Insmed Incorporated (INSM) Earnings Call Transcript & Summary

Good morning, and welcome to the Insmed Commercial Webinar and Conference Call. [Operator Instructions] Please be advised that today's conference call is being recorded. I would now like to hand over the conference to Bryan Dunn, Head of Investor Relations at Insmed. Please go ahead.

Thank you, and good day, everyone, and welcome to today's webinar to discuss the commercial outlook for Insmed's first 3 development assets. With us on the call today is Insmed's Chief Commercial Officer, Drayton Wise, who will be sharing some prepared remarks in conjunction with the presentation slides that were posted to our website this morning. After Drayton's remarks, he will be joined for the Q&A session by Will Lewis, Chair and Chief Executive Officer; Martina Flammer, Chief Medical Officer; and Sara Bonstein, Chief Financial Officer. Before we get started, let me emphasize that today's presentation will 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 anticipated future outcomes that will be discussed. Please refer to our filings with the Securities and Exchange Commission for more information concerning the risk factors that could affect the company. Today's presentation also includes previously disclosed references to blinded observations from our ongoing Phase II study of TPIP in pulmonary arterial hypertension. These observations may not be representative of results once the study is completed and all data is collected and analyzed. As a result, any future interim data readouts and the final data from this study may be materially different than these observations. Today's call is for the benefit of the investment community. It is not intended for promotional purposes and it is not sufficient for prescribing decisions. I will now turn the call over to Drayton for his prepared remarks.

Thank you, Bryan, and thank you to all of you who have tuned into today's webcast. It is an incredible time at Insmed with the continued double-digit growth of ARIKAYCE and our recent positive clinical readouts Insmed is undergoing a transformation that few biotech companies experience. The goal of our presentation today is to emphasize the profound impact we believe each of our programs may have across multiple diseases and the significant commercial opportunities that can result from effectively addressing those unmet patient needs. To begin, I want to ask you to fundamentally change how your thinking about Insmed from a commercial perspective. Understandably, the investment community has been focused on whether ASPEN would produce positive data and in the wake of that, it may feel like Insmed is profoundly different today than it was 9 months or even 9 days ago. However, we have been preparing for this outcome for years and investing at risk to expand our commercial launch engine to bring blockbuster solutions to patients. Insmed is a unique combination of 3 synergistic programs with multiple indications that represent possible first or best-in-class therapies, each with positive clinical data and each representing blockbuster or multi-blockbuster potential. In addition, the indications that are closest to market have little or no competition. During today's webinar, I will review the fundamentals of each of these programs, starting with TPIP, then ARIKAYCE and finally, brensocatib. I will also demonstrate that our commercial capabilities are well-prepared when it comes time to launch these blockbuster opportunities on behalf of patients. To illustrate the magnitude of the transformation that Insmed is now undergoing compare the approximately 30,000 patients who can be served today with our current ARIKAYCE indication, shown on the left of this slide to where we think we are going in the near future. The opportunities we will explore today represent an increase in our target patient population by more than 2.5 million patients, which is more than 90x our current addressable market. And even that is an understatement because the patient total for CRS without nasal polyps on this slide only reflects the annual incidents for that disease. While this may seem like a daunting expansion, it is important to understand what we feel so ready to take it on as a company. This stems from the overlap in our call point, our track record of success in this area and our early and well-resourced preparation that has been underway for years already. On this slide, you can see a summary of Insmed mid- to late-stage clinical programs and the recent clinical data for each. For TPIP, last month, we released positive top line safety and tolerability data in PH-ILD. And despite not being powered for it, we also observed a nominally statistically significant reduction in the risk of clinical worsening compared to placebo, a very meaningful endpoint for these patients. We also reported promising blended, blinded PVR data from our ongoing Phase II PAH Study, which among responders, surpassed what was seen with sotatercept and we still have further to go in dosing. For ARIKAYCE, we announced in September last year positive data from the ARISE trial in newly diagnosed patients with MAC lung disease, which not only validated a patient-reported outcome tool to be used in this disease [ state ] but also showed nominally statistically significant benefits on culture conversion compared to the control arm. And finally, a week ago, we shared the results from the landmark ASPEN Study of brensocatib in patients with bronchiectasis, which exceeded our own expectations. Treatment with brensocatib was shown to reduce rates of pulmonary exacerbations, increased the time to first exacerbation event, increased the odds that the patient will remain exacerbation free for a year and even showed that it can lead to significant and clinically meaningful reductions in lung function decline and improvements in patients' quality of life scores, all while demonstrating a safety profile that was comparable to placebo. We believe these data will prove to be incredibly meaningful to our patients, providers and payers. As a result, the ASPEN Study has now positioned brensocatib to potentially transform the treatment of patients with bronchiectasis by becoming the first ever approved treatment for these patients. These 3 programs individually represent blockbuster commercial opportunities. Taken together, they have the potential to achieve more than $8 billion in peak sales. And I have one more additional update I would like to share with you today, and it relates to the peak sales we believe we can achieve with brensocatib and bronchiectasis. If you take nothing else from today's presentation, please let it be this. In the past, we have guided to more than $5 billion peak sales as incorporating both the bronchiectasis and CRS without nasal polyps indications for brensocatib. Based on the strength of the ASPEN data and the compelling benefit risk profile of brensocatib, I am pleased today to share we now expect to achieve $5 billion in peak sales in the bronchiectasis indication alone, if approved. For context, the current consensus peak sales for brensocatib is around $3.5 billion. We believe that the pricing, total addressable market and peak penetration assumptions underlying that consensus are all conservative, and we intend to walk you through each of these inputs today. Let's start the discussion with a closer look at treprostinil palmitil inhalation powder, or TPIP, which is being developed for both PH-ILD and PAH. When our researchers first began developing a treprostinil drug, they set out to identify a product profile that could win with both superior clinical outcomes and improved convenience compared to available treprostinil products. The potential commercial attractiveness of such an asset was self-evident. Here, you have a drug treprostinil that is known to be effective but which was limited due to its form of delivery. When delivered systemically, it offered continuous effect, but this came with onerous side effects. When inhaled directly to where it is needed in the lung, the treatment effect wore off quickly, requiring frequent re-administration. A treprostinil prodrug had the potential to offer the best of both worlds, direct delivery to the lung, but also offering sustained treatment effects that last for an entire day or more, including nighttime coverage. In other words, this is a drug that we recognized immediately as having the potential to differentiate from other treatments, not just on convenience, but also on safety and efficacy through higher dosing. The recent clinical results I mentioned add to our conviction that TPIP is emerging as exactly the drug that we hoped it would be from the beginning. We look forward to updating you as this program progresses. Assuming clinical -- continued clinical success and regulatory approval, let's examine what the commercial opportunity would be for this program and the indications we are targeting. On this slide, we show the patient numbers for PH-ILD in the regions where we have commercial infrastructure. In total, there are approximately 135,000 patients who are diagnosed today with PH-ILD who could be on label for treatment with TPIP, if approved. Prostacyclins are expected to remain the standard of care for PH-ILD treatment for the foreseeable future, and our goal with TPIP is to become the prostacyclin of choice for physicians and their patients living with PH-ILD. Although it's premature today to discuss the potential pricing for this treatment, I would point out that the current market leader for treprostinil dry powder inhalation is priced at around $300,000 per year in the U.S. and sales for that product are growing quickly. In PAH, there are significantly fewer diagnosed patients at approximately 90,000 in the highlighted regions and patients with this disease have more treatment options than PH-ILD. This has led physicians who treat PAH patients to rely heavily on combination treatments to maximize the positive treatment effects for their patients. Prostacyclins are expected to continue to play a key role in those combination therapies, including combinations [ that employ ] the most recent entrants to the market such as sotatercept. We believe that these patients will continue to need the vasodilatory and anti-proliferative effects offered by treprostinil as part of their treatment journey. And once again, our goal of TPIP is to become the clear preferred choice by potentially offering once-a-day dosing, nighttime coverage and the ability to safely get to significantly higher doses. In our view, no other current option in [Technical Difficulty] can offer anything close to that. We aren't alone in thinking that prostacyclins will remain a critical part of PAH treatment. The Phase III STELLAR trial of sotatercept allowed for background treatment with prostacyclins in the trial. And we have heard from many KOLs in this space, a selection of which are highlighted here who believe not only that treprostinil will continue to play an important role in the treatment of PAH going forward, but also that the target profile for TPIP would represent a very attractive option for patients. We continue to expect the top line results from the ongoing Phase II study in PAH to read out in 2025. If we are successful, we believe that TPIP combined peak sales for PH-ILD and PAH can potentially exceed $2 billion. Now let's take a look at the opportunity for ARIKAYCE. ARIKAYCE is currently the only FDA-approved treatment with a strong recommendation for use in refractory MAC lung disease in the international treatment guidelines. We anticipate that the strong recommendation will be extended to the broader patient population, pending positive results from the ongoing Phase III ENCORE study, which is set to read out in 2025. Here is an illustration of the relative patient populations for our current label of refractory patients depicted in the dark green boxes compared to the patient numbers that would be included in a label for all MAC lung disease depicted in the gray boxes below. As a reminder, we are guiding to revenues for 2024 of $340 million to $360 million, and that is just in the refractory indication. We expect that the commercial opportunity would grow to more than $1 billion in peak sales under an expanded label. The positive results of the Phase III ARISE trial that only increase our confidence in the ultimate outcome of ENCORE, but in our view, are also likely to motivate physicians to treat patients with ARIKAYCE earlier. In ARISE around 80% of ARIKAYCE patients achieve culture conversion. By comparison, we know from our Phase III CONVERT trial that if you wait to treat patients with ARIKAYCE until they have refractory disease, the rate of culture conversion drops to 29%. When one considers how much larger the all MAC NTM population is and the obvious benefit of greater percentage probability of culture conversion, you can understand why we are confident this program can reach more than $1 billion in peak sales if the expanded label is approved. ARIKAYCE remains a very exciting program for us, first in disease and currently without obvious competition on the horizon. Add to that, the difficulty for the development of a generic version, and it becomes even more clear why this program represents a cornerstone for our company. It also serves as the commercial foundation for the third and arguably the most exciting program we will discuss today, brensocatib. Perhaps one of the most unique and remarkable aspects of ARIKAYCE in MAC lung disease and brensocatib in bronchiectasis is how much overlap there is between the prescribers, patient advocacy and medical communities who serve these patients. ARIKAYCE has established Insmed as the leader in the industry with this community. We have been building deep relationships and trust with them since before the launch of ARIKAYCE nearly 6 years ago. While this slide focuses on the U.S., we have similar strong ties in all geographies. As a result, as we approach a potential launch of brensocatib, these crucial relationships are already in place. We believe that the groundwork we have laid for ARIKAYCE will accelerate the launch trajectory of brensocatib and the resource expansion we are bringing to bear for brensocatib will, in turn, also benefit our efforts with ARIKAYCE. We are also encouraged by the fact that we have experience executing a highly successful launch in this space. The launch of ARIKAYCE ranked as one of the top 10 launches ever for a non-oncology rare disease product. It is important to remember that was our first launch, and we had to build the team, the infrastructure and capabilities from scratch. Now we will have the opportunity to launch brensocatib, if approved, with the core team who executed the successful ARIKAYCE launch. In addition, we have supplemented this core team with some of the best talent in the industry with deep experience launching multi-indication blockbusters. Last week's ASPEN data made the pathway to approval of brensocatib in bronchiectasis noncontroversial in our view. It also validated the DPP1 mechanism, increasing the probability for success in other neutrophil-mediated diseases, such as the ones listed on this slide. We will discuss each of these in turn. Starting with bronchiectasis, a chronic and progressive inflammatory disease of the lung; patients with bronchiectasis are highly susceptible to pulmonary exacerbations, a majority of which experienced 2 or more annually. These exacerbations are devastating to patients and can cause permanent lung damage. As of today, there are no approved treatments for this disease, and we're excited that brensocatib could change that. The current total addressable patients with the diagnosis of bronchiectasis in each of the regions where we have commercial presence is estimated at more than 1 million patients shown at the top of this slide. For the U.S., we conducted research of medical claims databases and search for the existing diagnosis code for bronchiectasis. Our review of these data yielded an existing diagnosed population of up to 500,000 patients in the U.S. We don't know how often these patients are exacerbating, but we presume that data is biased towards those with more active disease, which increases the likelihood of diagnosis. We believe this entire diagnosed population will be own label for therapy under a presumed label for non-CF bronchiectasis. However, we believe the opportunity could be substantially larger. In the middle gray box, there is a large, estimated population of undiagnosed or misdiagnosed patients who could be added to the addressable market totals. Many of these patients are misdiagnosed with other respiratory illnesses like asthma or COPD or are miscoded as physicians will often code patients for the symptoms, comorbid disease or infections they are managing. Diagnosis rates can rise substantially when a first in disease treatment comes to market. We expect that patients will be more properly coded and will report their exacerbations more often when pulmonologists have an approved therapy to treat this disease. If even a small percentage of diagnosed COPD and asthma patients are found to have bronchiectasis and are experiencing exacerbations, these patients would be eligible for and could potentially benefit from brensocatib. So while our initial focus will be on patients in the top of the pyramid, the actual population could be multiples of that initial target. Before we move on, I want to be very clear on this point. The $5 billion in peak sales estimate I mentioned earlier comes just from the purple boxes of currently diagnosed patients. Addressable patients from the gray boxes would represent upside to that peak sales estimate. Let's turn to pricing. Based on the strength of the ASPEN data, which included hitting on secondary endpoints that we believe could positively affect the value proposition, we think that the U.S. list price at launch is likely to settle between the list prices of FASENRA at around $40,000 and OFEV at around $96,000 per year. We have not made any pricing decisions yet, and we will announce the official price at launch. Our research also indicates that first-to-market and first disease products can capture at least a third of their total addressable markets. Based on the strong safety profile in the ASPEN Study, we believe those penetration rates could be even higher with brensocatib. Over the past year, we have been proactively laying the groundwork in anticipation of the ASPEN readout. This includes addressing the gaps in bronchiectasis research and bringing attention to brensocatib data through publications and global Congresses and advocacy engagement. In the U.S., we've been educating physician and patient communities on bronchiectasis at Congresses, live events and on digital platforms. Payer education began earlier this year. And to-date, our account teams have delivered disease education to all national and many regional accounts. We have also expanded our field medical and access teams. Even before ASPEN data in the U.S., we hired additional field sales leadership and posted over 120 new field sales roles to be added to our current field team of 64. These new hires will work to profile physician targets, educate on bronchiectasis and promote ARIKAYCE ahead of the expected brensocatib launch. This is a huge focus in the U.S. and similar preparations will follow in the EU and Japan to appropriately address those markets. As part of these launch preparations, we've also been working to better understand our stakeholders. The clear response we have received is that patients and physicians are excited for this treatment, and payers recognize the unmet need that it could fulfill. As I said earlier, physician enthusiasm for brensocatib is extremely high. In fact, 80% of physicians surveyed say they are likely to prescribe brensocatib. And this was before we knew the strength of the ASPEN data. In addition, our sponsored session at ATS drew so much interest that it became standing room only. We've been feeling this momentum grow at global Congresses and in the community for years. Also supporting our market research were the remarks from Dr. James Chalmers, a world renowned expert in this space, who said on our call last week that he believes clinician appetite to adopt brensocatib will be very high and that the patient community will also be looking for this treatment to be adopted as quickly as possible, if approved. In my experience, drugs that have a clean safety profile usually experienced the fastest update. Finally, we have also already opened dialogue with over 70 payer accounts, representing more than 85% of all patient lives in the U.S. These interactions add to our confidence that we will be able to establish strong patient access to brensocatib once it launches. The next indication we are actively pursuing with brensocatib is chronic rhinosinusitis without nasal polyps, another burdensome disease that is characterized by neutrophilic inflammation and can have a significant impact on patients' quality of life. Currently, the only approved treatment option for patients with CRS without nasal polyps is to administer a corticosteroid via a nasal spray device. Brensocatib would work differently to mitigate the cause of the inflammation by reducing the neutrophil serine proteases that lie at the heart of the condition. Our current Phase II BiRCh trial in patients with CRS without nasal polyps is actively recruiting patients who are candidates for surgical intervention as well as non -- steroid non-responders, which are represented by the purple and gray boxes on this slide. When we talk about the addressable market for CRS without nasal polyps, we start with the incidence population approximately 400,000 patients per year who require sinus surgery shown at the top of this pyramid, which are taken annually from the larger non-responder figures in the gray box below. This means that the 400,000 initial addressable patient population could continue to grow from that base every year as more patients who are progressing towards surgery look for a nonsurgical treatment option. The positive ASPEN data released this past week demonstrated that this treatment can improve patient-reported symptom scores in bronchiectasis patients. Given that the primary endpoint in BiRCh is also a patient-reported symptom score, this increases our confidence that brensocatib may work in CRS without nasal polyps as well. In fact, we shared recently that the blinded data from the first 50 patients in the study is already showing positive trends in patient-reported symptom scores. While early, these data are encouraging, and we expect to share the full data set in 2025. If successful, we believe this indication could be a blockbuster in its own right. While we do not have a preliminary estimate of peak sales for this indication, we are comfortably saying that if the target product profile is achieved, it also would reach sales in excess of $1 billion. Notably, this is not included in the $5 billion peak sales assumption for brensocatib. As we have indicated in the past, now that ASPEN results read out positively, the third indication we intend to pursue with brensocatib is hidradenitis suppurativa, a chronic and recurrent skin condition caused by neutrophilic inflammation. While there are multiple biologic treatments available for HS, there remains significant unmet need in this space, and brensocatib could represent a once-a-day oral treatment option, which we believe could be best in disease given its profile. We intend to move quickly to initiate our Phase II trial in HS in the second half of this year. Although there are between 1.2 million and 2.6 million HS patients globally, our intention is to focus on the Hurley Stage 2 & 3 for the moderate to severe subset of those patients. This includes more than 600,000 patients in the geographies where we have a presence, potentially representing another significant commercial opportunity for brensocatib. As ambitious as our plans already are for brensocatib and the now proven DPP1 mechanism, this is just the beginning. We will continue to work to understand how DPP1 inhibition might benefit additional patients with neutrophil-driven inflammatory diseases and the hopes of bringing a safe and effective treatment option to many more patients. Underpinning all of the assets we have discussed today is our commercial intellectual -- our strong intellectual property. As you can see from this slide, we currently have market exclusivity for all of these assets out until the mid-2030s. If I can spend just a moment on brensocatib, the current exclusivity dates on the left are supported by the composition of [ matter patent ] until January 2035 in the U.S. and which we expect will be eligible for a patent term extension that could push the market exclusivity out until late in that decade. Also, we believe that many of the current patent expiry dates you see on this slide for all 3 products will be extended in the future through patent term extensions or newly issued patents which could push market exclusivity for these products out into the late 2030s and beyond. In closing, I'd like to highlight the robust lineup of catalysts that are expected to come from these 3 programs just over the next 2 years. And remember, this doesn't include the catalysts expected from our early-stage research portfolio. Insmed so far has a 100% success rate across its late-stage portfolio, which is almost unheard of in this industry. Our talented research and development teams entrust their work to us with the expectation we will deliver these important medicines through the physicians who prescribe them to the appropriate patients with the highest standards of quality, care and efficiency. We have done it before with ARIKAYCE. Given that history of success, the tremendous overlap across our respiratory portfolio and the potential we see in new disease areas Insmed stands ready to deliver on the immense opportunities ahead on behalf of patients. Thank you for your attention today. We are now pleased to take your questions.

[Operator Instructions] Our first question comes from Jason Zemansky from Bank of America.

Congrats on the progress. Looking at the 500,000 or so diagnosed U.S. patients, I'm curious, what percentage do you think fit ASPEN's inclusion criteria of 2 or more pulmonary exacerbations in the year? Ultimately, what is the initial target population look like and what fraction are easily accessible? And then you kind of touched on this at JPM, but regarding TPIP, given the need to ensure a successful launch for brenso and expand the potential indications, is there a risk it becomes a distraction? I know a good problem to have. But at this point, what's the appetite for maybe spinning it out or out-licensing?

So I appreciate those questions. I'll turn it over to Drayton in a second to address the 500,000 U.S. patient question and how that relates to the entry criteria for the study. I will just observe that if you take nothing else away from today, other than the massive opportunity we see before us, it is that this scope of opportunity in terms of identifiable patients is clearly broader than just what the J-code might suggest. But let me turn to the TPIP question, and then I'll ask Drayton to comment on the brenso question. TPIP is the hidden gem, as I've referred to, within Insmed. This is an extremely strong and compelling profile, albeit early in its development. And it's understandable why. The underlying moiety is well known to be effective in these patient populations, and we've simply improved upon that. And we've done it in a way that I think has become intuitive to people who are in the field and experienced, and that's why we're hearing such a strong endorsement from the key opinion leaders in the pulmonary arterial hypertension and PH-ILD areas. So what will we do with it? I think that will be something we can continue to reflect upon. But right now, we certainly have the capability to bring all of these forward ourselves, whether we do or not as you point out, a luxury. The other comment I want you to take away as Drayton mentioned, we've been working on all of this in anticipation of success for years. I know it feels like the starting gun for Insmed went off about a week ago for most of the outside community. But for us, it went off several years ago internally, when we saw the profile of these products, Brenso got published in the New England Journal and the early TPIP data came back with such a compelling and clean profile so lots to choose from, lots to bring forward. And just like you all to understand, we're ready for it. But Drayton, maybe you want to comment on the population for Brenso.

Yes. I think it's an important question. And I want to reiterate the $5 billion in peak sales for just bronchiectasis alone comes from that currently diagnosed patient population who, particularly in the U.S., we know exactly where those patients are, the physicians who are treating them. And we believe that all of those patients based on our base case that our label will say for patients with non-CF bronchiectasis are all on label. I think that's a critical point. So of those 500,000 in the U.S., we expect them to all be on label. And in my experience, once you have an approved product, you're going to see those patients in that gray box who are either undiagnosed or patients in that asthma and COPD box who may be miscoded, they're going to come to their physicians. The physicians are going to have a reason to diagnose them with bronchiectasis, but we hear often now in research and in KOL interactions is why would I diagnose the patient with bronchiectasis if I don't have a therapeutic tool to treat them. So we are highly confident that not only will the $5 billion in peak sales come from that currently diagnosed. We think more patients are going to come forward, more physicians are going to be much more depth of diagnosing those patients and all of those patients will be on label at launch.

Our next question comes from Andrea Tan from Goldman Sachs.

Drayton, maybe one for you here. I appreciate the pricing analogs that you provided, ranging from FASENRA's list price to OFEV. Just wondering if you could maybe drill down on some of the considerations you would account for when ultimately deciding on a price point for brensocatib? And then, Will, one for you, maybe just given the portfolio that you and Drayton have outlined today, and each program does represent potential blockbuster opportunities across these multiple indications. So I was just wondering if you could characterize your continued interest in pursuing your fourth vertical of translational medicine versus maybe spinning that out.

Yes. I appreciate the questions. I'll take the fourth pillar question and then hand it back over to Drayton. I think, look, what's interesting about our current circumstance is that brensocatib has arrived on the scene is something that we've been investing in for years, and now it has achieved this incredible accomplishment that has generated so much interest and support for the company because of its potential impact on patients and consequently, its subsequent return to shareholders. I think the fourth pillar represents the same kind of opportunity, a modest investment for a period of time that will produce potentially equally impactful medicines. Will we take them all forward? That, again, like TPIP will be a luxury we can contemplate once we've seen that the clinical data has validated what they will do for those patient populations we're targeting. These are some of the most desperately needed therapies. I think the unmet medical need is very clear in each of them. We stand by our first or best-in-class ambition for every medicine we bring forward. And the point I always like to make and that Sara reminds us all is that these medicines go forward with proof that they are going to have that kind of profound impact. I think we're incredibly proud of where we are with the first 3 medicines and the deployment of capital in a careful way to bring those forward and ensure that they're going to be real winners. That same mindset is going to apply to anything coming out of the fourth pillar, and we will probably engage in some consideration for out-licensing or sale of assets if we find that we have too much on our plate. But right now, that's not the case. And I'm particularly excited in the coming year to be sharing with you some of the clinical data that we think will be the logical conclusion from what we've seen pre-clinically, which is incredibly exciting from that fourth pillar.

Andrea, I appreciate the question. Up until this point, you've heard us talk about our pricing considerations as FASENRA-like pricing would be the floor. Today, what I'd like you to consider is this is a range. And what gives me confidence in saying this is a range between FASENRA-like pricing of $40,000 a year and OFEV at $96,000 a year is the strength of the ASPEN data. It's very rare in my experience to have a product with a safety profile comparable to placebo that hits on both doses, the primary endpoint with that type of statistical significance. And then at least one dose having the ability to go out and say that not only can we improve the quality of life, but we may be able to preserve the lung function. So based on the strength of the ASPEN data and those characteristics, I believe that we have the opportunity to relook at pricing compared to what we've been saying up to this point. And again, what gives me confidence is up to this point, we've been testing our target product profile, not only internally, but with multiple expert firms who do this for a living and the best in the business, and they have come back with remarkably similar results to give us confidence to come out today and say our range is between FASENRA and OFEV-like pricing at launch. And again, we've not established a price yet. There's a lot more work to do, but I have a tremendous amount of confidence in putting this range out.

Our next question comes from Vamil Divan from Guggenheim Securities.

Great. Thanks for hosting this event and for taking my question. So I have 2 questions that are sort of connected and tied into this sort of patients with bronchiectasis who also have asthma and COPD. So one -- and then the other questions are more on the competitive side. So I noticed the [ BI ] trial, at least based on clinicaltrials.gov is reading out maybe sometime soon here a Phase II trial. So curious just your thoughts on sort of that as a potential competitor? And then tying in the second question, we noticed in their trial, they did not exclude patients with primary asthma or COPD from their study -- in ASPEN, obviously, you guys focused on patients with primary bronchiectasis. So I'm curious how you think that might impact the [ AGILE ] study results and then if you do have positive results, how it might impact throughout physicians or payers sort of view the 2 products given sort of a different patient population being obviously with the caveat that there's a Phase II trial and you guys obviously a Phase III data now, but any thoughts just again on asthma COPD and how BI fits in would be helpful.

Yes. So I'll start with the observation that we're looking forward to hearing the BI data. Our expectation is that it will probably be alongside our information at the World Bronchiectasis Conference, which is going to be taking place around the 4th of July. In fact, today is probably a good day to highlight that we're going to be putting out -- we can confirm we'll be putting out new clinical data from the ASPEN trial on July 4 at around, I think, it's 6:30 local time, 6:00 local time at that World Bronchiectasis Conference. We're very excited to be sharing that. When we think about BI, there's a lot going on there. We'll be interested to see. We know from our shared experience of looking at our Phase II data and what happens when it goes to Phase III that you really need a very expansive Phase III trial to understand what medicines do in this population. Nonetheless, it will be interesting to see where their Phase II data come out. I know that the entry criteria, our particular point of focus, and I'll turn it over to Drayton because he's just come from the American Thoracic Society Meeting, where we had a number of conversations with physicians and KOLs who he's had relationships with for well over a decade. And there were some thoughts that were shared there.

Yes. So I think what I've heard most from ATS and from other checks is everyone is excited about seeing the BI data this summer. The question you raised is, I think, a really good one. Lots of people are [ interested to ] see the study design -- the inclusion criteria, allowing so many patients with asthma and COPD, how that may affect the trial we'll know in a matter of weeks or months. So we'll see. In terms of it being a competitor, if it is -- has a successful Phase II and if it's able to enroll and be successful in Phase III and get approval, we believe we will have a significant head start, years head start, if not 3 to 4 or more head start. So that will allow brensocatib in bronchiectasis allow us to establish ourselves as the leader, and it will give physicians many years of experience, not only with us building out real-world experience from data we could generate here but also will allow us the physicians to be able to get real-world experience in their practice. So we feel very comfortable with our head start over any potential competitor. I believe there's one physician expert said last week. When you look -- if it's approved, if the BI product is approved, Insmed might be able to look back. They won't see the competitor, they may hear the competitor. And I think that was an interesting comment.

I would just add also, from our point of view, it's really important. The enemy here is the disease. The arrival of a very large player validating this mechanism of action is really quite a statement about how big pharma is now rethinking this class and this biological pathway, which we've now validated through both the Phase II that was published in the New England Journal and the Phase III study. I think this is just the beginning of the day for DPP1 in multiple diseases. And while we're not talking about it today, perhaps apropos of the fourth pillar, we have quite a bit of work going on, on additional DPP1 inhibitors in our labs that we intend to bring forward to look at other disease conditions. Now those are early days, but the intellectual property that surrounds those, I think, will give us what we really want here, which is to be the dominant player in DPP1.

Our next question comes from Jeffrey Hung from Morgan Stanley.

This is Michael Riad on for Jeff Hung. The first one, to what extent is the infrastructure already in place for a broad [ lunch ]versus potential for having to build the market given there's no approved therapies. Do you see differences in how well organized the medical system is or medical claims between U.S. and EU versus Japan? And we have a follow-up.

Drayton, do you want to take that?

Yes. So I appreciate the question. The infrastructure for brensocatib, I don't think you could ask for a more unique situation, one with better synergies to be able to launch a product like brensocatib in bronchiectasis after we've had 6 years in the market in the U.S. with ARIKAYCE. But effectively, our engagement with the community started 8 to 10 years ago, whether it was disease state awareness or going out and educate them. As I mentioned in the prepared remarks, the overlap is almost unheard of in the disease state. When you treat bronchiectasis, you are most likely treating NTM. And when you treat NTM, you're almost always treating bronchiectasis, and it's the same Centers of Excellence, the core Centers of Excellence, it's the same patient advocacy groups. It's the same professional societies. It's the same group of payors and it's the same exact patient mix in terms of the payer mix for the patients, they're predominantly Medicare. So we've had over 6 years to be in this space, establishing ourselves as the leader. And I will draw the one distinction. With ARIKAYCE, we were doing it for the first time. We had to build the infrastructure, the capabilities and the team from scratch, and we were able to deliver a top 10 rare disease non-oncology launch. That was when we launched, most people were not treating NTM. It was the only Centers of Excellence. It was really tough to get a diagnosis. Fast forward to today, we're in those exact same centers 6 years later with our teams, many of whom who launched this product who have been here for years, who have established those relationships, the core team, the architects for this launch. Today, we go into a therapeutic area like bronchiectasis with this overlap, but also with an established ICD-10 code, we know where these 500,000 patients are in the U.S. We know the treating physicians, and we have been in there. Now we are, to your question, we are going to expand because we're going to bring every resource to bear to deliver an incredible launch [ here ]. I know people have compared this to DUPIXENT and HUMIRA, and that's exactly my expectation as well. And we're going to expand from, say, 64 territories to approximately 180. We're going to expand our field access managers because what we're going to do is make sure this is a seamless experience and every resource we bring for bronchiectasis should and will benefit ARIKAYCE in this launch. So I feel very good about our plans. Again, the positions -- the additional positions have been posted. When I tell you that when we post a position for a therapeutic specialist role today, if we're getting hundreds upon hundreds of resumes who are incredibly qualified, we're excited about where we are, and we will be in the field educating 9 months in advance of this launch in the U.S., and we have similar plans in the EU and Japan to make sure we capitalize on the opportunity we have in front of us on behalf of patients.

And I'll just add this isn't just coming from us. Recently, the COPD Foundation launched an effort to establish across the United States, 100 centers that are focused on excellence in the treatment of both NTM and bronchiectasis. This is a major initiative, but what it's going to do is populate across the United States, best-in-class care and the overlap between these 2 disease states is evident to the COPD Foundation. So I think that when we talk about that gray box of patients and how many of them are actually bronchiectatic -- this is the first external confirmation that you can observe that the rest of the treating community already gets this relationship.

I really appreciate the color and context there. Maybe just a quick follow-up. Moving back to the ASPEN data. Looking at the 19% to 21% reduction on pulmonary exacerbations how did those results position brenso in terms of being a chronic therapy? Do you see it positioned as a chronic therapy for all those 1.25 million patients or does that require some sort of evidence of like minimal lung function or deterioration?

Yes. To be clear, we see it as a chronic therapy based on -- and the FDA will always look at the totality of the data as well the physician community. But here, the totality of the data is incredibly strong, not just on the primary endpoint, as we've mentioned, also on multiple secondary endpoints and importantly, on the safety. And it's perhaps to the safety I would draw your attention in the context of the question of chronic therapeutic use because that AE profile, whatever it may be, is typically what causes patients to drop off. And so to have such a clean profile, I think, sets us up for not only a rapid uptake, but also sustained use of the medicine over an extended period of time. And we can speak to that intelligently because we have an open-label extension in the Phase III study and 2-thirds of the patients that were in the ASPEN Study have chosen to go on into the open-label extension. That, interestingly, roughly parallels the 2 -- the quantity of patients that were on drug in the study. We haven't done the work to see which ones went in and which ones didn't. But I find that to be a striking alignment and I wouldn't be surprised to see if the majority of patients that chose to go in the open-label extension were those that were on therapy. As we said prior to the results, we had heard anecdotally the physicians felt they knew who was on therapy because patients were just reporting feeling better. You see that in the QOL-B trend in the 25-milligram dose. And the totality of all that gives us a lot of confidence that this is not only by prescription to chronic therapy, but one that will be utilized as such.

Our next question comes from Jessica Fye from J.P. Morgan.

This is [ Nick ] on for Jess. Two from us. So maybe just revisiting the patients who are comorbid with COPD and asthma that could be considered for treatment. Can you kind of walk through the pushes and pulls there -- impact at all if the initial diagnosed population if say, [ AZ ] were to develop brenso in those 2 indications? And maybe you noted that you will be sharing some additional ASPEN data at World Bronch. Can you maybe elaborate on the level of detail we should expect in any subcu populations that could be presented?

Sure. So we don't have a lot of additional specificity on the second question in terms of what additional data. I would just say the sub-analysis work is ongoing. We're -- we only have the data for about a week, but we're continuing to pour through it. And I think in the coming weeks, we intend to sit down and actually have a discussion about what we will bring forward. So we literally don't know as we sit here today, but we have committed to bringing more data forward at World Bronchiectasis. Of course, you'll see additional data at the European Respiratory Society Meeting in September in Austria, but the first and next chunk of data, if you will, will come at World Bronch. I want to be clear on the pushes and pulls that you're addressing with your first question. So as everyone is aware, there were 2 costless options to AZ that they chose to exercise that creates a moment where there is a period of time that's fixed where there's a discussion about whether or not they would like to take forward brensocatib for the development in COPD and asthma as an indication that would require Phase II, Phase III studies and then subsequent launch and commercial support for those indications. What we're talking about today is something very different. We're talking about patients who have COPD or asthma may be misdiagnosed, maybe correctly diagnosed but are also experiencing exacerbations on maximally treated therapy in those indications. And so the physician may want to examine whether they have bronchiectasis because that may be the origin of what is causing those exacerbations or materially contributing to them. So they are one CT scan away the way we like to think of it from being diagnosed as a bronchiectatic patient who would be on label for brensocatib. In our mind, that is the first and best pathway to ensure that the patients who will benefit the most who then are diagnosed as being bronchiectatic and can, therefore, receive the medicine on label. So I don't think there are a lot of pushes and pulls from -- in the sense of whether they go forward with their intention or not because, in my mind, all the patients that are likely to benefit who have COPD and asthma and bronchiectasis once diagnosed in the latter category would be on label. So there's really, in my mind, at least as a point of departure, not an obvious reason why it would make sense to develop it, at least this compound, specifically in COPD or asthma independent of bronchiectasis. We're obviously going to be very open-minded and give consideration to ideas that could be brought forward that we haven't perhaps considered. But where I sit today, that's sort of my perspective on the landscape. And I think it's an incredibly exciting opportunity. If you look at the literature, just to put a footnote to this, it's quite wide, but the range of expectation for COPD patients alone that are also bronchiectatic is between 4% and 54%. There are 20 million patients in the U.S. that have COPD. So if you just ripple those percentages at the extremes through that population, you can see the potential number of patients that could benefit from this therapy should they be diagnosed and designated as appropriate for the therapy as a bronchiectatic patient.

Our next question comes from Nicole Germino from Truist Securities.

It sounds like there are a lot of levers here for our model, and there's a lot to consider here. Just 2 questions on reimbursement. So number one, should physicians anticipate any payer pushback on brenso and access issues? And if so, how is Insmed planning on assisting with patient access? And then number 2, for the J-code, can you walk us through timelines and when you would file and what and when to expect a response?

Sure. On the filing, if you mean with regard to the NDA, that would be by the fourth quarter. If you're referring to something payer related, I'll turn the first question and the second over to Drayton.

Yes, I appreciate the question. So the goal of having our payer team, and we've expanded the payer team last year, and we brought in some of the best talent in the industry. And the goal is to not only starting January of this year is to start educating the payers, all payers. I think I mentioned earlier that the payers -- all the national payers have already been met with and over -- payers representing over 85% of patient lives. And the goal is to currently - a PIE discussion or preapproval exchange once we file and then start beginning to talk about the benefits and risk of brensocatib with that population. And the goal of doing that 18 months in advance is so the payers understand what the burden of this patient population is and the goal at launch with our payer community would be a simple attestation so a prior authorization where the physician would just simply check that the patient's had a CT scan, they're feeling symptomatic, they've had 2 or more exacerbations in the past. And that to us is what we're -- we've been pursuing since day one, and that's our goal for launch. And in terms of the J-code, just to be clear, this is an ICD-10 code. So we're not having to file for a J-code. It's a simple ICD code that they will just put on the form or in their records.

Our next question comes from Andy Chan from Wolfe Research.

So regarding the $2.4 million undiagnosed or misdiagnosed bronchiectasis patients in the U.S., we're guessing that this is because of similarity versus other diseases, so it's easily confused. I'm wondering if you can educate us a bit on why are they easily confused. And is there something special about the confusion that the confusion can be easily solved by Insmed? Is it because the CT scan is rarely done in clinical practice today? And then just separately quickly, regarding the 120 sales reps, when will they be fully trained and fully deployed? I'm just curious, like at what point will there be an inflection on ARIKAYCE sales?

Sure. On the misdiagnosis side, I mean, I think the thing to understand is that COPD is diagnosed by a simple spirometry test. So that's not particularly burdensome and a patient that comes in complaining would be examined by the physician and potentially given that diagnosis and immediately go on probably LABA kind of therapy. What I would say is that the CT scan is the definitive diagnosis for bronchiectasis, along with the pulmonologists review of symptoms. But that hurdle, which is not extreme in the current medical setting is nonetheless, not one physician would normally go to because what's the point? So you give them the CT scan, you now have the definitive diagnosis of bronchiectasis and you can tell the patient that, and then you can tell them I have nothing to give you to treat that condition. It's not a particularly gratifying exchange with the patient. When you're a physician, you've said you've identified a disease and can't do anything about it. I think what ASPEN suggests if we secure approval as we expect, is that that's going to change. And what you see in other disease settings where there's a first-in-disease therapy, people often say patients start to come forward in large quantity and physicians are armed with a new way of thinking about how to treat these patients and how they might benefit. And particularly given the permanent damage that can be done from exacerbations, it is the physician's incentive to pursue this. And the CT scan is not a burdensome hurdle. But that's why there is that misdiagnosis, A, because it's an easy test to diagnose COPD and give that a shot for therapeutic benefit. And B, if they decide that there is perhaps more disease there of a different nature, if there's nothing to treat it, then there's no reason to pursue its identification. And so the diagnosis stops. That's what we think is turning over right now as we speak. And we're excited to see where that will go. And I think the COPD Foundation's endorsement of Centers of Excellence across the country is going to further that and help it along. I don't know, Drayton, if you want to add anything?

So in terms of when the additional 120 sales reps will be in the field, I want to start by saying I'm incredibly proud of the 64 therapeutic specialists we've had out in the field for the past 6 years. To think that this team continues to deliver double-digit growth year-over-year, and we're in year 6, is incredibly impressive, in my opinion, and they just continue to deliver. As I believe Sarah mentioned on the last call, we're seeing leading indicators to track back to the early days of launch. So the team just continues to deliver on behalf of patients. For the 120 additional therapeutic specials, our teams are actively interviewing as we speak today. They will each be hired by the end of July and fully trained in the field start of the fourth quarter.

Our next question comes from Ritu Baral from TD Cowen.

I wanted to ask a little bit first about Europe and the alignment that you guys have at the current data just checks off all the boxes for regulatory approval, but also how treatment there, which can be more centralized than in the U.S., how treatment of bronchiectasis there is sort of distributed and managed? And then I have a follow-up.

So I can take the question about the patients. I'm happy to report that not only do we have a lot of patients from Europe in the trial as we do from Japan with a specific intention when we designed the trial to be able to secure regulatory approval in those territories. But we have actually prime designation from the European regulatory authorities. So there is already a predisposition. It's actually the first to the best of my knowledge and only a respiratory program that has received prime designation that's sort of like the breakthrough therapy designation equivalent over in Europe. So that lays the groundwork for a pretty open engagement and a belief that what we're going to be measuring here, we're very comfortable is going to address what the regulatory authorities need. Drayton, do you want to take the other question?

Yes. For the infrastructure, Europe has an incredibly organized infrastructure for bronchiectasis. I'm sure everyone's heard of the EMBARC registry. The EMBARC registry, the last I checked, had 10,000 to 15,000 patients with bronchiectasis in their registry, that's even bigger than the U.S. bronchiectasis and NTM registry. It's a very organized system, a great group of medical experts who are highly focused on bronchiectasis. And when you talk about publications, this is robust as anything in terms of -- it's not just James, Dr. James Chalmers. There are many, many physicians in his network who are continually publishing, who are continuously advancing the science of bronchiectasis, and we're really excited about the opportunity in front of us in Europe.

And I should say that patients in Europe and Japan were also afforded the opportunity for post-trial access. I misspoke earlier, it's not actually an open-label extension, it's a post-trial access program from ASPEN, but those data will also continue to be generated in all regions.

Got it. And my follow-up is just on the dose you guys are taking forward, now that you've had the chance to do some more commercial work, how are you seeing the advantages or disadvantages of taking both forward versus one, how does it get complicated across geographies and price?

Yes. So it's a really interesting question. The good news is we have the optionality of bringing 1 or 2 doses forward. Each has a slightly different profile because the data is only a little over a week old. We still have a lot more work to do to dig in and kind of make that assessment. I think it is fair to say that almost to a person on the physician community, those who have heard of the 25-milligram benefits in FEV1 slowing the decline of lung function and the strong p-value that was seen nominal though it was in the QOL-B endpoint at the 25-milligram dose, that's really caught a lot of attention and our internal market access perspective is that, that's valuable as well, but we haven't made any decisions yet. There's more work to be done. And I think, frankly, there are all kinds of strategies that might inform why you might bring 1 or 2 forward. The good news is we have the option to do both. We are comfortable saying that we believe both would secure regulatory approval based on our understanding in both U.S., Europe and Japan. So it's something we'll continue to evaluate. And when we come to a decision, we'll certainly share that.

Next question comes from Leiyang Wang from Barclays.

So on the claims data that you guys do work on for COPD and asthma, can you give any more color on what gives you the confidence that there is a misdiagnosis there rather these patients should have bronchiectasis. And you can ballpark what portion of patients are you seeing that signal in? And I have a follow-up.

Sure. So I can tell you that the confidence from this comes from talking to the treaters and the community and the literature that's published extensively. As I mentioned before, there is right now quite a wide range on what percentage are either misdiagnosed or may also have bronchiectasis that ranges from 4% to 54%, some have it even higher than that. I think the way we think about the market opportunity is based on what we're hearing from those who have started to systematically institute some CT scans of their COPD patients and they have come back and indicated that somewhere between 20% and 30% of those COPD patients are showing up as bronchiectatic. Now it's important to understand that there's more work to be done there. It's not as simple as they have bronchiectasis, therefore, they would get medicine potentially beyond label for brensocatib. We want to know that those patients are bronchiectatic that they're experiencing exacerbations and therefore, they would benefit from the medicine. And so it's probably a sub-population of that 20% to 30%. But as I said, there's more work to be done. And I think you would find a pretty universal support for that notion. Indeed, at the American Thoracic Society this year, there were stage presentations talking about this misdiagnosis of COPD patients. So I think you're going to hear a lot more about this in Congress as we roll forward.

And clarification, just the increase in peak sales, that's not part of like this portion of misdiagnosis patients are not part of the assumptions and increasing peak sales rate?

That is correct. That is additional. To be 100% clear, what we're seeing today, and this is new, is that the $5 billion peak sales number, greater than $5 billion comes from just the, what we call the purple box on that slide and not any of the misdiagnosed or comorbid patients in the gray boxes that appear below. That would be additional. And I think that's one of the things we really want people to take away because I know the weight of ASPEN getting clearing and working as a study was so almost distracting that the ability to look at the commercial opportunity behind it was something that people perhaps hadn't invested a lot of time in. The reason we're spending the time today going through not just this, but the other elements of our now multiproduct portfolio, at least in development and soon-to-be commercial is because of the enormity of what is there. We have unlocked a new mechanism of action here that is relevant in a very substantial initial population of bronchiectasis patients. And right behind that, we are in Phase II right now for CRS without nasal polyps. If you contemplate just looking at those data sets that we provided today for price point, penetration rate and first-in-disease status, addressing just those 2 populations, we are in an enormous opportunity, and it's one of the reasons why some of the legitimate observations of significant capital investment that we've made over the past years have been made. But the reason for that is because of this day today, we wanted to be ready for positive data and the possibility of additional positive data and be ready to launch this drug, and I'm happy to say that we're here and we are ready.

And just one other thing just for clarity. As you're building your model, I would just point that these peak sales estimates that we're providing are net sales. So across the board on the peak numbers that we provided are net sales.

Our next question comes from Jennifer Kim from Cantor Fitzgerald.

My first question is just based on your internal modeling. Is the size and peak sales that you're now planning to in bronchiectasis is achievable with the something like pricing? And when you think about launch pricing range, to what extent does the IRA play into that either inflation related or potential rough renegotiation. Then I have a follow-up.

Yes. When it comes to IRA and its implications, I'll hand that one over to Dayton.

So first, I'll take you through the $5 billion, at least $5 billion in peak sales that we've talked about today in just bronchiectasis. I'd ask you just to think about just the U.S. alone. So we're saying there are 500,000 diagnosed patients today. Again, we know where they are. We know the treating physicians. We're saying that at least the beginning of the range is $40,000. And we believe based on precedent, we believe on external research and our own experience and our own analogs that we should be able to achieve at least 33% penetration. You can get to significantly more than $5 billion in sales in just the U.S. in the currently diagnosed and that doesn't factor in Europe or Japan currently diagnosed and it certainly doesn't factor in any of the gray box, the misdiagnosed or undiagnosed. So to answer your question very specifically, yes, even at a $40,000 for central like price, we can get to well over $5 billion in sales and just the bronchiectasis alone. In terms of how we're thinking about the IRAs, as you can imagine, that consumes most of our thinking and time in terms of what the potential implications could be down the road. And the way we view IRA with our products, not only brensocatib, but ARIKAYCE being the first and only approved in a therapeutic area is, it's going to be a tailwind. And what I mean by that is patient affordability because the patients out-of-pocket is going to be capped for all medicines, not just one, but all medicines at $2,000, which can be spread across the year. So we believe that the patients are going to benefit and be able to access this product early on, and it couldn't come at a better time for the launch of brensocatib. So I view net-net with our product portfolio, the IRA to be a positive for patients.

It's a very important point, though. What you're asking about if we were to be at $40,000, one of the things I really want everyone to hear today is that we're putting before you a range of pricing. So while we have talked about Fasenra as a floor in the past, we really want that mind share to shift to is an understanding that we are putting out between $40,000 and $96,000 somewhere in that range is where we will ultimately decide our pricing will go. We haven't made that decision yet. We'll do it right before launch. But I think you can understand the message we're trying to convey here is that the strength of this product profile gives us the flexibility to think across that range.

That's helpful. And my follow-up is just thinking about CRS, I think similar to COPD, the customers for patients that have CRS and bronchiectasis all over the place. I guess what is your confidence that CRS can be a blockbuster indication separate from patients who already have CRS and bronchiectasis.

So the available data suggests there are 26 million patients in the U.S. right now with CRS without nasal polyps. It's an important distinction without nasal polyps. There is a CRS with nasal polyps and there are some products that are approved to treat that, but this is a different disease indication. And when we look at the enormity of that, and that's a well-established number, we are focused on the severe end of the spectrum as we have been for all of the diseases we target. When we look at ARIKAYCE, we went to the refractory population first and then expanded. When we look at bronchiectasis, we targeted 2 or more exacerbations in the last 12 months, the so-called moderate to severe end of the spectrum. And I think there is a belief that perhaps this drug will get used more broadly. When we think about CRS without nasal polyps, as enormous market opportunity as that represents, we want to start with the severe end of the spectrum. Those patients who have either undergone or eligible for surgery or who are failing the best available treatment that's out there and end up at that severe end of the spectrum. And we estimate that, that's 400,000 patients a year. So instead of prevalence, we're talking about incident population that we can target. We feel, although it's early, comfortable with the relevance of pricing in both indications. And that means because of the severity of what we're targeting, and that means you can do simple math around CRS in that 400,000 incidence population and quickly get to a number comfortably above $1 billion a year. What I would say is we still have data to produce there. It's going to be -- it's early days, but it is quite significant to us that in the early days and with all the caveats that are necessary, blended blinded data, only 50 patients, but we are already seeing patients with score improvements in that population. And given that we saw a symptomatic benefit using the DPP1 mechanism in bronchiectasis, the fact that we are tracking a symptomatic benefit for the CRS indication, and we are already seeing patients respond, we don't know if they're on drug or not, but my suspicion is that they are, and that gives us some confidence that, that market will soon be within our reach as well.

Got it. If I could squeeze 1 more in. Would you consider monetizing brenso for geographies that you haven't traditionally competed in, like China?

So it's a very interesting question, how we think about the opportunities outside the U.S., Europe and Japan, where we already have commercial infrastructure. The short answer is yes. We are looking at that right now, and we are thinking about what opportunities there may be and what is the most effective way to go after those opportunities. I don't have the ambition to build everywhere. I think that's actually not a great model. But there is an unmet medical need out there, and we want to find the most effective way to address it. And so we're exploring those alternatives as we sit here today.

Our next question comes from Seema Sheoran from Evercore.

I have a question on ARIKAYCE data that you presented at ATS, where you showed that over-time, how patients are doing on the quality applied bronchiectasis score? And we see that patients on drug are not doing better than placebo, and it's only after they stop the drug during month 7 that we see an improvement. So just wanted to know your thoughts on like what do you think how that's going to translate for ENCORE? Is this just patients are feeling well because they are off the drug? And is this trend going to continue for 3 months that's going off-treatment period, which is the case for ENCORE.

So I'll ask Martina to address that, but I'm not sure I'm following your question specifically. I will just make the observation of what we saw in ARISE, which is that we were able to culture convert basically 80% of patients in roughly 6 months. And that's quite an impressive outcome well in excess of what we thought we were going to accomplish. And if you go back to the discussion and the literature in advance of that trial, you would have heard people saying it was around 50% or 55% that they would have expected to culture convert. So it's quite a dramatic improvement. And certainly, as you go off drug, the durability that we see in ARISE was quite encouraging and parallel what we saw in convert. But Martina, I don't know if you want to address this more specifically with regard to QOL-B.

Yes, happy to. So first thing we have to remember, we see actually an improvement in the QOL-B with ARISE in the first months already. So it starts. It gets better as patients are treated. And it takes some time until you actually get rid of the symptom. So your improvement in the QOL-B how our patient feels, comes along with how do the patients get rid of symptoms. And we see that because the conversion, if you look at the conversion by month 6, you have 15.7 versus 3.5 conversion score. And 5-month 7 once a patient is off treatment, you see that actually increasing with ARIKAYCE, while patients who are on placebo start decreasing. And you always have to think about that also in context of which patients tend to convert. And if they convert, they also usually show an improvement in symptoms. Patients who convert and respond to treatment do so relatively early in the first 2 to 3 months of treatment. Patients who do not respond, there is, I mean, likely to catch up later, I think there is an expectation or a thought out there that somebody can catch up on standard of care if they are longer on the treatment. And that's not really what the data shows or what you also see in clinical practice. Patients who convert and patients who respond to treatment are doing so early in the treatment period within the first 2 or 3 months. You'll catch up a couple of those patients later on after 6 months, but the majority of them do so earlier. Otherwise, they tend to become refractory patients.

And the only thing I would observe in addition to that is the fact that the FDA shared that perspective, right? It was quite a substantial win for us that FDA wanted to look off treatment for the QOL-B score. Clearly, they want to track it while the patients are taking the medicine, and we fully expected to see this profile of patients needing to take the medicine and the experience of that is challenging, but the benefit is clear, and I think that's the most important point from the study.

Our next question comes from Graig Suvannavejh from Mizuho Securities.

I have 2 questions. The first is on pricing. I appreciate that you've offered now a range of pricing from $40,000 for Fasenra to $96,000 for Ofev in consideration that you have potentially over 1 million addressable patients, at least in those purple boxes across 3 indications. And given the patient population you outlined for us for where Fasenra is currently labeled in Ofev. Would you actually suggest that we consider modeling closer to the $40,000 versus the $96,000 just based on the addressable patient population. So just trying to get philosophically how you're thinking about that appreciating the strength of the data that you did show in ASPEN. And then my second question just has to do with the opportunities for brensocatib in CRS S&P and HS as well. I know it's early days, but any sense of what those clinical development programs look like? Just trying to get a sense of potential launch timing for those label extension opportunities.

So I'll take the second question first and ask Drayton to address the pricing question. Those programs obviously need to complete their Phase II work. They'll inform the design of the Phase III. So it's hard to give any kind of even broad-brush idea of what it will take. I will just say that much as is the case with TPIP, once some of the blended blinded data get out, we saw a dramatic improvement in the recruitment of those studies. I expect that to continue for that product. And similarly here, now that the ASPEN data is out, and this mechanism is validated, I think you're going to see an increase in the enrollment rate. So whatever the programs are, I think we're going to be going into a situation where there's real momentum behind this. So that, I think, is encouraging. But we'll hopefully have more perspective to give you -- I can't say today whether there will be 2 Phase IIIs or 1 Phase III below 0.01, like we did with ASPEN. It's just too early to be able to give that guidance. But once we have any sense of it, we certainly will share it, and that will begin with the Phase II data coming from CRS next year.

Graig, in terms of pricing, what I'd really like to point out is the 500,000, at least 500,000 diagnosed patients in the U.S., that's the range we gave today from -- that was U.S. pricing. So $40,000 to $96,000. What I'd guide you through as you're thinking about your model is when we were testing this earlier, again, we tested this with multiple different expert firms, and this is the range they gave. To be quite honest, I wasn't sure if we were going to get -- we knew we had a once-a-day oral. We certainly expected a significant reduction in exacerbations. But when you think about the preservation of lung function and the quality of life benefits, that leads me to believe, and that's why we've now said instead of a floor at Fasenra-like pricings, we're seeing a range. So I believe based on the strength of the data and the safety profile, we will be somewhere within that range in the U.S. And then the EU and Japan, we continue to look. With ARIKAYCE, we had 1 basically global list price. I think we're continuing to look at all options in terms of how we price brensocatib across the globe. So what I'd guide you to is really think about the U.S. range and think of that exactly as a range and reflect on the strength of the data, again, particularly the safety data and some of the secondaries.

And just 1 clarifying point, Graig, as you're thinking to build your models, as Drayton mentioned, with ARIKAYCE, we had list price parity across all 3 regions. That is not our expectation with brensocatib. So brensocatib that range of $40,000 to $96,000 is the U.S. range, and we would expect a lower price in Japan and in Europe. And the other thing I would just point out as you're thinking about modeling, as with all brands, we do expect the large majority of the sales from a net basis to be from the U.S.

Our next question comes from Trung Huynh from UBS.

Just 2 questions on brenso, please. First, I just wanted to follow up on some of that discussion on the undiagnosed population. So if you've got the first product here with meaningful benefit, you're providing education, field force and advocacy. Simply, just in a blue sky scenario of penetrating this population, are you willing to share what your expectations are for in undiagnosed patients? And if not, how should we all be thinking about this? And then second, on the diagnosed patients, how are you thinking about ex-U.S. pricing? And what's your expectations of the peak sales split between the U.S. and ex-U.S?

Yes. So this undiagnosed population or the misdiagnosed population that we've identified has the potential to be multiples of what's currently identified using the ICD-10 codes. Look, it's our belief that we're going to penetrate that market. Once they're diagnosed and identified to be bronchiectatic experiencing exacerbations the same way we would, the primary market that we've identified in the so-called purple boxes today, that 500,000 patients. I don't know, Drayton, if you want to add what we've said about that population, but it extends.

So we are actively in dialog with those patients. We're engaging those patients and what our campaign, which launched over a year ago to remarkable results has shown that these patients really want to know more. And what we're encouraging them to do is speak up when they have a flare-up. And that's basically exacerbation in a patient's voice because what we know with these patients is that there's not an approved therapy, so why bother my physician. Again, they're typically an elderly patient. So we're encouraging them to speak up and to talk to their physicians about their flare and to get a proper diagnosis. So that's in conjunction with the education we're doing with the physician community to say, let's talk about why it's important to diagnose and properly code these patients. So we're going from both angles, and that education again started well over a year ago. And when you talk about an engaged community, I believe we have over 20,000 patients already after a year who've chosen to engage with us and seek more information. And the more information is physician dialog charts and different questions they can ask their physicians. So while I'm not ready to give a percentage of those, what I've seen is a very engaged patient community in that gray box, of undiagnosed.

And then I can address the question on peak sales and sort of the split between U.S. and rest of world. We're not providing the specific split. I will say that the large majority of net sales, we would expect from the U.S. as you do for all global brands, but a couple of important points that I would like to highlight. On the $5 billion peak sales number that Drayton mentioned in the prepared remarks, and we've been highlighting here that is net sales on bronchiectasis only. So that is a very significant opportunity as you can all appreciate. Also as we go and entities into our territories, we will look to ensure that the infrastructure that we build are rightsized for the sales opportunities across the globe. There are significant patients that we feel like we can -- that can benefit from brensocatib, if approved, and we will right-size those areas based on those sales contributions.

Our next question comes from Joseph Schwartz from Leerink Partners.

I was wondering how much work have you done on the pharmacoeconomic benefits of brensocatib and how much does this influence how you're positioning brenso with payers. Could you talk about what's in it for them in terms of the value proposition. For example, what is the pharmacoeconomic impact in terms of the number needed to treat to prevent an exacerbation and what an exacerbation cost to health care system and where does pharmacoeconomic steer the price within the range that you've outlined?

So I'll just start and then ask Drayton to comment. And I can tell you that this is not going to be an argument made to say that the price matches the cost in this circumstance. There is tremendous benefit to be had, and you will hear this from the treating community universally. And I think it's already early on recognized that there is a desperate need for therapy here, including by the market access world. But there is certainly a contribution to be made when you keep a patient out of the hospital from an exacerbation, and it's the avoidance of the degradation of the lung function. It's hard to quantify, but it is clearly valuable and those things being identified are very meaningful. But I don't think this is an HEOR argument per se. But Drayton, maybe you can comment on where we are in the preparation. It's still early.

Joe, as you can imagine, this is something we've been working on for several years now in terms of building out the value proposition. And the one thing I'd like or a couple of things I'd like to really point out here is, as Dr. James Chalmers highlighted last week, any reduction in exacerbations is significant to the patient, the community and the physician and certainly, approximately a 20% reduction is significant and meaningful. And when you think about exacerbations, particularly exacerbations and bronchiectasis, on the median exacerbation is approximately 14 days. That could be anything from a hospitalization, that could be anything from being confined to your home, and it's devastating for these patients. We hear that across all of our geographies, how devastating these exacerbations are. And to Will's point, when you have an exacerbation, you lose lung function and you don't get that back in most cases. And that's why it's so important. So we believe that's going to be the value proposition for the patient or the payers is not only the reduction in exacerbations, but the preservation of lung function and the improvement of quality of life. But we will continue to work through our health economic store. We'll continue to work on our value proposition. And certainly, we'll be prepared when it comes to engage the payers.

That's helpful. And then how are you thinking about the time to reach peak sales in terms of the launch trajectory? Are there certain phases of the launch that you foresee or are there some patients that are more likely to adopt brenso at different stages in the launch. How should we think about that trajectory?

So Drayton can comment. But obviously, what we've described today is a significant patient population that we're going to be chasing for a number of years. I don't know if you want to give any commentary on the actual slope, it's a little early.

Yes. I think it's a little early, Joe. But yes, I think if you look at rule of thumb or you look at analogs with a product like this, you could say 4 to 5 years, what gives me a little bit of confidence that ours may be accelerated or a few points. Number one, we've been in these exact offices in this exact community for over 6 years. We've established ourselves as the key player. The second I would say is we're a once a day oral with a safety profile comparable to placebo. In my experience, you tend to see a quicker uptake in that. And I'll point you to the ARIKAYCE launch. I believe the consensus for ARIKAYCE in the first quarter launch was around $2 million. I believe we did over $9 million. And I think there were several analysts who said we'd do $40 million in our first year, and we did over $132 million. So my philosophy and having launched 14 products, this will be my 15th, and this will probably be my fourth and fifth where I was a key architect of it is overwhelming force in the beginning. You have one chance to launch a product and you better get it right. And Will and the Board has given us the opportunity to prepare at risk and to spend years preparing for this launch. So if I can do anything to accelerate that launch curve, I can assure you we'll do it.

Next question comes from Stephen Willey from Stifel.

So you talked about how brenso is the only respiratory asset to receive prime designation in Europe. And I guess I'm just kind of curious as to what kind of leverage you think this might give you relative to those ex U.S. pricing differential comps for other respiratory assets? And then I just have a follow-up.

Yes. I mean, again, this is my -- the best of my knowledge. I always want to qualify when I say things like that. Prime designation, I think when we got it, we were the first, and I'm not aware of anyone else that's received it since that could be inaccurate. But I think it's right. In any event, what's exciting about that is it is an outright acknowledgment much like we saw from the FDA of the promise of the medicine. And since the profile from Phase III was as clean at least in our mind, and compelling in terms of statistical significance, it looks like that support and that recognition was warranted. That should set us up for a very productive discussion from a regulatory and I think a pricing point of view. But once again, I would reemphasize that the majority of this is going to come from the U.S., but there is going to be a meaningful contribution from Europe and Japan. And we'll have more to say about that, I guess, as we get closer. I don't know that the prime designation per se changes the pricing negotiation. I would just say that it's another acknowledgment of the impressive promise of this mechanism of action.

Okay. And then just on HS, obviously, a number of novel agents here in development, mostly biologics. And I'm sure you probably want to interrogate single-agent activity for brenso in the Phase II. But also curious if a combination approach here could be part of the Phase II development plan as well, just given the ASPEN safety profile that we've seen.

Yes. So at this time, I don't think we anticipate a combination profile of being explored in Phase II. If there's something approved for Phase III by the time we launch, we would have to give some contemplation to that. But once again, I think of all 3 of these that we're pursuing, we feel fantastic about bronchiectasis. We are very encouraged by what we're seeing in CRS without nasal polyps. HS is the one that is perhaps one step further out. We don't have great animal models to explore this. It is a neutrophil-driven disease. There's good scientific logic for pursuing it. But Phase 2 is going to teach us a lot. And one thing I would just say, I mean, over to the concept of how we deploy our capital, this is something where we're going to structure the trial so that we can have an understanding of what the performance looks like after a finite period of time, perhaps 12 weeks, so that we know whether we're seeing response from patients. In a world where that does happen, this becomes a very exciting product because it's a once-a-day oral pill to complement the biologics that you're making reference to that are being developed extensively. I think those development programs are an endorsement of the unmet medical need here and the desperate opportunity that this would represent if it could be impactful. And in our minds, it would ultimately become a combination market between those biologics and our drug, ours being paired with any of those that have been approved.

We are now at the end of our session for today. Thank you so much for attending, and you may now all disconnect. Have a good day.