerve, what we do is we get a balled-up tongue in the mouth and it really doesn't do anything to benefit the patient. But we can exploit by very selectively stimulating the distal end of the nerve and this produces actually motion of the tongue forward and that motion of the tongue forward doesn't just address the tongue, it actually opens up the entire pharyngeal airway. And so this has been really a huge, huge advance in our ability to treat these sleep apnea patients. This is just a little bit of data that's publicly available, but basically, number one, you probably are aware that trials actually started quite many years ago in the 1990s. It is now actually an established therapy in multiple countries, and FDA approved the Inspire system in 2014 and most recent data is that there are 36,000 implants as of February 2023 with numbers that are rising. So what differentiates this system from the currently available system. There are a number of different things, many of which have appeal to patients and many of which have appeal to providers. So first, it's a single incision under the chin. And so that actually is important to patients, some more than others, but a single incision actually matters for patients, less to contend with in terms of infection risk, less to contend with in terms of recovery. So that is certainly an appeal. Second, it is stimulation of both hypoglossal nerves. This is unique. So the Inspire system and other systems that actually predated Inspire are all basically unilateral stimulation. And some of the data that exists on hypoglossal nerve stimulation suggests that when patients get bilateral protrusion of their tongue, they have better outcomes. And so this exploits again, that notion that we can basically stimulate both nerves to try to get better pharyngeal airway opening. Third, no battery. And so current systems basically employ a battery that will require change. And more components, the more potential for obviously issues and mishaps and technical problems. So the idea that patients don't ever have to come back for a battery change, again, is going to be appealing to many of them. And so there are patients, again, will have just a single implant or a single device that basically will be charged on the nightstand and then basically placed with a patch underneath the chin. So again, there's no having to be connected up to charging. There actually is no battery. It just basically is the single incision in the single device that they'll use. Last, and this is important as well, is that basically, it is MRI compatible, a huge issue because many of the patients we have, have other medical issues that, of course, require MRI and other imaging modalities. The fact that patients can have up to 3 tesla MRI compatibility is actually also unique and full body MRI is also indicated. So this is again just a little bit about the journey of the Genio system. First, again, original data from the BLAST study, we looked at 27 patients and those 27 patients -- of those, again, pretty significant reduction in the AHI from moderate down to mild. We generally think that's great because once patients get to the mild range, we think that they generally have very minimal health risks and then also actually corresponds with significant improvements in quality of life. So it's really important when you consider the outcomes that we don't just think about an AHI in those numbers, we actually have to think about the whole patient. And so when you start looking at outcomes, we want to basically sort of at least -- I always talk to my patients about 3 things. I do want to reduce their health risks, and that's evident by basically the reduction in their AHI but I want to improve their quality of sleep, and that basically something that was demonstrated in this. But I also want to look at the bed partner's quality of sleep. And so that's the snoring, the gasping, the pausing or sometimes it's actually the CPAP that the bed partner hates and wants basically to get the other -- get out of the bedroom because they can't stand the noise, the hissing that kind of thing. And so the beauty of the BLAST study is that it demonstrated improvements in all of the above. Fast forward into basically actually expansion into European market, which we already highlighted. Also, of course, now the pivotal trial, the DREAM trial, which is basically completed and can't talk much about that, but obviously, we're very excited to see results of that. And then as we go forward, the appeal of the CCC indication, and I'm not going to steal Dr. Suurna's thunder because she's going to talk in much more detail about CCC. But that is also a really important concept because we have a number of patients who we simply cannot offer therapy to because they have concentric collapse, which just currently is a contraindication to current therapy. So a brief summary here. First and foremost, we have just an incredibly prevalent disease with a huge, huge need for therapy because of all the health risk, the quality of life, everything else in between. We have therapies that exist but are unfortunately failing our patients. And so just again highlight where this is going. You can again see 36,000 implants occurring to date, but that actually doesn't even scratch the surface of the patient need and the potential volume of this therapy could reach. And so again, we have, again, a track record of a therapy that's well-tolerated, safe location to risks and again, already with well-established record of safety, efficacy and all of the above. And so really honored to have been here to speak to you. Obviously, happy to address any questions. But with that, I'll finish up and turn it over to Dr. Suurna. Sure. Sorry I didn't...

All good, thank you. All right. So first of all, Dr. Boon, thank you for the presentation. So building on both what Olivier touched on in terms of commercial readiness. And then what Dr. Boon discussed in terms of Genio's attributes, we conducted a survey, an independent question survey using Guidepoint, which pretty much everyone in this room is familiar with. We surveyed 25 clinicians, split between ENTs and sleep specialists. And obviously, most of those are U.S.-based, as you can see. And in terms of the patient profile, these are very high-volume users, right? You can see 40 implants annually, 47 refers annually. And the clinicians were at least somewhat familiar with Genio, so we captured -- get this independently. We don't know who the doctors were, but I'm sure we captured a number of our Genio implanters. So one of the questions we asked was look at Genio's key characteristics, key features and rank those in terms of order of importance. And what really resonated with the respondents was the patient-centric design of the system. So for starters, scalability. What do we mean by that? So scalability means that patients never need to get an implant, a new Genio implant to always have the latest technology. The upgrades to our system happens to the external component, the activation chip. Now are they either pushed to an existing activation chip or we send a patient anyone in mail. So patients will always have most up-to-date system, thinking about it sort of like an iPhone with iOS upgrades and apps. Genio does not have an implantable battery. So patients can rest assure they will never need a new procedure to replace a depleted battery. Genio has a full-body MRI compatibility for both 1.5 and 3T tesla. So patients never have to worry about getting a high strength MRI with Genio. And lastly, with the CCC label, which we have in Europe, and we are pursuing here in the U.S. with the ACCCESS study, patients no longer will need to get a drug-induced sleep endoscopy or DISE or an alternative to DISE prior to getting a Genio system. So what does that mean? The pathway to getting a Genio is faster and easier for the patient than with competing systems. So now that we understand how these clinicians value or what they value in the Genio system. The next question is, what does it mean? What does that imply for their use of Genio when it's introduced to the market in the U.S.? So as you can see, both ENTs and sleep specialists anticipate Genio being roughly 50% of their HGNS implants or HGNS referrals. So to not just us, this data is extremely exciting, and we confirm not only what we believe internally but also what we're experiencing in Germany, where we have our first full year with reimbursement, we are up to 34% market share. There is a lot more data in this survey. I'm happy to discuss it offline, please reach out to me, and we can set up a bit of a time to speak. So with that, I'll turn the program over to Jey.

Thank you, David. Good afternoon, everyone. My name is Jey Subbaroyan, I'm the VP of Medical Affairs and Clinical Research at Nyxoah. So I won't take too much time, but I wanted to spend a few minutes today talking about -- specifically about Nyxoah's clinical research strategy, but also spend a little bit of time talking about the patient journey. We've been talking about this a little bit in the DREAM study, how are we derisking the patients and how do we get them from where they start all the way to the study primary endpoint. So this is a slide that you have seen -- you may have seen previously. So the overall clinical strategy, there is no magic here, right? Like we are just like any other medical device company, where the idea is ascending the evidence pyramid, going all the way from observational case studies and whatnot to prospective case series to large, controlled studies. And finally, meta-analyses of randomized controlled trials, so to speak. So Dr. Boon talked a little bit about this, and that's probably what we see, it's probably like an inverted pyramid, if you want to imagine it like that. So we started with BLAST OSA even before that, there were a few studies that we did not publish, but that was the first-in-man study. But we went from the BLAST OSA study, we have the proof of concept, and you see we had a couple of publications. The responder rate was about 47% in those patient population. And then from there, the learnings we took that -- and when the [indiscernible] in Australia, [indiscernible] a clinical follow-up in Europe a post [indiscernible] clinical [ apnea ] in Europe. So what it did is while we are establishing and expanding and learning from this therapy in Europe in the commercial area, we're looking at both CCC and non-CCC patients, especially in the CCC population. It's more like a proof of concept in about 18 patients in Australia. Again, you can see, right, like it's a small case series to try and understand. So that led to the CE Mark for us in Europe. And the idea is, the learnings that we had from BLAST to EliSA and BETTER SLEEP, that culminated into this large study, the pivotal study here in the U.S. in DREAM for 115 patients. And again, learnings from the BETTER SLEEP CCC patient population, led us to designing the ACCCESS study, what type of outcomes, how do we see this simultaneously the learnings from DREAM, all fed into how we designed the ACCCESS study. We can talk about some of the specifics once things become public, what -- we are planning to do a publication of the study design. So I think it's a smarter study design in terms of how we manage the patient because being a patient-centric company, we are also conscious of the patient bed and when they have multiple visits and whatnot. So this is an overall strategy, so to speak, and it's been slow in coming, but I think we'll be publishing some data very soon. So that's like overall clinical strategy. It's no different from any of the other medical device companies that you have seen, or you have worked with. But I want to spend a few minutes here talking about how we manage specifically in the clinical study. So this is a clinical patient journey with Genio. I would like to call this the six A's to success. And if you can imagine on -- I mean, the flow diagram on the left is basically the patient funnel, patient follow-up. They go all the way from implant to therapy activation and you can see to month-12 PSQ, which is the primary endpoint. But how do we manage -- or how do you take a typical patient from -- right from, let's say, enrollment or implant all the way to a successful exit from the study. So it all starts with acquisition, right, like the first A. It's actually speaking of hypoglossal -- bilateral hypoglossal nerve stimulation. This acquisition happens on -- it's a bilateral acquisition. What do I mean by that? Physicians spend some time acquiring the patients. But on their end, they're also acquiring the skills to implant these patients, right? So that's what happens. That's the first bilateral A. The second one is at the therapy activation, 2 months later on when the patients come back after their wound is healed, this is the acquaintance, right? Again, it's a bilateral acquaintance. We, as field clinical engineers working with kind of the physician's direction, getting acquainted with the patient, their sleep architecture and their sleep hygiene, some of the idiosyncrasies that they have. But simultaneously them getting acquainted with the Genio system, how do you use this? When do you go to sleep, do you watch TV, 30 minutes later, so you can set the delay. So that's how we kind of acquaint them and personalize the therapy based on their requirements. So that's what happens at M2 or the activation. And this is where we kind of start talking about the third A, which is the acclimate. So we always start with this analogy of a marathon or weightlifting, right? Let's say, you want to do -- run a marathon, let's take a 250-pound clean and jerk lift, you're not going to be starting with 250 pounds. So we tell them, let's start with 20 pounds, right? Like get used to this feeling of unnaturally the tongue, just protruding out of your mouth, so to speak, some of them like, "wow, I didn't expect that, right?" Like so you slowly walk them through that to get them acclimated to the therapy and it starts at M2. But by 4 months, which is the first time we are actually putting them under a PSG overnight sleep lab, most compliant patients, I would say most of them in the study, that's what they do, right? Like they religiously use the device, and we have -- we follow them in the electronic data capture system that they're using the device. We look at their feedback. If there is any question, we always contact the PIs like, "hey, it looks like the subject has this feedback that stimulation's a little too strong, whatnot." So the acclimation process is between 2 months and 4 months, right, like most of the patients. So -- and at the 4 month PSG, that's when we test a lot of these ideas. We look at what are the site of collapses for the patient, what's the threshold required to open up the airway, what's their motor threshold, what's their uncomfortable threshold, it's all set up. So it's a lot of experimentation. We have all kinds of hypotheses to test, like which not to change, right? So it's a controlled experiment, right, like we try to do and learn as much as possible. And then that brings us to 6 months. So when they leave 4-month clinic with -- again, we show all of the results to the physicians under their direction, we obviously increase the amplitudes to a place where there are probably more therapeutics, so to speak. But at 6 months, when the patients come back, it's all about adaptation for us and for them, right? Like for instance, one example is we called ramp-up of [indiscernible], like we kind of slowly ramp up the stimulation for them to get used to. We either have the patients come back and say, "yes, just take it off. I'm comfortable," or we take that off because they're so used to it, unbeknownst to them, they're like, "oh, this feels good as well, right?" So all of that adaptation on that side happens under the sleep lab, we go with, like as it says, eliminate some of these other hypotheses or ideas that we're talking about based on patient usage and hone in on like 1 or 2 specific strategies, how to titrate this patient. So by this point, we have clearly established what works, what doesn't work. Is this patient a compliant patient, do they have insomnia, do they have high arousal threshold? Are we seeing any treatment image in central sleep apnea, all of this is well established by 6 months. So when it comes to 9 months, it's pretty much like dress rehearsal like for the responders. That's the fifth A asset in, right? So we're just making sure, okay, all of our assumptions are -- is good. Like the patients, is there any weight gain, medication change, whatnot. So essentially 9 months is pretty much a dress rehearsal for the responders. The non-responders, most of the time, it's like patients who are a little slow in terms of compliance and just other issues that they're dealing with. We had a couple of patients with family issues, so we had to bring them for like 8 and 10 months. But essentially, no large changes, right? Like at 9 and 10 months, you want to be sure like you're going to do the big dance, goes on really well. And the last one is achieve, right? Our goal there is, okay, everything is set. And again, you know it's a full night PSG, there is no titration. The only thing we do is either stop the stimulation, the patient wants to go to the bathroom, we stop the stim and turn it on. So it's a set therapeutic value whatever we choose based on all the PSGs and knowledge that we have gained. So -- and that's the idea for us to get these patients to be responders. So if I have to put this in a nutshell, right? Like this is a classical case of derisking, walking the patient off of the cliff, so to speak, and to the point where we are safely exiting them from the study. And I can say that the early data that we published, a good number of those patients that were in the -- mentioned in the abstract that they are in the long-term follow-up. And those 18 months, 24 months follow-ups are coming. So we will likely follow the path of our predecessor in this space by not only publishing the 12-month data, but successive hopefully 24, 36, 48 and 60 months. So that's the specific story. So what I would like to finish my talk with is, we hope we have set up a really good process, right? Like Nick Saban, the coach of Alabama Crimson Tide said, right, it's all about the process, right? Like we hope that the means justify the ends here, and we are hoping that all of these process that we set up ends up being successful in [indiscernible]. And over to Dr. Suurna.

All right. Thank you for directing me. All right, good afternoon. So it's a pleasure to be here and share with you my experience and my sort of thoughts and knowledge about hypoglossal nerve stimulator. And so my role is to discuss with you and address what everybody has been kind of mentioning briefly is complete concentric collapse. So what is -- first of all, like how do we identify complete concentric collapse. We identify by using drug-induced sleep endoscopy. So why is drug-induced sleep endoscopy important? Well, obstructive sleep apnea is obstruction of the airway during sleep. So when we are treating patients, we try to find out what is happening during sleep. When patient is awake, they have normal muscle tone. And when you do like airway exam during awake patient's visits, you don't really -- you can't really appreciate what happens to them when they fall asleep. And so still, we still -- today, we don't really understand why some people who have sleep apnea when they fall asleep lose their muscle tone and their airway starts to collapse because when they are awake, nothing happens. But then when they're sleep, airway collapses. And that leads to a lot of symptomatic sequelae, which Dr. Boon has presented and leads to some of the health problems and again, quality-of-life problems and the daytime functioning problems. So drug-induced sleep endoscopy has been introduced in 1991. And then -- what they first described as sleep nasoendoscopy. So what they tried -- attempted to do it when patients were sleeping but then try to think about how like a scope gets placed through the nose somebody who is sleeping, that's probably going to wake them up. And so that's why they introduced sedated endoscopy, where you try to give patients a little bit of sedation. If they fall asleep, you try to mimic their natural sleep and then you put a scope through the nose, and then you start examining the airway as they're sleeping. Most commonly propofol is the drug that's being administered to patients, and you titrate it gradually slowly and sort of get patient to that stage when they're not really under general anesthesia, but they're starting to experience the symptoms of obstructive sleep apnea like snoring, and then that's when you go in and you start looking at the airway. And there, we can obstruct the multiple sites. It's not just the nose, palate, base of tongue, epiglottis, lateral oropharyngeal walls. It's -- the entire airway sometimes can collapse, and it can collapse in different directions and in different variations and severity. So when we look at drug-induced sleep endoscopy, we try to grade it and see what are we actually examining. And so there is velopharynx. That's the part that's the top of the palatal level, then there is oropharynx. That's where the tonsils are, like and that's the site that we can actually -- when you open the mouth, you can see the uvula, you can see at the back, oropharynx. And then there is a base of tongue, which is not really easily visualized on the awake exam, and then there is also epiglottis. And those structures can collapse anterior-posteriorly, laterally, concentrically, and then we also look at the degree of the airway collapse, whether there's no obstruction, partial obstruction or complete obstruction. So velopharynx, that's the part that we're focusing on when we talk about complete concentric collapse. And this is the part exactly, and I just wanted to point out where that structure is, right? And so it can collapse anterior-posteriorly. It can collapse laterally, or it can collapse concentrically. And it can also collapse to different degrees. Sometimes you have absolutely no obstruction, and that's -- hopefully that's happening with patients who don't have sleep apnea or snoring. Sometimes you it collapse partially, and that will lead probably to some of the symptoms. So like, again, worsening of snoring and maybe even sleep apnea. And people who have like complete collapse at the velopharynx, probably with the severity and with the degree of sleep apnea and snoring that they're more likely to have more of a complete concentric -- or complete collapse. So here's an example. So this is what we're talking about. Anterior-posterior collapse is on your left and concentric collapse is on your right. And this is -- you can see how anterior-posteriorly just more of a directions of the collapse. And then concentric collapse, collapse happens in all directions. It's almost like a sphincter like appearance. And when we talk about hypoglossal nerve stimulation, -- so currently, for the current [ micro ] system, the good candidates who have a [indiscernible] in our stimulation is the person on the left with anterior-posterior collapse and people who have that concentric collapse, those are the bad candidates. And those are the ones that we usually try to screen out before offering them hypoglossal nerve stimulation therapy. So the reason why we do that is based on the preliminary data that the [indiscernible] published when they looked at responders and nonresponders. And they looked at about 20 patients whom they implanted with the device and then saw that there were some responders and there were some nonresponders. And they then further analyze the difference between those patient groups to kind of get a better sense, why some responded, and some didn't. And what they found that people who had complete concentric collapse were less likely to respond to hypoglossal nerve stimulation therapy as opposed to patients who had anterior-posterior collapse. Well, the problem with this study is that they only looked at a very small number of patients, and you can see that complete concentric collapse, the number of patients, only 5 patients. However, that's what they use when they were screening patients for STAR clinical trial, and that's what they -- who were enrolled in the clinical trial, and that's again now the recommendations for hypoglossal nerve stimulation to specifically exclude patients with complete concentric collapse. As it was mentioned earlier that about 20% to 30% of patients who have a moderate-to-severe sleep apnea do have complete concentric collapse and those patients are sort of being excluded. And so that's where like then there is some interest like, well, is that the case in every single situation? Are there people -- because we actually started noticing that there are people who have -- probably it's not just complete concentric collapse that leads to not being -- like nonresponder because we also have people who don't have complete concentric collapse, and they still don't respond. So with the Nyxoah, with the Genio system, they further wanted to explore well bilateral nerve stimulation -- better improvement of airway obstruction, they sort of eliminate and give the opportunity for patients with complete concentric collapse also be implanted and they benefit from the therapy. So this study was designed to -- and it was conducted in 8 Australian centers, they enrolled 42 patients with bilateral nerve stimulation implant by Genio device. And amongst those patients recruited, about 42% of patients actually had complete concentric collapse, almost 43. Currently, the data for 36 patients is available at 6 months and responder rate was about 64% based on the Sher criteria and Sher criteria is reduction of apnea-hypopnea index by 50% and to below 20, AHI of 20. And also, when they looked at the responder rate between complete concentric collapse and non-complete concentric collapse, reduction was very similar, and the reduction in AHI was pretty substantial in patients who actually did have complete concentric collapse. And so looking a little bit further at the data, this is again a little bit more visual looking at the mean change of apnea-hypopnea index at 6 months of the therapy use. And you can see that both complete concentric collapse and no complete concentric collapse, both groups have responded, and they had very similar reduction in AHI at 6 months. And if you even look at the patients who had like complete concentric collapse, their mean AHI was a little bit higher, but again, that's probably not significantly -- statistically significant. And when you look again in the bar graphs, you can see that, again, the data is very, very similar between patients with complete concentric collapse and no complete concentric collapse. So in looking at the percent reduction, so the great thing is like when you look at the responders, people who responded to therapy, they had very high reduction in AHI, 70% reduction, which basically brings patients from moderate-to-severe sleep apnea to mild sleep apnea or no sleep apnea, which is impressive outcomes. And when, again, looking at the groups who are responders in complete concentric collapse group and no complete concentric collapse group, they had a very similar reduction in AHI when looking at the responders. So in conclusion, there is a statistically significant reduction in AHI and ODI across all cohorts, meaning complete concentric collapse and no complete concentric collapse. And there were similar improvements in AHI and ODI for both of the participants in this and that sort of data, further led to -- in Europe, for example, if the labeling that -- CE Mark label for implantation for base of indication for people with obstructive sleep apnea, for more [indiscernible] sleep apnea. And there is no role for drug-induced sleep endoscopy to further identify complete concentric collapse and exclude those patients, meaning that in Europe right now, this is a therapy that is available for people regardless of how their airway obstructs. As long as they have moderate-to-sever sleep apnea and need to be in mild criteria, complete concentric collapse is no longer an issue. In the United States, Genio device received Breakthrough Device Designation for complete concentric collapse. And as you've already heard that there's already initiation of ACCCESS clinical trial to look specifically at patients who have complete concentric collapse and further achieve the FDA approval for implantation of the therapy for those -- that group of patients. And thank you very much. I'll take any questions.

So good afternoon. As an introduction, my name is Bruno Onkelinx. I'm the CTO of Nyxoah, responsible for R&D, but also for global supply chain and manufacturing operations. I'm very happy to have this opportunity to present to you our future offering, our future products. And let's take a glance into the future, starting with what we already have, and that's the Genio 2.1 system. Genio 2.1 system, it was already presented, but it has an implant that is bilaterally stimulating. It has a battery free, no leads, single-incision procedure and fully body MRI compatible. The activation chip is a new version of the activation chip with an extended resolution, but there is also an infrastructure already built in with sensors. With those sensors, we can measure position of the head as an example, and we have a patient app. And it's also a proof of our patient centricity. We give control to a certain extent -- control to the patient where the patient can tune the stimulation within a certain range. And it also gives feedback to the patients on the usage of their device. So what's coming? So the first thing that will come is a new implant design, and it's to provide the patients an implant for life. It's with a ceramic housing. And it's only -- not only for implant for life, but as well, it will be the platform for next-generation advanced electronics. And it's designed for manufacturing. So it will support high manufacturing volumes. Then we go through the activation chip, the next-generation activation chip. As you can see, it has improved ergonomics. And also, it will be a greener and more eco-friendly GP. And then we introduced a new product, and that's what we call the hub station, and that will be the infrastructure for future cloud connectivity, but also advanced patient -- feedback to the patient, how they are doing. So with those critical building blocks, we build Genio 3.0 system, and we introduce also advanced electronics. Why advanced electronics? Because we want to improve the efficiency of the 3. Like independent bilateral stimulation, so that we can tune left and right branch. We will also introduce some additional embedded sensors. And how will we use those embedded sensors is to use it in an [ adaptive ] therapy. So again, to make sleep simple again. So we want a smart device that is adapting itself to situation, to the patient. And then lastly, we will use the hub infrastructure to enable remote care and to connect to the cloud. And then last but not least, we are -- as you know, we have a collaboration going on with the Vanderbilt University, with Dr. Kent for the stimulation of the ansa cervicalis. There, we are preparing a product that will stimulate the ansa cervicalis. So as you can see, we have a very exciting future in front of us. And by this, I would like to give the word to Dr. Kent for his insight in ansa cervicalis stimulation.

Thank you, Bruno. Okay. Great. It's an honor to be here with all of you. An honor and a pleasure. Doctors, Boon and Suurna have, I think, set me up well. I'm going to take you on a bit of a physiology journey here. So stick with me, and I'll be happy to take any questions after all of this. We do have some federal as well as some foundation funding behind the work that we've been doing here. What I really want to talk to you about is what we've been researching for the last couple of years at Vanderbilt. So I tell my residents who joined me in the office during training that nothing frustrates me more than consulting with a 300-pound patient who's breathing just fine in front of me. That man has inboard physiologic mechanisms for keeping his own airway open. And if only we can take advantage of those mechanisms, we can treat a very large population of patients. So if we boil down these different mechanisms into the sort of their key components, there are really 3 physiologic supporting mechanisms for the upper airway. There's tongue tone. If the tongue is blocking the upper airway, it's like a ball bag that's in the way. It doesn't matter if the rest of the pipe is made from rubber or steel. If the tongue is in the way, you can't breathe. And so the first thing you've got to do is get the tongue out of the way. Once you do that, other mechanism starts coming into play, what is the tone or the rigidity of the rest of the upper airway. And frankly, tracheal traction, which we're going to talk about here today matters a whole lot. If you stretch out the upper airway, you're mechanically tensing all those upper airway muscles, and that's free many of the -- the rest of the muscles of the upper airway don't have to work as hard to keep it open. I'm going to demonstrate to you that we think that these opposing forces actually had synergistic effects on keeping the upper airway open. So Dr. Boon dug into this, and I don't want to spend a whole lot of time here, but hypoglossal nerve stimulation therapy as it currently exists, does exactly what we were just mentioning. It moves the tongue forward and unblocks the airway. And when we look at U.S. indications for individuals who can get this therapy right now, it's adults with moderate-to-severe sleep apnea. But importantly, they can't be too overweight. They have to have a body mass index less than 32 with some indications up to 35, and they have to have appropriate airway anatomy, which means there's no complete circumferential collapse to the palate. But why does that actually matter? So here's what hypoglossal nerve stimulation actually looks like in the upper airway and Dr. Suurna oriented you well to this. On the top, you're seeing the base of the patient's tongue and then you're seeing the palate that's collapsed from the bottom of the screen, which is towards the face, towards the back wall of the throat, which is at the top of the screen. Now in this particular instance, you're seeing unilateral hypoglossal nerve stimulation. You can see that base of the tongue snap forward. It moves forward. And hypoglossal nerve stimulation, if it's put in a patient correctly, does this in every patient. The trick is whether or not it opens up the rest of the airway. And that's what you're seeing on the right side here. The soft palate is also snapping forward with the base of the tongue to open the entire airway column. This therapy works pretty well. The data that was published out of the pivotal STAR trial, and we've got a pivotal bilateral hypoglossal nerve stimulation trial going on right now, but the pivotal STAR trial showed that the 1-year responder rates on patients here, the Sher criteria that Dr. Suurna mentioned to you was 66% and about 1/3 of these patients had a "cure" for their sleep apnea, an AHI lower than 5. 5-year follow-up on this group, we've had about half of this cohort continue to follow up, and we see a rather durable responder rate of about 63%. And again, of this follow-up cohort, almost half of them have an AHI less than 5. But there are nonresponders to this therapy. And I think it's important for us to face that and to talk about it. So why do patients fail hypoglossal nerve stimulation therapy? The data that we have available in our literature suggests that it's not because they've got persistent tongue-based collapse. Again, this therapy gets the tongue out of the way. When patients are not responding to this therapy, it's because you're not getting the soft palate out of the way, and you're not stabilizing the sidewalls or as Maria referred to, the oropharyngeal lateral walls of the upper airway. The left and right side, whether or not the tonsils are still in place. In fact, in this particular patient who was not somebody that I implanted, but who was referred to me by another provider, this patient had been implanted in the community. This guy is actually awake during him exam and you can see that when hypoglossal nerve stimulation therapy kicks in, not only does it not really open up his airway, it's actually narrowing the caliber of his airway. His really floppy sidewalls are actually sort of starting to squeeze in. And so the point here is that the tongue is not enough in every patient for this therapy and moving a palate forward, that's really not a complicated mechanism. It's just a traction, like having a rubber band attached from the tongue to the soft palate, and you're trying to pull the soft palate forward along with the tongue. And that's why you see the tongue move out of the mouth in some of the patients that have access to this therapy because that movement isn't required to get the tongue out of the way. It's required to drive the soft palate with it. So this complete circumferential collapse, we know affects responder rates. We know that lateral wall collapse affects responder rates and a very large case series that was published 2 years ago. And so when we think about who has access to this therapy, well, I can tell you that as body mass index goes up, we've got data that shows that the rate of complete circumferential collapse goes up and the rate of lateral wall collapse goes up. And frankly, the rate of tongue-based collapse that's seen in patients, goes down. It's the other components of the upper airway that are responsible for obstructing the throat, and we need to figure out how to treat these people because heavier and more severe sleep apnea patients have more complete circumferential collapse as well as more lateral wall collapse. So why isn't the palate opening with these patients? Well, what I want to sort of communicate to you here today is that how little advancement moving the palate forward, that's not actually physiologic. That's not how the 300-pound guy in my office is keeping his airway open. The palate opens like a trapdoor, it hinges downward. The cricopharyngeus muscle, in particular, the muscle connecting the palate to the sidewall of the throat, this lonely little muscle is responsible for opening the soft palate by dropping it into the airway. And none of the extrinsic muscles of the palate actually pull it forward. They really pull it down and stiffen and stabilize it by pulling it down towards the feet. You can actually see this in this Cine-MRI video that's actually available on YouTube. This is the guy who is beatboxing in an MRI machine. And what I want to show you here is that every time he breathes in, you can see the nasal valve suddenly dilate open. And at the same time, the entire upper airway complex slides down towards his feet and the soft palate snaps open again by dropping like a trapdoor. Those palatal muscles need an anchor to work again. Then it's these other structures at the upper airway that pull downwards that open up the upper airway. So we already started to talk about how CCC is -- rates are affected by obesity as well as lateral wall collapse. Well, we've got a problem here in the United States. There's an obesity epidemic. And in fact, it's a worldwide epidemic. And so that we know that rates of obesity are increasing. In fact, they're increasing rather dramatically. And here in the U.S., we've got data that suggests that increasing BMI actually leads to more obstructive sleep apnea. In men between the ages of 50 and 70, the incidence of moderate-to-severe sleep apnea is about 3%. When you start looking at individuals with the body mass index over 40, more than half of those individuals have severe sleep apnea. And we've got other data, as I've already showed you, that shows that the rates of palatal collapse, of oropharyngeal and lateral wall collapse go up as body weight goes up. And you've heard that worldwide, we've got 0.5 billion of these people that need some access to treatment because CPAP isn't getting it done and not all of these individuals are going to have a body mass index less than 30. So with that framework, what I want to start to dig into here are other mechanisms that support pharyngeal or upper airway patency. And the main one that we're going to dig into is tracheal traction. Again, these -- the idea here is that these opposing forces may have synergistic effects. And I realize this slide looks complicated, but I want to spend a little bit of time here because this is how we can study the collapsibility of the upper airway. What you're looking at here is how much air flow an individual gets in any single breath on the Y-axis. On the X-axis, you're seeing CPAP pressure. This individual or, this schematic is showing an individual who needs positive airway pressure to keep their airway open, even start to crack the airway open, to go from a complete apnea with 0 airflow to start to get some airflow I have to start turning up my CPAP pressure. And at that low end, where I just start to crack the airway open, that variable we call the critical closing pressure of the upper airway. As I increase CPAP pressure over that range, that patient still isn't getting all the airflow that they want, and it's the upper airway that's controlling airflow. If I alter the collapsibility of the upper airway over that range, I'll see the peak inspiratory airflow change, and I can map that and say, "Oh, I've changed the collapsibility of the upper airway." At the top end of the curve is what we call [ key opener ] the minimally effective CPAP pressure. That's when I transition from snoring and sleep apnea to normal flow limited breathing. That's what a CPAP machine is designed to do. If it takes somebody a CPAP pressure of 5 to open their airway up, that's their minimally effective CPAP pressure. If I can move that 5 across atmospheric, across 0, I've got a patient who has no sleep apnea and who can keep their airway open at night. So we've got a lot of data in our literature that I won't torture you with that shows that pulling down on the trachea stretches the upper airway, like a Chinese finger trap. And by stretching the upper airway, we can increase peak inspiratory airflow. We can decrease upper airway collapsibility. And there's data in our literature that actually shows that, that improves sleep apnea, and it lowers how much CPAP you have to give somebody. I'll demonstrate that here to you briefly. This particular paper that was published in 2010, they showed that individuals with or without sleep apnea. If you pull down on the upper airway by filling up the lungs with about 0.5 liter of air, you decrease that critical closing pressure of the upper airway by about 3 to 4 centimeters of water. 3 to 4 centimeters of water pressure is a lot. Hypoglossal nerve stimulation therapy drops upper airway collapsibility by about 3 to 4 centimeters of water pressure, effective upper airway [ soft tissue ] surgery, drops upper airway collapsibility by about 3 to 4 centimeters of water pressure. Maxillomandibular advancement even drops upper airway collapsibility by about 3 to 4 centimeters of water pressure. So if we can find ways to take advantage of this particular therapeutic mechanism, we can probably really dramatically affect people's upper airway collapsibility. We've got other data that shows that obesity significantly affects this upper airway collapsibility metric by shrinking lung volume. In fact, an overweight person has lungs that are less full than a not overweight person even when they are up [ upright ] and breathing. I can take a healthy person, I can lay them down, their belly pushes up into their diaphragm and shrinks their lung volume. And that healthy person still has more air in their lungs than the obese person does who's upright and walking around. That difference is typically about 500 DCs or 0.5 liter of air. And those obese individuals have more resistance of upper airways because their lungs are smaller and the upper airways crumpling like an accordion. So this particular experiment, they took a bunch of people that had moderate-to-severe sleep apnea and they stuck them in, they put a CPAP machine on them, but they also stuck them in an iron lung. An iron lung can control the volume of the lungs from the outside with a vacuum or by adding pressure. And we've been hearing a lot about this sort of 0.5 liter of air. And what they found in this study is that for patients that required 12 centimeters of water pressure to open their airway, if you added about 0.5 liter of air, you dropped their pressure requirements for CPAP by 7 centimeters of water pressure. That is a massive change in upper airway collapsibility going in the other direction. If you shrink their lungs down, you increased how much CPAP you had to give them to keep the airway open. That accordion is crumbling and it's taking more air to blow the upper airway open or more pressure rather. So these investigators themselves had a relatively small changes in lung volume, have an important effect on the upper airway and sleep apnea. So if I'm not putting a CPAP machine on somebody, how else can I take advantage of this mechanism to stretch the upper airway out? Well, it turns out with the human hyolaryngeal complex, the hyoid bone and the thyroid cartilage, which is commonly referred to as the Adam's apple, are highly mobile in a way that they are not even when you compare us to our closest primate ancestor. These are probably changes in our upper airway structure for the evolution of speech and swallowing and upright posture. In fact, some of these changes actually probably predisposed to us to uniquely having obstructive sleep apnea. The muscles that control the movement of these structures actually enable a wide degree of control, and they're innervated by this complex nerve plexus called the ansa cervicalis. The muscle that connects the sternum, the chest through the thyroid cartilage or the Adam's apple is called the sternothyroid muscle and it has multiple advantages that I won't particularly belabor you with here today, but the point is that stimulating that sternothyroid muscle and pull down on the upper airway in a way that some of the other muscles don't appear fully able to do. Now I hope none of you are squeamish, but here's a demonstration of actually what this looks like. So the sternothyroid nerve when a colleague of mine here stimulates it in the OR, you're going to see it has a dramatic effect on the tensing of these muscles that run between the sternum and the mandible, stimulating other muscles like the sternohyoid muscle connecting the sternum to the hyoid bone, much less significant effect because the sternothyroid muscle has a single point of innervation that can be found out in its lateral border in every patient about 1 to 2 centimeters above the clavicle. So we've taken advantage of that anatomy and over the last 5 years, we've been actually using ultrasound and needles to stimulate both the hypoglossal nerve as well as the ansa cervicalis in the operating room during drug-induced sleep endoscopy. And before I did this in any patient, I made sure it would work. And so this is actually me. And so there's a wire hanging out of my neck here, and I'm stimulating my own hypoglossal nerve, and you can see the tongue clicking forward. And then on the right side, with the ansa cervicalis, you can see my Adam's apple dropping as I stimulate the ansa cervicalis. So what's the data here? Well, that long history that Dr. Boon referred to of hypoglossal nerve stimulation trials starting back in the '90s. Well, it started with these initial experiments that showed that we increased peak inspiratory airflow for any particular breath and that we increased the cross-section of the upper airway. That proceeded to studies that showed -- that mapped that diagram, this diagram that I showed you earlier that showed that when you map the critical closing pressure of the upper airway, then you improve it, ultimately led to these pivotal trials where we show that hypoglossal nerve stimulation improves sleep apnea. And so in walking before we can run, we are starting to demonstrate some of the same with ansa cervicalis stimulation. So in this initial pilot study that we published at Vanderbilt in 2020, we showed that in 8 patients with severe sleep apnea, it's stimulating -- just the ansa cervicalis increased peak inspiratory airflow by about 300%. That's on par with early experiments of hypoglossal nerve stimulation therapy. Now while this study wasn't powered to show it, I think somewhat importantly, complete circumferential collapse in these patients, 3 of these 8 patients, actually didn't have any effect on the peak inspiratory air flow changes that were observed. Stimulating the ansa cervicalis, we also showed in a similar cohort of 8 patients that you open up the area behind the soft palate, you increase the retropalatal cross-sectional area. Ansa cervicalis stimulation opened up that retropalatal area by about 200%. That was not significantly different than isolated hypoglossal nerve stimulation therapy, which also opened up the retropalatal area by about 200%. When things really started to get interesting is when you combine the 2 therapies. So using fine wire electrodes, we studied both the hypoglossal and the ansa cervicalis in a group of patients. And we found that when airflow was still limited in patients who are getting hypoglossal nerve stimulation that adding the ansa cervicalis to it increased that peak inspiratory airflow by about 150%. And again, a CCC status didn't matter in these patients. When you use both of these therapies in a patient, you increase the retropalatal cross-sectional area by about 350%, which is 180% gain over isolated hypoglossal nerve stimulation, which again, CCC not significantly affecting these results. What we're just now starting to show is that when you stimulate the ansa cervicalis, you are altering that critical closing pressure, you're decreasing pharyngeal collapsibility, and a paper that we just published a month or 2 ago in the Blue Journal, the American Journal of Respiratory and Critical Care Medicine, we showed that bilateral ansa cervicalis stimulation. We mapped it along a range of CPAP pressure stimulating from that critical closing pressure all the way up to that opening pressure of the upper airway. And we found that bilateral ansa stimulation decreased the critical closing pressures and the opening pressures of the upper airway in all comers by about 2 to 3 centimeters of water pressure. The thing that was really important about this data is that if you look at the top 50% of responders in this cohort, greater BMI patients actually had a greater response to ansa cervicalis stimulation. That is the opposite direction that we see in any of the other surgically available therapies that we have for obstructive sleep apnea. And we think it's because these bigger bellies push against the diaphragm, push against the lungs, push against the trachea and crumple the upper airway. It's these patients with bigger bellies, who are more obese, who need a restoration of that traction on the upper airway to open it back up. Again, in this particular cohort, CCC did not affect outcomes. Now this is some early data, but it's not yet published, but I do want to share it with you all, and it's a little bit complicated to follow me. Ignore the red lines and really focus on the blue and the green lines. Dr. Suurna talked earlier about using the VOTE score to classify upper airway collapse. On the right side, the [ T=2 ] means that these patients had complete tongue-based obstruction of the upper airway. And so when you look at the bottom of the graph, that critical closing pressure, you see that ansa cervicalis stimulation by itself didn't really alter upper airway collapsibility a whole lot in those patients. Again, that's sort of the 2 to 3 centimeters of water pressure. But if you go to the other end of this graph, the [ T=0 ], where the tongue is out of the way, at that critical closing pressure where other parts of the airway are causing collapse. If you stimulate the ansa cervicalis at that point, you drop upper airway collapsibility by 7 to 8 centimeters of water pressure. That is a massive change in upper airway collapsibility, and we think if these particular patients that may be good responders to this treatment, and I think it is a harbinger for what happens when you combine both hypoglossal and ansa cervicalis stimulation. If you get the tongue out of the way, the rest of these mechanisms will do their job. So what do we think that ansa cervicalis stimulation is doing? We think it's adding tension to the palate and it's opening it by pulling it downwards. We think it's unloading the palate. It's taking the oral tongue off of the palate. It's reducing the pressure that the tongue applies to the palate and allows the palate to open up on its own. We think it stabilizes those sidewalls of the upper airway by pulling down on them and stiffening the length of the tube and a little bit more subtle by pulling down on the thyroid cartilage that actually rotates the epiglottis anteriorly and moves it away from the posterior pharyngeal wall as well. The data is nice, but everybody likes pictures. And so I want to share a video here in particular. This can be a little involved. And so the couple of things that I want you to pay attention to are the endoscopy. You're going to see this patient has complete circumferential collapse to the palate and you're also going to see the lateral walls collapsing. As these graph scrolls on the left side of the screen, the main things that matter are those red and blue blocks. When the scrolling line hits the red and blue blocks, that's when the ansa cervicalis stimulation turns on. The green line that you see in the middle of the graph is airflow, nice, rounded increases in airflow indicate non-flow limited breathing, a plateau does flow-limited breathing. And so this patient right now is experiencing circumferential upper airway collapse. But as soon as ansa cervicalis stimulation clicks on, you see this just stiffening and stabilizing the upper airway through the next couple of breaths. We turn it off, the airway collapses again. We snap it back on and the airway stiffens. This is an example of hypoglossal nerve stimulation and ansa cervicalis stimulation. So I'm going to start this video. And what you're going to see is that this patient is experiencing complete collapse of the palate, and there's a lateral wall component here as well. When I turn on hypoglossal nerve stimulation, which is a percutaneous wire on that nerve, there still is airflow limitation, that tongue is out of the way, but the palate is continuing to collapse on its own. This is going to go through 1 or 2 more breaths. And then I'm going to turn on ansa cervicalis stimulation, right about now. And you're going to see the whole upper airway sort of stiffen. It's a bit more subtle. It's not this big radial dilation. But that palate is standing out of the airway now through the next several breaths. And that patient goes from flow limited breathing to non-flow limited breathing. That palate is more stiff, it's more reliable to respond to that movement of the tongue. This is a fully opened airway. So in conclusion, sleep apnea isn't really just an upper airway disease, it's an upper body disease. And hypoglossal nerve stimulation is insufficient for many patients that have sleep apnea, especially those with higher BMIs and apnea-hypopnea indices that we don't currently have access to. We do think that ansa cervicalis stimulation is a viable and surgically accessible target. Again, using the sternothyroid trunk, and this is the technology that Nyxoah has licensed from Vanderbilt University. Our ongoing human research supports this as a potentially viable therapy, and we think it can ultimately complement hypoglossal nerve stimulation therapy to yield greater effects in either -- in isolation. Potential benefits here include a more comfortable therapy where we can deescalate single-channel stimulation, a more effective therapy with a reduced postoperative care burden for patients and ultimately, more treatable patients. We think expanded indication, CCC, which we obviously already have studies going on right now, but also increased BMI. So a big thanks to my research group and for all of you for having me here today. Thank you.

So with this, we are coming to the end of our first Analyst and Investor Day. I want to thank Dr. Suurna, I want to thank Dr. Boon and Dr. Kent for sharing their experiences with us. I think, and I hope you will agree with me that it's really -- we are really in a privileged situation as a company that we're able to work with them and all their colleagues in the U.S. and also in Europe in further developing the Nyxoah technology. Now what is left for me is to highlight what you can expect from Nyxoah this year, [ short term ] because time really flies. So what will we be focused on for 2023 are what we call it our strategic objectives. It's all about DREAM. DREAM having a world-class patient follow-up resulting in reaching our primary endpoints. But again, if we see what we published, if we see what we learn, we are really feeling confident that this is also being the next step to success resulting in regulatory approval and eventually resulting in commercialization in the U.S. In parallel, we stay with clinical and focus on ACCCESS -- ACCCESS, CCC. I think you heard enough already in the explanation, how important it is to also offer the solution to treat patients suffering from CCC. In parallel, we also start preparing slowly for the market readiness in the U.S., already touched on the fact that we are interacting and engaging, and you can expect a communication around CPT coding confirmation by AMA, then there is already the regulatory PMA submission. First submission has been done in February. So there are 4 modules in total. The first 3 modules will be done this year. And the last module, of course, goes together with the 12-month data on efficacy and on safety. And when it comes to Europe, there it's quite simple. We focus on showing that our proof of concept is really embraced by physicians and by patients. And how do we measure our success there? It's mainly focused on Germany because that is the largest country where competition -- and we are really competing market share gain in hypoglossal nerve accounts in Germany and of course, also accelerating market penetration due to investments in DTC and in referral programs. And then we also continue to focus on opening selectively new markets. The last slide is always the challenge how you close the presentation. Normally I try to be funny. This time, I want to keep it very short. We're on our way. I think that's clear. We are on our way. We feel very confident in this journey. And last, let's make sleep simple again. Thank you. And I invite you for the Q&A. Maybe all the speakers, we can sit if you have questions. I would also like to introduce Remi Renard who is responsible for the commercialization in Europe and then [ Lance ] for regulatory and clinical affair responsible. So if you want, feel free to join me and then we are opening it up for your questions. Thank you.

Mike Polark, Wolfe Research. I want to start Dr. Kent. That was great. Thank you so much. Form factor, too early to talk about that? Is it 2 widgets that work together, 1 place for hypoglossal 1 place for the onset? Or is it a single digit?

Yes. That's a fantastic question. I think the short answer would be that, that parts not up to me. So I think ultimately, it will be up to the engineering design team here to figure out the best way to implement and execute this. From an anatomy standpoint, these are anatomically, these are slightly different targets in terms of where you can get to them. But how we do that is part of the innovation that I think will have to look and look forward to.

Yes. And we are in the phase of defining that front steps right now. So we are in the -- preliminary design phase now.

So the ansa cervicalis runs sort of throughout the neck really. And so it's hard to state specifically, but on the order of a couple of centimeters.

And then just a follow up -- but then I'll -- Turn it back. The -- you mentioned reduced post-op care burden, the promise of this technique. What does that mean? Yes.

So my implication by that was that if you have a therapy that works out of the box because you're recruiting more of the mechanisms that are responsible for keeping the upper airway open, then you have less effort that's put into balancing comfort against efficacy. Next question? Yes.

Suraj from Oppenheimer. A few questions for the clinicians. Dr. Kent, let me start off with you. Following up on Michael's question, so I understand the product configuration could be different. I'm more interested in the titration the amplitude of the frequency for the ansa versus bilateral hype. I mean there would need to be a delicate dance. Is the expectation, let's say, 0.1 milli amp for both -- that would suffice. And how would the tangle happen?

The honest answer is we have no idea. These are very early physiology experiments. So far, what I can tell you is that the strap muscles of the upper airway are standard skeletal muscles. They respond to similar amperages in our early physiology experiments at the Genioglossus.

Any for Dr. Suurna or for Dr. Kent. When you talk about just bilateral stim versus unilateral, One of the things that is a little confusing to me is, let's say, hypothetically, you deliver 1 amp -- 1 milli amp, right? For unilateral. So let's -- comes in, does it mean now that bilaterally would get 0.5/0.5? Or would you get 1/1, which is in essence, how does that -- how does the decision tree work?

So I can start answering this question. And so every patient is a little bit different and stimulation of our nerve might require a slightly different stimulation level. And so the thought is if you simulate both nerves, you might actually, again, provide more comfortable set of things for the patients because now you're not like how to offer stimulate 1 side to achieve certain results, but you actually can distribute the stimulation between the 2 sides. And some of that is going to be -- has to be adjusted based on the patient's needs. But I think you could provide by simulating 2 nerves, you can provide broader, wider air opening, but possibly delivering lower stimulation levels and thus more comfort to the patient.

Fair enough. And final question, again for either of the clinicians. Dr. Kent, in one of your slides, that said a minority of patients are suitable for hypoglossal nerve stim, I'm paraphrasing. That was one of the comments. So I guess I'd love to understand, currently, in your practice, what is the throughput rate for unilateral hypoglossal that you're seeing, let's say, 10 patients come in, 5 get it, 1 get it, 0.5 get it? How is it shaping up?

Yes. For me, I think it's widely varies from clinician to clinician. And so I would not extend my own sort of my practice and experience to every provider in the community. All I do is obstructive sleep apnea, and some providers have gateways to entry for consultation in the clinic. That would mean that the number of patients who make it into -- see them regarding hypoglossal nerve stimulation therapy have a very high hit rate for candidates. Our clinic is very open to any individual that's seeking care for sleep apnea. And if you go back to that sort of demographics map, I live in one of the largest quadrants of the country in body mass index. They like their barbecue in that. So my own hit rate for hypoglossal nerve stimulation candidacy is less than half for sure, but I see patients of antibody masking, which is closer to a general sleep clinic than maybe a 100% surgically focused practice where if you've got good referral patterns set up in the community, you can have a very high hit rate for eligible patients blocking.

...make a comment in terms of like going back to what you're sort of saying in terms of patients who have like larger BMIs because there's definitely a correlation between having sleep apnea and increase in weight. And as your weight increases, you're snoring, your sleep apnea gets worse. But -- so that's one group of patients, right? So those patients, they lose weight, their sleep apnea goes away. But then there is a very significant number of patients who -- do -- who are not overweight. And that's more of a hormonal changes muscle tone, losing their muscle cell genetics that predispose them to having sleep apnea. It's not just weight. And those are the patients who cannot just lose weight and get away -- get rid of the sleep apnea. And so there's a slightly different population fraction. So those are probably going to be right now at the current state. Those are the better candidates for treatment of -- with hypoglossal nerve stimulation. But as we continue to look further at different types of phenotypes and expanding how we can open up the airway and serve as a bilateral stimulation. So I think that those stations with -- even like with a bigger BMI group might be also become more of candidates.

I'd also add, number one, this is part of a -- an algorithm that we have for treating patients. So we often use multimodality therapy for patients that don't just focus on 1 single therapy. With that in mind, I think this actually is a fairly high hit rate where it actually complements a lot of what else we do. So for example, we fix the nose, they can breathe better to reduce airhole limitations and then combine it with this therapy. So the hit rate can actually be pretty high, and the appeal of the therapy is because it is so well tolerated and it's so safe, it has become more prevalent in terms of its use.

Jon Block with Stifel. Maybe 2 questions, one for the doctors and Olivia, maybe 1 for you, and I'll start with you. Really compelling slides that you guys put up from both the soup specialists and the physicians on ultimate share and where that might shake out. And quite honestly, very much in line with some of the work that we've done a couple of years ago. But your competitor has made some significant investments in infrastructure -- commercial infrastructure reps. Can you talk at a high level -- what we can expect from you guys over the next 12 to 24 months. And earlier on, you talked about Germany going deep, not wide. Is that something you're going to try to replicate in the U.S.? Or will there be a different approach to market?

No, no, this is an excellent question. And it's a question also that internally, of course, we are discussing quite intense as well. So first of all, it's clear that we are made -- or hopeful we are making our first investments in preparing also a commercial strategic launch in the U.S. So it started all by having market access. I think I touched on this, starting by the work that you are doing and getting the correct coding for technology once we are commercially available. So that work is going on. Second thing is what you can expect this year is that we will invest further in hiring also the commercial leadership in the U.S. that we have really experts that we are bringing in that can start preparing and going more deep in what would be the most successful introduction that we can do commercially in the U.S. So that is the second thing concrete that we are doing. Next, we are learning in Germany. And to your point, so how will we invest -- how important is the role of sleep physician. What is the outcome of DTC. So we are really testing all these proof of concepts in Germany, taking the learnings and of course, also very carefully observing what our competitor is doing and what is working well and what we think maybe -- might increase or might have a better effect or a stronger effect in going forward. So that's what we are doing. But I also think what we already can say today is that if you look at the U.S. it's really important that you have the relationship with the ENT surgeons, the people who already have experience with hypoglossal nerve stim -- already treating all of these patients. So building that relationship, making sure that they understand what our technology can bring to them and how to position our technology compared looking at the patient and start making how do I select what patient will get what. And because in the end, let's not forget today, 20,000 patients in '22 got treatment in the U.S. Hypoglossal nerve stim but there were 500,000 patients out there. So the pie is extremely large as a matter of speak. So also there, we think it's time that there is a second company coming in and over time, maybe even a third to increase this therapy penetration. With on to answer complete, first steps, market access. We are taking concrete action, building commercial leadership in the U.S., you will hear from us during 2023, taking the learnings from Germany, very specific and also addressing and building relationships with the leading physicians in the U.S. and also with the leading referral 3 physicians in the U.S. That's what we are focusing on as we speak. -- in parallel, of course, the hot worry on getting of dream results in and and then also making sure we get this regulatory approval in place.

Understood. Very helpful. Maybe the second question for the physicians. Last slide, the data that we got, right, first 34 patients. I believe 320 centers. So you're looking at maybe a little bit less than 2 patients percent or on average. Olivier, earlier you talked about proficiency building after 4 or 5 but any of the doctors like to opine upon just how that proficiency improves, right? We're trying to take the 34 patients and extrapolate it out to 115. Arguably the first 34 they've been somewhat hindered by lack of proficiency. For those physicians up there, if you can talk about the journey that you were on and how that evolved over time. That would be very helpful.

Well, I mean, there's always a learning curve, right? And even with the clinical trials that other companies have performed, again, some of the centers should be planted like 1 patients centre in plan but now 20 patients. And there's definitely some process like a learning process at first, as you work with the therapy as you work with the device and techniques and techniques have evolved. And I think the same thing for this therapy. I mean this is a slightly different approach, and this is something that is -- there is a learning curve. And -- as we learn about -- more about the therapy, how device works, like -- little techniques, tweaks because -- that's something you cannot anticipate when you're just designing a therapy. Does sound like you actually have to have like hands-on experience to truly get like some nuances of -- and I think that's very good point because as experience grows, I think also looking at the outcomes and looking at the proficiency and efficiency and faster and being like safer, and that comes along with that as well.

Maybe, John, I would like to add something to this and a very simple, a very simple answer. So what we see in Europe as well is that the more you do it, the better you get. I mean, it's as simple as this, surgeons who are doing 10, 15, 20 implants. They are doing a better service than the first patient on the second patient, which I think is only logic. So what we expect and what we saw is that the first 34 patients, there is a lot of this learning that you find in them. So normally, if you extrapolate what we learned, the following patients can only get better. No, I do not want to be forward-looking, but that's what we expect. That's what we see. And that's why we are really so -- or shall I say, so motivated by these first results. And maybe I can answer this, I also would like to be a little bit collected. Why do we publish this abstract because when we were having a chat, I got this question like 4x. Why do we publish this abstract today? The reason is very simple. When Jey and Dan are interacting with physicians, what we see is that there is a clear need for physicians to share learnings with each other. They want to know how are you doing? How are your patients doing? What can we learn? There is the access to that is now launched. So of course, physicians want to know and understand from their colleagues and combine it with their own experience how can we get better? And how can we make access also successful. That is one thing. And the second thing, and I will be very open and you know I'm always open in these things. This is also helping us, of course, when we interact with physicians in Europe where there were commercial patients that we can show this data. And what this abstract will be publicly available that we can also use this and helping them also sharing the learning from their colleagues. So that's why it's so important that we have this and that we can talk about it already.

I think another point that can be made about that is that when we say that there's a learning curve for surgeons. Typically, what that learning curves evolve is sort of speed and efficiency of putting the device in, but not -- I would say that during this trial, those first patients are actually very closely proctored. And so it's not like the device is going in incorrectly, and there's no hope of working. And so I think something that speaking broadly, I've been very impressed by is -- the trial has gone on, where I think the learning and the evolution without being forward-looking has been impressive to watch has actually been on a solid side, something that is impressive about this therapy is just how many parameters there are that can be manipulated to get the result that you're looking for out of this therapy. And so much of the learning has not happened so much in the OR, but has actually been with being able to program the therapies of the interface as well with the patient.

Think can we have a question.

Just -- I'll start off with a question for you, Olivier and the team. Can you walk us through the reimbursement pathway in the U.S. ? And maybe provide a bit more color of what that would entail? I know today, you mentioned that you guys have hired a reimbursement expert who's been in contact with the AMA about coding. I think in our previous communications, you talked about using the existing deep brain stimulation codes for Genio. So I guess, what is the assumption for coding? And how quickly can you bring payers on board once that has been established?

Yes. Okay. So what we saw and then we have to go back and refer to competition again. the moment that Inspire entered in the U.S., what they did is they entered with an existing coding for neurostimulation, coding for Vagus nerve stimulation. So what we learned about this is, that if we will enter into the market into the U.S., what existing neurostimulation code would be as close to our technology or reflect our technology as much as possible. And it's not -- it's according to be very precise for cranial nerve stimulation, the 61 CPT 61886. That is the coding that reflects Mac Coding and then backed up by experts. The closest the technology that we are offering. So that is scenario one and that to your point, that is the one I was referring to when we spoke and I got this question in the past. Now what we learned by interacting with the physician association, the AAO is that today, there is a specific hypoglossal nerve stimulation coding existing. It's new. It's -- thanks to the work that inspired it, but there is not an existing hypoglossal nerve stim coding. And why am I saying an existing hypoglossal nerve stim coding? Because sometimes it's a little bit referred to us. There is an inspired coding. And that is not correct. So according -- it's not linked to a company, it's linked to what you do. So there is an AGNS coding existing in the U.S. today. So what we believe and what we are exploring is that -- it also might be a scenario to say we use the existing hypoglossal nerve stim coding -- but then we are challenged by the fact that if you read what the coding is saying, it's talking about an implantable pulse generator, we don't have an implantable pulse generator. So the coding is fitting because we are stimulating hypoglossal nerve. But it's not fitting because we don't have an implantable pulse generator. Now the good thing in the U.S. is there is something like modifiers so you can use a basic coding and then you can use modifiers to make sure that it fits to the need of your technology. Now these are the 2 scenarios. What I cannot say today is what coding will we get. What I can say is that there is a recommendation made by AAO like the process goes, you make a recommendation to the AMA. And then the AMA will follow the recommendation and also confirm this the moment we have this, you will be the first to know. But it will be one or the other. Or you go in a traditional approach, you use something that is existing or you go and scenario 2 immediately with an AGNS coding that you modify that your technology fits. I hope this is answering your question.

Yes, that answered it perfectly. And then it was really exciting to actually see the data from DREAM for those 34 patients I guess in the interim from today to when the last patient is finished in early March, what other data should we be on the lookout for? And I guess specifically, I'm referring to the EliSA post-market European study, I know the primary completion date according to clinicaltrials.gov was September 2022. So when will we get a readout on that primary endpoint?

No. So I don't know, Jey or Dan, if you want to cover this model of EliSA. But it's all about you prefer -- because you guys are working with this. And then maybe -- I -- to expand a little bit on this because you -- you really, you're saying it was supposed already to happen like in 2022 and it's totally correct. The only thing that we could not expect was the German commercialization. because most of the patients were supposed to come from German sites. So all of a sudden, we get a full reimbursement in place, and we get -- we start competing with our own clinical study. And yes, there, I think the choice that we made is obvious. If you see it in German result at this moment. But it will be that to Dan's point finished. And then of course, we will have 12 months, 24, 36 months data that you will see.

Great. If I could just squeeze one last -- one for the clinicians on the panel. I guess in your view, what's been the biggest hurdle to adoption of hypoglossal nerve stimulation technologies historically? Is it -- I know we covered BMI limitations, CCC, but even from just like a patient compliance perspective or other factors that might kind of hinder adoption. What might those be?

I'll say initially probably the biggest thing to adoption was physician acceptance of the therapy just with CPAP and so on. The good news is that, obviously, so much has changed in the landscape that acceptance is really -- it's really become at least well known and accepted. And so the barriers are really, for the most part, have been knocked down. The other big barrier that we faced originally was in reimbursement. When we didn't actually -- before the therapy became widespread. It was just basically a challenge. Obviously, if patients approved. And of course, Again, those barriers are now down. So we -- you really don't have, I would say, access issues any longer.

Also, when you talk about something new, I mean there's always like a question, well, does it work? I mean acceptance of something new is not -- doesn't come like overnight. And there are also a lot of physicians who have their patterns, how they treat the patients and sometimes also change the awareness of mentality or approach. It's also sometimes kind of like face a little bit of challenges to kind of change -- and if you know how your behaviors are like, right? Everybody has challenges with changing their behaviors right away. And so that's also like a change in the style of practice, pattern of practice, referral pattern and awareness of the therapy because, again, right now, it's -- we're talking about even though there's been 36,000 patients in planted with Inspire device. But again, that's a relatively small number of patients. And if you think about how how the therapy sort of gets integrated with clinical prices. There's still a lot of physicians. There's still a lot of patients that come in, they're like, "Oh, wow, this therapy has been available for that long?" Just awareness of that, it's just not there yet.

Yes, [ Larry Begle ] with Wells Fargo. Olivier or someone from Nyxoah, just a few questions on the data we saw last night First, I just want to confirm it's an intention-to-treat basis, was that correct?

That is correct. Yes. Also Jey -- also comment -- feel free -- because you are coming a little bit closer as well because I want to really -- I'll give you a really clear answer as well in the Jey's managing the super team, but it's the intention to treat, yes.

And it's unusual that we see preliminary data. So I just wanted to confirm that FDA signed off on this or you're not concerned about impacting the integrity of the study?

Yes. Correct. And then this was also a decision that we made very carefully and the best way to know whether FDA would be concerned or not is to talk to them. So we reached out. We show them the abstract, and we asked their advice. And because the last thing we want to do is jeopardize our DREAM study and -- in anyhow. So that's why we were very careful in this approach -- thought ask the advice. And the answer was that, of course, that we could show the data but we have to point out that it's not conclusive of the overall result, but that has to be very, very, very clear. and also in going forward, you cannot expect that we will start doing this on a regular base. So that after 6 months, 9 months, you will get all the timings updates. That's not the case. So first, we ask them. Second, also, the size of the code of 34 patients out of the 115 and also the clear disclaimer that it's not conclusive for the final results.

And last for me on the apnea data sleep what are we going to see there? I'm not the actual data, but are we going to have baseline characteristics and AHA and ODI drops, et cetera?

Yes. So one of the mandates from FDA, Ben can expand on this is -- not to do any kind of statistical analysis. So that's why we said it is a respond rate. The only thing you're probably going to see is a little bit on demographics, like what's the baseline AHI BMI, overall responder rate and then safety data.

I'm going to add 1 for the clinicians. What do you think it would take to move hypoglossal nerve stimulation to first-line therapy on the same plane as CPAP. Could you envision that at some point?

So obviously, we have patients that are fantastic responders to this therapy I think the challenge is identifying exactly who those correct patients will be with that level of certainty out of the gate. There's a lot of work that's being done in our field to phenotype obstructive sleep apnea. There's a lot of different disease states that all fall under the umbrella of sleep apnea clinically, a 35-year-old who's profoundly sleepy during the day with the BMI of 25 probably actually has very different underlying physiologic mechanisms than a 70-year-old with heart failure and severe sleep apnea. It feels like he seems like a baby. And so figuring out who that person will be with a high degree of confidence, I think, is an area that this field is moving towards. I would imagine the other part of that challenge would be the payer side, right? We're talking about a therapy that is not as inexpensive as the CPAP machine. But then when you look at the lifetime cost of the CPAP machine and consumables or compliance rates, et cetera, they may balance out. But the real question there will be convincing a commercial payer that is actually in this patient's best financial interest to get this therapy first instead of having to trial a CPAP machine and potentially being lost to follow-up.

CPAP machines. I mean, they've gone through a lot of evolution too. Like in the technology has evolved, masks have evolved even now people still complain about the discomfort of even very small mask. And I think with this therapy, one of the exciting parts is that the technology continues to evolve. I mean we're just at the beginning of the technological advancements and potential is just like sky is the limit really because you can stimulate different nerves, different configurations, different voltages, devices -- we're going to get smaller -- technique of implanting the device is going to get smaller, then programming is going to be different, patient compliance and how to track the patients progress for the therapy, how do you adjust the therapy. All of those technological advances, I think also are going to contribute to this therapy continue to get to the top of the choice by the primary choice group.

Last comment I'll make is -- it will be this -- as we move more towards personalization of care in the United States and so much discussion about that, the good news is on the work of people like Dr. Kent here, who just published a paper, with your guideline paper, recognizing that basically, there are obviously huge number of patients who fail CPAP and getting people to buy in, there are other therapies and that we can actually offer them these patients who are struggling something new. So I think the dial is actually moving because historically, our colleagues in [ Steve Medicine ] -- it was CPAP. And after they failed CPAP, it was CPAP. And I always joke me to my big residents and after the third trial of CPAP failure -- CPAP, it was CPAP again. And so now there is this introduction of these new therapies. And so I think actually, that's moving I think, again, there are moving parts because of, again, payers and things that will dictate that. But I think you are seeing acceptance that basically, we will move more into, again, personalized care where somebody will come in and actually have discussion about all the therapies that exist and patients can actually have some informed decision-making in that.

[ Rich Newitter ] from Truist Securities. Olivier, one for you and then one for the panel. Just going back to the reimbursement, you kind of gave a -- there's 2 ways this could play out from a coding standpoint. I'm curious to hear are you indifferent or agnostic as to which one ends up being the one that is your path? And what are the timeline considerations and potential actual economic remuneration considerations between the two?

Yes. So, to answer the first question, what is our preference? Our preference is to get as fast reimbursed in the U.S. That is the preference, both approaches from a price perspective of similar. There are differences. But I think at this moment, it's a little bit too early already to go deeper in this. That's the first answer. Second is, if you -- if I can walk you through the timelines of 12-month dream data Q1 next year, then of course, we will do our last regulatory module submission. We cannot control the speed of FDA, and we see that there is a lot of variance currently. But we do expect, based on what we see that by the end of 2024, we should be regulatory portend commercially available. So the immediate outcome of this is that we will have CMS approval. And CMS, they will either represents roughly 40% of all the U.S. citizens that are insured. That's what we know. So at the moment we have regulatory approval, we will be able to start launching the product and getting paid for it by CMS. In the meantime, in preparing this, we are working with the local MAX also to make sure that we get the maximum out of this. The next step will be the negotiation with the private payers. Now the big advantage that we have is that there was another company who did all the heavy lifting. So today, we don't need to convince what the cost is what it can do. I think that's already done. So also there, we think that normally it will take them 6 to 9 months after approval after CMS is paying that we can also be able to benefit from the commercial payers. And please correct me if I'm not correct -- but I think this is all the latest thinking.

Okay. And just following up on that, the actual -- getting the code and if you need to use a modified, it's using all of that will happen right when you get approval?

No, no, getting the code will happen this year already -- so the submission is done, so we are just waiting for the result and the outcome from AMA. So the code, we will have normally this year.

And then for the panel, I'm just curious, it looked like I saw up there. I think you're all obviously doing hypoglossal neurostimulation now. would love to hear your views. We saw the GuidePoint survey -- thank you. Hypoglossal nerve stimulation split might shake out once you have 2 therapies available?

No. for me, as long as they are reasonably comparable things on the reimbursement side, I'm actually really looking forward to the luxury of choice in that -- it often really comes down to what a patient wants to do. And I think on that front, I would point to the European market data in terms of what you have been told regarding European market penetration in Germany, right? With therapy, patients are selecting the therapy that they want. And Things are moving forward from there. And for me, I take a philosophy with my patients to present all of the available options and then to let them choose what best fits their own lifestyle and preferences. So I think that will control a lot of how this ultimately ends up being deployed.

I totally agree with Dr. Kent. I mean, it's nice to have a choice. And patients should be able to -- there's a lot of other technologies in the market that have patients are presented with an option, which technology works for them for very specific situation because -- some people like to incisions. Some people like one incision -- some people like having filters, so people don't, some people don't want to shape their facial here, some people they don't want to have like more incisions. So this is like it has to be a patient choice too. And I think also, as you introduce more companies, more technology in the market, the technology develops and involves and progresses. And I think that's going to help like just the field to grow. And so -- at the end of the day, we want our patients to do well, and we want to provide the best care that's out there. And I think that's only possible with the growth and evolution of technology.

I wholeheartedly agree. And I can only reference, I just had a family member who went for a console for deep-brain stimulation where there are 3 different products on the market and basically laid out, here are the advantages of one. Here the advantage of 2. Here's what you can expect in the future. One of the appeals of this actually is that the therapy has something new to offer that basically other therapy doesn't, which is the [ ANSYS ] potentially down the road. So that obviously may have appeal to patients where you can again inspect enhancements and things. But I think, again, it's going to boil down to what patients actually are comfortable with, and it will be a conversation that -- and patient preference will dictate. But it will be nice to be able to offer this 1 has X. This 1 has Y. And again, it may be I don't like a battery or I do, maybe I don't like the idea of X, Y and Z. So again, it will be a patient choice kind of thing.

Mike from Wolfe Research. I want to ask on the activation chip and the development road map there, Genio 3.0. The chip look different. What's different about it? And is it smaller notably? Any kind of -- why do that -- why make that progress? What's the benefit?

So there is a new agronomic design. And that's the first step. The second step, and that's in the Genio 3.0, there will be also additional new electronics in site with additional sensors. And those sensors will be used to the adaptive therapy input.

A follow-up on this topic. When I first met Nyxoah, we were dreaming dreams, and the concept of over-the-air powering is scientifically valid medically early. This platform has, I thought, potential to pursue that. Is that science fiction? Or is that -- is there a road map to that becoming a reality?

There is a road map, but it's not in the time frame I mentioned here. It's a little bit like we walk, then we start running, then we go sprinting, but we keep dreaming. I can really make sure. And these things are further explored.

Just one follow-up on the -- so Genio 2.1, what I saw on the slide, that the dates were 2023 to 2024, and it looked like that was the new ergonomic design. Is that correct? And what's the -- is that what we're going to see when you launch in the U.S.? Or when is that coming out in Europe? Maybe I misunderstood the slide.

So it's all part of the Genio 2.1 system. And what we file is the current Genio 2.1 AC. And then after approval, that's new ergonomic design will also be appended.

And shortly after you guys' approval, you would expect the new ergonomic design.

Yes.

In Europe, what's the timing for the new ergonomic design?

That's comparable. Yes.

Another question, Dr. Kent or Dr. Suurna. So are you currently implanting hypoglossal nerve stim in patients unwilling to try CPAP? I'm not saying failure or intolerant, unwilling to try CPAP.

So patients have to have tried and failed CPAP. And I -- personally like when I have a conversation with patients right now, I -- it's on label. Like that's basically the indications. That's the FDA recommendation. Patients have to have failed noninvasive, nonsurgical therapy first. And I think that's -- again, that's also fair to the patient before they undergo surgical implant, patients who are actually -- at least they can at least give a chance. So they were given a chance to see what they're giving up. So I think that's only fair to the patient.

So I agree with everything Maria is saying, and there are 2 barriers on that front. One is payers. Payers require that a patient have demonstrated some attempt at CPAP and ultimately failed it. I don't pursue and haven't heard of people having luck of just saying, a patient doesn't want to try CPAP. There has to have been some good faith effort towards filing it from the payer side. The other barrier to that is [ me ]. As Maria was saying, there's a growing field in terms of phenotyping patients for obstructive sleep apnea and trying to hit it out of the park in a first go, but we're not there yet. And I philosophically think -- I am a little different than some other surgeons in that I practice medicine. I prescribe and manage CPAP machines. And I do not -- I do frequently have patients that are surprised at how well they do it. So while we're still working on improving the patient selection process, I think that going through that process of making sure that patients really understand, that what they're "buying into" is an important part of the selection process for me.

Jon Block with Stifel again. So just maybe, Olivier, you can comment on CCC and ACCCESS, and that got off to a little bit of a later start. I think in the early days, the thought was to complete that within a year, there's more centers. Arguably, you're going to have some kick-outs from DREAM that you'll be able to apply. Maybe if you could talk to us, is the thought still a year from the first implanted patient, which just took place? How would that sort of feather into the U.S. launch should -- you can fast forward, right, in terms of a label expansion? Maybe for the doctors, just the best of your knowledge, how are people practicing in Germany, for example? I mean are they just avoiding the dice altogether and they're just moving forward because of the label expansion? Or how are they going ahead and handling things from a workflow perspective?

So first question, ACCCESS time lines. So it's all about setting priorities. In a company, at the stage where we are, we do not have unlimited resources. That's one thing. The #1 priority, as I already explained, this DREAM and making sure that we had our DREAM results, we get regulatory approval. Now ACCCESS was a little bit impacted due to this priority setting. You also see the current economic situation. We are having an extremely tight budget management. I think that's only what you can expect from a company, that we see where do we spend our money, how do we allocate our money in the best way to make sure that we reach our results, and that is DREAM, number one. So Jon, I think you are totally correct. We will not end ACCCESS in 2023, to be very precise. We have done our first implants. We are in the middle of further patient selection, also site activation and site screening. I think it's good sometimes to take a little bit more time. When you activate and select a site, this was one of the learnings that we had from DREAM. So to your point and try to answer very precise, we want to close all ACCCESS implants by the end of next year, so roughly 12 months later. And then if you stop, then you -- walk you through the time line, it's also a 12-month follow-up. So that will be done by '25, [ end ] '25, then we'll do a PMA supplement. And based on this, we expect 6 months later to also have the label expansion in the U.S.

Dr. Kent, maybe for you, you mentioned philosophically. Is your thought from a BMI perspective that hypoglossal nerve stim is the right approach for BMI going up to 40%? I think obviously, there's another player, right, that just took the BMI and raised from that [ 30, 35 to 40 ]. And at a recent conference, it seemed to hit a nerve with some physicians more than others. Maybe I'll just ask an open-ended question. I would love your feedback on if that's a right approach or is that going to compromise outcomes.

Yes. So how much time do you have? So I think one of the things I tried to communicate in my talk is that -- and to sort of -- I think maybe to boil it down or reduce it further, when I have this conversation with my patients, I described BMI stim as being a triple whammy or rather body weight as being a triple whammy for obstructive sleep apnea. We've got good anatomic data on our literature that shows actually the tongue gets fatter. And so the thinking is move that tongue out of the way, maybe that patient can breathe. But we've also got good physiologic data that shows that parapharyngeal fat pads get larger, pushing more on the airway. The upper airway becomes more collapsible, and it comes back to that concept of the pipe itself intrinsically being more floppy, where unblocking the pipe with the tongue can't get the job done in everybody. And then the third part of that triple whammy is that central obesity and the belly altering and expiratory lung volume and causing the airway to crumple on its longitudinal access and, again, making all of those muscles work harder to keep the upper airway open, and those patients have higher critical closing pressure. So the thing about body mass index is I think that if you've got a large database of patients with high BMI, there's going to be some patients in there who are responders to therapy because body mass index doesn't give you any indication of how that fat is distributed across the body. If you've got somebody who -- where the majority of their body weight is below the waste, they can have a high BMI, or if they're short, they can have a high BMI, but not necessarily a highly collapsible upper airway. So I think at the end of the day, BMI is an indicator of this airway collapsibility, but it's not a perfect metric for it. You'd have to start taking much more careful measurements of other measures of the body, like neck circumference, hip to waste ratio, et cetera, and then actually in some form being able to quantify that upper airway collapsibility because I think that's what ultimately is going to be the sort of best indicator of where this therapy will work and where is that airway collapse. All right, that was a really long-winded answer to the question.

Simran Kaur, Piper Sandler again. I know we touched on this a little bit earlier, but can you maybe just provide a bit more color on how you plan to scale the U.S. commercial organization? Specifically, when will you begin to make a hiring push? Do you have any expectations for headcount at launch? And then how do you plan to target U.S. setters? I'm assuming the initial focus will be on the DREAM trial sites and sort of ramping up commercial implants there?

So again, we are relatively far away, but also, on the other hand, very close. So again, we are preparing this commercial leadership. This is something that we will be investing in this year already. Now in looking forward, and you see that today, I think competition is clearly roughly -- or working with roughly 1 dozen sites in the U.S., 900 to 1,000 in the U.S. It's also clear that when we enter in the U.S., we really want to make a splash. And making a splash means you need people in the field, you need people building relationship, and of course, you need to have payer coverage behind you. So the way we are thinking is that we will enter in a phased approach. So first -- and when you're saying DREAM accounts, yes, DREAM accounts, but I think it will also be a combination of high volume hypoglossal nerve stimulation accounts well spread over the country. And for us, very important where we can see growth and a good patient follow-up. And that also includes, for example, well-trained nursing staff when the patients are coming back when there is a need [ for fine-tuning ]. So it will be a phased approach. We, of course -- when was also 1 of the questions. DREAM is an open-label study. So we will know a little bit earlier if we will -- where we stand compared to primary endpoints. So I think if you stay and you see and watching us closely, the moment we start making investments in really hiring people and then hiring like more than 1 -- like 10, 20, 30 people, I think that's also the confirmation that we feel extremely confident that we hit our primary endpoints. And normally, I'm looking at Jey a little bit. We should know more by the end of this year already. So stay tuned on this, and then you will see in the way we are communicating and what we're doing commercially investing.

Great. No, that was perfect. Maybe just a quick question on the ansa cervicalis program. Any color on the early feasibility trial design? I know that is expected to kick off this year.

Question about timing concept?

Just any trial design, how many patients, trial sites, just any kind of color.

That's still early phase. So we are now in the preliminary design phase of the concept itself. So that's the phase we are now.

Okay. And then -- do you -- can you talk about the design of the device? Is that still conceptual or you have...

It's so conceptual, yes. Yes. But I think it's clear, when you listen to Dr. Kent, the excitement, the opportunity behind. So there, the only thing I can say, and I think we are collaborating on this, we will move as fast as we can move also in making further developments. I think that's all we can comment at this moment.

Just two. One for Olivier, one for the clinicians. So for Olivier, have you said anything on pricing? Should we assume parity at this point? I know commercialization is still a year away. But since we're getting all these question -- you're getting all these questions on -- just curious on pricing. And then I have 1 follow-up for the physicians.

So pricing, you mean linked to the potential CPT coding in the U.S.?

Should we be thinking about your price being at parity to Inspire in the U.S.?

I explained the 2 potential scenarios that we are exploring, yes. So in both scenarios, it would be a comparable price. There might be an uplift depending on what direction we go, especially when we talk about modifiers. But for us, the aim is we align on price with competition, and we differentiate driven by our technology.

And then I'm just curious, we've been getting a lot of questions on tirzepatide, Mounjaro. Eli Lilly is doing the clinical trial for sleep apnea. Results are coming early next year. Do you see this as competitive or potentially complementary if you -- if patients are able to kind of lower their BMI? You see more -- and is the mechanism of action different in these patients? How do you think about -- I don't know. Just curious. We're getting a lot of questions on this.

I'm always profoundly excited for patients when they can lose weight. I -- this sort of general line that I give people is the probability of our surgical therapies [indiscernible] can go up as your weight goes down. And so it's -- I would -- I send a lot of patients out for consideration of this medical therapy with our weight loss providers. I am really not concerned about it affecting my patient flow and eligible candidates for therapy. One, as you heard Maria say, it's probably somewhere between 30% to 50% of people that have sleep apnea that actually aren't overweight, and they can lose a whole bunch of weight and they've still got sleep apnea, but now it's actually much more amenable to surgical therapy. And with even a baseline number of 500,000 to work with in the -- per year in just sort of the eligible candidacy criteria that we have already, that's a lot of people to treat. So I don't think that it will blunt the potential for these therapies.

And I agree with you. And in terms of sleep apnea, the more we treat sleep apnea, the more we realize how complex the disorder is. It's not everybody sleep apnea is exactly the same. And so that's why we're talking about combination therapy. That's why we talk about phenotyping with patients. And so there is -- the more variety of options people have, the better the outcome is going to be for every therapy. When you talk about outcomes for hypoglossal nerve stimulation, like Dr. Kent mentioned in weight loss treatment of -- insomnia treatment of other things will make our outcomes better.

Also, I want to invite you for the [indiscernible] after this. But maybe 1 thing, because most of you also listened yesterday to the earning call. So after the earning call, the team and I, we were sitting together, and there was 1 person who was really disappointed. That was our CFO. He was saying, an entire earnings call, not 1 single question on finance, nothing. Now we do an Analyst Day. I know he was extremely well prepared, but not one single question. So maybe Jon or [ Larry ], please, one question and then let's have a drink for the CFO. Okay. Let's have a drink.

No, the simple question is -- the simple answer, sorry, is, yes, 65% mainly linked to volume. We are suboptimal in term of -- because we have low volumes at the moment. But we expect when we grow in term of volumes across Europe, but specifically in U.S., that we have gross margin above 85% longer term, and we're talking about 2, 3 years. Yes. I was expecting also some questions about the cash. So you've seen we have cash runway until mid-2024. And between now and mid-2024, we will be opportunistic in term of cash. And you have seen today, we have announced a private placement for EUR 50 million for some of our historical insiders. Why we are doing this, first because there is a lot of appetite at this moment to invest in the company, specifically given the stage of development, the delisting of DREAM where we have now [indiscernible] existing plans. And also, we want to avoid any overhang on cash. So we remain opportunistic there. We have an ATM in place for EUR 50 million. So that will be our strategy for the next 12 months. Now then in 2023 will be -- will slightly increase versus 2022, yes, because we have ACCCESS and DREAM, but it will remain below EUR 5 million.

Okay. Then I would really -- first of all, thank you again. [ Michaela ], can you maybe come and give physicians a small sign of recognition for making the time to be with us a little present. We try to be innovative in our presents as well. Okay. So let's go first. Okay. I will wrap. So please -- thank you. So with this, I think we can conclude the Analyst Day. Let's have a drink, take the opportunity to ask more questions, and thanks again for joining us. Thank you.