Insmed Incorporated (INSM) Earnings Call Transcript & Summary

Hello. Thank you for standing by. My name is Sarah, and I will be your conference operator today. At this time, I would like to welcome everyone to the Insmed Phase III ASPEN top line results conference call. [Operator Instructions] I would now like to turn the conference over to Bryan Dunn, Head of Investor Relations. You may begin.

Thank you, Sarah. Good day, everyone, and welcome to today's conference call to discuss the top line results of the Phase III ASPEN study of brensocatib in patients with non-cystic fibrosis bronchiectasis. I am joined today by Will Lewis, Chair and Chief Executive Officer; and Martina Flammer, Chief Medical Officer. We are also very pleased to have with us Dr. James Chalmers, Professor and Consultant Respiratory Physician at the School of Medicine University of Dundee, and the primary investigator in the ASPEN study. The call will begin with opening remarks from Will before turning it over to Martina to walk us through the results. Following Martina, we will ask Dr. Chalmers to give his perspective and insights on the data before turning it back to Will to close out the presentation. After the prepared remarks, the presenters will be joined by Gene Sullivan, Chief Product Strategy Officer; Kevin Mange, Chief Development Officer; and Sara Bonstein, Chief Financial Officer, for the Q&A session. The slides we will review today were furnished with the 8-K we filed with the Securities and Exchange Commission this morning and can also be found on the Events and Presentations section of our website. Before we start, please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our SEC filings for more information. As a reminder, the information on today's call is for the benefit of the investment community. It is not intended for promotional purposes nor is it sufficient for prescribing decisions. And now let me turn the call over to Will Lewis.

Thank you, Bryan. Welcome, everyone. On behalf of everyone at Insmed around the world, I am incredibly gratified to be able to announce that the Phase III ASPEN study in patients with bronchiectasis is a winning study. The outcome today exactly matches the target product profile we set out to achieve and gives us both the statistical and clinical outcome we had hoped for. In short, this is an historic moment. Anytime a company has the opportunity to bring an effective medicine to a community of patients where there is no approved treatment, it is significant. Today's ASPEN trial results suggest that Insmed will be in that position for a second time. As a company, we're incredibly proud of having achieved breakthrough results for 2 therapies for diseases that previously had nothing approved to treat them. The first time was with the conditional approval of ARIKAYCE for refractory NTM. And now with these ASPEN results, we are on the cusp of accomplishing that same outcome for patients with bronchiectasis. In fact, today's news caps a string of positive readouts across our entire mid- to late-stage portfolio over the last 9-months, including the ARISE data last September and the TPIP data earlier this month. These readouts collectively validate our portfolio of 3 late-stage first-in-class or potentially best-in-class assets, ARIKAYCE, brensocatib and TPIP. My sincere thanks go out to the patients who participated in all of these trials to whom we owe these successes as well as to my colleagues and the investigators who contributed their skill and passion to bring us to this result. Before I ask Martina to walk you through the data in detail, let me say this. Today's result is an unequivocal success, both brensocatib doses achieved highly statistically significant as well as clinically meaningful reductions in pulmonary exacerbations compared to placebo. Each dose also achieved statistical significance on multiple secondary endpoint measures, combine that result with the very favorable safety profile that has emerged over this longer-term treatment time frame and these results make the pathway to approval, noncontroversial in our view. I would also add that today's data firmly support the pricing research and peak sales estimates we provided for brensocatib and the lead-up to this readout. We intend to file these data with the FDA by the end of the fourth quarter of this year, keeping us on track for a potential U.S. launch in mid-2025 followed by launches in the EU and Japan in the first half of 2026. In addition and even more significantly, today's data validate the DPP1 inhibition mechanism of action, adding to our confidence in the potential to provide benefits for patients with other neutrophil-mediated diseases such as CRS without nasal polyps and hidradenitis suppurativa, among others. In short, we are thrilled with today's results. I will now turn the call over to Martina to walk you through the data in more detail.

Thank you, Will, and good morning, everyone. I'm pleased to be with you today to share the top line results from our ASPEN study. I will begin with a brief review of the trial design. The ASPEN trial was more than 50% larger than any other Phase III program that has ever been conducted in this patient population. As part of the trials conduct, we engaged more than 460 trial sites in nearly 40 countries. After excluding sites that did not enroll any patients and all sites in Ukraine, the total number of active sites in ASPEN was 391 sites in 35 countries. A total of 1,680 adult patients with non-cystic fibrosis bronchiectasis were evaluated in ASPEN. These patients had 2 or more antibiotic treated pulmonary exacerbations in the prior 12-months. Today's readout also includes data from 41 adolescent patients. Treatment was administered over a 52-week period, followed by 4 weeks of treatment with all efficacy endpoints being measured through the end of the 52-week treatment period. Safety data was collected through week 56. The primary endpoint in ASPEN was the rate of pulmonary exacerbations over the 52-week treatment period with the 10-milligram and the 25-milligram brensocatib arm, each being compared separately against placebo. Secondary endpoints in the trial included the time to first pulmonary exacerbation, percentage of patients who remain free of any pulmonary exacerbation throughout the 52 weeks, change in FEV1, rate of severe pulmonary exacerbation and change in the quality of life bronchiectasis respiratory score from baseline at week 52. On Slide 7, you can see the baseline characteristics for ASPEN by study arm. Adults were stratified based on 3 criteria: patients with 3 or more exacerbations in the prior 12-months, patients who were positive for pseudomonas aeruginosa and by geographic region. As a result, the study arms were well balanced across these criteria. Beyond that, the other key characteristics were also well balanced as would be expected for a trial this size due to its natural ability to control for outliers based on large numbers. Now let's discuss the efficacy results from this trial. On the primary endpoint of rate of pulmonary exacerbations, the 10-milligram dose showed a 21.1% reduction in the rate of exacerbations compared to placebo, resulting in a p-value of 0.0019. The 25-milligram arm showed a 19.4% reduction compared to placebo, which generated a p-value of 0.0046. These p-values were well below 0.01, the threshold for approval with a single Phase III trial and are highly statistically significant. They are also clinically meaningful. Based on our discussions with physicians who treat these patients, who have generally cited reductions of 15% to 20% for clinical meaningfulness. Let's now walk through the results of our secondary efficacy endpoints in the ASPEN study, which were tested at the [ alpha ] level of 0.05 as prespecified in the studies, FDA agreed upon statistical plan. I will go through the secondary endpoints according to the prespecified statistical hierarchy. First, I'll start with the comparison of the time it took patients to have the first protocol defined pulmonary exacerbation. Treatment with brensocatib extended the time for a patient to have their first exacerbation by 18.7% in the 10-milligram arm and by 17.5% in the 25-milligram arm, compared to placebo. Both of these results were statistically significant. On the next secondary endpoint of proportion of patients who remained exacerbation-free at week 52, the treatment showed a statistically significant benefit compared to placebo for both doses. Brensocatib treatment increased the odds that a patient would remain exacerbation-free by 41.2% in the 10-milligram arm and by 40% in the 25-milligram arm. The third secondary endpoint measures the potential impact of brensocatib treatment on lung function by observing the change from baseline in post-bronchodilator forced expiratory volume over 1 second or FEV1. On this measure, in the 10-milligram arm, we saw less decline in lung function of 11-milliliters compared to placebo, which was not statistically significant. However, the 25-milligram arm showed 38-milliliter less reduction in lung function compared to placebo, which was statistically significant with a p-value of 0.0054. In addition, we looked at the annualized rate of severe pulmonary exacerbations in the trial, which were defined as dose requiring IV antibiotics or hospitalization. On this measure, we saw numerical reductions compared to placebo of around 26% for both doses. However, neither result was statistically significant due to the low event rate. Finally, we saw a numerical improvement in patient symptoms for both doses compared to placebo as measured by the change from baseline in the quality of life bronchiectatis Respiratory score. The improvement in the 10-milligram arm was not significant. However, for the 25-milligram dose, the improvement resulted in a key value of 0.0004. While this p-value is nominally significant, it is not considered statistically significant due to the testing hierarchy. Given that both doses met the threshold for statistical and clinical significance on the primary endpoint of annualized rate of pulmonary exacerbations and that there appear to be a flat dose response on that endpoint, additional detailed analysis of the data will be required to determine which dose would be the best option to make available for patients or if both should be brought forward. In particular, we are intrigued by the stronger responses we saw on FEV1 and QOL-B respiratory score for the 25-milligram arm, and we'll investigate that in greater detail. Now turning to the safety data observed in the trial. As you can see from this table, the ASPEN results confirm brensocatib's favorable safety and tolerability profile. In this section, I will be discussing various treatment emergent adverse events, which, for simplicity, I will refer to as AEs. The percentage of patients experiencing any AE, a severe AE or a serious AE were slightly lower in both treatment arms than the placebo arm. We find these results incredibly exciting and reassuring. Overall, there were 14 AEs leading to death reported during the treatment period in ASPEN. Of these, 3 were on 10-milligrams, 4 were on 25-milligrams and 7 were on placebo. [ No best ] were attributed to study treatment. Additionally, the percentage of patients who discontinued treatment due to an AE was comparable between the treatment arms and placebo, which highlights the tolerability of this treatment. With regards to a ease of special interest, investigators reported such events in 7.2% of patients on 10-milligrams and 9.8% of patients on 25-milligrams, compared to 9.4% of patients on placebo. In summary, the ASPEN trial supports the promising safety and efficacy profile of brensocatib, underscoring its potential as a long-term treatment for patients with bronchiectasis. With that, it is my pleasure to introduce Dr. James Chalmers, the lead investigator in the ASPEN trial and the world expert in this field, who will share his thoughts on how he views the significance of this data. Dr. Chalmers?

Thank you very much, Martina. This is a really great day for those of us who look after patients with bronchiectasis. And so thank you so much for giving me the opportunity to share my perspectives on the data. I'm absolutely delighted with the results of the ASPEN trial, which will have a potentially transformational impact on the management of bronchiectasis worldwide. Bronchiectasis is a devastating condition for which currently there's no license treatments. It affects more than 0.5 million people in the United States, more than 200,000 people in the U.K. where I practice, and millions more patients worldwide. And bronchiectasis patients have been desperate for a treatment that can reduce the frequency of pulmonary exacerbations and reduce the burden of this disease and for this reason, the patient community around the world will be delighted by this news today. I've been researching neutrophils and neutrophil serine proteases in bronchiectasis for more than 15-years. So this DPP1 mechanism has a deep and compelling foundation research from a number of international research consortia have shown that high levels of neutrophil elastase and other NSPs are associated with a higher risk of exacerbation were symptoms, poor quality of life and disease progression with rapid lung function decline. At the basic level, these NSPs impair the body's ability to fight infections, drive excess mucus production and cause airway damage and so being able to block these NSPs through DPP1 inhibition has the potential to boost host defense, reduce symptoms and prevent disease progression. I was the Chief Investigator on the WILLOW Phase II trial that provided that first key proof of concept of this approach, showing significant prolongation of the time to first exacerbation and profound anti-inflammatory effects in patients' airway samples taken during the trial. I'm delighted that those exciting results have now been confirmed and extended by the Phase III ASPEN trial. The reduction in pulmonary exacerbations demonstrated by both doses of brensocatib in the ASPEN trial is clinically relevant and important just as Martina said. It represents the same level or a greater level of efficacy on exacerbations as has been demonstrated in big Phase III trials of other treatments that we consider standard of care in pulmonary diseases like triple inhaled therapy in COPD. Of the many exciting statistics that Martina presented as a clinician, I imagine being able to say to my patients -- that my patients will have a 40% increase in the odds of being able to go an entire year without an exacerbation with brensocatib compared to placebo. Patients will be so excited about the idea that more of them may be able to live their lives free of exacerbations. When this is available to patients, it will represent the first and only treatment that can do this. What also excites me are the results on the secondary endpoints, particularly with the 25-milligrams of brensocatib. Bronchiectasis Is a progressive disease. It's one that gets worse over time and nothing that we currently use can slow down the progression of the disease and so the greater than 30ml slowing of the rate of decline of FEV1 with 25 milligrams of brensocatib represents a remarkable result and suggests that brensocatib may modify the course of the disease. That's a really important result for patients. I'm also excited to see that respiratory symptoms were improved with the 25-milligram dose. That's another excellent outcome, which could mean a lot for patients. I'm not surprised that we didn't see a difference in efficacy on the primary outcome between the 10-milligram and 25-milligram brensocatib doses. My laboratory in partnership with Insmed has been conducting further research into the anti-inflammatory effects of brensocatib using data from the WILLOW trial. And what we've seen is that the 10-milligram dose already achieves a very large reduction in NSPs as well as restoring normal levels of antimicrobial peptides in the airways. This is data that we just presented last week at the American Thoracic Society meeting. For the additional effect of the 25-milligram dose on these endpoints is small because the 10-milligram dose already has such a powerful effect. What I am delighted to see is that additional effect on symptoms and lung function with the 25-milligram dose and we've shown in the same study that we reported at the ATS meeting that the 25-milligram dose in Willow had a large effect on mucins, airway mucus, and this provides a potential understanding of why we see a degree of separation of those secondary endpoints between the 2 doses. So this is a really special day for those of us who look after patients with bronchiactisis and have worked in this field. This treatment and this mechanism of action have been validated. And if approved, brensocatib opens the way to better treatment for our patients and a reduction in the burden of this devastating disease, opening up a new era of treating inflammation to slow down the progression of bronchiectasis, as I say, a really special day for those of us who look after these patients. So with that, I'll turn it back to Will.

Dr. Chalmers, I want to thank you for your pioneering work in this space. And with this mechanism in particular, including your participation in both the WILLOW and now the ASPEN trial, we truly appreciate you joining us today and for providing your insights for our audience. To close, this is a great day for patients with bronchiectasis and for all employees at Insmed, who have believed in the potential of this product to make a difference. ASPEN has provided very compelling data based on a large, well-designed and well-controlled clinical trial, the brensocatib can offer a significant reduction in the frequency of pulmonary exacerbations to patients who, up until now, have had 0 approved treatment options. It has also shown significant benefits on time to first exacerbation and the likelihood that a patient will remain exacerbation free for both doses. In addition, the brensocatib 25-milligram arm showed a statistically significant signal on reducing the amount of lung function decline and a nominally significant improvement in a patient-reported outcome measure. All of this is supported by a favorable safety profile that is comparable to placebo. Today's result is the clear win scenario for which all of us have been hoping. We will now move with urgency to bring this potentially live changing treatment to the patients who need it with the goal of a U.S. launch in around a year from now. As I noted earlier, we have done this before. We secured approval and successfully launched ARIKAYCE around the world and now the same team that accomplished that, will do it again. That work was already underway prior to these results and hopes that they would be positive. As a consequence, we're able to move quickly to ensure this promising medicine is approved and launched in what we believe will be a best-in-class commercial program. With that in mind, we invite you to join us for a webinar, we will be hosting a week from today on June 4 at 8 a.m. Eastern Time to dig deeper into how we are thinking about the market opportunities we see our 3 most advanced programs, ARIKAYCE, brensocatib and TPIP. And finally, I cannot turn to questions without first taking a moment to thank all of you who are financial sponsors of the work at Insmed that has led to this important clinical advance, without your continued trust and capital, today's result would never have been achieved. Now I'd like to open the call to questions. Operator, can we take the first question, please?

[Operator Instructions] Your first question comes from the line of Jessica Fye with JPMorgan.

Congrats on the data. First question for Will. How should we think about the company's focus and kind of key priorities changing over the next year in light of these results? And then a question for Dr. Chalmers or maybe Dr. Flammer, how much read across is there from these results in bronchiectasis to things like nasal polyps and HS?

So on the company focus question, I mean I think all eyes and mental energy are now on execution. What this unlocks, which is part of your second question, is not just the potential for an approved treatment for bronchiectasis but also the DPP1 mechanism itself. And I think this is a really significant moment for that. This is a new -- this is new biology. This is the potential to play a role in any neutrophil-mediated disease. We are already underway with CRS without nasal polyps, and I'll let a little bit of additional information out right now. We have 50 patients in the CRS without nasal polyp study. It's blended and blinded. But we are already seeing improvement in some of the scores for some of the patients in that study. And that early sign and separation or distinction of performance is incredibly encouraging, particularly in light of the ASPEN results today. Now it's early but I can't help but share that in light of our ambition to take this mechanism beyond bronchiectasis and into CRS without nasal polyps, which is yet another condition that has nothing approved to treat it. And as we've said previously, we'll go into hidradenitis suppurativa in a Phase II study by the end of this year. So some very exciting data surrounding the DPP1 mechanism. In addition, as you know, ARISE came out last fall, and that was very positive data, ENCORE will be the completion of the potential for expansion of ARIKAYCE into all MAC NTM, which is another very significant opportunity and where there is nothing approved to treat the disease. And finally, but not least, TPIP, where we had recent data in PH-ILD top line results that were incredibly compelling, and we look forward to the PAH full results next year. So our focus is on executing across those 3 programs, each of which have the potential for multiple indications as well as our fourth pillar, which we'll be hearing more about in the next year or so as we begin to build the pipeline behind these first 3 strong candidates. With that, I guess I'll invite Dr. Chalmers to make any comments he'd like to about the read-through of this data in bronchiectasis for potential other neutrophil-mediated diseases, and then I'll invite anyone on the medical team from Insmed to add to that.

Yes. It's hard to overstate how important the result is today. Neutrophils are involved in the pathophysiology of a huge range of diseases, not just most of the airway diseases that I look after as a pulmonary physician. But as you say, chronic rhinosinusitis, multiple other diseases in other organ systems. And the data that's been generated with brensocatib with the profound effect that it has on neutrophil serine proteases and the downstream immunomodulator and anti-inflammatory effects that this medication has really makes this a potential breakthrough not just in bronchiectasis, but in treating neutrophil-driven disorders more broadly. So today, we're excited about bronchiectasis. Tomorrow, we may be excited about a whole range of other neutrophil-driven disorders. It's really, really exciting.

Yes. Just to add both of those studies already -- we already see that this enrollment is going well and that HS will start soon. We have to keep in mind that these are different endpoints, but both studies are neutrophil-mediated, and I think that is the important aspect for our product.

Your next question comes from the line of Andrea Tan with Goldman Sachs.

Congratulations on the data. Maybe for my first question, as a follow-up there to Martina or Dr. Chalmers. Curious, as you mentioned that these other indications will have different endpoints. Just curious the magnitude of benefit you would expect given what you've seen here with ASPEN, what would be clinically meaningful in those indications. And then my second question here, just wondering if you're able to share any details on how the placebo arm performed. Just curious how you think about the magnitude of benefit here relative to what you observed in WILLOW.

Yes. So I'll take the second question first on the placebo performance. We provided what we -- we spent a lot of time thinking about what data to put out today, and we obviously wanted to be a fulsome presentation. But there is much more to learn from this study. It's a very expansive study, as you all appreciate. And so there'll be a lot more work that's done. And that additional data, some of which you're asking for right now will be forthcoming in future medical meetings and publications. What I can tell you is the data that we gave you, I think it was 1.5 years ago that gave the blended blinded range of events across the entire study, which I think at the time was 1.12 to 1.15. We ended up at the end of this study right in the middle of that. So that ended up being very indicative, and I think there's -- what I can tell you generally about the data that we have not shared today is that there's nothing else in here that takes this in any other direction other than positive. It's everything that we expected [ at Insmed ]. And of course, there's much more to learn. On the potential impact in other indications, I mean I think the only thing we can say right now is that we're [ underway ] CRS without nasal polyps measures and scores there are obviously different than what you see in bronchiectasis. And I can say that we are doing a higher dose there. It's a different disease, different process. So we'll see what the impact is, but we're testing both 10 and 40 in that study as opposed to the 10 and 25 that were studied in bronchiectasis. I don't know if anyone from the medical team wants to add anything. Kevin?

Thanks, Will. So for the CRS without nasal polyposis, I think we're excited from the potential read-through from ASPEN we do see an effect on symptom score in bronchiectasis for CRS without nasal polyposis is the primary endpoint is a total symptom score. So I think this gives us even more confidence in the ability of inhibiting this mechanism to lead to symptom score. So as Will had said, early days seeing change in symptom scores -- but I think the read-through is something we're excited about for that specific days. And then potentially for HS, hidradenitis suppurativa later on as well. But I think the fundamental piece from the positive results we have in bronchiectasis, I think we read-through that we've got the ability to show improvement in symptom scores and potentially other diseases.

Your next question comes from the line of Jennifer Kim with Cantor Fitzgerald.

Congrats on just this -- congrats across the board for continuing the streak of wins. I guess the 2 questions that I have is, first, I guess the data is fresh, but have you run any subgroup analyses on exacerbation rates for some of the subtypes like eosinophilic patients or historic COPD or even any level at baseline? And were there any -- have you sensed any trends in those subgroups? And then my second question is, as you're thinking about which dose to take forward. I know one of the secondary outcome measures is also a plasma concentration of brensocatib [indiscernible] time points. Have you looked into that? And does that inform anything about the differences in effect that you've seen between the 2 doses?

So yes, there's obviously a lot more to be learned, as I mentioned before, on the data, and we'll be running a ton of different analyses. But maybe, Kevin, you'd like to comment on these 2 questions in particular.

Sure. Thanks, Jennifer. So right. So those subgroups, as you mentioned, those will be coming in the near future as well. I think Again, the primary results we have are very clear for both doses being statistically significant highly so. Yes, we're interested in some of the subgroups that you've elaborate on, and that is in progress, in motion, and we'll share that to future meetings.

And I think when we think about where we go from here, the opportunity that this represents is -- this is a landmark study. There's going to be data coming out of this and sub-analyses that are going to be coming out of this for a very long time. But I think the most striking thing about today's result is -- from our point of view, this is a noncontroversial review process from here to approval because of the strength of both the safety and the efficacy that we've seen.

Your next question comes from the line of Nicole Germino with Truist Securities.

Congrats on the data. Can you just talk a little bit about the adjudication process and how many doctors decisions were overturned by adjudicators and things of that nature?

Kevin, do you want to take that?

Sure. So there was a central committee for adjudicating the events to confirm that the investigator-reported events fulfilled the protocol definition of those events. Without giving a specific percentage, most of those extremely high number of those were, in fact, confirmed by the adjudication committee to fulfill this protocol definition of exacerbation. So the endpoint here is adjudicated. We did that to add even more veracity to the results that, as we've been saying or clearly win for both doses and highly statistically significant.

Your next question comes from the line of Liisa Bayko with Evercore ISI.

Congratulations on this very important data. Wanted to ask about any comments on baseline levels of neutrophil elastase? And did you see a similar pattern as you did in WILLOW where it seemed to almost have a protective effect on patients with -- who tended to have lower levels of baseline. Just curious on the mechanism of action there.

Yes, I'll ask Kevin to comment on that in 1 second. I would just remind everybody that we talked about what we saw in WILLOW, these are the best measures we have, the assays that are utilized to quantify the NSP levels, but they're not perfect. And that's because this is still very nascent science and we've done a lot to improve that. Since the last 8 years, we've been working on this program, real great advances have been made there, but a word of caution on over-interpreting the WILLOW data. And Kevin, I don't know if you want to add any comments about.

Yes. So we did a sub-study in ASPEN for those markers. Those results are still being generated and looked at. So we don't have them today. As Will said, I think the focus is again that the endpoints of exacerbations is really clear that both doses [ won ], and we'll be interested to see what happened to those NSPs, but it will be in a subgroup of patients who were willing to participate in that in the overall study. But so more to comment at a later time in a meeting.

Wonderful. I may ask a follow-up.

Sure.

I was wondering if you could comment on kind of any strategy about maximizing your market exclusivity.

Sure. So what I can tell you is that in the background, we have been very hard at work on other DPP1 molecules. And maybe, Gene, I don't know you want to chime in and talk a little bit about sort of where we are with that.

Yes, sure. Thanks for the question. I mean when we saw the WILLOW results, we really thought we were on to something with DPP1 inhibition and recognize that there may be a need for additional compounds to achieve DPP1 inhibition maybe to different degrees and that depending on the specific neutrophil-mediated disease that we'd be targeting, you might have a different say, risk benefit profile that would be acceptable and so forth. So we have been hard at work for quite some time, our chemists generating data on additional compounds that we could bring to bear on diseases beyond the ones that we've already begun working with brensocatib, the CRS, the HS. And so we look forward to informing you of future progress with those new candidates.

What I can tell you is that, Liisa, there's not always great preclinical animal models for all these diseases, but we've already done some work in areas like rheumatoid arthritis and lupus nephritis, and we've seen some very positive data there. So we're super excited about this full class and intend to be a leader in the development of DPP1.

Your next question comes from the line of Graig Suvannavejh with Mizuho Securities.

Great. Congrats team on the data. Just 2 questions, 1 for the company, 1 for Dr. Chalmers. Will, could you just remind us what your assumptions are or what they might be around base case pricing for brensocatib especially in light of your hope or intent to expand the label into CRSsNP and HS, -- in other words, would your launch price in bronchiectasis kind of stay the same, assuming you are able to launch in CRSsNP or HS? Or does that require some revised thinking about pricing? And then maybe my question for Dr. Chalmers. Curious, Dr. Just on the assumption that this drug gets approved in a timely fashion globally, what would you anticipate uptake of this product to look like? Would this be a rather swift adoption? Or is there a fair amount of education that is needed with regards to the novel DPP1 inhibition mechanism of action and that there haven't been or vis-a-vis that there haven't been any other drugs approved for bronchiectasis previously.

So Dr. Chalmers, why don't you go ahead and answer first, and then I'll follow up.

Yes. So my assumption is that there will be very swift adoption of this medication. And the reason for that is that currently, there are no other approved therapies for bronchiectasis. So our current management consists of physiotherapy and antibiotics, both of which are not particularly effective at preventing exacerbations. So I think the adoption, the clinician appetite to adopt this will be very high, and I think the patient community will be looking for this to be adopted as quickly as possible.

On the question of price, Graig, it's early to be sort of directing where that might go. I think we want to certainly navigate through the regulatory world and understand what the label is so that we can understand the value proposition we're going to be pursuing here. We've obviously done a lot of research. We have a pretty detailed understanding of what the landscape looks like. We've given you some direction in that regard by referencing something like Fasenra as a base case level. But what I would encourage you to do is attend next Tuesday commercial presentation, where we'll go into some of those questions and answers in a little bit more detail.

Your next question comes from the line of Jeff Hung with Morgan Stanley.

Congratulations on the results. I know the number of adolescent patients were relatively small, but qualitatively, were there any notable differences observed in adults versus adolescent patients? And then for Dr. Chalmers, can you just comment on how important the various secondary endpoints are to physicians and patients in the decision-making process versus reduction in annualized rate of pulmonary exacerbations. And how meaningful is the improvement in QOL-B with the 25-milligram dose, even though it's nominally significant.

Dr. Chalmers, I'll ask you to go first.

Yes, absolutely. So the most important endpoint for patients is pulmonary exacerbations. That's why it's the primary endpoint and why it leads all of these discussions. And the reduction that we've seen in ASPEN is highly clinically significant. But the other endpoints are also going to be important for the decision-making process. But currently, none of our other treatments that we use, all of which are off-label are associated with a significant treatment -- sorry, significant symptom benefit. So even though the 25-milligram dose symptom benefit is only nominally significant. That's going to be important in the minds of clinicians who want to be able to offer their patients something that is likely to improve their symptoms. And then I mentioned in my presentation, nothing else that we have slows down lung function decline. From a patient perspective, a medication that can prevent you from getting worse over time is potentially really important. And 30 -- more than 30 mLs is the magnitude of that benefit the normal decline in lung function for a healthy adult is 30 mLs. So the level of attenuation of that decline that we're seeing with brensocatib is highly clinically meaningful. It could it could stop patients from getting worse progressively over time. So I think for clinicians, all 3 of those end points, the exacerbations, the symptoms and the lung function decline collectively will be really important in the decision-making process.

Martina, do you want to take the adolescent question?

Yes, sure. So remember, we've like 41 adolescent patients in this study. And overall, we don't really see they deviate in any way from the adult population. Obviously, this is not a study that's powered to compare between 41 patient adolescents and 1,700 adults, but overall, fairly consistent. And we have to remember a patient population where bronchiectasis is not very common, but they currently certainly don't have any treatment options and reducing exacerbations and potentially improving how lung function decline behaves in these patients given their age would be even more important. So obviously, we hope to have that represented in what will be a regulatory pathway, hopefully, to approval.