Hello, thank you for standing by. My name is Sara, 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. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session, and if you would like to ask a question during this time, please press star one on your telephone keypad. I would now like to turn the conference over to Brian Dunn, Head of Investor Relations. You may begin.
Thank you, Sara. 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.
Now, let me turn the call over to Will Lewis.
Thank you, Brian. 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 two 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 nine months, including the ARISE data last September and the TPIP data earlier this month. These readouts collectively validate our portfolio of three 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 timeframe, and these results make the pathway to approval non-controversial in our view. I would also add that today's data firmly support the pricing research and peak sales estimates we provided for brensocatib in 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 E.U. 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 trial's 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 off 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 mg and the 25 mg brensocatib arms each being compared separately against placebo. Secondary endpoints in the trial included the time to first pulmonary exacerbation, percentage of patients who remained free of any pulmonary exacerbation throughout the 52 weeks, change in FEV1, rate of severe pulmonary exacerbations, 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-mg dose showed a 21.1% reduction in the rate of exacerbations compared to placebo, resulting in a p-value of 0.0019. The 25-mg 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 3 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%-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 pre-specified in the study's FDA agreed upon statistical plan. I will go through the secondary endpoints according to the pre-specified statistical hierarchy. First, I'll start with the comparison of the time it took patients to have their 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-mg arm and by 17.5% in the 25-mg 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-mg arm and by 40% in the 25-mg arm. The third secondary endpoint measured 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-mg arm, we saw less decline in lung function of 11 mL compared to placebo, which was not statistically significant. However, the 25 mg arm showed 38 mL 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 those 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 numerical improvement in patient symptoms for both doses compared to placebo, as measured by the change from baseline in the quality of life bronchiectasis respiratory score. The improvement in the 10-mg arm was not significant.
However, for the 25-mg dose, the improvement resulted in a p-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 appeared 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-mg 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 this result 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 mg, 4 were on 25 mg, and 7 were on placebo. No deaths were attributed to study treatments. 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 AEs of special interest, investigators reported such events in 7.2% of patients on 10 mg and 9.8% of patients on 25 mg, 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 a 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. 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 licensed treatments. It affects more than 500,000 people in the United States, more than 200,000 people in the U.K., where I practice, and millions more patients worldwide. Bronchiectasis patients have been desperate for a treatment that can reduce the frequency of pulmonary exacerbations and reduce the burden of this disease. 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, worse 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 greater level of efficacy on exacerbations, as has been demonstrated in big, big Phase III trials of other treatments that we consider standard of care in pulmonary diseases like triple inhaled therapy and 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 mg 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.
The greater than 30 mL slowing of the rate of decline of FEV1 with 25 mg 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 mg dose. That's another excellent outcome, which could mean a lot for patients... I'm not surprised that we didn't see difference in efficacy on the primary outcome between the 10 mg and 25 mg 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.
What we've seen is that the 10 mg 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. So the additional effect of the 25 mg dose on these endpoints is small, because the 10 mg 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 mg dose. We've shown in the same study that we reported at the ATS meeting, that the 25 mg dose in WILLOW had a large effect on mucins, airway mucus. This provides a potential understanding of why we see a degree of separation of those secondary endpoints between the two doses.
So this is a really special day for those of us who look after patients with bronchiectasis, 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, that brensocatib can offer a significant reduction in the frequency of pulmonary exacerbations to patients who, up until now, have had zero 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 mg 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 had been hoping. We will now move with urgency to bring this potentially life-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 in 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 8:00 A.M. Eastern Time, to dig deeper into how we are thinking about the market opportunities we see for our three 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 were financial sponsors of the work at Insmed that has led to this important clinical advance. Without your continued trust in 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?
Thank you. If you would like to ask a question, please press star one on your telephone keypad. If you would like to withdraw your question, simply press star one again. We ask that you keep questions to two per person, and if you wish to ask further questions, please rejoin the queue. Your first question comes from the line of Jessica Fye with J.P. Morgan. Your line is open.
Hey, guys. Good morning. Wow, 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 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? Thank you.
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, you know, 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 polyps 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 2 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 three 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 three 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.
Yeah, 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 immunomodulatory 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.
Yeah. Just to add, both of those studies, we already see that there's 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.
Great. Thanks.
Your next question comes from the line of Andrea Tan with Goldman Sachs. Your line is open.
Good morning. Thanks for taking our questions, and congratulations on the data. Maybe for my first question, as a follow-up there to Martina or Dr. Chalmers, curious, you know, 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. Thanks so much.
Yeah. So, I'll take the second question first on the placebo performance. We provided what we spent a lot of time thinking about what data to put out today, and we obviously wanted it to be a fulsome presentation. But there is a 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 a year and a half ago, that gave the blended, blinded range of events across the entire study, which I think at the time was 1.12-1.15.
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 us in any other direction, other than positive. It's everything that we expected and then some. 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. The 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, where we do see an effect on symptom score and bronchiectasis. For CRS without nasal polyposis, 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, you know, early days, seeing change in symptom scores, but I think the read-through is something we're excited about for that specific disease. And then potentially for HS or 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. Your line is open.
Hey, guys. Congrats on just this. Congrats across the board for continuing the streak of wins. I guess the two 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 history of COPD, or even any levels at baseline? And 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 was also plasma concentration of brensocatib at select time points. Have you looked into that, and does that inform anything about the differences in effect that you've seen between the two doses? Thanks.
Yeah, 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. Maybe, Kevin, you'd like to comment on these two questions in particular.
Sure. Thanks, Jennifer. So, right, those subgroups, as you mentioned, 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, and highly so. Yes, we're interested in some of those subgroups that you've elaborated on, and that is in progress, in motion, and we'll share that to future meetings.
I think, you know, when we think about where we go from here, the opportunity that this represents is this is a landmark study. There's gonna be data coming out of this, and sub-analyses are gonna 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 non-controversial review process from here to approval because of the strength of both the safety and the efficacy that we've seen.
Okay. Thank you.
Your next question comes from the line of Nicole Germino with Truist Securities. Your line is open.
Yes. Good morning. Thanks for taking our question, and congrats on the data. Can you just talk a little bit about the adjudication process and how many doctor decisions were overturned by adjudicators and things like of that nature?
Kevin, 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 those protocol definition of exacerbation. So the endpoint here is adjudicated. We did that to add even more veracity, you know, to the results that, as we've been saying, are clearly a win for both doses and highly statistically significant.
Great. Thanks.
Your next question comes from the line of Liisa Bayko with Evercore ISI. Your line is open.
Hi. Congratulations on this very important data. Wanted to ask about any comment 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. Thanks.
Yeah, I'll ask Kevin to comment on that in one second. I would just remind everybody that when we talk 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 eight years we've been working on this program, real great advances have been made there. But word of caution on overinterpreting the WILLOW data, and Kevin, I don't know if you want to add any comments about it.
Yeah, so we did a substudy 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 endpoint of exacerbations is really clear that both doses won, and we'll be interested to see, you know, what happened to those NSPs. But it'll be in a subgroup of patients who were willing to participate in that in the overall study. So more to come at a later time in a meeting.
Wonderful. May I ask a follow-up?
Sure.
I was wondering if you could comment on kind of any strategy about, you know, maximizing your market exclusivity. Thanks.
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-
Okay
... I don't know, you wanna chime in and talk a little bit about sort of where we are, with that?
Yeah, sure. Thanks for the question. I mean, when we saw the WILLOW results, we really thought we were onto something with DPP1 inhibition and recognized 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've 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, with brensocatib, the CRS, the HS. And so we look forward to, you know, informing you of future progress with those new candidates.
... What I can tell you is that, Lisa, you know, we, 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 whole class, and intend to be a leader in the development of DPP1.
Thank you.
Your next question comes from the line of Graig Suvannavejh with Mizuho Securities. Your line is open.
Great. Thanks so much for taking my questions. Congrats, team, on the data. Just two questions, one for the company, one 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 CRS and HS? In other words, would your launch price and bronchiectasis kind of stay the same, assuming you are able to launch in CRS, NCFB, or HS, or does that require some revised thinking about pricing? And then maybe my question for Dr. Chalmers, curious, doctor, just on the assumption that this drug gets approved, you know, in a timely fashion, you know, 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, you know, been, or vis-a-vis, that there haven't been any other drugs approved for bronchiectasis previously? Thanks.
So, Dr. Chalmers, why don't you go ahead and answer first, and then I'll follow up.
Yeah. 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, Greg, 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's commercial presentation, where we'll go into some of those questions and answers in a little bit more detail.
Okay, great. Thanks so much, and congratulations again.
Thank you.
Your next question comes from the line of Jeff Hung with Morgan Stanley. Your line is open.
Hey, congratulations on the results, and thank you for taking my questions. 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 mg dose, even though it's nominally significant? Thanks.
Dr. Chalmers, I'll ask you to go first.
Yep, 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. So currently, none of our other treatments that we use, all of which are off-label, are associated with a significant symptom benefit. So even though the 25 mg 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.
You know, from a patient perspective, a medication that can prevent you from getting worse over time is potentially really important. Thirty, more than 30 mL is the magnitude of that benefit. You know, the normal decline in lung function for a healthy adult is 30 mL. So the level of attenuation of that decline that we're seeing with brensocatib is highly clinically meaningful. You know, it could stop patients from getting worse progressively over time. So I think for clinicians, all three of those endpoints, 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 that they deviate in any way from the adult population. Obviously, this is not a study that's powered to compare between 41 adolescents and 1,700 adults, but overall, fairly consistent. And we have to remember, this is 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, more important. So obviously, we hope to have that, represented, in what will be a regulatory pathway, hopefully to approval.
Great. Thank you.
... Your next question comes from the line of Jason Zemansky with Bank of America. Your line is open.
Thanks. Good morning, and appreciate you taking our questions, and congratulations on the stellar data. One for Will, if I may. Where do you stand from a capital standpoint as far as supporting a launch goes, especially given there's a lot of current infrastructure that you can build on? And then I know it's early, but given the initial signals, it looks like early-stage patients are likely to experience a benefit. Have you changed or updated any of your assumptions about the addressable 450,000 population in the U.S. you estimated at launch?
Yeah, so thanks for that question. In a second, I'll ask Sara to comment on capital, other than to say that we started very deliberately in our design here to have adequate capital for this exact moment. And in particular, I wanna call out the decision that we took strategically to utilize convertible debt, which I know made some people a little bit uncomfortable coming into these results. But today really provides us the opportunity for the benefit of that less dilutive pathway to sourcing capital. So we're gratified that that is playing out as it is. On the balance of the capital question, I'll just ask Sara if you wanna comment.
Sure, happy to. And, you know, the outcome of the ASPEN trial today, it being the third successful readout for the company in the past nine months, it really sets us up for a period of significant revenue growth potential, and one that can really lead us to profitability. I could not be more proud of this team. These results not only provide us the path to a first treatment for patients in bronchiectasis, if it's approved, but also potentially unlocking a new mechanism and a new class, which really has the potential for additional neutrophil-mediated diseases. That said, as Will commented on, we've really been thoughtful on our balance sheet, minimizing dilution. We'll continue to be thoughtful on that front. These data now with these data now in hand, really gives us optionality as it relates to balance sheet and even more plentiful.
We have many levers we can pull, and we believe it will be at a, you know, attractive cost of capital. You know, we closed last quarter with around $600 million on the balance sheet. Couldn't be more proud of the team and its accomplishments.
And on your question, Jason, with regard to the addressable market and does this change our thinking? You know, what I would say is, tune in next Tuesday for our more thorough examination of the commercial dimension that is implied by this, by these data. I'll let a little bit of it out by just saying we are 100% confident, and confident plus in what we have said to date. So, next Tuesday, we'll dig in more, not just on brensocatib and its different areas, but the other two products, ARIKAYCE and TPIP.
Well, great! Looking forward to the color. Appreciate it. Thanks.
Your next question comes from the line of Andy Chen with Wolfe Research. Your line is open.
Hi, thank you for taking the question. So one question for Dr. Chalmers. So I know we saw 20%, roughly 20% reduction on the primary endpoint. Just given that this is an indication of high unmet need, does that actual number actually drive a difference in utilization? So let's say, hypothetically, we saw 25% or 30%, do you think commercial adoption will be, will be different just because of that? And then also, a separate question for management. So I know you talked about R&D spend, it was an 80-80-20 split. Now that you're winding down ASPEN, can you talk about whether you foresee lower R&D spend moving forward and what that split is going to be? Thank you.
I'll ask Dr. Chalmers to respond first, and then Sara can take the question on R&D.
Yeah. So I mean, the way I would answer that question is to say 20% is a highly clinically meaningful reduction in exacerbations. If it, you know, if hypothetically, that number was 25%, I don't think it's going to make any difference in the way that a clinician will think about using the medicine. I think what we have here is a meaningful reduction in exacerbations, and because of the unmet need that you've mentioned, you know, we have hundreds of thousands of patients who are frequently exacerbating. I think that data that we've seen will drive adoption. So I don't think small differences or slightly higher efficacy data would make any difference to how it's going to be adopted. I'm very confident it's going to be heavily adopted by the bronchiectasis community.
Great. Thanks, Dr. Chalmers. Andy, to address your spend question, the 80-20 split that we've spoken about, that is the split between the fourth pillar and our other three programs. As we think about more broadly on R&D spend, you know, we obviously couldn't be more pleased with this outcome. We'll now look to move brensocatib forward. Obviously, it's ongoing in CRS. We'll look to initiate HS as well as well as, you know, continue to progress TPIP and ARIKAYCE. Importantly, we are building our company with the mindset of becoming a profitable company, and so we will be thoughtful as we think about our investment and what level of investment we have, and balance that on the anticipated increased revenue to ensure that we build a self-sustaining biotech company.
Thank you, Sara. Thank you, Dr. Chalmers.
Your next question comes from the line of Ritu Baral with TD Cowen. Your line is open.
Good morning, guys. I wanna add my congratulations on the data. Both of my questions are actually for Dr. Chalmers. Dr. Chalmers-
... Chalmers, do you see a dose response in the data? And my follow-up question has to do with your comment on the mucin quality. Do you believe that that factors in more to the change in FEV1, or the and/or the change in quality of life, the QOL-B, change that we saw? And how much does the FEV1 factor into another comment you made about the disease, the potential disease-modifying nature of the drug? Is that also mucin-related, or could it be something more structural? Thanks.
Yeah. So I'll take the last part of your question first, because that's, that's probably the really important question. In terms of the mechanism, it's probably not all mucin-related in terms of slowing down the lung function decline. Neutrophil elastase breaks down elastin, which is one of the key structural components of the airway, and so we know neutrophil proteases drive remodeling, which is what drives lung function decline. And so the lung function decline in people with bronchiectasis is a combination of that destruction of the bronchial walls and blocking of the small airways with mucus. What the mechanistic work that we've done showing that brensocatib can reduce NSPs and seems to have an effect on mucus means that it hits both of those potential key mechanisms of lung function decline.
And so that helps to explain why, at the 25 mg dose, you see a significant and clinically relevant attenuation of lung function decline, presumably because it's both through the NSP effect and potentially through the mucus effect. Obviously, we need to do more digging into the data to understand what's driving the symptom differences, but the main symptom that patients with bronchiectasis complain of is excessive mucus production and productive cough. That's what drives the respiratory symptom domain of the QOL-B. So that also makes sense from the point of view of a larger symptom benefit was seen in the 25 mg group, and that's the group where analyzing the samples and the data from WILLOW, we see the effect on mucus.
So it's a plausible hypothesis, a strong mechanistic basis to understand the differentiation between the two doses. So I think there is. Clearly, from what Martina's presented today, there is a difference in the sense that there's a larger benefit on lung function and a larger benefit on symptoms with the 25 mg dose, and that may be because of what we've seen previously, which is this larger effect on NSPs and the downstream effects.
Great. Thank you. And if I could squeeze one more in. Will and Martina, plans for Europe and that filing?
So yeah, we plan to file and launch in Europe and Japan in the first half of 2026. So the filings will come obviously before that. We have PRIME designation in Europe. I think we're the only respiratory compound that does. But that should help facilitate a smooth regulatory process in Europe. And again, to be clear, we will launch. Our expectation is we're launching in Europe first and then Japan second, sometime in the first half of 2026.
Awesome. Thanks, guys. Congrats again.
Thank you.
Your next question comes from the line of Leon Wang with Barclays. Your line is open.
Hi, congrats on the data, and thanks for taking my question. One for Dr. Chalmers and two for the company. For Dr. Chalmers, you know, with the full data in hand, I guess, is there any particular patient profiles that you see responds best to brensocatib? And for the company, given the impressive results and your conversation with the FDA, do you expect a potential AdC om ahead of the approval, given the novelty of the bronchiectasis indication? And in terms of the potential to see full data, is World Lung perhaps a little too early, or would something like ERS Congress perhaps be more appropriate for that? Thank you.
So before I hand it over to Dr. Chalmers to answer the first question, he may have an opinion on the last question. But it's, it's certainly tongue in cheek here. It's, it's not... We haven't said anything in particular, but it would be hard for us to imagine a conference of that prominence focused on the topic of bronchiectasis taking place in Scotland, no less, where we would not have a very strong presence. Dr. Chalmers, do you want to take the first question as well?
Yes, so absolutely. I mean, I think whatever we do, this data is going to be a key topic of conversation. It's going to be on everybody's lips at the World Bronchiectasis Conference. This is, this is all, the bronchiectasis community is going to be talking about for the next few months. In terms of your question about the patient profile, what we saw in WILLOW when we looked at the subgroup analyses was that all of the groups of patients in that study seemed to respond very similarly. There wasn't an obvious patient that jumped out as being a brensocatib patient, allowing for the smaller sample size of that study. Obviously, we need to see the subgroup analysis from ASPEN. We're just seeing the top-line data today.
But what I would say is that neutrophilic inflammation is a dominant mechanism that we see across the bronchiectasis patient population. So it may well be that there isn't a subgroup or a particular patient group that will respond differently. It may be that this is a mechanism that's beneficial for the vast majority of patients with bronchiectasis. That's certainly what we see when we look in the biology. When you look in the sputum, neutrophilic inflammation is an almost universal mechanism that drives disease.
On the question of FDA AdCom, Gene, I don't know if you'd like to make a comment on that?
Yeah, sure. I mean, at this point, I frankly don't really see any data that would suggest the need for an AdCom. You know, the FDA will make that assessment during the first period of review, the so-called review period, and decide whether they think there's anything there to that would require an AdCom, and they let us know that in the filing letter. But it's not so much the fact that it's a new molecular entity, a new pathway, wouldn't really drive it. The FDA, in recent years, has sort of adopted this decision aid that they try to use across divisions to assess whether a new compound needs to go to an advisory committee.
The considerations are really there around uncertainties around safety or efficacy, or if there is a major safety concern that's been identified during the pivotal or earlier work, and we really don't see anything. It's very, the statistical and clinical significance of our primary endpoint, the secondary endpoints that have been discussed, is really unequivocal that those are positive. And what we haven't talked about a lot on today's call is the remarkable safety. So, you know, we can't say for sure. The FDA will let us know their decision on that in the 74-day letter. But as I look at it, I don't see that it meets any of the criteria that they would generally apply for deciding.
We actually looked back at recent approvals of new pathways, new novel drugs, and in fact, many of them weren't taken to an advisory committee meeting because of the factors that I mentioned earlier. The FDA didn't see anything unexpected or had no issues related to safety or efficacy. Right now, we don't know for sure, but I think there's a good possibility that we would not have one.
Thank you.
Once again, if you have a question, it is star one on your telephone keypad. Your next question comes from the line of Stephen Willey with Stifel. Stifel, sorry. Your line is open.
Yeah, good morning. Thanks for taking the questions, and let me also reiterate my congratulations on the data. Maybe just one clinical and one bigger picture follow-up. So on the clinical side, should we assume that the inability to demonstrate statistical significance on severe exacerbations reflects a low number of events that occurred during the study? Can you just qualitatively speak as to whether you think this might just be a dynamic range issue?
Martina, do you want to take that one? Kevin, if anyone else wants to add a comment, feel free.
Yeah. So yeah, right now, we're seeing an overall relatively low number of events, and that's probably the reason why we don't see that. But, you know, more analysis to be done.
Yeah, I think as part of it, I think directionally, as you see, you know, there is a reduction in severe exacerbation, so I think that's an important piece here. But fundamentally, whether there was powering there from the low event rate there, again, the diversity of this program across the world, and maybe Professor Chalmers wants to chime in on this a little bit, you know, the access to hospitalizations, and that is very different across the world. So that may have also driven some of the decisions in terms of admitting patients to hospitals or not. So, Professor Chalmers, anything to add?
Yeah, exactly. So I run registries, obviously, across Europe and collaborate with countries in Asia and also North America. The criteria for hospitalization across the world for bronchiectasis exacerbations varies enormously. Some countries, hospitalizations are quite frequent. Some countries, almost never do you see hospitalizations for severe exacerbations. And so that, I think that also feeds into this endpoint being more difficult to interpret than the other endpoints. As Kevin said, though, directionally, it's showing what we would expect in terms of being in line with the reduction overall in exacerbations. I suspect it is just driven by variations in care and the low number of hospitalizations overall.
Okay, that's helpful. And maybe just a question for Will. So just curious how today's data, I guess, if at all, impacts your relationship and ongoing dialogue with AstraZeneca. They obviously just opted in to develop brensocatib in asthma and COPD. I know that you've talked about there being a much larger number of patients with a primary diagnosis of asthma and COPD and a secondary diagnosis of bronchiectasis. And are there already guardrails in place with respect to how each party could detail the product in the event that AstraZeneca moves forward into the clinic and proves to be successful? Thanks.
Yeah, so thanks for the question. I think what I would say about that is, pursuant to the second option exercise under the, licensing agreement, we, are in good faith discussions, as is required by that, contract, and those will continue. Ultimately, we do have the ability to, make our own judgment, our own business judgment about whether or not a transaction of any kind, with regard to COPD and asthma development by AZ is something that we think makes sense. So that, that veto right, if you will, sits with us, without oversight. So I feel very good about our situation.
I think today's data certainly improve the outlook for both this drug and bronchiectasis and the mechanism more broadly, as you've heard several of the physicians on the call mention, and I'm sure that will inform the discussion as we move forward. But I don't foresee any change in our strategic intent or direction that we intend to travel. We are well underway in preparation on the medical affairs side, soon to be supplemented by the commercial team growing with absolute best-in-class talent that is gonna make it possible for us to, once again, once this is approved, launch this drug as effectively as we did launch ARIKAYCE.
I like to think back on those days because it was a Wall Street perspective at the time that we would probably not do more than about $40 million or $60 million in the first year based on the number of patients we would treat, and we pretty much tripled that. So I like to think about what that could mean for us in this setting, as we reach out to what we believe at launch in the three areas where we have existing infrastructure, numbering well over 1 million patients. It's a very exciting time for the company. We've been waiting a long time for it, but we're here, and we're ready.
Very helpful. Congrats again.
Your next question comes from the line of Vamil Divan with Guggenheim Securities. Your line is open.
Great. Thanks so much for taking the questions. Yeah, congrats as well on the data. So two questions if I could. One, I realize, obviously, it's still early here, so you probably can't get into too much detail, but curious if you can give a little more on the safety side. Looks like the rates are, you know, comparable, but curious on the, you know, treatment emergent AEs, those are the ones that led to death or treatment discontinuations. If you can't give much detail, just kinda what sorts of events were that led to those outcomes? And then for Dr. Chalmers, I just have one question for you as well. We've had a lot of conversation with investors and with other physicians around, obviously, a lot of patients with bronchiectasis have asthma and COPD, they're underlying as well.
How do you think about sort of these data suggesting the need to, you know, push to add a new product like brensocatib, or kinda be more aggressive on treating the other underlying conditions? I think there's just been some sort of debate about, you know, kinda adding a new mechanism on top versus optimizing patients maybe with their, you know, therapies that are already been available. So if you could just comment on how you think about treating patients with, you know, with those underlying conditions, that'd be helpful. Thanks.
Dr. Chalmers, why don't I let you go first?
Yeah, absolutely. So, I mean, the brensocatib won't take away the requirement for us to treat patients with bronchiectasis, with airway clearance, for example, which is treating the underlying condition, or if patients have comorbid COPD or asthma, to treat with, for example, bronchodilators. But I think the key thing that we've observed from multicenter registries and also from the number of patients that were enrolled into the ASPEN trial, is that a very large number of those patients continue to have frequent exacerbations despite what is current standard of care for those underlying conditions. And the current standard of care for those underlying conditions is not particularly effective. So I think there'll be a very important place for this new mechanism of action to treat those patients who continue to exacerbate despite what is our current standard of care.
And just on the question of, treatment-emergent adverse events and different profiles, you know, we don't have a lot more information on it other than to make the overarching observation that it's quite a remarkable, event to see, almost no matter how you measure them, at least comparability to placebo, and in certain cases, many cases, better than placebo, which for a, a medicine that's a once-a-day pill, for the treatment of a pulmonary condition is really, I think, extraordinary. I don't know, Kevin, if you wanna add anything on, on just some of the safety data we have.
Yeah, I think that's right, Will. I think on balance, everything was really well balanced across these adverse events leading to discontinuation across the study groups, severe or serious as well. And so it's not any specific event, to answer your question, if you will, but it's still really impressive, I think, from the safety profile we see overall here with both doses of brensocatib. And then linking back to the strong efficacy that we've seen as well, too, this is a really good safety profile. Some more details to come, but we're really excited about the overall benefit risk that this potentially will offer for patients here who really have no treatment options today.
The only thing I'll leave you with is, let's remember that this is a one-year study. So we had 1,700 patients with twice the exposure in terms of time for this study. And, you know, if you're gonna drill down on this particular mechanism of action, you'd go to the treatment-emergent adverse events of special interest. And there, you actually see a remarkably similar profile to placebo, and at the 10-mg dose, it's actually lower. So, I don't think it could be any better than it is, and hopefully, that addresses the question, at least until we get more data out and dig deeper. But we do not anticipate any change in the safety profile of this drug.
Your next question comes from the line of Joseph Schwartz with Leerink Partners. Your line is open.
Great. Congrats on yet another well-executed win. Hats off to the whole Insmed team. I wanted to ask about the lower rate of death in the brensocatib arms, as well as the reduction in the rate of severe PEs and improvement in quality of life. Obviously, the overall mortality rate is low, but it's around half as high in the drug arms relative to the placebo arm. So, Dr. Chalmers or, or Will, does anyone on your team have any thoughts on the potential importance of this? Since some literature suggests that bronchiectasis does not just have lung ramifications, but there are comorbidities which might impact morbidity, mortality, and maybe brensocatib's disease-modifying.
Dr. Chalmers, I'll invite you to speak first.
So, to the question about disease modification, you know, I think that there is very encouraging data there on the lung function. We know that lung function is one of the things that progressive decline in lung function is one of the things that drives patients towards ultimately poor outcomes, including mortality. You know, the data that's been reported today in terms of the treatment emergent adverse effects leading to death, the numbers are small, but they're certainly encouraging. So I think, you know, we need to drill more into the data, but the lung function data does suggest an extent to which this could be a disease-modifying therapy. And we know from the biology that neutrophil elastase, you know, high levels of neutrophil elastase, high levels of the target of DPP1, are associated with increased risk of mortality.
So it's not unreasonable to think that targeting this mechanism could have disease-modifying benefits. So these are, these are data that we need to explore in more detail, in my opinion.
Thanks very much, Dr. Chalmers.
Interesting. Can I just ask a follow-up? Will patients in ASPEN be able to receive brensocatib for longer than a year and be evaluated for potential benefits over a longer period of time?
I'll ask Kevin to respond.
Sure. So there's a patient—sorry, a post-trial access program that has been ongoing, so that when patients did complete their time in ASPEN, they could roll into that. That will remain, you know, available for the foreseeable future for patients who participate in the ASPEN study. And in that, you know, we'll collect data along the way as a post-trial access program. It'll be spontaneous safety reporting, and among that, and we'll have some information about exacerbations. But in answer to your question is, yes, we'll use this as a way of generating longer-term spontaneous safety data.
Great, thanks. Congrats again.
Thank you.
There are no further questions at this time. This will conclude today's call. Thank you for joining. You may now disconnect your lines.