Good morning, everyone, and welcome to Verona Pharma R&D Day. It's a pleasure to be here in person after a couple years and see everybody on this rainy New York day. Welcome to you. Welcome to everybody on the webcast as well. I'm Dave Zaccardelli, CEO of Verona Pharma, and what we'll do today is spend some just a few minutes grounding us in our presentation on ensifentrine, but more importantly, have the opportunity to hear from two amazing physicians treaters of COPD and KOLs. Very happy to have Dr. Igor Barjaktarevic with us today, as well as Dr. Jill Ohar. You won't have to hear too much from me, but we'll spend much of the time hearing from them and their views on ensifentrine. With that, I just wanna spend a few moments on having everyone really understand the landscape of COPD with regard to treatments. Really, the takeaway message on the slides is while there appears to be a lot of medications available for end users with the inhaled route of administration for COPD, it's really just three classes of drugs which have been used for decades to treat COPD. That's the LAMAs or long-acting muscarinic antagonists, LABAs, long-acting beta agonists, and inhaled corticosteroids. Really every product out there is either a single or combination of these agents. With this treatment, which has been, again, quite consistent over decades, there. In the U.S., there's still at least 1 million patients that are still symptomatic and need additional therapy. That's why we're very excited about ensifentrine having a novel mechanism of action. COPD also is a very large market. There are, of course, millions of patients, even in the U.S. and many more worldwide that have COPD. Something to keep in mind, in the U.S., most patients are treated on either a single, typically a LAMA or a dual therapy. Most patients with that need additional therapy because they remain symptomatic. When we look at ensifentrine and its mechanism of action, keep in mind it acts in three specific ways, which again makes it unique. One is, as a phosphodiesterase 3 and 4 inhibitor, it has effects on bronchodilation, which has been shown in numerous clinical studies. It's an acute bronchodilator, and that bronchodilation holds up over weeks of treatment. It also has anti-inflammatory effects, primarily through PDE4 inhibition, although there is crosstalk between PDE3 and PDE4. It also affects the CFTR, increases ciliary function, increases mucociliary clearance. You can imagine a product that has bronchodilation, anti-inflammatory activity, and increases mucociliary clearance could be used in various respiratory diseases. Although we're focused on COPD, you'll see as we present today, there are many opportunities for ensifentrine in other diseases. When we look at why we're confident and why we went to a phase 3 program with ensifentrine, it was really grounded in all of our clinical trials, but also specifically 2 large phase 2 trials, study 203 and 205. 203 was ensifentrine as monotherapy. Study 205, ensifentrine, on top of background therapy, in this case a LAMA, tiotropium. Really the takeaway message when you look at the effect of ensifentrine after 4 weeks of therapy on lung function via spirometry, you can see serial spirometry over a 12-hour period where in both instances, ensifentrine increases FEV1, and it's measured by peak FEV1. It happens quickly and holds up above the control group over the dosing interval. From these studies, of course, we determined effect size, variability, and really honed in on our primary endpoint for phase 3 trials, as you'll see. Very important studies, over 400 patients each, a very consistent performance on lung function. In addition to that, which was impressive enough, it also over a four-week trial showed very consistent improvements in symptoms and improvement and quality of life improvement. This, and just a snapshot of this data, you can see in study 203, a measurement of symptom relief by the E-RS score, improvements that happened fairly soon under treatment, about a week, continued to improve over the four-week duration while on ensifentrine. We did see that improvement for quality of life via the SGRQ in study 205. Again, improvements happening relatively quickly and improving over the four-week study duration. Our improvements on lung function as well as improvements in symptom and quality of life was really the cornerstone of us moving forward into phase 3, and we built off of this confidence in two large phase 2 trials. We talk a lot about efficacy, which is important and really a reason we move forward. Equally important is the safety we've seen with ensifentrine in the clinical development program. As noted here, it's been studied extensively, 19 clinical trials, close to 1,000 COPD patients. Really what we're seeing is that ensifentrine has a very favorable safety profile, very comparable to placebo. We don't see really any dose-related AEs. Specifically when you're looking at PDE3 and PDE4 mechanisms, you wanna look at gastrointestinal AEs through the PDE4, and we see that's very similar to placebo, c ardiovascular AEs via PDE3, and again, very similar to placebo, including a successful thorough QT study, which really looked at conduction after giving super therapeutic doses of ensifentrine with no effect on conduction. We are very comfortable with the safety profile seen to date over four-week studies. Really something to think about and take home is the benefit to risk that is emerging with ensifentrine. When you have efficacy at the level we're seeing with a safety profile that we're seeing, that is a very strong benefit to risk, and we think that is going to be the continued strength of ensifentrine as you look at it, commercially. I think one thing to look at about our studies in phase two and why we are confident in our phase three program is that we kept things fairly consistent, and where our learnings from phase two we carried over to phase three. When we look at the study population, the patient population, we're selecting the same types of patient, moderate, severe COPD. We selected the dose from phase two. We're moving on with that in phase three. The studies, while larger in phase three, are not substantially larger, going from 400 to 800 patients. Length of study, again, typical moving from in COPD from phase 2 to phase 3. You know, 12-week for the primary endpoint, 24-week for our secondary endpoints, and of course, 48-week for safety. Our endpoints and our entry criteria really are kept quite stable between our phase 2 and phase 3 studies. Picking up patients who are symptomatic at entry, which is important to make sure that we can detect improvements. They're all compromised lung function with 30%-70% predicted FEV1. As I mentioned, our key endpoints are very well characterized via our phase 2 program. Really, while there's always risk in clinical research, we feel very good about that we've mitigated that risk moving from phase 2 to phase 3. What should you keep an eye on, and where are we, and what's coming up? From our ENHANCE-2 study, which is our 24-week trial. We of course are in the back end of completing that study, and we expect top-line data in Q3, which of course, Q3 starts in a few weeks. Coming up real soon on getting the top-line data from ENHANCE-2. ENHANCE-1, which we announced we completed enrollment in just recently, and we're on track to report out the results of that around the end of 2022. That'll lead us to submitting an NDA in the first half of 2023. Based on that, we would expect an approval based on a PDUFA date of around first half of 2024 or pushing mid-2024. Of course, based on a favorable response, a commercial launch in the second half of 2024. A lot of progress has occurred in the past couple of years, and we're really at the end game as far as ensifentrine's performance in phase three trials. I talked a little bit about primary and secondary endpoints. This is just to remind us that we feel good that the trials are very well powered based on the results that we saw in phase 2. We're powered at 90% to detect a 59 milliliter difference in the improvement of lung function as measured by average forced expiratory volume in one second as FEV1 over 12 hours. That of course, we saw a much greater effect in phase 2, but we're powered at 59 milliliters in this trial. Secondary endpoints, again, powered at 90% levels that are below what we've seen in phase 2. So again, we think we're well structured in order to detect these differences in the trials. As always, safety will be powered. This will be our general outline of our top-line data that would come out in Q3. It's always helpful to remind us that we do have a number of other programs within Verona related to ensifentrine, both in a dry powder inhaler, metered-dose inhaler. We've provided that data previously, and we're very excited that we have proof of concept in different delivery devices. We've also looked at it in asthma, cystic fibrosis. A lot of opportunity for ensifentrine moving forward from our COPD trials. With that, I just want to convey, you know, we're very excited about where we're at, and we look forward to updating everyone in Q3 on the results from ENHANCE-2. I'm gonna turn it over to Chris Martin, who's gonna lead us through the next phase of the presentation and really hear, as I mentioned, from our KOLs that are with us today. Thank you very much. Thanks, Dave. We're gonna get the chair set up for our speakers real quick. Igor and Jill. I think we're excited to have both Igor and Jill here with us today. We have two chairs. Which one do you want? You can go right, Jill, right in the middle. Kathy, if you wanna- Oh, okay. Yeah. We'll hear it. Yeah. We're excited to have both Igor and Jill with us today. I'm gonna let each of them introduce themselves, and Kathy's gonna join the panel as well just to provide her perspective as our Chief Medical Officer here as well. Before we get started, I'd love Igor and then Jill, if you could just introduce yourself, talk about your practice, the patients that come into your practice, and what that looks like for you on a day-to-day basis, and how you deal with COPD. Oh, wow. Your mother would be proud. Sometimes. Very rarely. I'm Jill Ohar. I work at Wake Forest University School of Medicine. For those of you who don't know where that is, it's in Winston-Salem, North Carolina. If that doesn't say it, tell you a little bit about my practice, it should. It's one of the few cities in America named after two cigarettes. It's the home of RJR. Many of my patients actually grew up on tobacco farms. They raised tobacco. It is part of our fiber. What I can say about COPD is something that Igor Barjaktarevic and I were talking about a little earlier, which is the fact that COPD is an indolent disorder. Most people don't present to a doctor till they're in their mid-fifties or sixties. By then, Doug Mapel did a study published probably about 15 years ago that showed that people's FEV1, a measure of their lung function, is already sitting at 50% of predicted. They've already dealt with probably 10-15 years of significant symptoms, attributing it to a smoker's cough, attributing their shortness of breath to getting older, getting a little fatter, etc. There are a huge number of patients out there that, number one, discount their symptoms, and number two, that are undiagnosed. A huge market. In terms of therapies, I can't say that I have probably 10% of my patients that are really happy with their therapies. Most are feel that there's more out there, that they should be able to feel better. Some of that. I think that's reflected in the fact that if you look at pharma data, the refill rate, the persistence rate is around 30%. That means that the patients refill their scripts only about a third of the time for their maintenance meds. When you ask a patient what medicines they're on, they always talk about albuterol, their short-acting rescue, and you need to really pull from them what maintenance meds they're on. They clearly in their head discount their maintenance meds. Your turn. Thanks, Jill, for being here. Thanks guys for inviting us. Obviously, both Jill and I like to talk about COPD. Just like to ask it and we go on. To introduce myself, my name is Igor Barjaktarevic. I'm a pulmonologist and intensivist. I work at UCLA. I'm medical director of COPD Clinical and Research Program. It's a fairly large research program. We run multiple NIH and industry-based trials. We're very invested in COPD and kind of honestly use any opportunity to kind of really discuss this plague of, you know, twenty-first century, if I can put it this way. My background is I have translational background in COPD. My PhD is also in immunology of emphysema. Find this topic on a novel molecule that you guys have is very intriguing, and I'm happy to be here. We appreciate this. I know, Jill, you just mentioned kind of the patients dealing with symptoms throughout their life. Igor, could you provide some perspective on what are your treatment goals when you see these patients initially, and does that change over time? What are you trying to accomplish when a patient gets diagnosed with COPD, they're put on maintenance therapy. What are you looking to accomplish in those patients and try to help? No, that's a good question. I mean, really, the problem and frustration. Actually, Jill and I sat here as we're kind of waiting for this meeting and just like kind of sharing frustration of you use the word indolent or insidious process. This is something that is developing over a long time. It kind of comes in a sneaky way. Very often a smoker who, you know, coughs and can do less takes this like, "Oh, yeah. It's my smoking cough, and I'm aging." The fact is that actually it comes in that sneaky way, and very often or unfortunately the most often when we diagnose COPD and when we're at the point that it's bluntly obvious that someone has COPD, a lot of lung function is taken away without any ability to restore it. That is probably the most frustrating thing that we have. You know, just maybe a little reminder of like if we do a little bit zoom out, but we have around like 15 million-25 million people with COPD in the United States, and like over 300 million worldwide. When you look at the hospitalizations, we have, I think the numbers that we often use are around 700,000. Yeah. We are talking about 140,000 deaths of COPD. When you extend to other smoking related problems that kind of goes significantly higher. When we really look at the hospitalizations of people who are over the age of 40, I mean, fifth or 20% or 25% of all hospitalizations are actually related to COPD. You know, probably when I give these numbers, it's easy to see why we are as frustrated as we are. Back to simply try to give the answer to your question is, when we see a person who is suspected to have COPD and then confirmed having COPD, everything first starts with the non-pharmacological interventions and lifestyle modifications. One of frustrating things in COPD is that over 60 years or 70 years that we have this defined entity and over 200 years that we know about emphysema from the pathologic perspective and multiple medications that we have for decades, the only two interventions that have clear mortality impact at this point is stop smoking and use oxygen if you need oxygen. Certainly those are first interventions that we certainly need to do and then address these non-pharmacological. Then on the pharmacological side, obviously, you know, GOLD that I'm sure that you guys are familiar with the GOLD initiative and GOLD report, which is one in my mind, like non-presumptuous document that really is not trying to make guidelines what absolutely needs to happen, but really summarizes current evidence of where do we stand. Based on current guidelines, there is a kind of fairly clear algorithm of how do you build up. Essentially, the answer is if you're going from short-acting inhalers as needed to the steady daily regimens of long-acting drug, and then the escalation goes in terms of the type of bronchodilators, inhaled corticosteroids, et cetera. I don't know whether this answers. No, that helps a lot. Jill, on that note, when you're putting on a LAMA or a LABA, and what is the effect you're looking at for these patients? When they come back into your office, what are you hoping to hear the patient talk to you about? Or what are you trying to gauge from their perspective after they've gone on a treatment? Well, you know, GOLD changed. Yeah. Several years ago, and focused on symptoms. I mean, really, that's what patients really care about anyway. So I use a validated symptom score for both a baseline and then follow-up because while I have a litany of symptoms I ask for, I find that I get very different answers if I ask them the symptom score. I use the CAT. It's one of the symptom scores that GOLD uses. It's the COPD assessment test. It's funny, I'll say to a patient, "Do you have a chronic cough?" "No." "So you don't bring up any sputum then?" "No." "You wheeze?" "sometimes." You know, that kind of thing. When I actually get to the CAT, which says, you know, rate your cough on a scale of 0 to 5, and they'll go, "3." It's like, rate your sputum. I have this, I have no phlegm in my chest, 0. My chest is full of phlegm, 5, 4. You know, it's shocking how patients, number one, this underlies the fact patients deny their symptoms, both to their physician and to themselves and their family. Number two, these patients are symptomatic despite medications. Number three, a symptom score is helpful to decide, geez, I'm not right where I need to be yet. I need to move on to a double or a triple or, you know, roflumilast, et cetera. Furthermore, I think I have to say that Igor stabbed me through the heart when he failed to mention pulmonary rehab, which has also been shown in recent publications to improve quality of life, but is only used in 3% of eligible patients. Another modality that we're ignoring. I'd love both your perspectives on this. When you're thinking about these treatments, how does device selection come into play? Like, how do I choose a DPI, MDI or an inhaler, a nebulizer? How do you think about those in your mind? Well, we have a world expert in actually this here. You're more welcome for it. Yeah, I can humbly start. No. No, like the reality is that we have, you know, inhaled therapies are delivered through nebulizers and handheld devices and all kind of go back like over 50, 60, 70 years. Nebulizers started as a kind of devices that were used earlier and with the drugs that go every four or six hours, noisy, big. Kind of when we got with handheld devices in 1950, 1960s, either with dry powder inhalers followed by MDIs or metered dose inhalers, followed by more recently by soft mist inhalers, kind of handheld devices had advantage of being handy, being around. The fact is that nowadays, when we have long-acting drugs, those and with development of nebulizers that are better, smaller, easier to maintain, we got actually now a spectrum that we have both nebulizers, handheld devices as a very useful, and then useful in terms of tailoring to what is the patient that I'm treating. Very briefly, that's gonna be probably intro to Jill to kind of come with the more details. In general, each of those approaches has some pros and cons obviously. Certainly nebulizers have the advantage that it's a normal tidal volume breathing. Someone who's demented, who has lack of ability to pull hard, who has problems with rheumatological diseases, is actually hospitalized, for example, certainly a good candidate. On the other hand, when we talk about dry powder inhalers or MDIs, dry powder inhalers have a powder, so significant peak inspiratory flow is necessary for adequate distribution of the particles to the distal airways. Metered-dose inhalers, again, very comfortable, very easy. But again, require a lot of hand-mouth coordination because the device requires an immediate press the button and inhale at the same time. As you can see, when you look at the patient and spectrum of COPD, especially understanding that COPD is a disease of aging, then it's easy to recognize that it's not that each device fits each particular patient. I don't know whether it's a good intro for you to- That's good. Yeah. Went very well. Each of these devices is outstanding in its own right, and I think that's really important to understand. You know, whereby metered-dose inhalers are small and compact, most people can't manage that hand-mouth coordination. You really, for the most part, even the newer HFA devices require about this much space between the mouth and the nozzle, the inhaler, to let the diluent and propellant evaporate off the drug and also to get it a little more slowly moving. Otherwise, it ends up on the back of the throat, and you get an oral dose. Something that's small, compact, and easy becomes actually bigger and bulkier because of a spacing device that really helps get the drug where it needs to be. Frequently, rescue medicines like Albuterol or Combivent, which is Albuterol and Atrovent together in a rescue device, a single device, come in metered-dose inhalers. Every patient has a controller medicine and a rescue medicine, and the rescue medicines tend to come in metered-dose inhalers. A lot of the controller medicines come in dry powders. Dry powders require. I'm looking at age groups here, but how many people remember the old school cap guns that had the cap on a ribbon? You know, you were involved in the development of this. The dry powders literally use that technology. It's a ribbon of compressed drug. When you open the cap, and they're very easy to use. As opposed to a metered-dose inhaler, you know, I have to inhale slowly, I have to coordinate, I have to have it, you know, this far out, and it ends up in my eyebrow or my ear. A dry powder is wonderful. You open it up, you exhale fully outside of it, you ram it in your mouth, and you inhale as hard and as fast as you can. Why? Because you have to pull that dry powder through a filter to break it down into a particle that's respirable, less than five microns, okay? If instead you don't get the drug in your lungs, you get it in the back of your throat, and you get an oral dose. Now you have a metered-dose inhaler that you need to inhale slowly and deliberately, which is your rescue medicine. You have a maintenance drug, which is your dry powder, which you have to inhale hard and fast. Now, remember, you got a guy here or a woman here, and it's like, "Which one? Which one?" and they need a rescue. "Is this the hard and fast? Is this the slow and deep?" There's that. Nebs, while they used to be considered really clunky, there are nebulizer machines now that you can plug into your cigarette lighter. You're guaranteed for the most part that your patient gets the drug, because of the fact that they have their mask, they sit there, all they have to do is breathe. There's not a whole lot of volitional issues. They're not so clunky anymore, but they do require cleanup, so that makes them a little more difficult. With a med that's BID, you know, there's much. It's not like you're cleaning them four times a day. Furthermore, we have a paper coming out probably next week that shows that about 56-57% of people coming out of the hospital probably don't have the strength to use a dry powder inhaler. That impacts not only on the fact that they may or may not be getting their meds, we don't know that, but we know that they don't do well. Their chances of being re-hospitalized in the next year, number of days in the hospital, number of days in the ICU, admissions to the ICU, admissions to the ED all are increased compared to people who do have the strength. Finally, we thought, "Well, just maybe it's just 'cause they're frail." We have an eFrailty Index on them, and the eFrailty Index, there's no difference between the groups. It seems that this really is impacting on their healthcare utilization. Each is outstanding. I love dry powders. I use them a lot, but they have to be used in the right situation. Same with metered-dose inhalers, but I tend to get a spacer. Do you use a lot of spacers? Yeah. Actually. This debilitated population, that's another way to kind of help those who do not have strength. If I may add pretty much to kind of wrap this up, the new and novel molecules are developed for all devices. While we had maybe in early 2000s more like push on the novel molecules in the handheld devices, we had explosion of the new approaches with nebulizer recently, with long-acting muscarinic agents, with long-acting beta-agonist, with Alpha-1 Antitrypsin deliverable therapies, these type of molecules with mucociliary clearance approach. In that sense, I think like right, I feel that there is future for absolutely all- Everything All will continue developing. Each is outstanding in its own right, including soft mist, which we haven't talked about. Yes. That's really helpful perspective on the device. One thing that comes up a lot in the conversations that I have with physicians like yourself is how do I deal with ICS and steroids in the treatment regimen? What's your perspective on ICS's role, how it fits in, where should it be used? Are we overusing it? What are your perspectives there? Igor, you wanna start, or? Sure. Inhaled corticosteroids, I mean, probably if I use this word, and I'm often thinking, is it too harsh of a word? There is a little of a controversy about the role of corticosteroids in COPD. COPD is inflammatory condition, and being inflammatory condition, by default, there is a role for anti-inflammatory approach. Nevertheless, the controversy, if I really try to simplify it, goes to the point that there are pros and cons of steroids. Even if they are just inhaled corticosteroids, before all that relates to suppression of immune responses in the lung microenvironment, thus leading to potentially lower respiratory infections and pneumonias. At the same time, there is anti-inflammatory effect, but you could argue that theoretically, there is some trade-off, that you may have less inflammation, but more infections and the other way around. Besides, there are the other kind of general concerns that there is some cumulative systemic effect of steroids. There are also like complications or side effects, thrush, et cetera, that relates to the use of inhaled corticosteroids. More important than anything else, the steroid approach to inflammation is really pretty much using the overall let's shut down, you know, like let's use the sprinklers to get that little fire in the corner. That is the reason why actually over past years, we have a lot of kind of development of the molecules that are trying to tackle the inflammation in its particular kind of pathways, lower down, upstream in the inflammation, et cetera, and trying to customize the approach. With steroids, if I try to explain when I mentioned the word controversy, there is, I think that the most of us pulmonologists involved in COPD almost feel that you have these groups of like really those very much into steroids and against. We know that when you do a snapshot of people who are treated for COPD with inhalers, with long-acting drugs, at some point, 70% of COPDers are actually on the steroid-containing products, usually combination of ICS LABA. The reasons why is that the case is partly because LABA had black box warning at some point, so there was easy pretty much jump from short-acting drugs to combinations of LABA and ICS. Essentially, the studies and how this controversy really manifests in the scientific world is that over past years, we had studies that are very clearly showing that inhaled corticosteroids reduced exacerbations. Then we had couple of studies such as FLAME, SHINE, WISDOM trial that actually showed both that LABA/LAMA combinations bronchodilators, long-acting bronchodilators, reduce exacerbations, that taking person off inhaled corticosteroids, a person who does not have exacerbation is safe. Nevertheless, in the past three years, with IMPACT and ETHOS, we got couple of big trials, well-done trials that again recruited select cohort of patients who exacerbate, who are sick, who are symptomatic, and then show very clear benefits of adding inhaled corticosteroids and triple therapies regimens to reduction of exacerbations and even with to some mortality. That's maybe I'm trying to simply present why there is that little controversy. The role of steroids is not very clear. Currently in the GOLD guidelines, GOLD guidelines defines COPD or kind of tries to describe a patient that is sitting in front of me, not based on what the FEV1 is, but based on how symptomatic this patient is and how many exacerbations and flare-ups patient has. Based on this, as you know, patients are divided into group A, B, C, D. A being no exacerbations, no symptoms, D being the opposite. Currently, GOLD guidelines in group D recommend that when the patient has exacerbations, the patient has symptoms to go for adding inhaled corticosteroids. Nevertheless, one interesting tweak there in comparison to previous editions was that for the first time, actually in 20- 20. 20. Mm-hmm. What about inhaled corticosteroids are even potentially bypassed in select patients who actually have low eosinophils. Based on eosinophils, we saw more eosinophils, better response to steroids and vice versa. In that sense, currently steroids are recommended to be the next step after the patient is generally treated with long-acting bronchodilators and symptoms and exacerbations are not adequately controlled. I'm gonna stop here and maybe. Yeah, I just wanna summarize that. I think, you know, GOLD's quite clear that, you know, if you have at least one severe, defined by hospitalization, or two moderate exacerbations in the preceding year, you're a candidate for inhaled glucocorticoids. You know, if you don't have that, but maybe, you know, are having poor control, so to speak. A lot of times what will be defined as a mild exacerbation is something that's treated at home with an increased amount of rescue medicine. or maybe in spells like that and maybe one moderate, which means that you've at home had to have a steroid or an antibiotic script, that maybe those people certainly if they have a high eosinophil count at 300. You know, really people argue about this. It's kind of like prunes. You know, is three too many? Is two enough? It's the same way with eosinophils. There are people who say 100, there are people who say 200, and there are people who say 300. But I think all of us could agree that if you hit 300 with some regularity and you have poor control, that's also in addition to somebody who's had at least two moderate or one severe exacerbation in the last year should be on an inhaled glucocorticoid. I think everybody agrees that they're overused as well. They're overused, and you know, maybe practical situation that we face very often is that someone who is at that stage, significant symptoms, exacerbations, oftentimes has colonization with different bacteria. Nontuberculous mycobacteria, Pseudomonas, Aspergillus. Bugs that we see very often with chronic bronchitis, bronchiectasis. You get into this like logical dilemma, right? Am I hurting my patients with giving these steroids or I'm helping? That unfortunately is very common. In that sense, you know, we're learning over time that the therapy in COPD needs to be customized and need to be adjusted to the patient, and we're hopefully moving in the right direction. That is why again, the role of steroids absolutely is there, and they're a significant group of drugs, but it's just they're not meant to just follow absolute cliché. That's really helpful. Jill, you mentioned something there about symptoms and FEV1. How does FEV1 correlate to symptom reduction or other items that a patient may be feeling? Is there any data out there on that, or how does that? You know, very loosely. I mean, if you have 1,000 patients, you're gonna have a scattergram with a line that goes through that. But we don't treat FEV1 anymore. Back early in my career, we treated an FEV1. You know, just like we don't treat X-rays. We treat the patient. We treat symptoms. Really, in this age, we. An FEV1 is important to make a diagnosis. An FEV1 is important for prognosis. It's probably the single best laboratory item that we choose, whether it's the glucose, the cholesterol panel, the hemoglobin. Actually, the FEV1 is the single best predictor of all-cause mortality, and that kind of factors into the fact that COPD is a disorder that's characterized by a disproportionate prevalence of common comorbidities. If you think about all smokers, Venn diagrams, remember third grade, Venn diagrams? Okay. The 40% that get COPD. All smokers, 40% get COPD. If you look at coronary artery disease, cerebral vascular disease, osteoporosis, diabetes, metabolic syndrome, and lung cancer, all of those have a much, much higher prevalence in the 40% of smokers who get COPD compared to the 60% who don't. All of this impacts on these patients as well on your treatment decisions. Yeah. I mean practically speaking, all of us see these two patients sitting in front of us with FEV1 of 50%. It's notorious fact that one can actually be jumping from hospitalization to hospitalization, and it's easy to predict poor outcomes, versus the other one that can have like fairly preserved quality of life without exacerbations. That actually drove us to the fact that by no means like FEV1 is irrelevant piece of information. We can only diagnose COPD after we have FEV1, right? As Jill mentioned, it's a great predictor of outcomes. Nevertheless, the how bad or good our patient is doing is not like really reflected in that number. Okay. That's really helpful. I think as we close up this section about the landscape, and you talk about symptomatic patients that you still have, you talk about these patients, the struggles you have with ICS and maybe the bacteria that may be in their lungs. What are some of the unmet needs that are there for you as a clinician today within COPD? What do you need from a- As I mentioned before, I often use the CAT score to see where my patients are. You know, in reality, GOLD wants you to have a CAT of less than 10. That's, you know, that's not a reality in any of my patients. I mean, do you have any patients who have a CAT of less than 10? No, you're right. I mean, CAT of 10 may not be actually sensitive. Well, I got that now, yeah. I mean, people are starting to talk about that. I think it's a construct that, you know, if I'm in the teens in terms of a symptom score with the CAT, I'm feeling like I'm doing pretty well. My point is that despite my best therapies. My patients are still symptomatic. They still feel like they need something more. I remember a couple, 2- 3 years back, getting a call from a colleague about, you know, literally I think she called it a tragedy that there was nothing in the pipeline, that pharma was going to cancer, and that we needed to work with the COPD Foundation. Would I get on this call with the COPD Foundation because there were no drugs in the pipeline for our patients that, you know, they. What you have is what you got. Have a nice day. Yeah, no, that's actually like very big and important thing that really in COPD, first of all, we do not have ability to restore the lung function. That's frustrating. Secondly, we don't have like, really mortality impactful drug. Third, we are really spinning about the three basic classes of bronchodilators, meaning beta agonist and muscarinic antagonist. That's really sympathetic and parasympathetic activation that we know for 60 years we're developing better and more sophisticated drugs within the class, but it's the same class, and inhaled corticosteroids. I think we can agree that we're in desperate need for new molecules. I do not know whether you guys are going to be able to at some point impact mortality, et cetera. We physicians treating COPD need new, new molecules. That's really helpful. That leads us into the next topic, which is ensifentrine. That's a new molecule that we're talking about. It has PDE3, PDE4 mechanism. What's your initial reaction to being able to inhibit PDE3, PDE4, a different pathway than what you're used to? How do you interpret that potential mechanism in your mind? Igor and then Jill, if you wanna add to that. Yeah. Phosphodiesterase inhibitors actually are pretty broad class. I mean, I bet that most of us had at least one this morning with a coffee, right? Caffeine actually is just non-selective. Theophylline is PDE inhibitor. PDE inhibitors come through various kind of flavors and very different diseases, right? When we use like milrinone for the heart, it's PDE3, I think, or 4. When you talk about Viagra, it's PDE5. In COPD, we actually have experience and now, like, have a fairly substantial experience with PDE4, which is anti-inflammatory kind of mechanism with the Daliresp, with oral medication that we use quite a lot despite its kind of a little bit of GI or safety profile that comes occasionally difficult for certain patients. PDE3 has not been really explored, and neither PDE3 and PDE4 have been previously explored as an inhalational approach. We are combining two completely different mechanisms, right? Through PDE3, we're talking about bronchodilation. Through PDE4, we're talking about anti-inflammation. It's very unique. The first time I heard about this molecule, I certainly was impressed that pretty much with these two properties, you are covering everything that all other classes that we have so far are tackling. Certainly very comprehensive approach. Yeah. Yeah, I would agree. I think, you know, being old enough to have used theophylline and being aware of all of its toxicities, where the therapeutic area, the doses or where the actual serum levels for therapeutic versus toxic actually overlapped. You never knew where you were. You know, am I hurting them? Am I making them better? Roflumilast, Daliresp, same drug, different name, was a different concept in that it was more specific. It certainly does have the GI side effects. It does give you some FEV1. It's just not enough to make the FDA approve it for a bronchodilator, but it was approved to reduce exacerbation frequency. I think the dosing on it, the delivery format also is also an interesting concept. It's probably the only pill we really have for COPD. Because of patients' inability and doctors' lack of time and the inability to have somebody else in your practice tell people how to use a device correctly, a pill sometimes ends up being more effective because it's slow and fast, hard and, you know, within my mouth and far away. All of those vagaries of the inhalation devices are obviated by a pill. It was good, but the GI effects were bad. I mean, I don't have a single patient on 500. I only have one at 250 dose, and I have never increased them because whenever I do, I get into trouble, so I just don't bother. I try to increase, but you're right. It's very frequent, especially in elderly. Yeah. I just don't do it. I like the idea of this new molecule, which is both PDE3 and 4. You're gonna get the bronchodilation, in theory, the bronchodilation that you don't get with roflumilast, and you also get the anti-inflammatory. I like the fact that it's a nebulized medicine because it will actually get where it needs to go, and you don't have to fuss about are they using the device correctly. I'm actually thrilled, number one, that it's available, and number two, that it's in the delivery format that it currently is. I think it'll gain traction faster that way, and then as the other device formats become available, it will have a pathway to glide on. Cool. That's helpful. As we think about that mechanism, we've seen Dave showed some data earlier regarding the phase 2 on FEV1 and symptoms. Jill, what's your perspective on that early phase 2 work that we've shown on ensifentrine? What's your takeaway from that? Alone at 200, I mean, it's right up there. We were talking about Tio, the original Tio study. At 200, that's very impressive. It's twice the MCID. Then as an add-on, you never anticipate that you're going to get the MCID for a single agent, and you did. You know, as an add-on, you got 100, 123 in that range. You know, I think that you know, this is a very impressive first blush set of data. I'm very impressed by it. Igor, any others? Well, when you add the quality of life that you add to the FEV1 change, I think certainly, you know, this is way to go. I think that it's been now like, what, 3 or 4 years since we know about these, like 2 or 2B results. Honestly, that gave the most enthusiasm why I'm here also today. Yeah. I think that was the right. I mean, it probably as good as it could have been- Okay in 2B, in my mind. That's very helpful. Jill, you mentioned something there about MCID, and can you kinda walk through that concept? How do you apply it as an add-on? What is the data out there on MCID? How does that? It's a validated measure that's been anchored on several endpoints, and it goes through a very strict process to determine. For FEV1, it's peak FEV1. It's not average, it's peak FEV1. It's 100, about 100 cc's. You know, there's some argument, should it be a little higher, should it be a little lower? That's a single agent. We don't know. No one knows when you pair a drug with another agent on background. In this case, if you put ensifentrine on top of TIO, tiotropium, we do not have a defined MCID for what we would anticipate on top of that. The fact that you got a peak of 123, 100, you know, well above 100, that's very impressive. It's very, very impressive because a lot of studies, and you guys have been part of some of those drug developments. You're looking at 70, 60, you know, 80 as an add-on. I'm very impressed with it. Got it. I mean, if I may add just the whole concept of minimal clinical important difference is there that we do not get stuck with the statistics, right? You may have a study proving that there is statistically significant, but we are adding this as a kind of double control measure. You prove statistical significance and then show that you're making clinical significance. That's the idea behind MCID's, both in FEV1 or as St. George's Respiratory Questionnaire as a quality of life. If I heard correctly, what you're saying is MCID on peak is established, but not necessarily on add-on or an average or- Not on average, not on add-on. I guess, like what I've neglected to mention is what does it really mean to a patient? Yeah. This is the value that a patient should feel a difference. I mean, a lot of times, I remember early in my career, drug reps showing me statistical significance and, you know, that there's that old saying, there's lies, damn lies and statistics. If you put enough patients into a study, you can get statistical significance with 4 cc's difference in FEV1. Does that mean anything to your patient? That's where that concept of MCID came into is, what does that really mean to my patient? Can my patient feel a difference? This has been defined by many endpoint measures that are used in pharma trials now. It's important to not get all wrapped around the axle to know exactly, number one, it's peak, it's not average. Number two, it's for a single agent, it's not for multiple agents or an add-on agent. That's pretty much it. There is more complexity to this. Like, for example, the study actually had to look UPLIFT last night- Did you? before this call. Yeah. Yeah. Yeah. You know, like the trial, for example, that got Spiriva and that got LAMA into the clinical practice, the primary endpoint was actually FEV1 loss, right? Decline normally after the age of 25. Oh, that's right. It was. You're right. We lose around 30, 20-30 cc's FEV1. Arguably, someone with COPD with exacerbations loses more. In general, when you are taking FEV1 as a primary endpoint in longer lasting trials, you are putting yourself in danger to really see what is improvement versus what is kind of natural decline. FEV1 is a great endpoint in the short, like your 2B was 4 weeks, right? Yeah. That's more like manifesting pharmacokinetics of the medication and really showing the acute effect. Longer term, in COPD in general, we avoid taking the FEV1 exactly because of that kind of natural decline. I can tell you that right now, by the way, we're doing analysis of UPLIFT, like with Don. Mm-hmm. UPLIFT had 4 years with 8 measurements, and we're actually trying to even see, like what is the frequency of really measurements and how many, how long and how many instances we have to have the best estimates of the decline. That gets kind of incorporated in your 3B- Yeah. that you need to take it a little bit with a grain of salt, the improvement that FEV1 has. The symptoms and quality of life become an important aspect. More important. Yeah. Yeah. Okay. Let's go to that phase three design. What are your thoughts on the phase three design? Igor, when you look at that phase three design that Dave showed, what are your initial reaction to the design and how it applies to what you deal with on a day-to-day basis? No, I think that actually the design, obviously, you applied this pretty much the design that you used in your 2B, so you've applied the concept that works. You selected well-validated endpoints. Yes. I don't know what's gonna happen with this. I think in terms of methodology that you selected, I think that's adequate, and that in my mind is something that is achievable. Understanding the concept that you're extending the duration. Mm-hmm. We'll see actually how it turns out. Yes. Jill, any other thoughts? Yeah. I agree. I think, you know, clearly, the 3-milligram dose was an important, you know, decision. I like the idea of symptom endpoints, because again, it, you know, a change in FEV1 without really making a difference in the patient's life is really not where I wanna be. No, that's really helpful. Let's take this. Let's put you in a time machine. We go forward, we have data. In your mind, what would you wanna see out of that data from a result standpoint? It's not about the numbers, but in your mind, what would you like to see out of that? Jill, you wanna go first, or I'm putting you on the spot here first. Yeah. I think what I'd like to see, you know, is an MCID for your symptom scores. I think that's probably the first thing. I, you know, as an add-on, again, you want some FEV1 change. That kinda internally validates that. You know, what's that number? Oh, geez, you know. Certainly not at 100. Maybe in the 70s, somewhere around there is 'cause it's an add-on. You have an incredible safety profile. Mm-hmm. In the short range, so I'd be interested in the ongoing safety profile. Does it continue to be that good? I'd like to look at the dropout rate, 'cause I think that there's hidden messages in you know, who dropped and why. Mm-hmm. I think those are the things I'd be interested in. That's- Igor? Yeah, no. First of all, I would say that really, that nice safety profile that you have is going to be, like, very important to the proven. In terms of your endpoints, I would look at this as whether they are aligned and whether you're getting into both fields. In terms of really quantifying, I think that you I mean, I could tell you that as a clinician, results that are positive would be amazing. If you get what's powered there, that's like you're golden. Even if that's not exactly reached, I would not kinda really look this in a way to discredit the results because you do have a couple of obstacles that we learn in COPD research. For SGRQ, there is kind of seasonal, also placebo effect that every so often surprises us. We got, like, in a recent study, everything that we've done. We've just completed the drugs that obviously showed great improvement in FEV1, in SGRQ, et cetera, still hit placebo SGRQ effect that blunted the statistical size of SGRQ. Pretty much what I'm trying to say is that I hope you're gonna have them as nicely aligned as in 2B. If either SGRQ or FEV1 is around those numbers, I would not say that this percent means already that you are not actually achieving what you need to do. That's helpful. Now let's go forward. Now we got the data. You talked about the symptomatic patient in your practice. How do you use this? How do you see ensifentrine being used in your practice? I'm gonna ask both of you on that one, so I'll let you guys fight over who's gonna do this first. No, it's fine. All right. Since you just talked, I'll let you rest. I think you could use it a lot of different ways. I think in practice out there in the hinterlands, you know, not here, but out there, a lot of times doctors will use a drug that's in their supply cabinet. You know, frustrated with how the patient's doing and say, "Hey, try this." Or it's a new patient, "Hey, try this." I think that it has applicability as a first-line agent as well as an add-on. Okay. Yeah, no. You know, I was thinking, like, the answer to this question is, like, it's a million dollar, but not million, multimillion-dollar question. Is that you-- I think you guys have this little bit of a sweet pain with this because the concept that you're tackling, the mechanistically how you're approaching the problem puts you in a, in multiple stages. I mean, you literally, theoretically, if I'm as a physician treating COPD, looking at the new drug that has these properties, you really range from being the very first drug that someone with COPD needs all the way to being add-on to already maximize inhalational therapies. I remember when your first data came out, that was the dilemma, and obviously, the dilemma even nowadays can be looked at. I think that you probably picked, in my mind, a reasonable approach, that you really look what's happening in earlier stages. You obviously are recruiting population of patients who are symptomatic. We're talking about group B, potentially group D. You're looking for people who are already on bronchodilators, which logically, it's difficult to tackle right away. We have enough decades of experience with bronchodilators. I would expect that probably the foot in the door would be as somewhere in between inhaled corticosteroids and bronchodilators that are initiated. Okay. That's helpful. I'm gonna shift gears now as you've talked about that to the future and what is out there from a competitive standpoint or a development standpoint. Jill, I don't know, from a development standpoint, is there anything there that you know about or what's? Yeah, certainly, there are biologics that are out there, and we also had that conversation sitting here earlier. It is the idea that actually Kathy's mentor, Steve Renard, one time said in a lecture that COPD is an orphan disease. You know, orphan diseases, you know, you think of as affecting, you know, very small numbers of patients. What he meant by that is that it really is a grouping of many different kinds of orphan diseases because there are so many different phenotypes of COPD that it's difficult to quantify, you know, who's affected by which, and I think especially the biologics are affected by this. I mean, bronchodilators are bronchodilators. You have obstruction, you give them bronchodilators. You have inflammation, you give them ICS or maybe a PDE inhibitor. other than that's, you know, kind of the landscape for the broad COPD patient. Once you get into biologics, which are, you know, I think probably the only landscape right now coming down the path, you're gonna have to find a very specific subset, phenotype of patients who have COPD that they're gonna be helpful in. We've just not been successful at this point. Would you agree? No, that's absolutely correct. Yeah. I mean, first of all, what's in the pipeline of the small molecules, you know, maybe first of all, LABA/ LAMA, we have multitude of medications that developed. They are longer lasting, they are novel concepts. We do have small molecules, maybe combination molecule of MABA, so combination. Yeah, MABA. Of muscarinic and beta-agonists. The PDE3, PDE4 inhalational is a completely different thing that is in the group of small molecules and medications that you could see that applies to a wide variety of phenotypes. When we get to biologics, I mean, yeah, I agree with what Jill said. Theoretically, like, science can make antibody to anything that you want right now. The problem that we scientists are actually kind of failing to provide adequate biomarker. The fact that the industry can develop particular antibody, just we know that it doesn't work for everybody. We know that COPD has multiple different inflammatory pathways, TH2, TH1, TH17 pathways, that biologics, that whenever we actually even identify some biomarker in one of those long-lasting cohorts where we try to bioprofile COPD and understand heterogeneity, the next cohort, the neighboring cohort is failing to validate that biomarker. You know, we're sticking to it. You know, it feels like crazy right now that they are affect themselves, but we don't even know. Is it tackling them or they are kind of consequence of the inflammation. That's why, like, we're tackling inflammation more upstream, more recently. Remember lymphocytes, though. We used to be very excited about lymphocytes. Exactly. We do not have enough biomarkers to be able to do endotypization that leads to adequate phenotypization and biomarkers. In that sense, I would say simply, biomarkers will be developing, but biomarkers require from, you know, one-size-fits-all to personalized and hopefully toward precision medicine. Mm-hmm. We're not there enough. I think pretty much development of biologics is a completely separate and doesn't have much to do with the- Forward. this kind of thing. That's great. I appreciate that conversation. I think what we wanna do now is bring David up here as well and kinda open it up to the audience and our attendees online as well, for additional questions that maybe Jill and Igor weren't able to ask or answer during that. If Dave or anybody else has questions, we can answer that as well. We'll go to a larger group. Tom. Thank you. Thomas Shrader from BTIG. Fantastic. All of these events are great. To return to roflumilast, if that were a completely clean drug, how exciting would it be? What fraction of your patients? I'm curious, is ensifentrine gonna be mostly a bronchodilator drug in patients' minds, or will the exacerbations be meaningful? Well, if I start roflumilast, you know, clean drug. It's an oral drug that has a GI kind of side effect. It has its limitations because of this. Its position currently based on GOLD guidelines, go after the inhalational approach has been exhausted. Usually, that's a drug that comes for people who are already on triple therapies. Majority of my patients who are on Daliresp are already on triple therapies. Extremely rarely that someone who cannot be on steroids and go there. Daliresp is not the only pill that GOLD recommends, right? Nowadays, we have three pills that technically are in the scope of regular interventions in COPD. One is Daliresp, the other is azithromycin, an antibiotic that have anti-inflammatory. We have N-acetylcysteine that also has some kind of data that show it toward reduced exacerbations. We try to expand. Daliresp is more recommended in former smokers with exacerbations as opposed to azithromycin. No, azithromycin is in former smokers and Daliresp with people with exacerbations. Severe mucus producers. To get insurance to pay for it, they have to have severe COPD. You have to document chronic bronchitis, mucus production, and an exercise frequency. Frequency. Yeah, exacerbation frequency. It has its limited kind of positioning already. This drug, you asked whether we would see it more as a bronchodilator. I think that at this point, what we are seeing and what the data from the phase 2b is kind of making this more a bronchodilatory drug with additional flavor of anti-inflammation rather than the other way around. That does not mean that by the way, that it wouldn't change, and once it's in, I use foot in the door as approach. But if that's to be added to corticosteroids, probably it would be counting on anti-inflammatory. A quick commercial question. In your world, where is price gonna matter? Say this drug comes out, you love it. How hard is it gonna be to get for patients? What are you expecting, at least initially, for step-throughs? Or just describe the commercial side of your world. Yeah. You noticed that I said with roflumilast, what does insurance pay for? That is a big deal. I have to, you know, in full disclosure, my gym buddy is a Pharm.D. who works for PBMs and understands these things. When Chris told me first-in-class, because I was very worried. I have to tell you that revefenacin, Yupelri. I was involved in some of the studies, early publications, et cetera, I've not been able to successfully write for that drug because of insurers. Your question is very valid and important. It was not a first-in-class. Apparently, first-in-class gives it a special, and Chris or these people can tell you more about that, but it will make it much easier for me to be able to get that and have the insurer pay for it. I think that's a big deal. Hopefully. Hopefully. You know, I mean, you know, a disinterested gym buddy said, "Oh, yeah, that's a big deal." You know? Yeah. Yeah. Thank you. Yeah. It's Rahimi from Piper Sandler. Thank you so much for putting this together this morning. You both did, all of you, a fantastic job. A few questions. One is, you spoke quite a bit about the heterogeneity of COPD patients in terms of symptoms and characterization. As an analyst, we always look at phase 2, phase 2b data, and when we get to close to phase 3, we try to figure out what is the predictability of that data could be reproduced. Given your involvement with many clinical studies, can you help us understand? I mean, Verona has done a phenomenal job on matching the patients, the endpoints, the doses. What would you cap, right? Like, what probability would you assign that we should be able to see, you know, a reproducibility of the phase 2b into phase 3? You really are putting us on spot. Yeah, I did it. We love it. That's my job. Yeah. That's one. Good question. The second question that will come up upon the ENHANCE-2 data for many of us will be, how do I take that in trying to extrapolate exacerbation into the ENHANCE-1 study? I would love to hear your thoughts on both of these because we really spend a lot of time thinking about it, and then I have, like, a commercial question, if I may, if I am allowed to ask one more. You can ask another. Well, I can start with the real first question is what gives me hope that I can say that again. I'm observer from the outside, but the way that how nicely aligned two 2B studies were a fairly significant number of patients, right, 400 patients. I have actually, like, I think it is highly likely to expect alignment given that methodology's fairly similar. The real difference is in, obviously, in that kind of little extended period, longer duration. I would guess that it's definitely more likely than not. More than 70%? You know what that means. You cannot. In regards to ENHANCE-2 ENHANCE-1 translation from the data, given the two studies. What do you mean in particular? What exactly is when you mean, like, how what translation? There's two studies, ENHANCE -2 and ENHANCE -1. We'll get data from ENHANCE -2. Mm-hmm. The question will come up upon top-line data is, like, will the data from ENHANCE-1 be very similar or replicate the ENHANCE-2 studies given and/or can we also make some predictions about exacerbations and others when we combine the data sets? I think you know that there's an issue here in that I don't remember that exacerbations were not a primary endpoint. When they are a primary endpoint, the studies are designed differently. What they tend to do is enrich for exacerbations, so you have to have a history of exacerbations. While I think it will be whatever exacerbation data comes out at six months or a year will be titillating, I don't think you can take that to the bank, and you're a financial analyst, and you wanna take it to the bank. I think. What I would say about the design, basic design, and anticipation that things like the patient-reported outcomes and FEV1 values, I think the fact that this enrolled patients with a wide variety, way out, 70% predicted. Studies usually, you know, that's unusual. You can have bronchoreactivity, 20% on inhaled glucocorticoids. I think the fact that A was similar. I mean, there's more people with inhaled glucocorticoids, I think, in the initial studies, but similar in design. I think they also went from 80 to 70, so tightened it up a little bit. If anything, it would maybe give you better data. I don't know. The fact that you've got pretty well patients as opposed to very sick patients, I think all would portend well that you're gonna see similar data. You know, as they say in the vernacular, shit happens. Yeah. Then, both of you, just if you could quantify how many COPD patients do you see in one year? Upon ensifentrine being available to you, like, what percentage of those patients you would be really eager to put on ensifentrine? Those are questions that- How many do you see in a year? They ask me that all the time, it's like, I don't know. They're repeat offenders. Let me just say, I'm gonna answer this quickly for you. That is that, so our system, our medical system was bought out or not actually, merged with, not bought out, but merged with Atrium Health Center, which is a system, which is a huge. I'm on two of the integration committees. We first started out with, you know, all pulmonary diseases and what should we do with this and that. Finally, I was like, "Really? Just really, we have limited time here. We need to focus on COPD." What underpins that is 80% of all chronic respiratory diseases are COPD. In theory, we spend 80% of our time, or at least our outpatient time, and probably a pretty significant amount of our inpatient time on COPD patients, and we spend a lot of hours working. You know, maybe to add that, assuming that probably these studies would not show significance in exacerbations because they are not made for the Schedule six. Okay. Yeah. Assumption that I can make is that the approval would not go and target people who are in group B with exacerbation, but like addressing the symptomatic side. You're getting to really group B patients- Mm-hmm. which are already on long-acting muscarinic agonist. I would say that in that population of patients who do not have adequately controlled symptoms, that you would have actually high percentage of those who may be candidates. Simply put, of those group B LAMA/ LABA patients who are not satisfactory, who do not have, like, satisfactory control, whose FEV1 continues to decline. If this data stay clinically good with a good safety profile, and then as we mentioned, insurance and stuff, I think that actually you could easily get it, easily 50% of those patients can be considered early for this. Hi. Boobalan from H.C. Wainwright. A couple of questions to the panel. There were a lot of discussions about the primary endpoint, which is FEV1. I'm just curious, do patients actually care or give more importance to the FEV1 value as opposed to, say, shortness of breath or recurrent cough? What are your thoughts on that? I have a follow-up. I mean, if I start. No, I'm just kidding. I did start already. No, I think that you're getting in the right direction. The patient-reported outcomes matter. Actually, you wanna have objective measure and subjective. The way to go actually is combining. I think that it would be a riskier business to take a primary endpoint to be patient-reported outcome because of what I mentioned to you with it. I think if you have these two aligned, that's absolutely the best. There is. I think that they very appropriately are not neglecting PROs. Sorry. There were questions about exacerbation characteristics. Just curious, assuming ensifentrine is approved, assuming, let's just say, is it worth investing resources to study the impact of ensifentrine on exacerbation profile? Absolutely. How does it help the company from a commercial standpoint? You see us, we cannot even wait to say like. Yeah. No, these guys, if they actually Hands down. Yeah. If this gets to approval, I think that they owe us like a longer- Absolutely. longer lasting trial at some point to see whether, actually, they can expand the. Okay, one final from me. Can you comment? He's holding the mic. Go on. Can you comment on the drug-drug interaction profile of ensifentrine, especially maybe with antibiotics, assuming maybe the severe patients might be taking antibiotics? Or is it a valid question to ask you? I think it's a valid question. You guys know more about the drug-to-drug interaction. Kathy, do you wanna provide on drug-to-drug interactions? What the data's been on drug-to-drug interactions with us. On products in particular. Did you mean like QT prolongation of azithromycin or anything in particular with antibiotics? Overall, because this could be delivered on top of standard of care. Yeah, the patients in the study, they're not allowed to be on chronic antibiotics. That doesn't mean they haven't had them, 'cause if they have an exacerbation that doesn't require hospitalization, yes, we have groups of patients that have had antibiotics. We haven't seen any differences from that perspective. I did wanna go back to your point about the FEV1 just quickly, just to make sure you understand that the FEV1 is a regulatory endpoint that the FDA has not gone away from for decades. We have to do it, basically. Joon Lee. Hi, Joon Lee from Truist. Both of you, emphasize safety as a key, you know, metric you wanna look out for. Is there anything in particular you're looking for in safety, given, you know, broad distribution of PDE and the heart and the lung are tightly correlated, and also these patient groups tend to have a lot of comorbidities? It'd be helpful if you help us narrow down some key safety things that you're looking f or the data. If you look at the safety profile, it's shockingly clean in the initial trials. I mean, to the point where it's like, you mentioned that there was an abstract presented at the ATS about QT. Not being prolonged, you know, so that's been looked at. I think, you know, based on the previous PDE inhibitors, so theophylline, roflumilast, you're certainly gonna look at GI side effects. Again, if you look at the study and look at the list of side effects, you know, there was a long list of side effects, but there was, like, one patient. So when you have to drill down to putting in your chart of side effects, well, one patient had this because it was just that. I mean, when you think about it, when you run a study, you're running a, you know, six weeks, 12 weeks, whatever. What happens to people in a 12-week period? Will they get headaches? People do. Have you had a headache in the last three months? Have you had nausea in the last three months? The fact that it was one or two patients in each of these studies who had. They were equal numbers in the placebo group as well as the treatment groups. I was incredibly reassured from the initial data, from the phase 2 data. Did you get a chance to review the poster presentation at ATS? Which one? The T- The QT one? The QT. Yeah. Kathleen was telling me about it. I did not have a chance to look at it personally. Yeah. I did take a look at it, and I mean, it was fairly reassuring. I'm not getting into irregularities, but I saw the poster. Mm-hmm. Did you see the poster? Is there something we're missing? Well... Later. Any, Suji? Hi, I'm Suji Jeong from Jefferies. Thanks for your insightful discussion. So, sorry I missed this earlier, but could you tell us a little bit more about the characteristics of the patients that you might consider using ensifentrine for? I have a follow-up question. You wanna take that first? I've already answered it once. Yeah. I mean, as I mentioned, that there is a wide spectrum, pretty broad spectrum of people who may benefit. I think probably people that I would be first looking for, that I think this may align with, would be symptomatic COPDers, with or without exacerbations, who are already on a long-acting bronchodilator. I might even use it as a first line, especially in the older frail that you know already has a nebulizer at home, and I might just use it as a first line to see, get some bronchodilator, get some anti-inflammatory. I you know clearly think it has a role indeed for you know the person you've already pulled your hair out because you've given them everything else except the kitchen sink. I really think you know given the fact that there were patients from 30%-80% in the phase 2 trial baseline FEV1 you can feel that there's data to underpin using it as a first-line agent as well. I don't disagree with this. Yeah. Especially in somebody who you're gonna use a nebulizer anyway. When you're talking about using it as first-line, are you saying that ensifentrine is a monotherapy or on top of other bronchodilators? Monotherapy. I think you could use it as a monotherapy. I mean, 200 cc's in the phase 2 when used alone, you know. Why would you necessarily have to have it on top of something else? That makes sense. My second question is about trough FEV1. I think there is some debate about whether MCID of 100 ml for trough FEV1 is fair or not. You're shaking your head, so I guess it's not. It does. That doesn't exist. It's a non-concept. Mm-hmm. It's for peak FEV1, not trough. I see. When you are seeing the phase 2b data, the trough FEV1, it gets narrower to about 50 ml-ish, I would say. Does that concern you as for using ensifentrine as a twice-daily dosing regimen? Not really. Igor, do you have any thoughts on like the? Like, no, I mean, listen. This is, you know, the drug was both investigated as three times daily, twice daily. I don't think the trough per se is here, like the effect. If we're talking about bronchodilatory effect, that trough is still, like, significant and positive. With such significant peak, I'm not concerned, but it's impossible to say, right, that definitely does not make a difference. I think, though, with the data in twice-daily dosing, even accepting maybe lower trough than theoretically you could have with triple dosing, that is still worth making this. I think triple dose, triple three times a day would not be convenient like drug. I think this is a good kind of balance. I think the other point is just what is the impact of trough on symptoms? I don't- I think there was a paper saying that the trough FEV1 can correlate well with the patient-reported outcome, like St. George's questionnaire. By St. George's Respiratory Questionnaire, how many points difference? 2.5. Two point- Per 100 ml. 2.5 per 100 ml. Still not an MCID. For SGRQ, it's 4. I mean, that's again one of those drug company. Well, we had 10 cc difference, but it was statistically significant 'cause we have 5 million people in the trial. I don't know what that means. Yeah, it's hard. It would be purely speculative, right? Yeah. Maybe it's irrelevant. Maybe it is more relevant. I guess the results of this study also are gonna- Yeah. That answer. I think if you have clinical endpoints that are satisfactory, then probably that's the answer already to the question. Any other questions? Go ahead. You have to pay extra. One follow-up. The frail patient's intriguing, but what would they have to show to get it paid for? What would you have to. How do you get that past the insurance company? Failure. That's how you do it. It's failure. Assuming that there, I'm sure there will be some criteria that an insurer somewhere will make. As I say, this first-in-class thing is gonna make it, you know, much easier. My point is that it's just a neb is easier for somebody who cannot use a dry powder and because they're not strong enough to actually break those particles down to a small enough respirable level. Those people often also have the coordination issues with a metered dose. Metered dose is really, if you've ever tried to use one, and I use them frequently in demonstrations, and you know, invariably I get the stuff in my eye or my nose or whatever. They're very difficult to learn to use appropriately. Think about all the steps. Blow out fully, away from the inhaler. Put the inhaler this far away from the mouth. Actuate it. Inhale slowly and deliberately. Breath hold. Exhale. Let it do it again. And aiming it without the, you know, bulk of a spacer. I think the practical point is that the insurer is gonna say, "Show me that you used these other cheaper agents first, and they failed." That's probably what they're gonna require. Just one quick follow-up. Can you use that argument to get patients on Yupelri? You said I've given up. Even though there's so much time in the day, I don't bang my head against the wall anymore. I figured at some point the rep's gonna work with the insurer, and it'll be taken care of. You know, like, probably it's important to say that, yeah, Yupelri, we went through these struggles, but actually that's why the company has been proactive. For example, Theravance was proactive, and I start with the free specimens, and then they have these coupons with add to Medicare Part D. See, we're not allowed to have free. Yeah, we do. In that sense, like, with a proactive company, we were able to start, and we actually just made revefenacin nebulizer formulation right now. I've been trying that for- Yeah 3 years. It was a struggle of six months. Oh, yeah. Eventually we were there. I mean, that makes sense. Again, the things that you don't understand is like there's silos in hospitals, so there's respiratory care and there's pharmacy. If it costs the pharmacy a bunch, even though it saves even more for the pharmacy, if they're not for the respiratory care, they're not integrated. You know, for the entire hospital system, Revefenacin would be much cheaper than Atrovent 3 or 4 times a day because of the savings on the respiratory therapist costs. They're silos, so it's just kinda interesting. Sure. Quick follow-up question. Are PDE inhibitors, in your experience, generally resistant to tachyphylaxis? I'm only asking because the prior studies were shorter. Yeah, you know, these are for this agent, they're short studies, but my experience with roflumilast is tachyphylaxis is not an issue. It's not like beta, you know, LABAs. Does that mean that it's not gonna be the case in inhalational studies? Doesn't seem likely. Doesn't seem based on PDE- Right. Doesn't seem based on this, but- I don't know. I don't know the answer to this question. No. I don't know, Kathy, whether there's any data on tachyphylaxis. Well, we don't see any tachyphylaxis. I mean, in beta agonists and all, because the receptors are on the surface, and they internalize. There is nothing for this to do that with. To experience. There's no mechanism that- There's no theoretical mechanism. Yeah. Yeah. Yeah. A separate question. Why is LABA used so little compared to LAMA in the treatment? Mm-hmm. Is that the case also in Europe, outside of the U.S.? It's a practice pattern? ENHANCE-1 and ENHANCE-2 are trials. Yeah, I think it's advertising. Yeah. That it was, you know, it was bad for you, and it killed people. None of that was true, but it was, you know, retrospective studies, you know, that were not well-designed and so people got afraid of them. You know what we're referring to, right? Yeah. Cardiotoxicity. Yeah. LABA alone had the black box warning, and that was the reason why, I mentioned this earlier, that once Advair and Symbicort came up, and Kathy was part of that's why, like, there was amazing embracement of those drugs from pretty much someone who was on albuterol PRN. The next step was jump to ICS/LABAs. Again, it's really based on asthma data, not COPD data. Yeah. This is what it is, yeah. When it relates on asthma mortality. Right These patients may have been using their beta agonist without the short-acting, and so they're not dying due to the drug. They're dying because they don't have appropriate therapy from that, and that's been in big studies shown to not be a Yeah not an issue now, and it never was for COPD. I think the other thing too is generally held among clinicians, and something we haven't talked about yet, but I think is a really important concept is hyperinflation. While LABAs do deflate the lung, I think, you know, if you set up all the studies of LAMAs, LABAs, I think the data is clearly clearer, and that's personal opinion because there's data both ways. I think LAMAs do a little bit better job with deflation. That means that residual volume drops a little bit better with the LAMAs. We really haven't talked about the impact of that on symptoms. You have some data on that, but we talked about the indolent nature of COPD and the fact that people don't present until they're really in the throes of the disease. Some of the early abnormalities really are part of this dynamic hyperinflation, where when you're sitting at rest, you're fine, you're not short-winded. When you exert yourself, and so you increase your minute ventilation, increase your tidal volume, you begin to not be able to exhale fully. Your residual volume, your FRC starts to decline. What that does is it puts you way up on the compliance curve, so it's much harder to breathe. I do this with the medical students. I'll do it with you all. If you take a big deep breath in, and don't let it out, but now try to take your tidal breaths on top of it. It hurts. If it doesn't hurt, do it while you're on a flight of stairs. This is what makes people with early COPD take to the couch. I think it's, you know, again, why do I think this might be a good drug for as a first-line? Because it's also a good dilator like the LAMAs. You take the next question. Sorry. Maybe this one is a little easier and straightforward. Have you guys seen sort of behavioral changes in the ability to answer these questionnaires in your patients post-COVID or during the COVID pandemic? 'Cause you did point out that some patients don't recognize, you know, like, their symptoms or don't wanna admit that. Do you think, like, with COVID, during the COVID era, wouldn't COPD patients maybe a little bit be, you know, worried, right, and maybe say, you know, "My symptoms are far worse." Is there a change in their behavior in answering questions during the pandemic that you noticed are really not really there? No, that's a good question. First of all, we are exploring that effect. I can tell you that the most of observational longitudinal cohorts right now that are ongoing are joining forces to recognize the impact of COVID, and actually people who had it and people who did not have it. You could argue that the effect of pandemic goes both ways. You know, we've got data that COPDers are doing poorly with this, but on the other hand, in experience, our COPDers had the best years in their life. Absolutely. Right? Yeah. Which by pretty much shows that the triggers for exacerbations are very often the exchange of viruses, right? Paradoxically, they had a fairly stable year without many exacerbations. As you know, like, exacerbations do make the lung function and have the impact and predictors of future exacerbations. I would say that really theoretical consequence can go both ways, that they go either toward better or worse symptoms. The other thing is that independent of pandemic, the PROs are also a little bit dependent on many other outside factors such as seasonal effect, et cetera. Fluctuation is very possible. I read somewhere yesterday, day before yesterday, that exacerbations are down by 50%. I don't know about you, but, you know, in studies that require exacerbations, they've been much harder to recruit. Yeah. I felt much better that, geez, I haven't lost my touch in recruitment, that exacerbations really are down 50%. Yeah. Yeah. I think that might have been the last question. I wanna thank Igor and Jill for spending the day with us today. We have a few slides to kinda just close the meeting out. Again, thank you both for coming out of your practices, spending the day with us. It was really helpful. They'll be around afterwards, so if there's questions you wanna ask, I'm sure Jill and Igor wouldn't mind answering them during that time as well. Again, thank you very much for the time. Thank you. Thank you, actually. You have great questions from you guys. Yes. Do you want us to move the chairs or you can? We can leave them. You can project the project. Yeah. with chairs there. Okay. Yeah. All righty. As we think about the opportunity that exists with ensifentrine and what Jill and Igor talked about today, there are over 1 million patients that are still symptomatic today, and those patients are in search of new mechanisms. They're in search of new drugs. I think Igor and Jill both talked about this today, of a need to be able to do something outside of the LAMA or the LABA to help these patients. These million patients are very receptive to the idea of ensifentrine. If we think about how that applies to what the opportunity for ensifentrine looks like, if we have a million patients here, what we see from our market research is very similar to what Igor and Jill said. We're gonna use ensifentrine on a lot of our COPD patients. In a third of their patients in COPD, they believe they'd use ensifentrine in. You take that to where's the patient? We heard Jill say, I'd use it early, I'd use it late, and that it spans. There's about two-thirds of the patients are on dual or triple because they don't have any other options. They see ensifentrine as a very broad molecule within their practices. The last thing here is what the pricing is for nebulizers today. Ensifentrine will be an N of one in the compendium. There's no other PDE3, PDE4 that's on the market. That has market access implications. The pricing for those products are at about $1,100. If you take $1,100 with the 1 million patients and the share, you see a significant opportunity for ensifentrine at launch. The key thing here is it's in the physicians, the physician community like Igor and Jill. It's in pulmonology. 100 reps can reach that opportunity and allow us to be very effective in getting ensifentrine to the patients and the physicians that need it. That's just the tip of the iceberg. Dave talked about this a little bit too. You know, we're talking about COPD today with the nebulizer, but we have data in a DPI or MDI. We could combine it with another product, a LAMA. We also have data within cystic fibrosis or asthma as well. This product has utility outside of what we're talking about today. Our upcoming data milestones allow us to tap into the potential of where ensifentrine can go. We're well positioned. If we think about Verona as a whole, Dave said we have 2 data readouts potentially this year. ENHANCE-2 is in Q3 of this year. ENHANCE-1 will be around the end of the year. We have a large market, 1 million patients, very focused. Finally, our cash runway gets us through the end of 2023 so that the work that we have to do internally is funded as well. We feel very confident in how we can capitalize on this opportunity with ensifentrine. Again, you guys spent an hour and a half of your day with us. We greatly appreciate the time. We will be here afterwards if anybody has any questions. Happy to answer questions commercially or medically as well. We appreciate everybody spending the morning with us, and thanks again.