Verona Pharma plc (VRNA) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to Verona Pharma R&D Day. It's a pleasure to be here in person after a couple of years and see everybody on this rainy New York Day, but welcome to you. Welcome to everybody on the webcast as well. I'm Dave Zaccardelli, CEO of Verona Pharma. And what we plan to do today is spend some -- just a few minutes grounding us in a presentation on ensifentrine but, more importantly, have the opportunity to hear from 2 amazing physicians, treaters of COPD and KOLs. And very happy to have Dr. Igor Barjaktarevic with us today as well as Dr. Jill Ohar. And 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. So with that, I just want to spend a few moments on having everyone really understand the landscape of the COPD with regard to treatments. Really, the takeaway message on the slides is while there appears to be a lot of medications available for -- with the inhaled route of administration for COPD, it's really just 3 classes of drugs which have been used for decades to treat COPD. And that's the LAMAs, or long-acting muscarinic antagonists; LABAs, long-acting beta agonists; and inhaled corticosteroids. And really, every product out there is either a single or combination of these agents. And with this treatment, which has been, again, quite consistent over decades, there -- in the U.S., there is still at least 1 million patients that are still symptomatic and need additional therapy. And 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. And something to keep in mind in the U.S., most patients are treated on either a single, typically a LAMA or a dual therapy. And most patients with that need additional therapy that -- because they remain symptomatic. When we look at ensifentrine and its mechanism of action, keep in mind it acts in 3 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 and 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. And 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 III program with ensifentrine, it was really grounded in all of our clinical trials, but also specifically 2 large Phase II trials, Study 203 and 205. 203 was ensifentrine as monotherapy; and Study 205, ensifentrine on top of background therapy, in this case, LAMA, tiotropium. But 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 is measured by peak FEV1. And 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 III trials, as you'll see. But very important studies, over 400 patients each, a very consistent performance on lung function. But in addition to that, which was impressive enough, it also over a 4-week trial showed very consistent improvements in symptoms and improvement -- and quality of life improvement. And this is 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 4-week duration while on ensifentrine. And also, we did see that improvement for quality of life via the SGRQ in Study 205, again, improvements happening relatively quickly and improving over the 4-week study duration. So our improvements on lung function as well as improvements in symptoms and quality of life was really the cornerstone of us moving forward into Phase III. And we've built off this confidence in two large Phase II trials. We talk a lot about efficacy which is important and really reason we move forward but equally important is the safety we've seen with ensifentrine in the clinical development program. And as noted here, it's been studied extensively, 19 clinical trials, close to 1,000 COPD patients. And 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 and specifically when you're looking at PDE3 and PDE4 mechanisms, you want to look at gastrointestinal AEs through PDE4 and we see that's very similar to placebo, cardiovascular AEs via PDE3 and again very similar to placebo, including a successful thorough QT study which really looked at conduction after giving supratherapeutic doses of ensifentrine with no effect on conduction. So we are very comfortable with the safety profile seen to date over 4-week studies and 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. So I think one thing to look at about our studies in Phase II and why we are confident in our Phase III program is that we kept things fairly consistent and where our learnings from Phase II, we carried over to Phase III. When we look at the study of the population, the patient population, we're selecting the same types of patients, moderate to severe COPD. We selected the dose from Phase II. We're moving on with that in Phase III. The studies while larger in Phase III are not substantially larger, going from 400 to 800 patients. Length of study, again, typical, moving from -- in COPD from Phase II to Phase III but 12-week for the primary endpoint, 24-week for our secondary endpoints and, of course, 48-week for safety. But our endpoints and our entry criteria really are kept quite stable between our Phase II and Phase III 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% to 70% predicted FEV1. And as I mentioned, our key endpoints are very well characterized via our Phase II program and so really are -- while there's always risk in clinical research, we feel very good about that we've mitigated that risk moving from Phase II to Phase III. So what should you keep an eye on and where are we and what's coming up? So we have guided to, and we continue to that 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. So 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 will lead us to submitting an NDA in the first half of '23. Based on that, we would expect an approval, based on a PDUFA date of around first half of '24 or pushing mid-'24; and then, of course, based on a favorable response a commercial launch in the second half of '24. So a lot of progress has occurred in the past couple of years, and we're really at the endgame as far as ensifentrine's performance in Phase III 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 II. We're powered at 90% to detect a 59-milliliter difference in the improvement of lung function as measured by average forced exploratory volume in 1 second, that's FEV1 over 12 hours. And that, of course, we saw a much greater effects in Phase II, but we're powered at 59 milliliters in this trial. Secondary endpoints, again, power -- 90% powered at levels that are below what we've seen in Phase II. So again, we think we're well structured in order to detect these differences in the trials. And as always, safety will be part. And 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 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. So with that, I just want to convey we're very excited about where we're at. And we look forward to updating everyone in Q3 on the results from ENHANCE-2. So I'm going to turn it over to Chris Martin, who's going to lead us through the next phase of the presentation and really here, as I mentioned, from our KOLs that are with us today. So thank you very much.

Thanks, Dave. So I think we're excited to have both Igor and Jill with us today. I'm going to let each of them introduce themselves, and Kathy is going to join the panel as well just to provide her perspective as our Chief Medical Officer here as well. But 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.

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, I'll tell you a little bit about my practice. It should. It's one of the few cities in America named after 2 cigarettes. It's the home of RJR. Many of my patients actually grew up on tobacco farms. They raise tobacco, so it is part of our fiber. What I can say about COPD is something that Igor and I were talking about a little earlier, which is the fact that, that COPD is an indolent disorder. Most people don't present to a doctor until they're in their mid-50s or 60s. By then, Doug Maple 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. So they've already dealt with probably 10 to 15 years of significant symptoms attributing it to a smoker's cough, attributing their shortness of breath to getting older, getting a little fatter, et cetera. And so there are a huge number of patients out there that, number one, discount their symptoms; and number two, that are undiagnosed. So a huge, 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 -- and 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 patients refill their scripts only about 1/3 of the time for their maintenance meds. When you asked 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. So they clearly in their head discount their maintenance meds. Your turn.

Well, no, thanks, first of all, for being here. And thanks, guys, for inviting us. Obviously, both Jill and I like to talk about COPD, so you just like -- ask it, and then we go on. But 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 21st 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 and I then find this topic on a novel molecule that you guys have is very intriguing. And I'm happy to be here.

We appreciate this. And 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?

We'll, that's a good question. I mean really, the problem and frustration is -- actually Jill and I sat here as we're kind of waiting for this meeting and just like kind of sharing frustration of, you used the word indolent or insidious process. But this is something that is developing over a long time. It kind of comes in a sneaky way. Very often, a smoker who coughs and can do less takes this like, "Yes, it's my smoking cough and I'm aging." But the fact is that actually it comes in that sneaky way in very often or, unfortunately, the most often when we've diagnosed 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. And that is probably the most frustrating thing that we have. So just maybe a little reminder of like if we do a little bit zoom out, but we have around like 15 million to 25 million of people with COPD in the United States and over 300 million in the year -- in worldwide. And when you look at the hospitalizations, we have, I think, the numbers that we often use are around 700,000. We are talking about 140,000 deaths of COPD. Then when you extend to other smoking-related problems that kind of goes significantly higher. And then when we really look at the hospitalizations of people who are over the age of 40, I think 1/5 or 20% or 25% of all hospitalizations are actually related to COPD. So probably when I give these numbers, it's easy to see why are we as frustrated as we are. So 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 confirm having COPD, everything first starts with the nonpharmacological 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 2 interventions that are mortality -- have clear mortality impact at this point is, stop smoking and use oxygen if you need oxygen. So certainly, those are first interventions that we certainly need to do and then address this nonpharmacological. And then on the pharmacological side, obviously, 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. And based on current guidelines, there is a kind of fairly clear algorithm of how do you build up. But 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, what is the effect you're looking at for these patients? When they come back in 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, GOLD changed several years ago and focused on symptoms. And I mean, really, that's what patients really care about anyway. And so -- I use a validated symptom score for both the baseline and then follow-up because I -- 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. So I use the CAT. It's one of the symptom scores that GOLD uses. It's the COPD Assessment Test. And 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." "Do you Wheeze?" "Sometimes." That kind of thing. Then when I actually get to the CAT, which says, "rate your cough on a scale of 0 to 5." And they'll go 3. It's like, rate your sputum. I have no phlegm in my chest, 0. My chest is full of phlegm, 5, 4. And so I think 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, "Jeez, I'm not right where I need to be yet, I need to move on to a double or a triple or 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. So another modality that we're ignoring.

Yes. So -- and 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 you -- like how do I choose a DPI, MDI or an inhaled nebulizer? And what -- how do you think about those in your mind?

Well, we have a world expert that's here. So I can humbly start. The reality is that we have inhaled therapies are delivered through nebulizers and handheld devices and all kind of go back like over 50, 60, 70 years. Nebulizer started as a kind of devices that were used earlier and with the drugs that go every 4 or 6 hours, noisy, big. So kind of when we got with handheld devices in 1950s, '60s, 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. But the fact is that nowadays, when we have long-acting drugs dose -- and with development of nebulizers that are better, smaller, easier to maintain, we got actually in our spectrum that we have both nebulizers, handheld devices is very useful and then useful in terms of tailoring to what is the patient that I'm treating. And very briefly, and that's going to be probably intro to Jill to kind of come with more details. But in general, each of those approaches have some pros and cons, obviously. So certainly, nebulizers have the advantage that it's a normal tidal volume reading. So someone who's demented, who has lack of ability to take, to pull hard, actually who has problems with rheumatological diseases, is actually hospitalized, for example, is 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-to-mouth coordination because the device requires an immediate press, press the button and inhale at the same time. So as you can see, when you look at the patient in 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. But I don't know whether it's a good intro for you to...

That's good. Yes. Very well. So each of these devices is outstanding in its own right. And I think that's really important to understand. Whereby metered dose inhalers are small and compact, most people can't manage that hand-mouth coordination. And you really, for the most part, even the newer HFA devices require about this much space between the mouth and the nozzle or 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, you get an oral dose. So 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. And every patient has a controller medicine and a rescue medicine. The rescue medicines tend to come in metered dose inhalers. A lot of the controller medicines come in dry powders. Dry powders require the -- if you -- and 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 were involved in the development of this. And so the dry powders literally use that technology. It's a ribbon of compressed drug. And so the drug -- so when you open the cap, and they're very easy to use. As opposed to a metered dose inhaler, I have to inhale slowly, I have to coordinate, I have to have it this far out and it ends up in my eyebrow or my ear. 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 5 microns, okay? If you -- instead of -- you don't get the drug in your lungs, you get it in the back of your throat, and you get an oral dose. So 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 draw and 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? And so there's that. So 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 patients -- for the most part that your patient gets the drug, because of the fact that they have their mask, they sit there, they -- all they have to do is breathe. There's not a whole lot of volitional issues. Now so they're not so clunky anymore, but they do require cleanup. So that makes them a little more difficult. But with the med, this BID, there's much -- it's not like you're cleaning them 4 times a day. Furthermore, we have people 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 powdered inhaler. And 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 rehospitalized 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. And finally, we thought, well, just maybe it's because they're frail. So we have an e-frailty index on them and the e-frailty index, there's no difference between the groups. So it seems that this really is impacting on their health care 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?

Yes. Actually, this ability for the population, that's another way to kind of help those who do not have strength. But if I may add, pretty much to kind of wrap this up, the new and novel molecules are developed for all devices. So while we had maybe in early 2000s more like push on the novel molecules in the handheld devices, we have explosion of the new approaches with nebulizer recently, with long-acting muscarinic agents, with long-acting beta agonist, with alpha-1 antitrypsin deliverable therapies, this type of molecules with mucociliary clearance approach. So in that sense, I think like, I feel that there is future for absolutely all and all need to 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. So what's your perspective on ICS's role, how it fits in? Where should it be used? Are we over using it? What are your perspectives there? Igor, do you want to start? Or...

Sure. So 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, it goes to the point that there are pros and cons of steroids. And even if they are just inhaled corticosteroids before all that relates to suppression of immune responses in the micro -- lung microenvironment, thus leading to potentially lower respiratory infections and pneumonias. And at the same time, there is anti-inflammatory effect, but you could argue that, theoretical, there is some trade-off, that you may have less inflammation but more infections and the other way around. But 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. But more important than anything else, the steroid approach to inflammation is really pretty much using the overall, let's shut down, let's use the sprinklers to get that little fire in the corner. And that is the reason why actually, over the 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 most of us, pulmonologists, involve in COPD almost feel that you have these groups of really those very much into steroids and against. We know that when you do a snapshot into 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 a combination of ICS and LABA. The reason 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. But 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 reduce exacerbations. Then we have couple of studies such as FLAME, SHINE, WISDOM trial that actually showed both that LABA/LAMA combination, bronchodilators, long-acting bronchodilators reduce exacerbations that taking person off inhaled corticosteroids, a person who does not have exacerbation is safe. But nevertheless, in the past 3 years, right, with the IMPACT and ETHOS, we got a couple of big trials, the 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 -- to some mortality. So that's maybe I'm trying to simply present why there is that little controversy. So the role of steroids is not very clear. And currently, in the GOLD guidelines, GOLD guidelines defines COPD or kind of tries to describe the patient that is sitting in front of me not based on what the FEV1 is but based on how symptomatic that patient is and how many exacerbations and flare-ups patient has. And based on this, as you know, patients are divided into group A, B, C, D. A being no exacerbations, no symptoms. B being the opposite. So currently, GOLD guidelines in group D recommends 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 2020...

'20.

2020 was that inhaled corticosteroids are even potentially bypassed in select patients who actually have low eosinophils. Based on eosinophils, we saw more eosinophils with better response to steroids and vice versa. So 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 going to stop here and maybe...

Yes, I just want to summarize it. I think GOLD'S quite clear that if you have at least one severe, defined by hospitalization, or 2 moderate exacerbations in the preceding year, you're candidate for inhaled glucocorticoids. If you're -- if you don't have that, but maybe you're having poor control, so to speak. So 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 spells like that. Maybe one moderate, which means that at home had to have a steroid or an antibiotic script, maybe those people, certainly, if they have a high eosinophil count -- and really people argue about this. It's kind of like prunes, is 3 too many, is 2 enough. And 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 can agree that if you hit 300 with some regularity and you have poor control that's also, in addition to somebody who has had at least 2 moderate or 1 severe exacerbation in the last year should be on an inhaled glucocorticoid. But I think everybody agrees that they're overused as well.

They're overused. And maybe a practical situation that we face very often is that someone who is at that stage, significant symptoms of exacerbations oftentimes has colonization with different bacteria, nontuberculous mycobacteria, Pseudomonas, Aspergillus, bugs that we see very often with chronic bronchitis, bronchiectasis. And you get into this like logical dilemma, right, am I hurting my patients with giving these steroids or I'm helping. And that, unfortunately, is very common. So in that sense, we're learning over time that the therapy in COPD needs to be customized. They need to be adjusted to the patients. And we're hopefully moving in the right direction. But that is why, again, the role of steroids absolutely is there. And they are very significant group of drugs. But it's just -- they're not meant to just follow absolute cliche.

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...

Very, very, very loosely, I mean, if you have 1,000 patients, you're going to have a scattergram with a line that goes through that. But we don't treat FEV1 anymore. Back early in my career, we treated FEV1. Just like we don't treat X-rays, we treat the patient, we treat symptoms, and so really, in this age, we -- and FEV1 is important to make a diagnosis, and 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 disproportional prevalence of common comorbidities. So if you think about all smokers, Venn diagrams, remember third grade, Venn diagrams, okay? The 40% that get COPD, so all smokers, 40% gets COPD. If you look at coronary artery disease, cerebrovascular disease, osteoporosis, diabetes, metabolic syndrome, 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. So all of this impacts on these patients as well on your treatment decisions.

Yes, maybe practically speaking, all of us see these 2 patients sitting in front of us with FEV1 of 50%. And that 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 fairly preserved quality of life without exacerbations. So that actually drove us to the fact that, by no means FEV1 is a relevant piece of information. We can only diagnose COPD after we have FEV1, right? And 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 do you think -- what are some of the unmet needs that are there for you as a clinician today within COPD? What do you guys -- what do you need from them?

Yes. So as I mentioned before, I often use a CAT score to see where my patients are. And in reality, GOLD wants you to have a CAT of less than 10. And that's not a reality in any of my patients. I mean -- do you have any patients who have CAT of less than 10?

No, you're right. CAT of 10 may not be actually sensitive...

Well, I got that now. Yes, but I mean people are starting to talk about that. But I think it's a construct that if I'm in the teens in terms of a symptom score with the CAT, I'm feeling like I'm doing pretty well. So my point is that despite my best therapies, my patients are still symptomatic. They still feel like they need something more. And I remember a couple -- 2, 3 years back, getting a call from a colleague about, 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 what you have is what you got, have a nice day.

Yes. No, that's actually very big and important thing that really in COPD, first of all, we do not have ability to restore the lung function. So that's frustrating. Secondly, we don't have really mortality impactful drug. Third, we are really spinning about the 3 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, more sophisticated drugs within the class, but it's the same class and inhaled corticosteroids. So I think we can agree that we are 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, but we, physicians treating COPD need new molecules.

That's really helpful and 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, different pathway than what you're used to? So how do you interpret that potential mechanism in your mind. Igor, and then, Jill, if you want to add to that?

So phosphodiesterase inhibitors, actually, are pretty broad class. I mean I bet that most of us had at least one this morning with coffee, right, so caffeine actually is just not selective. Theophylline is PDE inhibitor. PDE inhibitors come through various kind of flavors and very different diseases, right? So 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 experienced and now have fairly substantial experience with PDE4, which is an anti-inflammatory kind of a mechanism with Daliresp, with oral medication that we use quite a lot despite it's 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 with inhalation approach. So we are combining 2 different completely mechanisms, right? Through PDE3, we're talking about bronchodilation; through PDE4, we're talking about anti-inflammation. So it's very unique. So the first time I heard about this molecule, I certainly was impressed that pretty much with these 2 properties you are covering everything that all other classes that we have so far are tackling. Certainly, very comprehensive approach.

Yes, I would agree. I think being old enough to have used theophylline and being aware of all of its toxicities, where the therapeutic area or the doses or where the actual serum levels for therapeutic versus toxic actually overlapped. And so you never knew where you were. Or 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, in my mouth and far away. All of those vagaries of the inhalation devices are obviated by a pill. So 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 the 250 dose, and I have not really -- I've 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.

Yes, just don't do it. So I like the idea of this new molecule, which is both PDE3 and 4, so you're going to get the bronchodilatation. In theory, the bronchodilatation 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. So 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 will break traction faster that way. Then as the other device formats become available, it will have a pathway to glide on.

That's helpful. As we think about that mechanism, we've seen Dave showed some data earlier regarding the Phase II on FEV1 and symptoms. Jill, what's your perspective on that early -- the Phase II work that we've shown on ensifentrine? What's your takeaway from that?

So alone at 200, I mean, it's right up there. We were talking about tio, the original tio study. So the 200, that's very impressive. It's twice the MCID. And then as an add-on, you never anticipate that you're going to get the MCID for a single agent, and you did. As an add-on, you got 100, 123, in that range. So I think that this is a very impressive first blush set of data. I'm very impressed by it.

Igor, any other thought?

Well, when you add the quality of life that you add to the FEV1 change, I think, certainly, this is way to go. So I think that it's been now like, what, 3, 4 years since we know about these like 2a or 2b results. Honestly that gave the most enthusiasm why I am here also today. I think that was the right -- I mean it's probably as good as it could have been, in my mind.

That's very helpful. Jill, you mentioned something there about MCID. Can you kind of walk through that concept of what the MCID? 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. And there's some argument it should be a little higher, it should be a little lower. But that's a single agent. We don't know. No one knows when you pair a drug with another agent on background, so in this case, if you put ensifentrine on top of tio, tiotropium, what's -- we have -- do not have a defined MCID for what we would anticipate on top of that. But the fact that you got a peak of 123, 100, 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, 80 as an add-on. So I'm very impressed with it.

I mean if I may add just the whole concept of minimal clinically important difference is there that we do not get stuck with the statistics, right? You may have a study proving that they're statistically significant, but we are adding this as a kind of double control measure. So you prove statistical significance and then show that you're making clinical significance. That's the idea behind MCIDs both in FEV1 or as St. George's Respiratory Questionnaire as a quality of life.

And if I heard correctly, what you're saying is MCID on peak is established but not necessarily on add-on or an average.

Not on average. And I guess like what I neglected mentioning is what does it really mean to a patient. So 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 the statistical significance. And there's that old saying, there's lies, damned lies and statistics. And if you put enough patients into to a study, you can get statistical significance with 4 cc difference in FEV1. Does that mean anything to your patients? So that's where that concept of MCID came into is what does that really mean to my patient. Can my patient feel a difference? And so this has been defined by many endpoint measures that are used in pharma trials now. But 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 and that's pretty much it.

There is more complexity to this. Like for example, the study, actually, I had to look UPLIFT last night. But like the trial, for example, that got Spiriva and then got LAMA into the clinical practice. The primary endpoint was actually FEV1 loss, right, declined normally after the age of 25...

That's right, it was, you're right.

We lose around 30 -- 20 to 30 cc FEV1. Arguably someone with COPD with exacerbations losses more. So 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, what is kind of natural decline. So everyone is a great endpoint in the short -- like your 2B was 4 weeks, right? So that's more like manifesting pharmacokinetics of the medication and really showing the acute effect. But 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 with Don. 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 do you have to have the best estimate of the decline. So that gets kind of incorporated in your 3b that you need to take it a little bit with the grain of salt, the improvement.

And so then the symptoms and quality of life become an important aspect.

More important, yes.

Yes. Okay. So let me -- let's go to that Phase III design. What are your thoughts on the Phase III design, Igor? When you look at that Phase III 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 apply the concept that works. You selected the well-validated endpoints. So I don't know what's going to happen with this. But 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. So we'll see actually how it pans out.

Jill, any other thoughts?

Yes, I agree. I think, clearly, the 3-milligram dose was an important decision. I like the idea of symptom endpoints because, again, a change in FEV1 without really making a difference in the patient's life is really not where I want to be.

No, that's really helpful. So let's -- now let's take this -- let's put you in a time machine. We go forward. We have data. What is -- in your mind, what would you want to see out of that data from a result standpoint? Like again, we're -- it's not about the numbers, but in your mind, what would you like to see out of that? Jill, do you want to go first? I'm putting you on the spot here first.

Yes. I think that -- I think what I'd like to see is an MCID for your symptom scores, I think that's probably the first thing. As an add-on, again, how many -- you want some FEV1 change. That's kind of internally validates that. What's that number? Certainly not at 100, maybe in the 70, somewhere around there because it's an add-on. You have an incredible safety profile in the short range, so I'd be interested in the ongoing safety profile. Does it continue to be that good? Also, I'd like to look at the dropout rate because I think that there's hidden messages in who dropped and why. So I think those are the things I'd be Interested in. Igor?

Yes. No, first of all, I would say that, really, that nice safety profile that you have is going to be like very important to be 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. So if you get what's powered there that's like you're golden. But even if that's not exactly reached, I would not kind of 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 in the recent study we think that we've done, just completed, the drugs that obviously showed great improvement in FEV1, in SGRQ, et cetera, still hit placebo SGRQ effect that blunted the statistical side of SGRQ. So I would -- pretty much what I'm trying to say is that I hope you're going to 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 going to ask both of you on that one. So I'll let you guys fight over who's going to do this first.

No, it's fine. Let's do it.

Since you just talked, I'll let you rest. I think you could use it a lot of different ways. And I think in practice, out there in the hinterlands, not here but out there, a lot of times, doctors will use a drug that's in their supply cabinet, frustrated with how the patient is doing and say, hey, try this. Or they'll -- it's a new patient, hey, try this. So I think that it has applicability as a first-line agent as well as an add-on.

I was thinking like the answer to this question is like, it's a million dollar but not million, multimillion. Obviously, the question is that 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 multiple stages, I mean, you literally, theoretically, if I am 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 maximized inhalational therapies. I remember when your first data came out that was the dilemma. And obviously, this dilemma even nowadays can be looked at. But I think that you probably picked in my mind a reasonable approach that you really look what's happening in earlier stages. You always are recruiting population of patients who is symptomatic. So I think that -- so 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. So 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 going to turn gears now as you've talked about that to the future and what's 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...

Certainly, there are biologics that are out there. And we also had that conversation sitting here earlier is the idea that -- actually Kathy's mentor, Steve Renard, one time said in a lecture that COPD is an orphan disease. Orphan diseases, you think of as affecting very small numbers of patients. And what he meant by that is, is that it really is a grouping of many, many different kinds of orphan diseases because there are so many different phenotypes of COPD that it's difficult to quantify who's affected by which. And I think especially the biologics are affected by this. I mean bronchodilators are bronchodilators. You have obstruction, you're in bronchodilators. You have inflammation, you give them ICS or maybe a PDE inhibitor. But other than that, that's kind of the landscape for the broad COPD patient. Once you get into biologics, which are, I think, probably the only landscape right now coming down the path, you're going to have to find a very specific subset phenotype of patients who have COPD that they're going to be helpful in. And we've just not been successful at this point. Would you agree?

No, no, that's absolutely correct. I mean -- so first of all, what's in the pipeline of the small molecules, maybe first of all, LABA/LAMA, we have multitude of medications that are developed. They are longer lasting. They are novel concept. We do have small molecules, maybe combination molecule of MABAs or combination of muscarinic and beta-agonist. But 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, yes, 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. So we're sticking to this, it feels like crazy right now, that they are effector cells. 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 in biomarkers. In that sense, I would say simply, biomarkers will be developing, but biomarkers require from one size fits all to personalized and, hopefully, toward precision medicine. And we're not there enough. I think pretty much development of biologics is a completely separate and doesn't have much to do with this kind of thing.

That's great. I appreciate that conversation. I think what we want to do now is bring David up here as well and kind of have 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. And if Dave or anybody else has questions, we can answer that as well. So we'll go to a larger group.

Tom Shrader from BTIG. All of these events are great. But to return to roflumilast, if that were a completely clean drug, how exciting would it be? What fraction are your patients? I'm curious, is ensifentrine going to be mostly a bronchodilator drug in patients' minds? Or will the exacerbations be meaningful?

Well, if I start, roflumilast is a clean drug. It's an oral drug, it has a GI kind of side effects. It has its limitations because of this. But again, its position currently based on GOLD guidelines go after the inhalational approach has been exhausted. Usually, that's a drug that comes -- or for people who are already on triple therapies. The 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 we actually -- that GOLD recommends, right? So nowadays, we have 3 pills that technically are in the scope of regular interventions in COPD. One is Daliresp, the other is azithromycin, antibiotics and anti-inflammatory. And then we have N-acetylcysteine that also has some kind of data that show towards reduced exacerbations. So 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. So you have to get insurance to pay for it, you have to have severe COPD. You have to document chronic bronchitis, mucus production and exacerbation frequencies.

So 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 IIb is making this more of 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. Once it's in, I use foot in the door as a approach, but if that's to be added to inhaled corticosteroids, probably it would be counting on anti-inflammatory.

Then a quick commercial question. In your world, where is price going to matter? Say this drug comes out. You love it. How hard is it going to be to get for patients? What are you expecting at least initially for step-throughs? Just describe the commercial side of your world?

Yes. So you noticed that I said, with roflumilast, what does insurance pay for? And that is a -- that's a big deal. And so -- and I have to -- in full disclosure, my gym buddy is a PharmD who works for PPOs and understands these things. And so 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. But 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, much easier for me to be able to get that and have the insurer pay for it. So I think that's a big deal.

Hopefully.

Hopefully. But from what -- I mean a disinterested gym buddy said, "Oh, yes. That's a big deal."

Yas Rahimi from Piper Sandler. Few questions. One is, you spoke quite a bit about the heterogeneity of COPD patients in terms of symptoms and characterization. And so as an analyst, we always look at Phase IIb data. And when we get to close to Phase III, we try to figure out what is the predictability of that data could be reproduced. So 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 reproducibility of the Phase IIb into Phase III?

You really are putting us on the spot.

Yes, I did -- that's my job. That's one. And then maybe...

Good question, though.

And then the second question that will come up upon the ENHANCE-2 data from many of us will be, how do I take that and trying to extrapolate exacerbation into the ENHANCE-1 study. So 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'm allowed to ask one more.

Well, I can start with the really first question is what gives me hope that I can say that, again, we're -- I'm observer from the outside. But the way that how nicely aligned IIb studies were a fairly significant number of patients, right, with 400 patients. I have actually, like, I think that it's highly likely that to expect alignment given that methodology is fairly similar. The real difference is obviously in that kind of little extended period, longer duration. So I would guess that it's definitely more likely than not.

More than 70%? And then in regards to ENHANCE-2 -- ENHANCE-1 translation from the data given the 2 studies?

But what do you mean in particular what exactly is -- what do you mean, like how -- what translation?

So there's 2 studies, ENHANCE-2 and ENHANCE-1. So we'll get data from ENHANCE 2. And the question will come up upon top line data is like, will the data from ENHANCE-1 be very similar or reciprocate of the ENHANCE-2 studies given? Can we also make some predictions about exacerbations and others when we combine the data sets?

I think there's an issue here in that. I don't remember that exacerbations -- they were not a primary endpoint. And 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. So while I think it will be whatever exacerbation data comes out at 6 months or a year, we'll be titillating. I don't think you can take that to the bank, and you're a financial analyst and you want to take it to the bank.

I think.

But 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% are predicted, somebody is usually -- that's unusual. You can have broncho reactivity, 20% on inhaled glucocorticoids. So I think the fact that it 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, Tightened it up a little bit. If anything, it would maybe give you better data, I don't know. But -- and the fact that you've got pretty well patients as opposed to very sick patients, I think all would portend well that you're going to see similar data. But as they say in the vernacular, s*** happens.

And then both of you, just if you could quantify how many COPD patients do you see in 1 year. And 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? it's been a long time, I'd say day don't know. They're repeat offenders. Let me just say here's -- I'm going to answer this quickly for you. And that is that -- so our system, our medical system is bought out -- not actually, merged with -- not bought out but merged with Atrium Health Center, which is a system which is huge, huge, huge. And I'm on 2 of the integration committees. And we first started out with all pulmonary diseases and what should we do with this and that. And finally, I was like, really, just really, we have limited time here. We need to focus on COPD. And what underpins that is 80%, 80% of all chronic respiratory diseases are COPD. So 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.

Maybe to add that assuming that we cannot -- probably these studies would not show significance in exacerbations because they are not made for [indiscernible]. So assumption that I can make is that the approval would not go and target people who are in Group D with exacerbation but addressing the symptomatic side. So you're getting to really group B patients, 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 a high percentage of those who maybe candidates. So 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 the -- easily 50% of those patients can be considered early for this.

Boobalan from H.C. Wainwright. So a couple of questions to the panel. So there were a lot of discussions about the primary endpoint, which is FEV1. So I'm just curious, do patients actually care or give more importance to the FEV1 value as supposed to say shortness of breath or recurrent cough? Or what are your thoughts on that? And I have a follow-up.

And if I start and then -- I did start already. No, I think that you're getting in the right direction. The patient reported outcomes matter. But actually, you want to have objective measure and subjective. So the way to go actually is combining. And 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. So I think if you get these 2 aligned that's absolutely the best. But there is -- I think that they very appropriately are not neglecting those.

And then there were questions about exacerbation characteristics. So 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? And how does it help the company from a commercial standpoint?

Yes, we cannot even wait to say, like, no. These guys, if that actually -- if this gets to approval, I think that they owe us like a longer-lasting trial at some point to see whether they -- actually, if they can expand.

Okay. One final from me. 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 here?

I think it's a valid question. You guys know more about the drug-drug interactions.

Kathy, do you want to provide drug to drug interactions, what the data has been on drug-to-drug interactions with us?

Antibiotics in particular. Did you mean like QT prolongation of azithromycin or anything in particular with antibiotics?

Overall because this could be delivered on almost standard of care, so...

Yes. The patients in the studies are not allowed to be on chronic antibiotics. That doesn't mean they haven't had them because they -- if they have an exacerbation that doesn't require hospitalization, yes, we have groups of patients that had antibiotics. We haven't seen any differences from that perspective. I did want to 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. So we have to do it, basically.

Joon Lee from Truist. Both of you emphasized safety as a key metric you want to look out for. Is there anything in particular you're looking for in safety given 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 for in the data.

So 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 and so that's been looked at. I think based on the previous PDE inhibitors, so theophylline, roflumilast, you're certainly going to look at GI side effects. And again, if you look at the study and look at the list of side effects, 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 6 weeks, 12 weeks, whatever, what happens to people in a 12-week period? Will they get headaches? People do. If you had a headache in the last 3 months -- have you had nausea in the last 3 months? And the fact that it was 1 or 2 patients in each of these studies who had -- and there were equal numbers in the placebo group as well as the treatment groups. I was incredibly reassured from the initial data, from the Phase II data.

Did you get a chance to review the poster of presentation at ATS?

Which one? The QT one?

QT.

QT.

Yes. Kathy was telling me about it. I did not have a chance to look at it personally.

I did take a look at it and it was fairly reassuring. I'm not getting into granularities, but I saw that poster.

Did you see the poster? Is there something we're missing?

I'm Suji Jeong from Jefferies. 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.

Do you want to take that first? I've already answered once.

Yes. As I mentioned that there is a wide spectrum, a pretty broad spectrum of people who may benefit. I think that 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 old fragile that already has a nebulizer at home. I might just use it as the first line to see, get some bronchodilator, get some anti-inflammatory. Clearly, I think it has a role indeed for the person you've already pulled your hair out because you've given them everything else except the kitchen sink. But I really think, given the fact that there were patients from 30% to 80% in the Phase II trial baseline FEV1, you can feel that there's data to underpin using it as a first-line agent as well.

And I didn't disagree with this.

Yes, especially in somebody who you're going to use a nebulizer anyway.

So when you're talking about using it as first line, are you saying that ensifentrine is a monotherapy or on top of other bronchodilator?

Monotherapy. I think you could use it as a monotherapy. I mean 200 cc in the Phase II when used alone, 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's some debate about whether MCID of 100 ml for trough FEV1 is fair or not -- oh, you're shaking your head. So it's not?

That doesn't exist. It's a nonconcept. It's for peak FEV1, not trough.

I see. So when you are seeing the Phase IIb 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 it?

Apparently, not. Listen, this is -- the drug was both investigated as a 3 times daily, twice daily. I don't think the trough per se is here like the effect. If we're talking about bronchodilator effect, that trough is still like significant and positive. So 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 and 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 -- 3 times a day would not be convenient like drug. So I think this is a good kind of balance.

And I think the other point is just what is the impact of trough on symptoms? And I don't...

There's a paper saying that the trough FEV1 can correlate well with the patient reported outcome, like St. George's Questionnaire.

By St. George Respiratory Questionnaire, how many points are different?

2.5 per 100 ml.

2.5 per 100 ml. It's still not an MCID. For SGRQ, it's 4. So I mean that's -- again, that's one of those drug company -- well, we had 10 cc difference, but it was statistically significant because we have 5 million people in the trial. I don't know what that means.

Yes, it's hard. It would be purely speculative, right? Maybe it's irrelevant. Maybe it is more relevant. I guess the results of this study also are going to show [indiscernible] 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?

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. So to get -- so assuming that there are -- and I'm sure there will be some criteria that an insurer or somewhere will make. And as I say, this first-in-class thing is going to make it much, much, much easier. My point is that it's just -- a neb is easier for somebody who cannot use a dry powder 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 invariably, I get the stuff in my eye or my nose or whatever. They're very difficult to learn to use appropriately. You 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 bulk of the spacer. So I think the practical point is, is that the insurer is going to say show me that you use these other cheaper agents first and they failed. That's probably what they're going to require.

Just one quick follow-up. Can you use that argument to get patients on YUPELRI?

I've given up. Even though there's so much time in the day, I don't bang my head against the wall. I figured at some point the rep is going to work with the insurer and it will be taken care of.

But probably it's important to say that, yes, we went through these struggles. But actually, that's why the company has been proactive. For example, Theravance was proactive. And I do manage actually because I start with the free specimens that they have these coupons would add to Medicare Part B.

We're not allowed to have free.

Yes, we do. So in that sense, like with the proactive company, we were able to start and we actually just made revefenacin formulary now.

I've been trying that for years.

It was a struggle of 6 months, but eventually, we were there.

It makes sense. But again, the things that you don't understand is like there are silos in hospitals. So there's respiratory care and there's pharmacy. And so 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. And so 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. But they're silos, so it's just kind of interesting.

So a quick follow-up question. Are PDE inhibitors in your experience generally resistant to tachyphylaxis? I'm only asking because the prior studies were shorter.

Yes, these are -- for this agent, they are short studies. But my experience with roflumilast is, tachyphylaxis is not an issue. It's not like beta -- LABAs.

But it doesn't mean that this is not going to be the case in the inhalation studies. It doesn't seem likely, it doesn't seem based on PDE4, it doesn't seem based on this. But I don't know the answer to this question. I don't know, Kathy, whether there's any data on tachyphylaxis.

Well, we don't see any tachyphylaxis, I mean, in beta agonist and all because the receptors are on the surface and they internalize, there is nothing for this to do that with. So there is no mechanism that...

So there's no theoretical mechanism.

And a separate question, why is LABA used so little compared to LAMA in the treatment? And is that the case also in Europe, outside of the U.S.? It's a practice pattern?

Yes, I think it's advertising, yes, that it was bad for you and it kill people. And none of that was true, but it was retrospective studies that were not well designed, and so people got afraid of them.

You know what we're referring, right, cardiac toxicity. So LABA alone has the black box warning, and that was the reason why I mentioned this earlier that once Advair and Symbicort came up, and Kathy was a part of that. 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...

Yes, it's really based on asthma data, not COPD data, and it relates to some asthma mortality because patients may have been using their beta agonist without their 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 an issue now. And it never was for COPD.

I think the other thing too is it's generally held among clinicians, it's something we haven't talked about yet, but I think it's a really important concept is hyperinflation. While LABAs do deflate the lung, I think if you set up all the studies of LAMAs do deflate the lung, I think if you set up all the studies of LAMAs, LABAs, I think the data is clearly clearer, and that's a personal opinion because there's data both ways. But I think LAMAs do a little bit better job with deflation. That means that residual volume drops a little bit better with the LAMAs. And we really haven't talked about the impact of that on symptoms. And 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 their early abnormalities really are part of this dynamic hyperinflation where when you're sitting at rest, you're fine, you're not short winded. But when you exert yourself, and so you increase your ventilation, you increase your tidal volumes, you begin to not be able to exhale fully. And so your residual volume, your FRC starts to decline. And what that does is it puts you way up on the compliance curve. So it's much, much, much harder to breathe. I do this with the medical students. I'll do it with you all. So 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. And 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 -- again, why do I think this might be a good drug for -- as a first line because it's also a good deflator like the LAMAs.

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? Because you did point out that some patients don't recognize like their symptoms or don't want to admit that. So do you think like with COVID, during the COVID era, wouldn't COPD patients may be a little bit be worried, right? And maybe say, "My symptoms are far worse?" So is there a change in their behavior on 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. And 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 in actually people who had it and people who didn't have it. But you could argue that the effect of pandemic goes both ways. We've got data that COPDers are doing poor with this. But on the other hand, in experience, our COPDers had the best years in their life.

Absolutely.

Which pretty much shows that the triggers for exacerbations are very often the exchange of viruses, right? So paradoxically, they had a fairly stable year without many exacerbations. And as you know, like exacerbations do nick the lung function and have the impact and predictors of future exacerbations. So I would say that really theoretical consequence can go both ways. They go either toward better or worse symptoms. But the other thing is that independent of pandemic, the PROs are also a little bit dependent on many other outside factors such as seasonal effects, et cetera. So a fluctuation is very possible.

I read somewhere yesterday, day before yesterday, that exacerbations are down by 50%. And I don't know about you, but in studies that require exacerbations, they've been much harder to recruit. And I felt much better that, jeez, I haven't lost my touch in recruitment but exacerbations really are down 50%.

Yes.

I think that might have been the last question. I want to thank Igor and Jill for spending the day with us today. We have a few slides to kind of just close the moment out. But again, thank you both for coming out of your practices, spending the day with us. it was really helpful. And they'll be around afterwards, so if there's questions you want to ask, I'm sure Jill and Igor wouldn't mind answering them during that time as well. But again, thank you very much.

Thank you. Actually, we have great questions.

Yes.

Do you want us to move the chairs or you can project the -- project with chairs there?

So 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 the need to be able to do something outside of the LAMA or the LABA to help these patients. And these 1 million patients are very receptive to the idea of ensifentrine. And if we think about how that applies to what the opportunity for ensifentrine looks like, if we have 1 million patients here, what we see from our market research is very similar to what Igor and Jill said. We're going to use ensifentrine on a lot of our COPD patients. 1/3 of their use -- 1/3 of their patients in COPD they believe they'd use ensifentrine in. And then you take that to where's the patient. And we heard Jill say I'd use it early, I'd use it late and that it spreads. So there's about 2/3 of the patients are on dual or triple because they don't have any other options. But they see ensifentrine as a very broad molecule within their practices. And then the last thing here is what the pricing is for nebulizers today. Ensifentrine will be an N-of-1 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. And the key thing here is it's in physicians -- the physician community like Igor and Jill. It's in pulmonology. Its 100 reps can reach that opportunity and allow us to be a very effective in getting ensifentrine to the patients and the physicians that need it. And that's just the tip of the iceberg. Dave talked about this a little bit too. We're talking about COPD today with a 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. So this product has utility outside of what we're talking about today. And our upcoming data milestones allow us to tap into the potential of where ensifentrine can go. And we're well positioned. So 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, million patients, very focused. And then finally, our cash runway gets us through the end of 2023. So the work that we have to do internally is funded as well. So we feel very confident in how we can capitalize on this opportunity with ensifentrine. So again, you guys spend 1.5 hours 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, but we appreciate everybody spending the morning with us and thanks again.