Lyra Therapeutics, Inc. (LYRA) Earnings Call Transcript & Summary

Welcome, everyone, and thank you for joining us for Lyra's Key Opinion Leader Event. We'll be making forward-looking statements today. Please refer to our current filings with the SEC to review our risk factors. We are very fortunate to have 2 distinguished guests with us today, Dr. Zachary Soler and Randy Ow, both are well-known experts in chronic rhinosinusitis. Dr. Soler is Associate Professor of Otolaryngology at the Medical University of South Carolina, and he's a practicing otolaryngologist at the MUSC Sinus Center. He is Global Coordinating Principal Investigator for our LYR-210 Phase III ENLIGHTEN program. Dr. Ow is a practicing otolaryngologist at Sacramento Ear, Nose & Throat and President and Chief Medical Officer of DaVinci Research. He was the Principal Investigator in the LYR-210 pharmacokinetic study. Also, we have Dr. Robert Kern here with us today. He is Lyra's Chief Medical Officer and is a key opinion leader and practicing ENT. He is also the Professor and Chair at the Department of Otolaryngology at Northwestern University. Before I turn the call over to our group of experts, I'll take a couple of minutes to introduce our CRS pipeline. Dr. Soler today will review the new 6-month follow-up data from the LANTERN Phase II study of LYR-210. This data was presented at the annual meeting of the American Rhinologic Society earlier this month. Next, Dr. Ow will present the full data from the LYR-210 PK study that he also presented at the American Rhinologic Society. Dr. Kern will then review our plans for the pivotal Phase III ENLIGHTEN study, and he'll share the Phase II BEACON study for LYR-220. After that, we'll open it up for questions, and we've reserved the majority of the meeting for Q&A today. [Operator Instructions] Each year in the United States, 50% of patients treated for chronic rhinosinusitis fail medical management. That's equivalent to about 4 million patients annually. Their next line of treatment is an invasive surgery or repeat surgery. In response to that substantial unmet need in patients who fail treatment, Lyra has leveraged our proprietary XTreo platform to develop 2 product candidates, LYR-210 for surgically naive patients and LYR-220 designed for the post-surgical anatomy. We've now demonstrated in 3 separate trials both safety and efficacy of our lead product LYR-210. We're also pleased to report that we remain on track to initiate 2 clinical programs very soon, the LYR-210 ENLIGHTEN Phase III pivotal program and the BEACON Phase II study for 2020. Dr. Kern will provide updates on these programs a little later in the presentation. CRS patients who enter an ENT's office fall into 2 categories, those who have never had a surgery and those who have had a surgical intervention and continue to require medical management. LYR-210 is designed to be used early in the treatment paradigm after topical steroid sprays have failed. We estimate this population to represent about 2 million patients in the United States each year. The market opportunity for 220 is just as significant at about 1.6 million patients each year who continue to require therapy despite having had a surgery. 220 is designed to fit the larger cavity of a patient who has had an operation. As you can see in the chart here on Slide 5, the vast majority of these patients do not have a CRS-approved drug. Recent marketed products only target the treatment of polyps. It's a small fraction of the overall CRS market. As a result, there are millions of patients each year that are undertreated and continue to struggle with debilitating symptoms from their CRS. In this disease, the treatment obstacle is not finding an appropriate anti-inflammatory drug. Steroids are the established foundation of treatment for CRS. However, the issue is that to date, there has not been an effective method to deliver the drug deep into the sinuses at the nidus of the disease and the way to maintain a high dose of drug locally over time such that the disease can be modified. LYR-210 and LYR-220 are designed as small matrix implants that are placed deep in the nasal passage at the central region of the disease as we show on the figure here to the right. This has done through the nostril in a noninvasive procedure in an ENT's office with just topical anesthetic. Dr. Ow will show you an actual placement in a few minutes. Once in place, the matrix releases a known anti-inflammatory steroid mometasone furoate, released consistently over a 6-month period after just 1 administration. LYR-210 is designed to sustain a therapeutic dose of the steroid right where it's needed for a period of 6 months to affect the disease and to improve patient symptoms. We'll now move to the presentations by the physicians. But first, I want to state that neither Dr. Soler or Dr. Ow are employees of Lyra Therapeutics. They have been compensated for their time in relation to this event. All opinions expressed by these physicians belong to Dr. Soler and Dr. Ow and do not necessarily reflect the opinions of their affiliated institutions. Dr. Soler, maybe you can start off with a bit of your background and an overview of your practice?

All right. Thanks, Maria. So for the next couple of minutes, I'm going to focus on data from the LANTERN study with an emphasis on what happens in the 6 months after the implant is removed. As a bit background, my name is Zach Soler. I'm an Associate Professor at the Medical University of South Carolina in Charleston. My clinical practice is focused almost entirely on patients with chronic sinusitis. From a research standpoint, my expertise is in outcomes research, specifically in outcomes after sinus surgery. So this is an area of real interest of mine. So let's just dive in. I think most probably have seen results from the LANTERN study. This was the Phase II study that looked at LYR-210 compared to a sham control. And what I wanted to focus on first is the SNOT-22 data. As a clinician, this is really what's interesting to me and to my patients, for those who aren't familiar, the SNOT-22 is a quality of life instrument. So it captures how sinus disease impacts the patient and how they feel. And it's really what guides decision-making. So this is really kind of the core of what's interesting to me. And if you look at this graph here, this shows sort of what happens in the 6 months after LYR-210 is placed. And there's a couple of things I wanted to point out. First, is just to look at how robust the changes are. So if you look at -- it's about a 40-point improvement from baseline to about 6 months. And to put that in context, that's a really significant change. Really, that's equivalent or maybe greater than what we see across surgical cohorts and even most of the biologic studies that have been published. So that's number one. Number two, just to focus on sort of the durability. So when you give somebody a burst of oral steroids, you'll see a big improvement for a couple of weeks and then really by a month or 2 that has worn off. But what you see here is really durable improvements up to 6 months. And then the last thing to point out it's just a difference compared to the placebo control. You see a difference of about 19 points. So to put that in perspective, that's really twice the minimal clinically important difference. So a 19-point difference is quite large. So that's something that's both clinically relevant and actually it's pretty easy to show statistical change. So that's a pretty small sample size that you would need to show that kind of benefit. So that's SNOT-22, but let's look at the cardinal symptoms. So the 3 cardinal symptoms are those classic symptoms for chronic sinusitis patients. So we're talking about nasal congestion, facial pain and pressure and nasal drainage. And these 3 are of interest really to the FDA because the FDA is focused on these kind of symptoms specifically. And really, what you'll see here is basically the same thing we saw with SNOT-22. You see a really robust change at 6 months, you see a durability and you see a big difference compared to control. So the cardinal symptoms really are very similar to what you saw with the SNOT-22 data. So that's the LANTERN study, that's what we saw at 6 months. But then the question is what happens once you take it out? So once the implants removed, what happens in the next 6 months after that? And that's what this follow-up study looked at: looking at safety, rescue treatment, cardinal symptoms. So on the left of here is what of the data I just showed you and on the right is the post-treatment period. And if you look at the control group, that's the group that's in gray here, you see what you expect to see, which is worsening over time. So since they didn't have active treatment, their disease worsens over time, their symptoms start to worsen over that period of 6 months. If you look at the LYR-210 group, you see durability or even some improvement that happens in the weeks and months that follow implant removal. So this is a pretty big distinction compared to something like Dupixent. If you look at the dupilumab data from their study when they took patients off in their open label and followed them for 6 months, you saw a really significant worsening of those patients and almost back to where they were baselines. So that -- after -- once you stop giving them that treatment, basically, they're no better. And that's really important, and that factors into how I discuss that with patients. So when somebody comes in and we're talking about putting them somebody on the biologic and say, "Look, once this comes off, you're going to be back to where you are. So this is kind of something you have to be on forever or at least for the foreseeable future." Whereas what we see in this data is in the LYR-210 group, although the average main patient had durability, it's a mixture, right? So there's a group of patients who have -- about half that have a durable response and there's about half that actually worsen over time versus controls where they most all worsen. And this really makes sense clinically because we know that chronic sinusitis is a heterogeneous population. And the LANTERN study was fairly lax on who was in there. So you had patients with and without polyps, et cetera. So it's pretty much a real-world experience. And we know there are some patients that have type 2 disease, they have chronic inflammatory. They're not going to cure those patients. It's about control. They're going to need something like LYR-210 on a regular basis. But then there's a group that are going to do well and potentially 1 device, 1 implant may be what they need to then have a long, durable response. So at this point, I'm going to hand things over to Dr. Ow. He's going to talk about the PK data. This was actually presented at the ARS really recently. And he's also going to talk about real-world experience since he has personal -- probably the most personal experience of anybody in the U.S. of actually placing this in a patient.

Thank you very much, Dr. Soler. My name is Randy Ow, and it's my pleasure to be presenting the LYR-210 pharmacokinetic trial data, a study that I was 1 of 4 U.S. sites that participated in. I am a general otolaryngologist in practice in Sacramento, California. My practice is a full-time ENT practice, seeing patients with cerumen, patients with trauma, cancer and sinuses. I don't focus on any one area. But what I'd like to say is that I do a lot of clinical research, but 90% of what I do is what my colleagues across the country do. The next slide shows the study design of the LYR-210 study. As I stated earlier, it was done at 4 U.S. sites and 24 patients were enrolled to receive either LYR-210 at 7,500 micrograms or LYR-210 at 2,500 micrograms. They were divided into 12 patients into each group. They all have to meet diagnostic criteria for chronic rhinosinusitis, and they all had never had sinus surgery. Patients were implanted for a total of 56 days. And at 9 specified time points, blood was sampled and mometasone concentrations in their serum was measured. Of the 24 patients, all were successfully and bilaterally implanted, so a total of 48 implants were placed. One patient experienced a premature early extrusion, but that gave a 96% retention rate by day 56. The next slide shows the key data that was obtained from this study. It's quite amazing to me. I didn't know these results until quite recently. But the steady states were achieved very quickly, and they were maintained over the entire 56 days. The upper red line shows the LYR-210 7,500-microgram plasma levels that reached a steady-state concentration of 41 picograms per milliliter. And the lower blue line shows the LYR-210 2,500-microgram implant that shows a very tight steady-state concentration. And it is, I think, important for me as a physician to see that a concentration of the drug that's measured in the plasma doesn't fluctuate greatly, and I think that's what these 2 data plots show very clearly. The next slide shows some of the clinical data or clinical symptoms that we monitored our patients for throughout this study. And again, realizing that we only had 24 patients, it's not a large study, but the SNOT-22 patient-reported outcome survey was applied to these patients at several time points. And what we see is an amazing decrease in the disease burden measured clinically by this survey over the 56 days, and this is a combined group of both doses, but the p values are highly significant. You can see them at each time point. A 1/3 of the patients reached the normal SNOT score by the end of treatment, and almost 2/3 of the patients reached a SNOT score of less than 20. I do want to point out that in contrast to the LANTERN study that Dr. Soler reported earlier, the entry baseline SNOT score of the LANTERN study was about 68. This study showed a patient population which met with quite a bit less disease burden. They entered at with a SNOT score of 38. So it appears to us that even in this small population, LYR-210 at both concentrations can be significantly beneficial for patients even in the mild to moderate amount of disease. The next slide shows a patient that I implanted in my office. And I want to say, again, I feel like I have a very average ENT practice, very busy. I do a lot of office procedures. And of all the procedures I do in the office, especially rhinologic, I was extremely pleased that this one was so simple and efficient to perform in the office. And I think even without showing or narrating what I just did in this patient, you could see a LYR-210 implant deployed easily, accurately and what appears to be very comfortably into the space that it's meant to occupy and deliver drug to the tissues and surrounding sinuses over, hopefully, in clinical use 6 months of treatment. Going into this study, I had no idea what I was in for or what the patients were as far as how easy it would be for them to tolerate the implant. I was very concerned as to whether or not an implant that was put into this space would stay in place for 56 days, and I didn't know if I'd be able to find it or retrieve it very easily if it was able to stay in place. And what I was surprised to find throughout the study through all 13 patients that I was fortunate to treat was that they experienced symptomatic improvement in their sinus symptoms. And at the end of the study, all 13 of my patients had all 26 of their implants retrieved without any incident or problem. So I was very pleased with the experience I had with LYR-210. Again, this was my first experience and the first experience in the United States. The patients tolerated it very well. I feel that this will be a very successful program. But Dr. Kern will now discuss the future plans in the clinical studies that are up and coming. Thank you very much.

Thanks, Randy. My name is Robert Kern. I'm the Chief Medical Officer of Lyra Therapeutics, and I'm also the George A. Sisson Professor and Chair of the Department of Otolaryngology at Northwestern University. I've been a practicing rhinologist for 30 years, it means I take care of patients with sinus problems medically and surgically. And I also have the pleasure and honor of working with a large team of investigators here at Northwestern. We have multiple NIH grants and clinical trials going on at all times. And I joined Lyra Therapeutics because I think their products have the potential to really make major changes in the way we treat patients with sinusitis. So let's talk about the LYR-210 Phase III program here. As you can see, 350 patients divided between 2 staggered studies slated to begin later this year. The single primary endpoint of 3 cardinal symptoms, we're also tracking other endpoints. It's largely similar to the Phase II LANTERN study. And the LANTERN study had really been very successful. The change -- sinusitis is a quality-of-life disease, and the change, the improvement in quality of life is similar to what you would see at 6 months with surgery. And also about the LANTERN study that was presented in our spring meeting, and it won the award for best contribution, best research contribution. And in my 30 years as a rhinologist and a member of that society, I can never recall an industry-sponsored project ever winning that award. So that's quite an accomplishment. Can I have the next slide? Now we don't talk very much about LYR-220, at least we haven't so far. But if you look at the graph in the middle here, it's about 4 million patients who fail standard medical therapy. And of those, about 60% have never had surgery before and that's 2.4 million. Those patients would be candidates for LYR-220. Now patients who have had prior surgery, the other 40%, they can still fail. Almost all of them need ongoing medical therapy, but sometimes even a combination of surgery and ongoing medical therapy fails. That's about 1.6 million patients or 40% of our target. Now those patients, if you use LYR-220, it really wouldn't fit very well that the -- after surgery, there's a large space created. And so the LYR-220 is really same drug, same dose, but it's a larger matrix to more readily conform to this new size. So we can take a look at the next slide, please. Now this is the BEACON trial, which is slated to begin in November next month. This is a Phase II trial. The primary endpoint here is safety and feasibility of 24 weeks, although we will be tracking all the same endpoints that we are in the Phase III for 210. It's 3 arms, 2 slightly different matrix designs and in a control. Now we're very optimistic that this data where we will be able to leverage the LYR-210 data with the 220 data. And so we're optimistic that we can achieve an expedited approval for 220. Can I have the next slide? And here's basically the study design here: randomized trial, 3 arms, the sham and the 2 different designs for the product. At this point, I'd like to open it up to any questions. I'd be happy to answer, either myself or one of the other KOLs on the call would be happy to address whatever questions you have.

[Operator Instructions] The first question we will take is from Tim Lugo.

This is Lachlan on for Tim. I just wanted to dig in a bit more on the durability though, I think, after removal of LYR-210. Should we expect that would be sort of maintained permanently? Would you expect those patients will, at some point, require another dose? Or are we looking at sort of potentially no longer needing surgery or anything more in the future? And then for Dr. Kern on the LYR-210 expedited pathway, given the similarities -- sorry, the 220 pathway, given the similarities with 210, would you expect to be able to file based on strongly positive results of BEACON or would you still expect to need a Phase III, but maybe only 1 instead of 2?

Well, I'll answer first. That's -- we're obviously not sure, but we're optimistic that given the fact that it's the same drug, the same matrix that we will be able to label that -- it's really just a different size of matrix. So -- but we'll see. I mean you offered 2 options or basically 3 options there that we have to do 2 trials, we can get away with 1 Phase III or maybe 0. I think we're hoping for 0, but that will depend on many things that haven't happened yet. The other question I think you had was maybe -- I mean we could all give our opinion, maybe Dr. Soler would want to be -- go first, if you want?

Sure. I mean you asked if we anticipate that some patients would need more than 1, meaning they would need an implant, say, every 6 months versus just 1? I think the answer is, I think it's going to depend on the patient and their underlying pathophysiology. Chronic sinusitis is not short of one single disease. We know there's a group of patients who have sort of chronic inflammatory disease and for those patients I think repetitive doses, whether it's every 6 months or whether they need it at some period of time is probably going to make sense, where I think there's another group of patients where the data certainly suggests that it may be 1 sustained treatment gets them to the point where they're controlled such that they don't need any treatment or maybe they just need steroid nasal sprays moving forward.

Randy, do you recall any comments from the patients in your study about when the trial was over, whether they would want another one or what? Maybe -- I mean you have the real world experience here. So...

Well, yes, so I had 13 of the 24 patients in the trial. So I got to kind of see how they did through it. And what I was impressed with was a lot of them did comment that they were starting to smell or sense things that I don't typically ask and even the SNOT-22 doesn't ask for. So it is a quality-of-life disease condition, as you pointed out. But they would say things that I feel more open, I -- they sense -- a sense of well-being in their head and their sinuses that I think those of us who aren't sufferers may have a hard time grasping. So my relation with these patients is, I relate to them when I get that viral URI. I feel miserable. I don't like the feeling. I can't wait till I get better. And I see these patients as suffering that, fluctuating over months at a time without relief. And what I saw in these patients was that, yes, the smell seem to change or improve. I think sometimes it wasn't totally pleasant smells, they could smell things that they couldn't smell before. And I think as the steroids work on the mucosa high in the nasal cavity where we are afraid to operate because of complications that the medical treatment kind of gets to that problem quite nicely. So a small group of patients, but the overall response was positive. And there were a couple of patients who -- they knew it was a study, but they did say, "Can I come back when this is available?" Because I think from my point of view and their perspective, seeing me or an ENT twice a year for this type of treatment was a huge positive experience over daily use of nose sprays, daily use of irrigation. And we don't know what it's going to supplant, but this is just early experience that's quite positive and new.

I think that to try and answer that question more globally, I think there's going to be a range of responses. Some people with milder disease are going to essentially be cured. And they may have a -- from what we can tell, about half of them will have a durable response. In other words, they'll stay cured. Other people with more severe disease will be improved. But even if it's durable, they're still not quite there. They're not happy. Those people will -- they'll want a little bit better. So you put another one in, and they will continue to improve. So I think there's a range of responses. The important take-home point for me as a clinician is you don't have to worry about a rebound effect. In other words, when the matrix doesn't have any more drug in it, it's not like the patients are going to boomerang back, which is what you see with -- certainly with the biologic products out there that are $38,000 a year. If you stop giving them, they lose everything. And I think that that's kind of what you would sort of expect with a steroid, slow on, slow off. Do we have any other -- wait, I got a question here. Can you please expand on why some patients have durability of response and others don't? Is polyps versus nonpolyps important? Is disease severity involved? Well, I sort of tried. I think disease severity will be involved because there are people who are better, but they still have symptoms. That's not uncommon. In other words, their SNOT-22, which is sort of a measure, isn't in the normal range. Normal person will have a SNOT-22 less than 10. So we can -- we started with -- in the LANTERN trial with the average of 68, and we improved to 20 at 40. They're much better. They're very happy, but they're not cured. So yes, disease severity is going to matter. And we don't know exactly why some people have durability and others don't. We did not see a difference between the polyps versus nonpolyps, although we'll be able to weigh in more on that maybe after the Phase III. But we don't see a distinction there. I don't know -- I think that addresses everything. And please, others chime in there. I don't want to dominate the conversation here.

I think you answered it well and it's a heterogeneous, yes, population. It's impressive results. I don't -- to me, it's too early to say how durable or long term the treatment will be given what we know about these patients. So I think they'll need some ongoing treatment, but it was impressive to see lack of rebound and 6 months after removal, consistent symptom improvement. But they are -- I believe those patients, Dr. Kern, remind me, I mean, they were on daily saline -- they weren't maintenance free at that point, but they were on pretty standard maintenance therapy that seem to control their symptoms much better than they were pretreatment.

Yes, they all stay within nasal saline. And -- or not all, I think it was like 70% or 80%, but it was extraordinarily high percentage. So that's also part of it.

Okay. So the next question will come from with Bert Hazlett with BTIG.

I've got 1 or 2. Just with regard to the procedure itself, the implant and the procedure. Can you just describe how long the procedure took kind of soup to nuts preparation to actually insertion? And then do you have any -- we have the data from LANTERN with regard to how the outcomes were, with regard to the SNOT score and 4 CS and 3 CS. Do you have any anecdotal evidence about the patients, how well they tolerated the implant itself, either polyp patients or nonpolyp patients? Any feelings or sensations that were out of the ordinary?

Randy, why don't you take the first one there?

Okay. The question -- first question was, I guess, practically speaking, how long does this procedure take, run through it? So first of all, in clinical research, there's so much data being captured. It's not -- we're not speeding through as we would in a day-to-day practice. And I think your question probably leads more to how do I see this applying assuming FDA approval and it's out there for these patients? And I would say, I do all the sinus procedures that are on the market in office. And this is the simplest and I would say, quite frankly, the easiest. It would take 10 to 15 minutes to get this done in a patient that you had scheduled that you thought needed it. And that's whether or not you needed prior authorization to have the product in your office. But as far as doing the procedure, it's a very simple topical anesthetic in the middle meatus I would do this. I did not use any needles or injections and that implant that you saw, I mean, it actually was slow. It looked like it was in slow motion. It could be done in just a few seconds. So numb them up, decongest them, place it. This is a 10-minute office visit.

Yes. And I'll just chime in that. With a number of -- with sort of the shift that's happened in ENT to office-based procedures, just the average person is very comfortable with this type of thing of having somebody come in, spraying their nose, putting some topical or you maybe go to see 1 patient, you come back 10 minutes later, they're all numbed up, you put it in, out and they leave. So when it comes to comparing this to in-office balloon surgery or LATERA implants or whatever, this is pretty straightforward on the simple side. And I think would be something that pretty much all general ENTs would be comfortable doing.

Yes, I would agree. I mean it's pretty straightforward and pretty easy. 15 minutes, 10 to 15 minutes is a typical office visit. So it would -- it really would not slow down office management. I think the other question was more about tolerance from the LANTERN trial. And this was a question that I had at the very beginning when I became involved with Lyra. It wasn't even called Lyra back then, in 2015-'16. How well tolerated this product would be for 6 weeks? And it's -- I'm sorry, 6 months, which is extraordinarily well tolerated. And the patients are unaware. Even in the control patients is thought they had the product. So there really wasn't -- and no, they couldn't tell a difference. So this product is very well tolerated, and there doesn't appear to be a difference in the polyp or nonpolyp patients. So that isn't an issue. And patients are unaware that they have this thing in their nose.

I have one other question maybe for the company. But just with regard to 220, just kind of given the successful data that you have with 210, could you go on a little bit more about why -- what you're thinking about in terms of the matrix design differences? What you're trying to accomplish there? Is it really trying to maintain the implantation and the patients with the larger area you're trying to cover? Or is it something with the delivery or distribution of the active? Just a little more about the dual matrixes that you have with regard to 220 and how you're exploring those?

Well, there may really be no difference between the 2 products. The difference is relatively subtle, but placing the product in an unoperated patient is pretty straightforward. In an operated patient, every one of those sinus cavities is going to be a little bit different. And this is an attempt to see which is easier to place, which is easier to which -- whether they have the same performance and tolerance, there's a lot of unknowns with regard to that. So giving us 2 different devices, they are a little bit different in the way they're structured, we may see some differences. My personal bias is that they're not going to be much different. But we'll see. That's really the reason -- the main reason to do it.

Okay. Terrific.

I might add one comment. I remember realizing, I wasn't positive, but I had a sense that the first patient we had in the PK study was the first patient in the U.S. to be implanted. The engineer, obviously, the company was here. We got everything ready. We had the patient anesthetized. I put the delivery device in the middle meatus, and I slowly delivered it. And very quickly, it was in the correct place and my -- I remember turning to the engineer and piling at her and saying, what a beautiful design. I mean it was easy. And Dr. Soler and Dr. Kern are rhinologists, I am a general ENT and what Dr. Soler said, this is something that all ENTs can do and probably will adopt. But it conforms to that cavity in a way that I think when you see it, it's just intuitively perfect for the cavity. And that's -- that can be different with other experiences that you've probably heard. And I have had patients who've had other products that have asked after you put in devices, say that, "It's so uncomfortable and even though I want to see the end result, I kind of -- I'd like you to remove it." And that would -- I don't ever see that happening with this product because of how comfortably it fit. And that's why my first fear was it's sitting in there so comfortably, is it going to fall out when they irrigate or sneeze? And again, 26 of the implants that I implanted were there. I was expecting: this is a first trial, first design here, we're not going to find some come out. I mean some of the other products did. But this was there. And when I found them there, I worried that some would be kind of overgrown or stuck in place. So I've used some malleable nitinol metal implants and those are -- they're very strong springs and removing those from a patient after they've been in 2 months was extremely difficult for me as a surgeon and also the patient. And this kind of -- you could tell it wasn't going to move because you had to wiggle it a little, and then it just slid out. So I wish we had an explant, but to me, it's doing what it's meant to do and to see the clinical data, the PK and the clinical improvement, I was -- I'm really happy to be involved and I look forward to seeing how this is going to change the way we treat our patients.

The next question we have comes from Chris Howerton from Jefferies.

Great. I think Dr. Kern and I had a little bit of a webcast problem, but you read one of my first questions. But the second question, second and third question that I had is, if you would indulge me is, how do you think about treating a patient on the severe end of CRS with either 210 in the situation where it would be commercially available versus surgery? What are the features or clinical presentation of that patient that would shift you one way or the other? And then I guess just from a very kind of like CRAS modeling perspective, can each of the physicians estimate what percentage of their CRS patients they would use 210 on?

Well, okay. Well, I'll go first. I don't think severity in terms of -- I mean how do you measure severity? Well, the most common way is that's SNOT-22. If their numbers, we've already treated 68 is very high. That's much higher than the biologic trials. They're at least 10 points lower and more in some cases. So we can reach into the far end of this. As long as we can insert it without a problem, there is nothing wrong with trying. Now that doesn't mean it's going to work in everybody, but it just means that severity would not dissuade me. It's -- I think the majority -- and the answer to your second question, I think the majority of CRS patients would be a candidate -- the vast majority would be a candidate for 1 of these 2 products. 4 million that the number that we presented is a conservative number. The number could actually be larger. But just going with that, I think the majority of them would be candidates. The only patients that really would not would be those patients with massive nasal polyps that you can't readily insert the -- and that's -- maybe of the 4 million, that's maybe 100,000. So the rest of them, it's obviously a discussion between the doctor and the patient, et cetera, et cetera, et cetera. But I think that it's conceivable that all of them would be candidates. And then there's an unknown number, which I alluded to that maybe we're not capturing with the analysis, the one that comes up with 4 million. I don't know, but please, again, the other KOLs should chime in.

Sure. I'll just chime in. I think sometimes people think about like, let's say you have somebody with cancer or something, you basically say, "Look, this is what you need to do. You need surgery followed by chemotherapy or whatever." But the vast majority of chronic sinusitis is a quality-of-life issue. It's not life-threatening. You don't technically have to do anything. So really patients have options. And when you talk about someone who's failed medical management who is potentially at a point where they might be a candidate for surgery or something. That's where you get to the point where you say, "Look, we've tried the basic stuff, you were on some antibiotics and some steroid sprays and maybe you did an oral steroid course and that's not working." And you say, "All right, we can put an implant in like 210, we could do surgery, et cetera." You lay those options out to people and through decision-making, people come to the option that fits them. And you'd be surprised there are certain patients who say who are so against surgery they almost live their life miserably. And then there's other patients who they're like, "I want to do surgery tomorrow. So I think LYR-210 is going to fit. It's going to be one of these tools in your toolbox. And I think it's going to appeal to a lot of patients because one, the results are positive, are really significant. It's so easy to do in the office, and it's a 6-month thing. So I think you're going to -- it's positioned right there at that point where I'm about to have that surgery discussion, and I say, "Hey, you're a candidate for surgery. There's one other thing that you could think about, it's this implant." And I think there's going to be a lot of patients who that makes a lot of sense to. So it isn't like I'm going to tell them exactly what to do. I'm going present this to them and then based on life and circumstance and their goals, et cetera, they're going to choose one pathway or the other.

Yes, I agree with everything that's been said. I guess the one caveat that I see in my practice is if patients who are presented with that surgical option as well, if you look at, well, what do you have to lose by trying LYR-210? You don't have much at all. The one thing I think that would probably sway my guiding a patient is of the 4 cardinal symptoms that they come in complaining of, obstruction is probably the one that drives most of their desire for treatment. And if they had a severely deviated septum or very large turbinates, I think I know that surgery would help that. And I might be inclined if they're really someone who's struggling with obstruction, unilateral you see the structural problem. I don't feel that LYR-210 would address that. I would probably lean towards saying we can get the obstruction with surgery. And the question then is do we just straighten up the septum and not do sinus procedures or do you kind of get them through that surgery, including a sinus procedure at the same time is what I see. But I think it's going to be a great offer or option for us to discuss with patients if all the trials are successful.

The next question comes from Ashwani Verma from Bank of America.

I just had a quick one. So just trying to understand from a retention standpoint, 220. So we know that in a -- when surgery is done, the nasal cavities enlarged and you are using a bigger matrix size here for 220. Just -- does that fit on the contours of the enlarged nasal cavity? Or how can we be sure that the retention would not be an issue similar to 210?

Well, let me answer or take that first. I mean the nose -- the nasal cavity is not enlarged, the sinus cavity is in enlarged. So the middle turbinate will still be there. So there's a space, and we're putting the product in that enlarged space. When it hasn't been operated, it's a slit. When it's -- when you take the ethmoid sinuses out, there's a larger -- basically, the way to look at it would be think of an egg crate. When you do surgery, you take out the partitions between the eggs. So if you were to put 1 in egg in there, it might flop out. But if you put something large in there, it would fit more snugly and be retained and also it would touch all the surface area so that you can deliver the drug. That -- I mean, this is where the competitor device SINUVA, what they do. They put it in the cavity and it's a fairly large device. Our device will be much more -- how should I say? Space-friendly and -- but it's a similar idea. You need a larger product to fill the space. But the other KOLs, please feel free to weigh in.

I mean my understanding is that 2 different designs have slightly different -- there's sort of more spacing between the edges. So one has a bit more surface area to contact the edges, one has a bit less. And it's not 100% clear which one, if you -- if there's a difference in retention between one versus the other. But I think to me, I don't think it's going to be a major issue. I think there are some patients who structurally have had such severe surgery, they've had so much middle turbinate resections, et cetera, where it's not going to be an option. But for most people, most surgeons do a relatively conservative surgery the first time. So they most -- for the most part, the middle turbinates are intact, et cetera. So I think at least for my patient population, I think the large majority would be still candidates for something like 220.

So I'm going to one thing that I thought about when I was implanting these patients. I see my wife and women in the family wear clothing that they seem to love. And I don't own Lululemon, but they seem to love to buy Lululemon and they say it feels great. I think, "Oh, that costs a lot.," but they say, "No, it feels great." Last Christmas, I get my first Lululemon, I put it on and I'm like this feels great. It feels comfortable, it feels snug, it's not tight. I love the way that feels and I don't know how to explain it, but that's when you see the implant go into the 210, I only have experience with 210 , that's what happens in the middle meatus. You could tell that it's touching comfortably, gently, not too much. I mean they didn't dislodge 1 out of 46 and not too hard. I was able to remove it. So it's a comfortable fit. My understanding of this XTreo, the engineering behind the polymer is that it self expands to fit spaces and expanding -- what it does is it expands. And I think for those of us who have used other products, they disintegrate fairly quickly, and there's no expansion to them. They either stay or they fall out or they fragment. And this -- it was completely intact at 2 months in the study I was at. It's meant to go 6, but overseas, it was removed at 6 months. But I could not tell that there was a change in the integrity of the device. I mean, it almost looked like I just placed it, it was snug. I did have to tuck it a little, but I'm sure that the design of the 220 is meant to be something that will stay in place comfortably for 6 months and deliver drug to that operated sinus for 6 months.

Yes. And maybe I misunderstood the question whether it was -- if you wanted us to kind of differentiate the 2 implants. I think that for the 220, I think that -- again, my bias is they're not going to be much different. But one maybe be a little easier to insert, it may conform to the spaces more readily, it may be better tolerated. It may be -- it gives us essentially 2 bites at the apple, but they're very similar. The drug dose is similar. The weave pattern is a little more dense in one versus the other. And so it's really -- and how should I say to give us a little broader experience that there might be some distinction that they would -- may make us like one versus the other. But I think that the efficacy results -- again, I'm not a betting person, but I think they're likely going to be very, very similar.

Okay. That concludes our audio questions. I will hand it over to Maria for any of the webcast questions.

Thank you, Macy. Yes. So we do have a question here. I'll start with this one right here. We have a few minutes left. There are many treatments for polyp patients. Can you comment on how you manage the nonpolyp patients? The nature of the unmet need in these patients? And how can LYR-210 address the nonpolyp?

Yes. I mean I'll start real quick. I mean nonpolyp group has been the one that's been ignored. And I think the reason is it's a bit -- polyps are -- they're easier to identify, the CRS group without -- is a little more heterogeneous, but the reality is that most of the treatments for polyps group were basically coapted from something else, right? They weren't designed for polyps. They were just designed for something else and people realize that they might work for polyps. So it's been a group that's been ignored, but it's -- by a much larger group than the polyps. I mean people estimate, you can argue about these numbers, 10% to 15% of U.S. population has chronic sinusitis, but only 1% to 3% has nasal polyps. So it's a much larger group. So in my mind, this is -- what's exciting about it is that we actually have a product or potentially will have a product for this patient population.

Yes. I mean it is -- the real unmet need, completely unmet need is for the nonpolyp group. It's larger, and there are no FDA-approved drugs for it. We still give a lot of antibiotics for this problem. They don't work well. They have side effects. So this is where the game potentially could really be affected, the CRS paradigm. And the link of sinusitis even in the nonpolypoid one is kind of heterogeneous as Dr. Soler alluded to, it's all inflammation. That's the common pathway and steroids are the best, most effective, broadest anti-inflammatory agent, safest anti-inflammatory agent we have out there and delivering them locally makes perfect sense.

I guess I'd just reiterate, there are no -- for all the patients that come in with chronic sinusitis without polyps, there are no FDA-approved treatments. We -- everything we do is off-label. It's well studied, widely studied, but there is nothing out there and doing lots of research like my co-presenters. I mean there is a lot of research being done. A lot of companies looking for that, that indication. There's a lot of sufferers and we need things studied, indicated and out there for us to use.

Thank you, Randy. There's one other question here. We have a couple of minutes. So why don't we take this one, too? How does the efficacy data from the PK study, which shows a benefit in patients with more mild disease, what does that mean in terms of positioning the product? Can you see LYR-210 moving even early on the treatment paradigm?

Okay. So I guess the first thing I would say is I realize that is a small group of patients, 24 patients. But the responses were -- they look remarkable. It was a group that had less disease, but this PK study wasn't designed to look at an effect on a severe disease patient. It was to look at the serum levels, are they safe, which they are. So it does show a broader effect that does hint or clue in that this product could be used potentially in patients with lesser amounts of disease. And I think there are so many factors that will come into play. What's the cost of the product? But again, a 10-, 15-minute procedure, that's cost effective twice a month in the office, I think could move way up in the treatment paradigm of these patients. It's like you think of what else we use off-label, once every 6 months come into our office and have a quite a simple procedure done, easier than going to the dentist. I think it needs a lot more study though. I mean this was a small group of patients.

Yes, I mean, I think of it less about where does it fit in the paradigm and which patients will then choose that. So I mean there are definitely a group of patients who have disease, but at this point in time with your options with you fail basic medical treatment is surgery or nothing or just continuing what you're doing. And there is a group of patients who -- what you said, they're not bothered enough or they're not bothered severely enough that at $15,000 surgery in the recovery and all that sort of stuff makes sense to them, where something like this definitely would. So I think there is a group of patients who aren't being treated. I mean, for example, when we hang up here, I have to call somebody who very much has had disease for a year, but she just -- she's had a bad experience with another surgery, not for sinuses, but for something else, and she can't bring herself to do it, and she has no other options. This would be an option for somebody like that.

Yes. I mean, I agree. I mean the point -- the take home from that PK study clinically is that we can treat the full range of the problem. In other words, even when people have lesser degree of disease, we're still seeing a measurable substantial response. If -- the really -- this is a way of asking, could we see the product being "first line therapy" is -- now first line therapy or nasal steroid sprays, even though they're off-label and saltwater rinses, could this position ahead of that? Well, I mean if costs were not an issue, and as from a -- if I wore my patient hat, and I do have sinusitis, as a matter of fact, I would prefer the product rather than using nasal sprays or saltwater rinses once or twice a day. So -- and I see my dentist every 6 months. So why wouldn't I do that? But that's not really -- we're not at the point of having that discussion. Right now, we're trying to establish in a Phase III, how effective this product is. And I think we have every reason to be extremely enthusiastic about our prospects.

I mean you actually bring up something that we haven't really talked much about, which is patients who are controlled on a certain regimen, whether it's a steroid rinse or a nasal spray on a regular basis, but either don't like doing it, can't be compliant or whatever and would potentially prefer to switch to something like this every 6 months. I mean we haven't even talked about that, but I just know from experience that is a group of patients that I have that something like this would be -- because it's a quick, easy, onetime thing, and I need to see those people every 6 months anyway, that it would make sense rather than them not ever using their medications and then becoming uncontrolled repetitively.

Yes, nasal sprays, I don't know, I'm sure many on the call have used them, they're unpleasant. And they cause bleeding sometimes, you have to remember to use them. There's a lot of negatives. But that's maybe beyond where we're really focused right now it is beyond where we're focused right now, but it's an interesting discussion.

Great. Thank you, Rob, it's a little after 3. And I do want to make one comment about 220, there are some questions around the 2 designs and how they may work. The -- we're -- as a company, we're really careful to not make too many assumptions around which design will work in the patients. I think we have to put them in the physicians' hands, and we have to see. And our objective here is to make sure that with 220, we don't make assumptions that we have 2 what we think are really good options. Perhaps they both will be shown to be effective. I think that will be great, but there may be one that physicians like more. And it really speaks to the versatility of our platform that we can make it more open, telling more [ close sale ]. And I think we're really excited to see in the BEACON study how each design will perform, and then we'll move forward with the one that we get the best feedback from. So I know we've gone a little over, I want to thank Dr. Ow, I want to thank Dr. Soler and Dr. Kern. This has been a great discussion. We're looking forward to your involvement also in the ENLIGHTEN pivotal program and continue to help us as we continue to develop products in the CRS space. I'd like to thank the audience for participating, and please enjoy the rest of your afternoon. Thank you. Bye-bye.