Verona Pharma plc (VRNA) Earnings Call Transcript & Summary

Good day, and welcome to the Verona Pharma ATS 2023 data call. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to David Zaccardelli, Chief Executive Officer. Please go ahead.

Good afternoon, everyone. Thank you for joining the call. With me today are Dr. Tara Rheault, our Head of Research and Development; Dr. Kathy Rickard, our Chief Medical Officer; Chris Martin, Head of Commercial; and Mark Hahn, our Chief Financial Officer. Before we begin, let me remind you that we may be making forward-looking statements, and as such, refer you to our Risk Section in our recent SEC filings. It has been a very exciting and productive past few days at the ATS meeting in Washington, D.C. Ensifentrine has been on full display with a comprehensive review of the Phase III ENHANCE trial results. This has included a symposium presentation and 12 abstracts, including subset analyses and pooled analyses from ENHANCE-1 and ENHANCE-2 trials. Now let me take a few minutes to review ensifentrine in the ENHANCE program. As you can see on the slide, I'd remind you that ensifentrine is a novel molecule, providing phosphodiesterase 3 and 4 inhibition and as such, has very unique characteristics, including bronchodilation, primarily through PDE3, anti-inflammatory effects, primarily through PDE4, and also increases mucociliary clearance through CFTR activation. As you can imagine, that pharmacology has played out very well in the treatment of COPD. If we take a look at the pivotal Phase III program, and just to remind you, consist of 2 large Phase III trials called ENHANCE-1 and ENHANCE-2, both enrolling approximately 800 patients in which patients are randomized to receive either ensifentrine 3 milligrams BID or placebo for 24 weeks, with ENHANCE-1 having an additional subset of patients going for an additional 24 weeks or a total of 48 weeks. As you recall, we've reported out top line data on these trials in 2022. And just as a reminder of the patient population, they could have been receiving background therapy, either a LAMA or LABA, or not on background therapy as well as up to 20% of the patient population was receiving ICS in addition to a LAMA or a LABA. They were all symptomatic and all had compromised lung function. With that patient population enrolled, you can see on the next slide the actual demographics and baseline characteristics of both trials, ENHANCE-1, ENHANCE-2. Please note, of course, that the balance between ensifentrine and placebo in both trials is incredibly well-balanced and very representative of typical COPD Phase III trials. Note that background therapy in both trials exceeded 50% with ENHANCE-2 approximately 55% and ENHANCE-1 greater than that, closer to 70%. And you can see there the breakdown of the background therapy between LAMA, LABA and LABA ICS as the primary background therapy. Please note also the E-RS and the SGRQ showing symptomatic patients as well as smokers, which was approximately 50% of patients in the study, very characteristic of Phase III COPD trials. And just to summarize, before we actually get into the specific data from the presentations here at ATS, remind you of the results from both ENHANCE-1, ENHANCE-2, which were incredibly positive and compelling. As you remember, we did hit the primary endpoint average FEV1 AUC 0 to 12 hours in both studies with approximately 900-milliliter improvement. Also, of course, in lung function peak FEV1, trough FEV1 were met as well as clinically and statistically meaningful results. E-RS, SGRQ showed positive results in improving symptoms and quality of life in these patients. And absolutely noteworthy is the exacerbation rate reduction and time to first exacerbation in both trials with approximately a 40% reduction in exacerbation rate across the ENHANCE program. And of course, remind you of the adverse events, which we'll review in more detail today, but were very comparable to placebo, between the ensifentrine and the placebo group, with no AEs that were really differentiated between either ensifentrine or placebo and very few adverse experiences as we'll review today in the program. With that, I'm going to turn it over to Dr. Tara Rheault to walk us through the top line data from the abstracts and give us a comprehensive review of the trials.

Great. Thanks, Dave. Thanks to everyone for joining the call. So we'll start with a review of our expanded analyses of our lung function data. So here, you see our primary endpoint, average FEV1 0 to 12 hours at week 12. We have conducted some group analyses across both trials and show very consistent results across all of the clinically relevant subgroups that we've assessed, including subjects with and without background medication, inhaled corticosteroid use, chronic bronchitis, yes or no, reversibility and COPD severity that was consistent, showing improvements with ensifentrine over placebo across both studies. In addition, we also did a similar analysis looking at peak FEV1. A similar look at subgroups, clinically relevant subgroups, showed a similar consistent effect across all subgroups assessed in both studies. Moving on to our analyses of exacerbation data and inflammatory biomarker data. Just briefly remind everyone the definition of exacerbations that was used in the trials was the industry standard. Exacerbations were defined as a worsening of symptoms, at least 2 major symptoms or 1 major and 1 minor symptom, requiring at least 3 days of treatment with oral or systemic corticosteroids and/or antibiotics for a moderate COPD exacerbation or hospitalization for a severe exacerbation. And exacerbation events were verified in the analysis with the symptoms and treatment required. So here, we're showing subgroup analyses of our exacerbation data, both across the ENHANCE-2 trial and also cooled with ENHANCE-2 and ENHANCE-1. So on the left-hand side, you'll see the forest plot looking at exacerbation rate reduction in the ENHANCE-2 trial Here, you can see a very consistent effect showing improvement with ensifentrine compared to placebo in all clinically relevant subgroups favoring ensifentrine, and these include subjects on any background medication, including inhaled corticosteroids, subjects with and without chronic bronchitis and in subjects with either low-baseline eosinophils less than or equal to 150 cells per microliter or in patients with greater than 150 cells per microliter. Pooling the data, you see similar effects, consistent effects across all clinically relevant subgroups. The next slide shows similar analysis, but this time on our second exacerbation endpoint, time to first moderate or severe COPD exacerbation. Here again, this analysis in the ENHANCE-2 population and also pooled across ENHANCE-2 and ENHANCE-1 continues to show consistent effects in all clinically relevant subgroups, showing a longer time to first in those patient groups that need important additional treatments for the reduction in exacerbations. In addition, we presented data this week on exacerbation rate and risk reduction over 48 weeks. You'll remember in the ENHANCE-1 trial, we have a 48-week subset where we collected exacerbation through the entire 48-week duration of the trial. And here, we're showing effects that are consistent with those that were shown over 24 weeks, even slightly greater effects over 48 weeks, both on exacerbation rate reduction of 44% and also exacerbation risk reduction as measured by time to first of 52%. In ENHANCE-2, we also evaluated inflammatory biomarkers, circulating inflammatory biomarkers, and here, we're showing a positive trend on decreasing circulating inflammatory biomarkers, both in terms of IL-6 reduction and reduction in IL-8. IL-6 is a pro-inflammatory cytokine implicated in systemic inflammation in patients with COPD, and IL-8 is a chemokine that induces neutrophil migration to the airways. And so these are important markers, giving us a mechanistic basis for exacerbation reduction relating to the anti-inflammatory effects associated with PDE4 inhibition that Dave mentioned in our mechanism slide. Moving on to the symptom and quality of life and health care resource utilization data. Here, we've presented a responder analysis of our symptom and quality of life assessments in the ENHANCE-1 data. Here, we're looking at E-RS responder analysis, and that is E-RS symptoms. The minimal clinically important difference here was minus 2 units, and this was looking at the proportion of patients meeting that threshold of minus 2 units as a change from baseline. Here, you can see we show a substantial proportion of patients showing -- meeting the MCID in the study over week 6, 12 and 24 that was statistically significant at week 12 and 24 compared to placebo, and then a similar analysis looking at SGRQ, with a minus 4 unit responder, where the MCID is minus 4 units, is showing a very large proportion of responders, up to almost 60% of patients, meeting the MCID at week 24 and statistically significant differences from placebo at all weeks. In addition, in ENHANCE-1, we did an expanded analysis of E-RS subdomains, and this includes not only the total score, which we've presented previously, but also the subdomain of breathlessness, cough and sputum and chest symptoms, three of the major areas of concern for patients with COPD. And here, looking at these results, comparing ensifentrine and placebo at week 6, 12 and 24, were showing improvements in all 3 domains at all weeks. Similar analysis of subdomains across the SGRQ. These include symptoms, activity and impacts in ENHANCE-1 are showing, again, very large improvements in symptoms, as you would expect, based on the E-RS data at week 6, 12 and 24 but also contributions in terms of improvements in activity and impacts in patients with COPD, also very important features of ensifentrine and important properties that are -- drives patient utilization. Here at ATS, we've also presented data on our Transitional Dyspnea Index and rescue medication use. So here, we're looking at the data from ENHANCE-1 and ENHANCE-2 on the Transitional Dyspnea Index. Dyspnea is the most debilitating symptom impacting patients with COPD and is often the symptom that are driving patients into the physician's office requesting a change in therapy. Here, you can see we have very strong results with ensifentrine in the trial in both studies showing statistically significant improvement versus placebo on dyspnea at all weeks in both trials. And rescue medication use shows a similar trend as the other symptom and quality of life endpoints showing results favoring ensifentrine over placebo that were statistically significant at all weeks in ENHANCE-1 and statistically significant at week 6 and 12 with a numerical improvement at week 24 in ENHANCE-2, supporting the improvement in symptoms with reduction in rescue medication use in these patients. And here, we've also, in the ENHANCE-2 study, taken a look at health care utilization over 24 weeks. What we're looking at here is overall health care utilization, which includes both COPD-related health care resource utilization and non-COPD-related health care utilization. And in this group, we see a lower health care utilization in the ensifentrine-treated subjects compared to placebo-treated subjects, with 11.8% of subjects reporting health care utilization in the ensifentrine group and 15.1% in the placebo group. And this difference is largely driven by unscheduled visits to physicians' office, which were lower in the ensifentrine group, and unplanned hospital admissions, which were also lower in the ensifentrine group compared to placebo. Moving on to safety. So we mentioned early on, and you've seen the data supporting the safety profile with ensifentrine as similar to placebo. Here, we've done an expanded analysis of the ENHANCE-2 data looking specifically at cardiac adverse events and gastrointestinal adverse events. So on the left-hand side, you see a full list of cardiovascular adverse events that were present in at least more than 1 subject. And here, you can see we have numerically fewer subjects reporting cardiovascular adverse events in the ensifentrine group and the placebo group. Within the cardiovascular safety profile and ENHANCE-2, there were no clinically meaningful changes from baseline in either treatment group on ECG parameters, which includes heart rate and TQT, systolic blood pressure, diastolic blood pressure or pulse rate. No subjects in the ENHANCE-2 study met the ECG withdrawal criteria. In terms of gastrointestinal adverse events, this is of interest, of course, because there are oral inhibitors of PDE4 that are marketed drugs, including for COPD, that do have substantial gastrointestinal side effects. These include rates of diarrhea, nausea and vomiting up to -- including 10% of subjects. So here, you can see the rates of gastrointestinal disorders in the ENHANCE-2 trials, overall, similar in the ensifentrine and placebo arms and very low rates in the ensifentrine and placebo arms in terms of diarrhea events, nausea and vomiting. Regarding the few diarrhea events that occurred in this trial, we were looking at a potential temporal association with ensifentrine dosing with other oral inhibitors of PDE4. You typically see these occur related to treatment quite early on, within 2 weeks to 4 weeks. Here, 7 out of 8 events in the ensifentrine arm occurred after 3 months of therapy. So we concluded that these were not temporally associated with ensifentrine treatment. The eighth event that occurred was due to atorvastatin and magnesium treatment. And we had one additional treatment emergent adverse event of vomiting in the ensifentrine group that was due to amphetamine withdrawal. So in conclusion, we were able to present this week a broad analysis of the results across ENHANCE-1, ENHANCE-2 and even some pooled analyses that support a replicate effect in lung function across clinically relevant subgroups, both on peak FEV1 and also average FEV1 over 12 hours. We were able to show results supporting exacerbation reduction in clinically relevant subgroups that was substantiated over 48 weeks of treatment. We demonstrated improvement in symptoms, quality of life and health care utilization, which included over 50% of subjects showing a clinically meaningful response on symptoms and quality of life in ENHANCE-1 and improvements in Transitional Dyspnea Index and reductions in rescue medication use in both studies. And finally, showed an adverse event profile that continues to be consistent with placebo, including cardiovascular and gastrointestinal adverse events. So this is not all of the study data yet from both studies. We do have additional data that we are presenting at the ERS conference in Milan later this year and at CHEST in October. So please do stay tuned for that additional data output. And with that, I believe we'll turn it back over to the operator for questions.

[Operator Instructions] The first question comes from Yasmeen Rahimi with Piper Sandler.

Team, thank you so much for sharing the fantastic results, and congrats on a very strong presentation at ATS. I would love to -- given that a lot of clients who are listening to this call had not the opportunity to be at ATS, could you maybe comment on sort of the receptivity on this data from the community when the data was presented? What was the sort of audience participation? What were the commentary? So could you may be really maybe help us sort of capture the sentiment in response to this really outstanding results that you received from physicians who attended the session? And then more specifically, what were some attributes of this data that really resonated very well to them? Again, this is quite important for a lot of clients of ours who are listening but were not able to be present at ATS.

Great. Thanks, Yas, for the question. It has been an absolute enthusiastic response, I can just characterize. The presentation in the symposia was a very large room, very full, a lot of questions after the presentation of -- by Dr. Anzueto, very engaging. I think that the mood was very upbeat, with enthusiasm around the consistency of the results, the magnitude of the results. And I think for sure, many people were just exposed to it with the depth at ATS that we had. I think the poster sessions, again, extremely well attended and involved with both physicians and the health care community were there. So I think we're very pleased with the reception. And maybe I'll turn it over to Chris and Tara to comment any more.

Sure. I think one of the things we're hearing is excitement around utility across the broad COPD population. I think they were very interested to get hopefully an ensifentrine approval and be able to use this in their patients, I think we're understanding that there are a lot of different areas where they would find this type of treatment useful. The other data that I think -- well, 2 pieces of data that I think they're really excited about is the exacerbation subgroup data showing that we really have not identified a subgroup where ensifentrine will not produce a benefit. And I think that's exciting, and it doesn't require assessment of blood markers or anything like that when they're making treatment decisions for their patients. I think for me, finally, the last thing I'm hearing is around the improvement in dyspnea. The results that we show on the TDI are really remarkable and unlike things that they've seen previously. So that's a scale that's more physician-friendly. They understand that it's been around for a long time and something that they can use in their practice as well. So I think there's definitely some interest in that.

Just to continue on what Tara is talking about on the dyspnea index, I think when we talk to physicians today, that's -- the dyspnea is the reason why they make treatment changes. The patients come in and complaining about an inability to breathe. So the ability to show this marked difference is something that allows them to really make a treatment decision or treatment change. So that's an exciting aspect of the data. I think the other thing that it does is it continues to confirm across all the data end points that we have this early response, either through bronchodilation or through symptoms or through TDI, all the way to a sustained response where you see now exacerbation data that holds true to 48 weeks as well. So it really plays to this totality of the story of an early response in the -- early and sustained response with the patient.

Sorry, one logistical question. I know that you guys have worked also really hard on the publication. Maybe -- and I know that those items take a while, but any update there on, I think, in terms of the proximity of whether we may see a publication before NDA filing, around NDA filing or a little later? So -- and I know these things take a long time, so appreciate any color.

I can't give any granularity around the timing of the publication regarding the NDA filing. That's out of our control. But I can say we're in the late stages of manuscript finalization and that should be out sooner rather than later.

Our next question comes from Andreas Argyrides with Wedbush.

Congrats on the presentations at ATS. Just continuing from the point on exacerbations, maybe you can give us a bit of a sense of how that might play into the commercial strategy and how the medical community views it and how then subsequently they prescribe it?

Thanks, Andreas, for the question. I think when we talk to physicians, not only here at ATS, but keep in mind, I think we're up to close to -- I mean somewhere between 700 to 1,000 physicians that we've talked to through market research on ensifentrine. What's remarkable to me is we have consistent results across ENHANCE-1 and ENHANCE-2. But when we get into the market research, our results when we do market research is as consistent as the data we see in our clinical trials. The reasons why physicians are first intrigued by ensifentrine is the fact that you have a novel mechanism of action that provides bronchodilation and anti-inflammatory -- nonsteroidal anti-inflammatory effects. And this MOA allows for conversation to be had. And within that conversation becomes the totality of the data. When they're dealing with patients every day that are symptomatic, they're looking to help these patients reduce the burden of the symptoms and be able to get back to some semblance of the quality of life that probably we all take for granted on the call or in the room here that we're in. And then the other thing, they're trying to manage a risk of exacerbation. So they need to balance both things every day with these patients. So when they look at the ensifentrine data, what they see is the ability to provide an acute bronchodilator where they're getting lung function improvement at a very rapid rate, which provides the patients to breathe better, which you see in the dyspnea index score that eventually translates into improvements in symptoms and quality of life and then down the road, the improvement in exacerbations. So for the research and the discussion, it really becomes a totality of the data, and there's not one single piece that maybe drives utilization. I think the other thing with the totality of the efficacy data is it's balanced by a safety profile, as Tara described, that's similar to placebo. So they can try this drug in a patient and see very quickly how a patient is going to respond with very low risk. And so that's a benefit risk profile. It's very attractive to a physician who's looking for trying to help patients in a variety of different ways as they remain symptomatic.

Fantastic. Could you just remind us the size of that market, given the totality of the data?

Yes. Great question. Yes. So within the U.S., it's about 8.5 million treated COPD patients. There's about 1.7 million of those patients are on a single bronchodilator, LAMA or LABA. There's about 4 million of those patients on LABA ICS. So if you think about that, it's close to 6 million patients that are on what we would consider the ENHANCE -- directly, the ENHANCE patient population. And then if you look at the patients that have very limited treatment options, those on dual bronchodilators or triple therapy, that's about another like 2.8 million patients between the 2 of those. And across that group and across that set spectrum, we see patients being symptomatic between 40% to 50% of the time. And the real thing here is how a new mechanism can be layered on top of these patients because in the past, what they've just continued to do is add the same drugs in a different delivery, different device to help these patients try to get a little better. And this reality is it's the first time they're really being able to add broadly a new mechanism that can provide benefit across a broad set of patients within their practice.

Our next question comes from Andrew Tsai with Jefferies.

Appreciate you guys sharing all these new analyses with us. So clearly, you've generated a wealth of data across these Phase III study. So looking ahead, how much of this information do you think can get into the eventual label, for instance, the relatively fast exacerbation benefit over placebo? And you have this nice forest plot, for instance, [indiscernible] your eosinophil count, you're seeing equal benefits. So the question is just how much do you think can get into the label?

Yes. So I think where we're at in the COPD space, right, there is a lot of precedent, and there is a lot of drugs that are approved for the maintenance treatment of COPD. And you'll see a lot of consistency across the labeling there. So I think I would go back to review recently approved drugs and see what's in there. I mean we expect the lung function to be in there, quality of life, of course, and exacerbation data as informative for physicians who will be prescribing the drug.

Makes sense. And then moving ahead, again, you do plan to file NDA soon. So do you plan to file for a priority review or standard review? And secondly, if we think about some of the more recent COPD drugs that have been approved, did they end up having an AdCom? So I'm also curious if you're anticipating an AdCom for ensifentrine.

Yes. Thanks, Andrew, for the question. So we think that ensifentrine and the results that you've seen here and previously justify a priority review. We think we meet the standard as we understand it. Clearly, we'll make that case in the submission, and we'll see what the agency will provide their response to that. We expect that in that 60-day period related to acceptance to understand whether they would give a priority review. As you know, there are many products approved for COPD. So that -- providing priority review maybe a bit complicated with precedent, et cetera, for them. But we think we met the standard. Regardless, if you could plan on a standard review, that's our base case. And I think priority review is upside to that. So -- and then your second question, sorry? Yes. Well, again, curious, item. I mean, I think because it's a new pharmacology mechanism of action, PD3, PD4 inhibition, new chemical entity and a first drug of that mechanism for COPD, I think those are typical triggers for an AdCom. But I balance that with -- as we know it today, based on everything we've seen and you've seen as well, the efficacy, the primary endpoint, which has been used previously, the safety and overall benefit, the risk being so compelling, I'm not sure what an AdCom would be reviewing at this time. So clearly, we'll be prepared for one, but it's not clear to me that there's a topic for AdCom at this time.

Next question comes from Joon Lee with Truist Securities.

Congrats on the data. So you have data as monotherapy and as add-on to LAMA or LABA. So as you're talking to pulmonologists here at ATS, approximately what proportion of COPD patients do you think ensifentrine would be used as monotherapy in frontline or as an add-on to either LAMA or LABA? Or do you think it will be relegated to an add-on to maximal triple therapy? And I have a follow-up question.

Yes. Well, Joon, I think it's an interesting question. Actually, I think that the data could speak to utilizing it across the spectrum of COPD patients' frontline therapy. Clearly, those were included, frontline in the sense that they were not concurrently on background therapy included in the study -- on top of a LAMA, LABA, LABA ICS are included in the study. Because of the benefit, the risk that exists with ensifentrine I also think it makes sense to use it in symptomatic patients in general with regard to whatever background therapy they may be on, those are patients that we studied as far as being symptomatic. And because of the ability to look at the effects fairly quickly, its bronchodilation can occur after the first dose, and of course, symptom improvement we've seen in that 4- to 6-week time frame, exacerbation, rate reduction has seemed to separate at that 6-week period, all of those lend itself to looking at ensifentrine and seeing if it can help patients who are symptomatic. So in many ways, I think it's up to the physician to utilize it where they see fit, and I think there's a roll forward across the spectrum of COPD patients.

Great. And it was interesting to see roflumilast and antimicrobial are added in the GOLD 2023 guideline algorithm. Do you think ensifentrine could be included in an algorithmic way in the treatment of COPD? And I have one last follow-up.

Yes, absolutely. Once the drug is approved, assuming that it gets approved, it will certainly be assessed by those committees for where they think the appropriate use is. Guidelines or strategy document, whatever you're looking at, I think physicians, especially in the U.S., are inclined to treat the patients the way they feel that they need to be treated. And so while those can be aspirational documents, I think today, what we understand is that most patients are still being treated by ICS LABAs and LAMAs, and that's also who we had enrolled in our trial.

All right. Last question. After Dr. Anzueto's late-breaker presentation, one of the audience member asked, maybe because he thought the exacerbation data was too good to be true, if social distancing during the pandemic had anything to do with your exacerbation data. I couldn't really hear Dr. Anzueto's response, but what would be your response to that question?

Sure. So we've looked at the exacerbation rates, both in our trial, and that would be in the placebo arm, of course, and also other trials that did not enrich for patients with exacerbations. So if you're looking across those rates, the rates we saw in our trial are very consistent with other trials that have not enriched for exacerbations and also are very aligned with general population rates in moderate-to-severe COPD patients, which show that you typically see a COPD exacerbation in 26 to 40 patients a year, and that's right where we were in terms of exacerbation rate. And I think in terms of background therapy used in the ENHANCE trials and also the exacerbation rate that we saw is very, very consistent with the broad COPD population and makes the results of the ENHANCE program very translatable to the real world setting.

Our next question comes from Boobalan Pachaiyappan with H.C. Wainright.

Congrats on the presentation. Two from us. Maybe firstly, in Slide 18, where you talked about your responder analysis of E-RS and SGRQ. So I'm just curious why there is a greater separation at week 12 versus at week 6 and week 24. Just curious if there is any particular reason because the delta appears to be fairly large versus the delta at week 6 or week 24.

Sure. I don't think that's signaling maybe a real increase at week 12 versus week 24, and there's no statistical difference between those 2 numbers. I think we would look at that and see essentially 50% of the subjects are responders, no matter what. I mean, you're seeing that consistency in response over time.

All right. Maybe one more. So there is this general consensus, at least in multiple publications have suggested, there is a link between PDE4 inhibition and incidence of adverse GI symptoms. So have this notion in any way changed in light of your ENHANCE study data? If not, why not?

Sure. I think with oral drugs, obviously, you get that GI direct exposure just from taking the drug, right? And so you get a much, much higher concentration of PDE4 inhibition locally, and it makes perfect sense actually that if you have PDE4-mediated gastrointestinal effects, that you're going to see them with oral drugs. Now ensifentrine is delivered to the lungs, to the site of action, for patients with COPD. And our systemic exposures are quite low by design in order to avoid systemic effects, because it's really the local effects that we're looking for here. So I think that the data that we have definitely supports our premise for the development of ensifentrine as an inhaled drug to avoid seeing such effects.

Our next question comes from David Risinger with SVB Securities.

This is Dan Tarjan on for Dave. Congrats on the data. So I would like to ask about the speed of uptake across the spectrum of patient severity. In the past, you've talked about physicians telling you they want ensifentrine first as an add-on in their symptomatic patients kind of maxed out on double, triple therapy, and then moving to patients on single therapy later. Can you give us some more color on how quickly you expect prescribers to get comfortable with using ensifentrine in later lines and then perhaps to the earlier lines or if that's the wrong way to think about it? And then what have you heard at the conference on this topic?

Yes. I think, David, as we think about like speed of uptake, I think the thing that we have to ground everybody in is no matter what drug they're on today, we know that there are a significant number of patients that are symptomatic within the physician's office. Those symptomatic patients today are looking for new therapies. They're being transitioned to new therapies when they have increased symptoms like dyspnea or when they have a risk of exacerbation. So that allows ensifentrine to really insert itself many times and very quickly into a treatment conversation with a physician. I think when we look at our market research and our discussions with the physicians, their excitement of being able to do something different in COPD and adding a new novel mechanism is an extremely compelling thing for them as they think about these patients that come into their practice, which allows the physician to potentially use that drug very soon and allowing them to see the benefit within these patients. I think the important thing is when a physician does try ensifentrine, we believe that what they're going to see is, in many of these patients, they're going to see a marked improvement in lung function and symptoms. As Tara talked about, 50% of these patients respond to at least an MCID level within both E-RS, the symptoms and the quality of life scale. So in that situation, the physician is going to be able to see very quickly with very minimal risk how these patients are doing, which further encourages use in other patient populations as they get that experience. So I think that feedback loop and that mechanism of seeing patients do well, trying ensifentrine, seeing patients do well only enhances how quickly a physician will eventually uptake the product in their practice.

Got it. That's super helpful. And maybe one more, if I may. So on the exacerbation rate, it looked like the 48-week data were consistent with the 24-week data, if I saw that right, just kind of 0.2 annualized event rate reduction across the arms. Correct me if I'm wrong on that. So how have physicians kind of been reacting to that kind of effect size? And where does that figure into the prescribing decision? I think a lot of what we've heard today is more about kind of the dyspnea and the symptomatic improvements. I get that. So where does the exacerbation rate reduction come in for the prescribing decision? Or is this kind of more important in the payer conversation?

This is Chris again. From a prescriber situation, exacerbation is just another piece of the equation. Remember, the symptoms in dyspnea are stuff they deal with every day, but even in an exacerbation ENRICH trial, you're talking about a patient who have maybe 1 exacerbation a year. So you're preventing 1 or 2 events with exacerbation, so it's a balance of helping that patient feel better, while reducing that long-term risk of exacerbations. And I think the data for -- we believe the data from ensifentrine is very compelling in being able to give the physician the opportunity to do both with a novel mechanism of action. Your conversation around the payer is an important one because exacerbations lead to direct health care utilization costs. And as you saw in the data, there is a trend and a sign that ensifentrine has reduced health care utilization. As we think about plans outside of Medicare Part B, as in boy, remember ensifentrine is primarily reimbursed for Medicare Part B. But that exacerbation data further enhances the overall value that ensifentrine brings to a payer. It also helps us as we think about how we're going to price ensifentrine in the future, because exacerbations do have a value to the overall cost of the health care system that are important for us to consider.

This concludes our question-and-answer session. I would like to turn the call back over to David Zaccardelli for any closing remarks.

Great. Thank you, operator, and thank you, everybody, for your questions. It was great to review all the data with you today, and we look forward to keeping you updated on our progress, which we would expect next up is our NDA filing. So look forward to speaking with you on the future.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.