Verona Pharma plc (VRNA) Earnings Call Transcript & Summary

Welcome to Verona Pharma's conference call. [Operator Instructions] Earlier this morning, Verona Pharma issued a press release announcing top line results from its Phase III ENHANCE-1 trial evaluating nebulized ensifentrine for the maintenance treatment of COPD. A copy can be found in the Investor Relations tab on the corporate website, www.veronapharma.com. Before we begin, I'd like to mention -- excuse me, I'd like to remind you that during today's call, statements about the company's future expectations, plans and prospects are forward-looking statements. These forward-looking statements are based on management's current expectations. These statements are neither promises nor guarantees and involve known and unknown risks, uncertainties, and other important factors that may cause our actual results, performance or achievements to be materially different from our expectations expressed or implied by the forward-looking statements, including our regulatory plans for ensifentrine and the timing of those plans, the treatment potential for ensifentrine and its potential impact on patients. Any forward-looking statements represent management's estimates as of the date of this conference call. While the company may elect to update such forward-looking statements at some point in the future, it disclaims any obligation to do so even if subsequent events cause its views to change. As a reminder, this call is being recorded and will remain available for 90 days. [Operator Instructions] I'd now like to turn the call over to Dr. David Zaccardelli, Chief Executive Officer.

Good morning, everyone. Thank you, and welcome to today's call to discuss the positive top line results from our Phase III ENHANCE-1 trial. With me today are Mark Hahn, our Chief Financial Officer; Dr. Kathy Rickard, our Chief Medical Officer; Chris Martin, our Senior Vice President of Commercial; and Dr. Tara Rheault, our Senior Vice President of Research and Development. In addition, we are very pleased that Dr. Antonio Anzueto, Professor of Medicine and Section Chief of Pulmonary at South Texas Veterans Health Care System is joining us today to share his thoughts on the exciting study results and will be available during the Q&A part of the call. Note, the slides we are showing today will be available on our website after this call. Today is a momentous stay for ensifentrine, Verona Pharma, and most importantly, the millions of patients suffering from COPD. The ENHANCE-1 results confirm the impressive results from the ENHANCE-2 trial earlier this year. Patients and physicians are in need of an effective new therapy, and ensifentrine, with its novel mechanism as a selective PDE3 and PDE4 inhibitor providing increased lung function, improved symptoms and quality of life measures and remarkably reduced rate and risk of exacerbations are groundbreaking for the field of COPD management. Along with its favorable long-term safety profile, ensifentrine provides a compelling benefit to risk profile. To be clear, we believe ensifentrine will change the treatment paradigm for COPD by providing bronchodilation and nonsteroidal anti-inflammatory pharmacology with 1 compound. Before we discuss the exciting results, let's briefly review the ENHANCE program. As a reminder, the ENHANCE-1 and ENHANCE-2 trials replicated measurements of efficacy and safety data over 24 weeks, and ENHANCE-1 also evaluated longer-term safety over 48 weeks for a subset of patients. The trials are designed to enroll approximately 800 moderate to severe symptomatic COPD subjects for a total of approximately 1,600 subjects across sites primarily in the United States and Europe. Subjects received ensifentrine or placebo as either monotherapy or added on to a single long-acting bronchodilator, with approximately 50% of subjects receiving either a long-acting muscarinic antagonist or LAMA or long-acting beta agonist or LABA. Additionally, approximately 20% of subjects receiving inhaled corticosteroids, or ICS, with their concomitant LAMA or LABA. In summary, ensifentrine successfully met the primary endpoint and key secondary endpoints in the ENHANCE-1 trial, demonstrating statistically significant improvements in lung function, symptoms and quality of life measures. In addition, ensifentrine treatment resulted in substantial reduction in both the rate and risk of exacerbations. Ensifentrine was well tolerated over 24 and 48 weeks. So now let's walk through these exciting results. First, let's review the types of subjects enrolled in ENHANCE-1. Overall, the demographic and disease characteristics were very well balanced between the ensifentrine and placebo groups. The COPD patients enrolled had compromised lung function with a predicted post-bronchodilator FEV1 of approximately 52% in both groups. The study population included approximately 66% of patients on background therapy, including either a LAMA or LABA, and approximately 21% of subjects received ICS in addition to the bronchodilator medication. On the next slide, let's review in detail each of the lung function endpoints by looking at serial FEV1 curve over 12 hours at week 12. The primary endpoint of average FEV1 AUC 0 to 12 hours post dose at week 12 demonstrated a placebo-corrected highly statistically significant and clinically meaningful improvement at week 12 of 87 milliliters, p less than 0.0001. We are also pleased with secondary endpoints evaluating lung function were met. Statistically significant and clinically meaningful increases in placebo-corrected peak FEV1 of 147-milliliter p less than 0.0001, and morning trough FEV1 of 35 milliliters p less than 0.5 were observed at week 12, supporting a twice daily dosing regimen. As noted on the next slide, all subgroups, including gender, age, smoking status, COPD severity, background medication, ICS use, chronic bronchitis diagnosis, FEV1 reversibility, and geographic region demonstrated consistent improvements in the change from baseline in average FEV1 AUC 0 to 12 at week 12 with ensifentrine. We are very pleased to show on the next slide that subjects receiving treatment with ensifentrine had a substantial 36% reduction in the rate of moderate or severe COPD exacerbations compared with placebo over 24 weeks with a p-value of 0.05. As a reminder, an exacerbation was defined in the protocol as a worsening of symptoms requiring either a minimum of 3 days of treatment with oral or systemic steroids and/or antibiotics or hospitalization. On the next slide is the Kaplan-Meier graph, which displays the exacerbation events in each group over the study period. The occurrence of exacerbation separated early, and the ensifentrine treatment group continued to demonstrate a reduced rate of exacerbation events over 24 weeks. Treatment with ensifentrine significantly decreased the risk of an exacerbation as measured by time to first exacerbation when compared with placebo by 38%, p less than 0.5. We are extremely pleased by the reduction in exacerbations as seen in ENHANCE-1. When pooled with ENHANCE-2 data, as prespecified in the protocol, subjects receiving treatment with ensifentrine had a 40% reduction in the rate of exacerbations compared with placebo over 24 weeks, p equals 0.0012. In addition, in the pooled analysis, treatment with ensifentrine decreased the risk of an exacerbation as measured by time to first exacerbation when compared with placebo by 41%, p equals 0.0008. We believe this magnitude of reduction in exacerbation rate and risk further highlights the importance of this new mechanism, including nonsteroidal anti-inflammatory activity in addition to bronchodilation for the treatment of patients with COPD. On the next slide, let's review the secondary endpoint measurements of symptoms and health-related quality of life measures. Ensifentrine significantly improved daily symptoms as measured by the evaluating respiratory symptoms, or ERS, total score, in the ensifentrine group exceeding the minimally clinically important difference, or MCID, of minus 2 units with a statistically significant improvement compared to placebo at week 24. Furthermore, the improvement in health-related quality of life as measured by the St. George's Respiratory Questionnaire, or SGRQ, total score in the ensifentrine group exceeded the MCID of minus 4 units with a statistically significant improvement compared with placebo at week 24. The improvement in both measures were early and sustained with statistical significant versus placebo at weeks 6, 12, and 24. Turning to safety results on the next slide. Ensifentrine was well tolerated with very few events occurring in more than 1% of subjects and greater than placebo over 24 and 48 weeks. The next slide summarizes the top line data from ENHANCE-1 trial. We are delighted with the highly positive results that also includes meeting key secondary endpoints. Finally, when evaluating the results of both the ENHANCE-1 and ENHANCE-2 trials, we note the consistency of the positive results between the trials. The totality of the data from the ENHANCE trials, including improvements in lung function, symptoms and quality of life measures and exacerbation reductions coupled with the consistent favorable safety profile of ensifentrine confirmed the strong benefit to risk and support our belief that ensifentrine will change the treatment paradigm for COPD. Our next steps are to submit a New Drug Application to the FDA in the first half of 2023 for inhaled ensifentrine for the maintenance treatment of COPD and to continue preparations for our planned U.S. commercial launch through the NDA submission so we are fully prepared for the potential U.S. launch of ensifentrine in 2024. We expect to release additional information from the ENHANCE trials at upcoming scientific conferences. I will now turn the call over to the operator for the Q&A.

We will now begin the question-and-answer session. [Operator Instructions] The first question comes from Yasmeen Rahimi with Piper Sandler.

Congrats to the outstanding data set from ENHANCE-1. A couple of questions for you. Maybe the first question is, is there an opportunity to conclude that if you combine ENHANCE-2 and ENHANCE-1, you're able to also pick up statistical separation in the patient-reported questionnaires and instruments that were used in the ENHANCE-1, that would be really helpful, and what the importance of getting that data into the label means in terms of commercial preparedness? And then the second question for you is now how much of the NDA filing or the process has been completed? How soon can you get it done? And then the third question is, how are you thinking about partnerships here in the U.S. and ex U.S?

Great. Maybe I'll just start with the NDA filing and turn it over to Dr. Rheault for her comments about patient-reported outcomes. But we are very well progressing on the NDA, which I'm very pleased to report. We talk about clinical, of course, enormous amount. But as everyone knows, an NDA comprises many aspects, including nonclinical, CMC, and those sections are proceeding very nicely. And so we're quite confident in our progress. As we mentioned, we do plan to file in the first half of 2023. I think for practical purposes, that probably lands us in Q2. And we look forward to updating everybody on our progress in upcoming calls. I'll just touch on partnerships. Of course, I think many partners were looking to see the ENHANCE-1 data, which is, as you know, just announced today. So I expect that activity to pick up very quickly and be very well informed on our next steps on partnerships in Q1. With that, I'll turn it over to Dr. Rheault on patient-reported outcomes.

Sure. I think as part of any NDA, the pooling of efficacy measures across pivotal studies is an important aspect of the assessment of efficacy for NDA submissions. And we will be doing that for symptoms and quality of life in our NDA submission, too. We don't have the pooled data yet. Of course, we just received the ENHANCE-1 data readout. But we do intend to do that certainly with both studies showing an improvement favoring ensifentrine. Already, I think we're positioned very well to look at that pooled analysis.

And if I may just ask one quick -- one more quick follow-up. Can you maybe put into context what this additional statistical separation on a pooled analysis of exacerbation means for physicians? Is there a magnitude that's considered clinically meaningful? Or is it just the ability to explain to a patient that you should be able to see exacerbation reductions? Any commentary on the statistical significance of the pooled analysis from a commercial positioning perspective would be really helpful for us.

Thanks. Maybe I'll have Dr. Anzueto comment on the exacerbation data and then Chris can comment on the commercial aspects of it. Dr. Antonio Anzueto?

Thank you for your question. Certainly, it's very exciting to see more than 30% reduction in the rate of exacerbations. Remember that if you look at the Kaplan-Meier graph, the separation starts occurring early in the course of around 4 weeks, and this is a 3-month study that shows the separation. And I think it's more exciting when you put it all together and also the reduction in the time to the first exacerbation. So those are endpoints that we have recognized and we have done large clinical studies over 1 year. But the fact that we're seeing early in the course of the therapy, I think, is very encouraging and very exciting for also the clinician and for our patients.

Yes. And Yas, just from a commercial perspective, one of the things that's really important to keep in mind about exacerbations is it's, by definition, a worsening of symptoms. So when you look at the SGRQ data, you look at the exacerbation data, what you see is that ensifentrine is having an effect on the symptoms that these patients feel every single day. And when we hear and talk to physicians like Dr. Anzueto, what they tell us is this idea that ensifentrine has the ability to provide an early benefit for these patients, which they're always struggling and hoping to feel better, be able to get to some of the activities that they do reduce the risk of exacerbations. But more importantly that, that reduction is sustained over time and you see that in the data across all measures. And I think these are really important aspects as we get to commercialization that will encourage physicians to initially try ensifentrine but more importantly, keep their patients on it and encourage your future use as well.

Congrats again.

The next question comes from Andreas Argyrides with Wedbush Securities.

Congrats on these fantastic results. So these are -- two for Dr. Anzueto to start here. So thinking about the commercial opportunity based on these results, where do you see ensifentrine being first used when available? Would you use this to treat exacerbations and include it in the insert? And then maybe just some of your comments on the safety profile of 48 weeks.

Sure, thank you for your question. So let me address the later issue, the safety profile. Our safety profile is outstanding. I mean, actually, it's nothing that we have not seen before. It's very -- there is no any issues that we saw with phosphodiesterase inhibitors on oral therapy. So the safety profile is very, very clear. There's minimum side effect that the patients have. From the efficacy point of view that is encouraging is this is a cohort that is not an exacerbation-enriched cohort. So this is a moderate COPD population, that even in this population can impact the rate of their exacerbation. And I think this is what makes it more exciting. Now as a clinician, we're going to be able to offer the patient both a bronchodilator and an anti-inflammatory. And we need to look at further analysis in combination with other concomitant medications to understand exactly who they're going to position. But I can clearly see this medication to be as a first line of therapy in patients with symptomatic COPD.

Yes, just one quick follow-up. Just lung function improvements were consistent across both trials, fantastic. What do you think contributed to the significant achievement symptoms and quality of life in this study versus the other one, which again, another fantastic result?

So let me comment on the quality of life. In this one, if you see at the end of the study, halfway through the study, that St. George improvement in lung function is minus 6 points so it's well beyond the clinical significant. But you also can see in the placebo is close to 3-point something. So in the prior study, it was probably the combination that the cohort that was enrolled, that there was a larger dropout. The patients who dropped out in the placebo group were the people who were sicker. So the patients that actually stayed were "healthier" in the 3 months period of the duration of the study. There was a signal, there was an improvement in quality of life. But here, you can see in the St. George, the improvements are much more dramatic that we have seen before. This is very comparable of the improvements in St. George that we have seen with dual fixed long-acting bronchodilators.

Congrats again, guys.

The next question comes from Suji Jeong with Jefferies.

Congratulations on the data again. From the ENHANCE-1 trial, just a quick question. What percentage of the patients came from Europe and also outside the U.S.? And also, I noticed a bit of different patient characteristics between the 2 trials, ENHANCE-1 and ENHANCE-2 such as the higher number of moderate patients and a higher number of patients with chronic bronchitis and also a higher percentage of patients on the background therapy. Are there any aspects of the patient demographics from 2 trials that differ from each other that make you concerned about the regulatory action? My third question is on the exacerbation, was it mostly driven by the moderate exacerbation or severe exacerbation?

Great. Thanks, Suji. So I think Tara can speak to any demographic numerical differences, although I would say that when running large Phase III programs, we consider them incredibly comparable and you'll always find some numerical differences. The fact that we had slightly higher background therapy, I think, is only helpful in the sense that more patients were receiving background therapy and still had a benefit. And I think, Tara, I don't know on the percentage of patients that were from Europe versus the U.S.

Yes, yes. So in this trial, we did have more patients from Europe. I think it was around half of the subjects enrolled were from Europe. Here, we had about 20% of subjects in the U.S. It was essentially more or less flipped in ENHANCE-2. In terms of moderate to severe COPD exacerbations, typically, when you conduct these studies, you do see more moderate exacerbations than severe exacerbations. Severe exacerbations are fairly rare events where the subjects are hospitalized. So the assessment of effect on moderate and severe exacerbations is typically best done in a pooled fashion across both of the studies. So we don't have that data in hand yet.

And I think just to add, our view is there's no regulatory impact at all based on the types of patients that were enrolled. We find them to be incredibly consistent, representative of past COPD trials, and if anything, I think strengthens the submission based on the patients we enrolled.

Great. Just 1 last question. So in 2023, it seems like the focus will be prepping for the NDA submission as well as building out commercial capability. So what are the strategies and activities you have planned? You have a plan for building commercial efforts? And what is your cash runway?

Suji, this is Chris. I'll let Mark answer the cash runway question. But from a commercial standpoint, we've always taken the approach of using milestones to drive our commercial activity. Of course, the first milestone that the organization reached was the ENHANCE-2 trial results. And at that time, I strengthened my leadership team by bringing in our head of market access and trade, sales and marketing and also operations so that we could start to set the foundation for the commercial organization. With this data, we'll continue to build on that. So some specific examples in 2023 that we'll be working toward is on the market access and trade side, we'll be working within the Medicare Part B channel to establish our distribution pathway and our ability to make sure that patients can get this product very quickly when we're launched. I think that's a very defined pathway too. So we know the steps which are required. We also know that in the Medicare Part B pathway, we believe we fall under an existing policy code. So when ensifentrine is launched, there's access for physicians to write this. So that's on the market access and trade side. On the sales and marketing side, we start to work on market shaping the environment for the first novel therapy in 20-plus years for physicians. Remember, the last 10 launches in COPD -- 10-plus launches in COPD have been the same product, either in combination or in different devices. So there's some work that we can do to educate physicians on the need within COPD, the number of patients that remain symptomatic and how new mechanisms are needed to help both bronchodilation and anti-inflammatory effects within these patients. So that will be work that we do this year. And then the last thing that we really need to do is set the foundation for our sales organization, so that becomes refining our targeting and our deployment strategies, and that will all be done during this year as well.

Yes. And Suji, with respect to the runway, we've talked about this on prior calls as well. We did a fairly substantial raise back in August. And we also put in place a $150 million credit facility with Oxford in October. And when you pool our existing, I think, at the end of September, we had about $230 million of cash. So you pool that together with the proceeds from the loan facility, that provides us with enough cash to get through at least the end of 2025, including all the work that Chris just walked you through in terms of prepping the company and actually launching the drug.

The next question comes from Edward Nash with Canaccord Genuity.

A resounding congratulations on the data. Just wanted to go on the subgroups. Patients in ICS had a lower FEV1 improvement than those not on ICS. And just wanted to know if we could read anything from this with regards to future commercial positioning of the drug.

Sure. I think what you need to just take with a grain of salt on the subgroup analyses is that the confidence intervals here on these are very much overlapping, entirely overlapping, I would say. So I wouldn't read too much into a numerical difference in the means here. I think those responses are essentially the same in the 2 groups.

Okay. And then could you just maybe just discuss a little bit maybe about how the -- with regards to quality of life measures, how are these viewed differently between the FDA and EMA?

I think they are considered by both FDA and EMA. I think there's actually a lot of consistency between the 2. I think we do expect SGRQ data certainly to be in the label. I think in EMA symptoms, including Transition Dyspnea Index, which we haven't shown yet, will also be included in the label. I think in the U.S., they're more inclined to stick with the SGRQ data.

The next question comes from Joon Lee with Truist Securities.

Congrats on the impressive data. Would a prospective EU or a global partner who may want to develop ensifentrine as DPI or MDI formulation need to run a new Phase III program? And how much of ensifentrine's efficacy in COPD as a nebulizer do you think will be captured as MDI or DPI formulation? And also, remind us if you have an open-label extension ongoing, and if so, what percent opted in for the OLE? And I have a follow-up.

Thanks, Joon. I'll sort of work backward. No, we do not have an open-label extension study ongoing so there are no open COPD trials at this time. With regard to DPI, MDI, yes, we do think that, that formulation would need to conduct proper dose-ranging Phase II and Phase III trials. As you can imagine, it is typical for the dose to be somewhat different for a DPI or an MDI versus the nebulized. The deposition characteristics typically can be -- are different. So right now, we would anticipate that it would require additional clinical studies in order for that formulation to be approved. I don't think we have done a deep analysis on any sort of capture or transition from nebulized to MDI or DPI. I think we firmly believe in the U.S. that the nebulized approach is the best approach for ensifentrine for patients, and the best strategy for us to make sure that patients have the access to the best treatment for ensifentrine as we've developed. So because it is nebulized, we find that to be completely acceptable, I know Dr. Anzueto also can comment on that. But we're very confident in that approach in the U.S. And any partner that would want to develop an MDI or DPI for either COPD or other indications, much like ourselves in the U.S., asthma, for example, ILD or other respiratory conditions, clearly that would make some sense based on the types of patients that have those diseases, et cetera. So I'll sort of leave it at that. I don't know, Dr. Anzueto, if you want to comment on the acceptability of nebulized formulation for COPD patients.

Sure. So I think nebulized medication for COPD patients in the last 5 to 8 years had a tremendous revolution mainly in the fact that the more medication that are non-active bronchodilators are becoming available. The nebulizer systems are highly efficient, portable, very easy to handle. I can tell you that I had at least 30% of my COPD patients in my practice that they are in nebulized therapy and they love it. Really they like the medications, they like the delivery system. More important, they don't have to worry about, do I get the medication or I don't get the medication because certainly, the nebulized systems are highly efficient for drug delivery.

That's very helpful. And sorry, I have a question for you, doctor. Now that you have both Phase III data, would you now push the envelope a little further and say, would you like to see data as an add-on to LAMA and LABA with or without ISC (sic) [ ICS ]? Is that important to you? If not, why not?

Sure. So we have the standard of care today that are long-acting bronchodilators. If we look at the demographic data from the ENHANCE-1 study, we see that 1/3 of the patients are on LAMAs, there is 18% of LAMAs and another 20-ish percent of ICS/LABA. So I think it's going to be very important to understand how do the medication works in combination and without combination therapy? And which combination therapies that does work, how much of efficacy we see. The beauty now is we have both ENHANCE-1 and ENHANCE-2 studies so we have a much larger number of patients, more diverse baseline therapy that will further help us to understand that the additional -- this is an additional to the therapy that we're using or it can be a stand-alone. Remember, like in ENHANCE-1, close to 35% to 44% of the patients were not on prior background medication. So we're going to have the whole spectrum to analyze, to understand how to use this medication.

Great. Congrats on the data again.

[Operator Instructions] The next question comes from Boobalan Pachaiyappan with H.C. Wainwright.

Congrats on outstanding data. Just a few from us. Firstly, can you comment on your CMC capabilities?

CMC capabilities? Yes, so I think as a company, we've had a very targeted strategic approach to CMC. We do manage it internally but outsource the actual activities of API synthesis and also drug product manufacturing. Both of those are either made in Europe or in the U.S., and we have a very strong relationship with those contractors. Both of them make commercial product for the U.S. market and have a very strong regulatory history. So we're very comfortable with that. In addition, because of the development time line for ensifentrine, we have an incredibly strong handle on the CMC from an API manufacturing synthesis perspective and the ability to make quantities that satisfy commercial amounts and going through the validation of that. We also have incredible stability data already in hand. And I think we're very comfortable with our CMC overall and our drug product.

This question maybe for Dr. Antonio. So how does the ENHANCE-1 and ENHANCE-2 study results inform the future development of dual PDE3 and PDE4 inhibitors for COPD and other indications?

So these 2 studies clearly show the benefits of lung function, reduction in exacerbation and in quality of life of this combination of medication. So I think it's very exciting to have different mechanisms of action. This is, as it was mentioned at the beginning of the presentation, this is a novel medication. It's a completely different mechanism that we have had in the last 20, 25 years of a bronchodilator and is showing the benefit in lung function as well as the other endpoints that were mentioned as well as the safety, I think, is the most important part because this is very well tolerated.

Okay, great. And then one final question from me. This is for Chris. So Chris, hypothetically speaking, if ensifentrine is priced premium over LABA or LAMA, do patients have to fail dual or triple therapy prior to receiving ensifentrine treatment?

So based on our discussions with the payers, and we have to keep in mind that ensifentrine will primarily be reimbursed through the Medicare Part B channel, within the Medicare Part B channel, which we anticipate about 60% of the patients going through, that's an open access network where physicians have access to ensifentrine and we don't anticipate any step-throughs there. I think the other thing that's really important is that we believe that ensifentrine has the potential based on the data to be priced at a premium versus the current nebulized products. I think the other thing that's really important here despite the pricing, what we see in the nebulized market, when you look at other branded products is that 80% of patients pay less than $10. So that's a really key factor in this market. Because of the way Medicare Part B works, you actually can get these patients the drug at a very low cost, and that allows them to stay on the medicine and get the benefits that we see in the trial. I think the other channels that we've talked to, when we talked to Medicare Part D, Medicare Advantage, what they've told us is that ensifentrine is an extraordinarily novel compound. They've not seen anything like this before in COPD. They're excited about that mechanism. They're excited about the data, and they anticipate putting ensifentrine on formulary and having access to ensifentrine within those channels as well. I will say that one area where there may be a step-through is if a patient is a newly diagnosed patient. Most payers have said they would like a patient to at least try a generic LAMA or LABA before trying ensifentrine. But that's not a large step-through for many of these physicians. And we believe that when we talk about the patient that will be on ensifentrine like Dr. Anzueto said, which is the patient that's symptomatic, these symptomatic patients have already tried therapies. So going to ensifentrine will be a low burden within the payer community as well.

Congrats on the outstanding data.

The next question comes from Tom Shrader with BTIG.

Congratulations on the long successful journey, it's nice to see. I have a little bit of a picky question for Dr. Anzueto or a detailed question. The way exacerbations are defined in the trial, is that what you care about or do you care about keeping patients out of the hospital? Is this the meaningful parameter that you and your colleagues think about?

Sure. So exacerbations are bad any way you look at it. We know that even exacerbations that are not reported, those mild in some extent are also bad for the patients in the lung function. So just -- I think it's important to put into context, this is not an exacerbation cohort. This is not an exacerbation study. This is a cohort of patients with moderate COPD. And we learned from the ECLIPSE trial in the New England Journal publication in 2010 with John Hurst that patients doesn't have to have very severe lung function to develop exacerbations. Patients with moderate disease can develop exacerbations and those can be significant. But the context of this study show you, yes, you can further reduce these exacerbations if you have the right mechanisms or the right medications on board. Certainly, we would like to have also a reduction in hospitalization of very severe exacerbations. But this is going to be a completely different cohort because we know that the people who's going to be hospitalized are people who was hospitalized in the past, who had comorbidities. And this is not a patient who had moderate COPD. These are patients who have more severe COPD or significant comorbid conditions. But in the context of this patient population, I believe that the data is very exciting because you have the triple win-win. You have the improvement in lung function, you have the reduction in exacerbations and improvement in quality of life and it's safe.

Do you see any reason why it wouldn't translate what we see today to these more serious patients?

No, I don't see any reason at all. I think I will say that if you go into a cohort of individuals who are more serious or have an exacerbation cohort, you will see exactly this and you will see a significant reduction in hospitalizations.

Okay. And maybe one quick one for the statisticians. I think the biggest difference between ENHANCE-1 and ENHANCE-2 is the trough FEV. Is there anything you can ascribe that to? Is it driven by placebo? To me, it's the biggest difference between the 2 trials. Can you make any sense out of it?

Yes. I think really a 14-milliliter difference in mean values, given the confidence intervals to us doesn't represent a real difference in effect, right? Both of these are statistically significant. So we have confidence that there is an effect with ensifentrine over placebo.

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

Thank you very much. So we would like to thank you for your questions and thank the patients and health care professionals who participated in the ENHANCE program. Finally, I'd like to thank our shareholders for their continued support and the dedicated and talented team at Verona for their commitment. We look forward to discussing these highly positive results with many of you in the coming weeks and to keeping you posted on our progress. That concludes today's call.

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