Thank you for standing by. My name is Enrique, and I'll be your conference operator today. At this time, I would like to welcome everyone to the Insmed Second Quarter 2023 Financial Results Conference Call. [Operator Instructions] Now I would like to turn the call over to Bryan Dunn, Executive Director, Investor Relations. Please go ahead..

Thank you, Enrique. Good day, everyone, and welcome to today's conference call to discuss Insmed's second quarter 2023 financial results and provide a business update.

I am joined today by Will Lewis, Chair and Chief Executive Officer; and Sara Bonstein, Chief Financial Officer, who will each provide prepared remarks before we open it up for your questions. Before we start, please note that today's call 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 results discussed.

Please refer to our filings with the Securities and Exchange Commission, which are available at www.sec.gov and on our website, for more information concerning the risk factors that could affect the company. As a reminder, the information on 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 Will Lewis for prepared remarks..

Thank you, Brian. And good morning, everyone. What an incredibly exciting moment we are in at Insmed. From a commercial perspective, in the second quarter of 2023, we achieved the highest quarterly sales in our history, up 18% compared to an already strong first quarter.

As a result of this outperformance, we are raising our revenue guidance for the year, making what was the best-case scenario under our previous range of expectations, now the midpoint of our current guidance. Clearly, the commercial engine at Insmed is really humming.

And I want to thank the customer-facing part of our organization throughout the world for their extraordinary efforts, which led us to this result.

If we are successful with clinical trials and approvals, these same colleagues will one day be the teams to launch brensocatib and our other pipeline assets, which increases my confidence in the company's future as a profitable and sustainable commercial organization.

As impressive as this quarter's performance has been even more exciting is what we have in store.

We are now finally arriving at the time we have been anticipating for years when we expect to produce meaningful data across our entire research and development portfolio, culminating in the release of the ASPEN data for brensocatib in the second quarter of next year.

I mentioned ASPEN as the culmination of this period of catalyst because it will undoubtedly mark a huge milestone in the history of this company. But ASPEN is by no means the end of our meaningful R&D updates. Let me give you a taste of what I mean, and please keep in mind that this list will not be exhausted.

In 2024, we anticipate a steady stream of updates from our gene therapy program, including first patient data in DMD and an additional one to two IND filings for other gene therapy programs, including Stargardt disease.

In parallel, we believe we will have accomplished the production of complete capsids using Algae, potentially validating our AlgaeneX manufacturing platform.

Then moving into 2025, we expect our first IND submission from our de-immunized by design platform and potentially the successful scale up to full commercial manufacturing of proteins using Algae. We also expect to file an IND for Ataxia-telangiectasia, which is related to a recent acquisition that I will tell you more about in a moment.

All of these data catalysts would be in addition to potential top line results from several other studies from our first three pillars, which could significantly derisk large commercial opportunities for Insmed, if they are successful. One of those is our ongoing study of TPIP in patients with pulmonary arterial hypertension.

Another is a study, which we plan to initiate before the end of this year for our second indication using brensocatib in patients with chronic rhinosinusitis without nasal polyps. Much like bronchiectasis, CRS without nasal polyps is an area of high unmet need with few or no treatment options and very large numbers of affected patients.

The timing for top line readouts from each of these studies will ultimately be determined by the respective pace of enrollment. All of that is to say that the next year, as exciting as it is, is only the beginning for Insmed, and we can't wait to deliver it.

It will all start next month with the release of top line results from our ARISE study of ARIKAYCE in patients with newly diagnosed or recurrent MAC lung infection who have not started antibiotics. I spoke about this data set at length last quarter.

But as a reminder, the goal of this data readout is to validate a patient-reported outcome tool, which will be used as the primary endpoint in the registration-enabling ENCORE trial. I'm often asked, what good would look like in this data set? From my perspective, the ideal outcome would include three key elements.

First, we will, of course, want to see that the medicine demonstrates a safe and well-tolerated profile for use in this patient population. Second, ideal data would clearly show that we have a PRO that works without the need for a significant amount of modification.

This would give us confidence that the PRO can be relied upon to predict when patients are feeling a meaningful improvement in their symptoms and can therefore be used as the primary endpoint measure in ENCORE.

And third, we would want to see at least a trend toward PRO and culture conversion superiority for the ARIKAYCE arm compared to the control arm. Both the PRO and culture conversion trends would ideally be at levels, which give us a clear path to achieve a statistically significant outcome in the ENCORE study.

To be more specific on culture conversion, if we can achieve a placebo-adjusted improvement in the conversion rates in the 10% to 20% range and ARISE and/or if we see meaningful improvements in time to conversion in the ARIKAYCE arm of the trial, we believe that would be very encouraging.

If ARISE checks all of those boxes, then I would consider it an extremely positive result, one which would significantly add to our confidence in the ARIKAYCE opportunity in the broader MAC lung disease indication, which is 3x to 5x larger than the current refractory indication in which even on its own, we believe, would greatly strengthen our financial position by adding a potentially significant source of revenue growth as we move towards financial sustainability.

As a reminder, we will host a conference call to discuss the data once the ARISE top line results are shared. While we are discussing the ARIKAYCE development program, let me give you an update on ENCORE as well. Enrollment in the trial has remained strong, and we continue to expect to enroll 250 patients by the end of this year.

Following the ARISE data, we will quickly have another data set to share, this time from our Treprostinil Palmitil Inhalation Powder, or TPIP, program, which we currently are studying in Pulmonary Hypertension associated with Interstitial Lung Disease, PH-ILD, and Pulmonary Arterial Hypertension, PAH.

We continue to expect to share blinded dose titration data from our Phase 2 PAH and PH-ILD studies in the second half of 2023, with the Phase 2 PH-ILD top line readout expected to follow in the first half of 2024. In my opinion, TPIP is probably Insmed's most underappreciated pipeline asset.

Given that treprostinil is a well-known and well used medicine for patients with PAH and PH-ILD, we already know quite a lot about its profile. First, we know that administering higher doses of treprostinil results in a dose-dependent improvement in patient response.

Second, we know that treprostinil has a relatively short half-life, which requires patients to inhale doses of it four or more times per day in an attempt to maximize the dose delivery. This results in spikes and troughs of drug exposure throughout the day and these patients unable to maintain the drug's effect during a full night of sleep.

And finally, we know that there is already a large and rapidly growing market for treprostinil in these indications. TPIP is a prodrug, which gets converted slowly and steadily to treprostinil once inside the lungs.

If successful, TPIP could allow patients to cut their dosing schedule down to once a day while maintaining a steady treatment effect throughout the day and even while they sleep.

Beyond that, we believe that TPIP has the potential to safely deliver treprostinil at significantly larger quantities than even the highest approved dose of the currently available inhaled treprostinil products. We believe that these higher daily doses could result in enhanced efficacy.

Now you might say that blinded dose titration data from a study that is still ongoing is not likely to be very meaningful. And normally, I would agree with you. However, TPIP could be an exception given that what we already know about treprostinil and how it is currently dosed.

For context, the highest FDA-approved maintenance dose of Tyvaso DPI is 64 micrograms, 4 times per day, totaling 256 micrograms being delivered to the lung each day. Our Phase 2 studies are designed to titrate up to 640 micrograms once per day.

That is nearly a 60% higher daily amount of treprostinil being delivered when you exclude the weight of the 16 carbon chain of our molecule. This blinded data will show us whether that can be done in a safe and tolerable manner.

If this blinded data show that we can successfully titrate patients up to 640 micrograms per day, I would argue, given the history of the mechanism that it is a very encouraging early sign of the potential for TPIP to provide greater benefits for these patients.

To emphasize that point about efficacy, we are also watching with great interest some of the key efficacy signals from those studies, such as reduction in pulmonary vascular resistance. Granted, the patient numbers are small and the data is still blinded at this point. But what we see so far is very encouraging.

We look forward to sharing more about the blinded efficacy signals we've seen with you in the future, apart from the dose titration data. The next exciting clinical data readout we expect will come from our early-stage research engine or our fourth pillar, which we unveiled at our recent R&D Day.

In the first half of 2024, we anticipate releasing biopsy data for at least one patient from our Duchenne Muscular Dystrophy gene therapy program.

This will be our first look at human data using intrathecal dosing, which we believe could lead to enhanced safety and efficacy for these patients based on the preclinical work that we showed you in May and have continued to produce since that time.

Importantly, this data readout for DMD, if successful, could also serve as an important point of validation for our gene therapy platform more broadly, which would add to our confidence in the additional INDs that I mentioned earlier. Now I want to conclude with the clinical development program.

I'm the most enthusiastic about at the company, our ASPEN trial of brensocatib in non-CF bronchiectasis. This is clearly the single most important trial running right now at Insmed, and I remain as confident as ever in its likelihood for success.

The ASPEN top line readout in the second quarter of next year will be the most impactful event in the company's history, and we can't wait for it. I can tell you that we aren't the only ones excited about this program.

Just two weeks ago at the World Bronchiectasis Conference in New York City, one KOL said to us that they believe this data set next year will change everything and will be the most exciting time in the history of bronchiectasis for that patient community. We agree 100%.

Before I turn it over to Sara for some remarks on the quarter's financials, I want to briefly touch on another important development within our early-stage research, which we could not yet discuss at our R&D event. In June, we completed the acquisition of a privately held company out of Cambridge in the United Kingdom called Adrestia Therapeutics.

Adrestia's focus has been in the area of synthetic rescue, which could open up the possibility of addressing diseases which have been untreatable in the past even with gene therapies. Through the application of advanced CRISPR screens, combined with human genetics, Adrestia is identifying novel targets across a broad range of diseases.

They then select the best modality for these targets based on the intended patient population, be it small molecules, oligonucleotides, such as ASOs and siRNA or gene therapy.

The first indication will be Ataxia telangiectasia, a devastating condition that is often fatal by the second or third decade of life and currently has nothing approved to treat it.

Although Adrestia is a relatively lean company in terms of head count, they have made tremendous strides in terms of establishing themselves with patient advocacy groups and moving their work forward on behalf of that community. We expect to have an IND filed for this indication in 2025.

This acquisition would make sense just for the technologies being brought into Insmed alone.

But in addition to that, we also welcomed some of the brightest and most impressive scientists and colleagues you will find anywhere in the world, including Professor, Sir Steve Jackson from the University of Cambridge, whose past work in the DNA damage repair space led to what we know today as Lynparza, the world's first synthetic lethal medicine, which is now a blockbuster medication, benefiting thousands of cancer patients around the world.

As good as the people at Adrestia are, history has shown that combining companies only works well when culture is aligned. I'm pleased to say that we couldn't have asked for a better fit. What we have found with Adrestia is not just a group of great scientists but kindred spirits with the culture of Insmed.

There will undoubtedly be much more to share about Adrestia in the future. For now, we are excited by the developments coming from this team's work and the early interactions and plans for collaboration between the Adrestia team and our other researchers at sites in New Hampshire, New Jersey and San Diego.

We look forward to updating you on the cutting-edge work being done and giving you a chance to meet some of the incredible people behind it. Importantly, this acquisition changes nothing about our previous commitment to keep the investment in our fourth pillar activities to less than 20% of our overall spending.

Furthermore, as we look to the future, our estimates for the revenue production flowing from our first two pillars will more than cover the anticipated cash needs of the early-stage programs we are currently contemplating, putting Insmed on a path to financial sustainability even as we bring multiple new medicines through clinical development to the market for the benefit of patients around the world.

I'll now turn the call over to Sara to walk through our second quarter financials..

Thank you, Will. And good morning, everyone. I am pleased to share some of the details of Insmed's financial performance for the second quarter of 2023. We ended the quarter with approximately $918 million in cash, cash equivalents and marketable securities.

Consistent with what we told you on our last quarterly call, this represents a significantly lower cash burn in the second quarter compared to the first quarter of the year.

We continue to believe that our current cash on hand positions us to be able to read out all of our expected clinical updates through the ASPEN results in the second quarter of 2024, leaving a meaningful amount of cash remaining on the balance sheet at that time. Now turning to our commercial performance in the second quarter of 2023.

Total net revenue for ARIKAYCE was $77.2 million, reflecting 18% growth year-over-year. This represents the strongest quarter for ARIKAYCE sales since its launch. On a regional basis, net revenue was $57.7 million in the U.S., $15.6 million in Japan and $4 million in Europe and rest of world.

Notably, each of these regions posted meaningful sequential growth compared to the first quarter.

Based on this strong performance to date and our continued confidence in ARIKAYCE's growth trajectory for the remainder of the year, today, we are raising our full year 2023 revenue guidance range to $295 million to $305 million compared to the previous range of $285 million to $300 million.

This new range reflects year-over-year sales growth for the company in excess of 20%. In the U.S., ARIKAYCE delivered an exceptional quarter and the best in its history, up 22% compared to the prior year second quarter and up 18% compared to the first quarter of this year.

This quarter's results further support our belief that ARIKAYCE is still in a growth phase. Sequential growth in the U.S. in the second quarter was driven primarily by the exceptional execution of our field force, which is delivering the highest level of engagement since prior to the COVID-19 pandemic.

In Japan, ARIKAYCE grew 19% this quarter compared to the first quarter of 2023 despite the 9% price decrease, which went into effect in June and which I discussed on our last call.

This improvement in performance, although anticipated, began even earlier than we expected and again speaks to the potential for growth in Japan now that COVID restrictions have loosened and our access to physicians have begun to normalize.

In fact, our engagement with health care providers in Japan has roughly doubled compared to just one quarter ago, which highlights the great work being done by our new commercial leadership in Japan as well as our dedicated sales colleagues in that region.

We continue to believe that ARIKAYCE can produce solid growth in the second half of the year under these conditions. Finally, Europe saw a 33% sequential growth this quarter, driven primarily by our targeted patient identification efforts in both Germany and the U.K. Let me now turn to a few additional financial items.

In the second quarter of 2023, our gross CNS in the U.S. were approximately 14%, which is consistent with our expectations for the second quarter. We continue to expect our gross CNS to be in the mid-teen range for the full year, in line with historical performance.

Cost of product revenues for the second quarter of 2023 was $16.6 million or 21.5% of revenues, which is comparable with the past several quarters on a percentage basis. Turning to our GAAP operating expenses.

In the second quarter of 2023, research and development expenses were $197 million and SG&A expenses were $84.4 million, reflecting continued investment in both our early and mid- to late-stage pipelines as well as launch readiness activities for brensocatib.

Excluding noncash charges related to acquisitions, R&D expenses this quarter were comparable with R&D spending in the first quarter of this year. R&D expenses this quarter included a noncash charge of $76.5 million related to the acquisition of Adrestia Therapeutics in June, which Will mentioned a few moments ago.

In closing, Insmed continues to deliver on its promises with strong commercial execution and a cash position that can support its business through the exciting period of data readouts ahead. I'll now turn the call back to Will for closing remarks..

Thank you, Sara. Before we move to Q&A, I want to mention a couple of other recent updates that continue to make me proud to be a part of this company. We are an organization made up of people driven by a singular purpose to deliver life-changing treatments for patients in need. And I see that passion in the people around me every single day.

We recently learned that for the third year in a row, Insmed has been designated as a great place to work in the U.S., reflecting our exceptional workplace culture. I am enormously proud that 97% of our employees said that this is a great place to work, our highest rating yet.

I also want to draw your attention to the first-ever World NTM Awareness Day being held tomorrow. This effort being led by the incredible people at NTM Info & Research aims to educate and support physicians, patients and caregivers who are impacted by this disease. This is expected to be an annual event, and we are honored to be a part of it.

As we strive to do the right thing for our patients, we are also mindful of our broader commitments to those around us. We recently released our first-ever responsibility report, which you can find on our website.

The report which will be updated annually details the commitments and actions we undertake as an organization to act responsibly in everything we do, from serving patients and our employees to supporting our communities and natural environment.

What we've built and continue to build in Insmed is what I like to refer to as an intentional community, a place where people check in with each other and offer help when needed so that all people feel cared for and supported. This results in an environment where people are motivated and can do their best work.

Please take a moment to look over the report. If you want to learn more about the ways we are ensuring that Insmed is a responsible corporate citizen, both now and as we grow into the future.

Finally, I would like to again thank all of those who have been on this journey with us, our patients, our investors, our colleagues and all of our other stakeholders. The future is bright for Insmed, and we look forward to continuing to deliver on our promises to each of you.

Our long-held ambition to build the next great biotechnology company is finally coming to pass. With that, I'd like to open the call to questions.

Operator, can we take the first question, please?.

[Operator Instructions] Your first question comes from Ritu Baral from TD Cowen. Ritu, please go ahead..

Hi, guys. This is Yaneel (ph) on for Ritu. So, my first question is on the frontline program. Are you thinking of an MCID for your fatigue and cost measures for the PRO? And is there a delta on these that you're looking for? And then a quick follow-up..

I'm not sure I understood the question.

Are we looking for a what on the PRO?.

A minimum clinically important difference on the PRO.

Like what are you thinking in terms of the scale and the delta that's desirable that you're looking for?.

I see. Well, the truth of the ARISE program is that it is designed to answer that exact question, right, because no PRO has ever been developed for NTM. There really is no frame of reference.

So, if you think about what is the goal of the ARISE study is to both establish that the PRO works by showing that it can measure changes in how patients feel and also the degree of change needed to capture a patient feeling better. So, if you think about it this way, we're using two measures in parallel.

One is a general measure that says today, I feel better or more specifically over the last seven days, I feel good, worse, much better, those kinds of very simple definitions. That one -- that scale that we use is about five runs on it from best to worst.

So, a patient has to improve on that one step in order for us to conclude that a clinically meaningful change has taken place in that patient's condition. That's as established by the FDA. We then use the more detailed quality of life bronchiectasis questionnaire and the fatigue PRO to determine a numeric change on those scales.

So, if there is a one-step change on the overall symptom score, we then correlate that to the number of -- the value change on each of the PROs. That's how we establish what constitutes a clinically meaningful change on the PROs. Once we know that, then we can determine whether or not we've seen that degree of change in this study.

I know that's a lot of complexity and a lot of detail, but I'm hoping to really get to the heart of the question, which is how will we know that this is working? How will we quantify, how it works? And what information we intend to share with you.

So, I hope -- is that responsive to your question?.

Yes, it is. Thank you for taking that. And then a quick follow-up on the TPIP program.

Can you give a little more granularity on the data points that you'll be reporting? And what you're hoping to see just sort of setting expectations there?.

Yes. So, what we're doing right now is, obviously, we have some ability to observe in the earliest patients blinded blended data. And I think we look at the same kinds of measures that others look at for other products that are on the market.

There's a good frame of reference out there for what constitutes an impressive change in certain metrics, things like pulmonary vascular resistance. These are measures that don't idiosyncratically change in very sick patients, typically. So, if we're seeing a significant change on those measures, we consider that encouraging.

What we don't know is, of course, which arm they're in. I'll just remind you that in PH-ILD, patients are randomized 3:1 on the drug treatment to placebo. And in the PAH program, it's 2:1. So there's a good number of patients that are on drug in all likelihood, even with early patient numbers.

As we look at these blended blinded details, we see some encouraging signs, we think, within them. And so, as we amass more data and gain greater conviction that these are not sort of one-offs, I think we will look to share some of that potentially with the market. We think TPIP as an incredibly valuable asset.

And we base that on the precedence of what has happened in this space with programs that have been able to demonstrate impact on some of these parameters, the haemodynamic parameter of pulmonary vascular resistance, for example, at the upper end in this entire space is Sotatercept at its highest dose.

It's a reduction of about 33% on pulmonary vascular resistance on average. And at the lower end, I think I can't remember the product, but it's down as low as a 14% reduction. So, seeing something in that range would mean we are directly competitive with those.

And if we were to be able to see something above that range, I think that, that would be encouraging. It's early. We have to continue to amass data. But as we do so, and we see these data, we will be thinking of ways to be transparent about what is getting us excited with the market. We're aware of the precedents out there about sharing data early.

We do not intend to put out data and run statistical hypotheticals on it. We would just share raw data if we were to do anything. And then, I would leave it to the market to make its own judgments about the potential promise of this program.

But I can tell you today, although it's early and there are low patient numbers, what we're seeing is incredibly exciting..

Thank you. That was helpful..

Next question please operator..

Your next question comes from Judah Frommer from Credit Suisse. Judah, please go ahead..

Yeah. Hi, guys. Congrats on the quarter and thanks for taking the questions. Maybe just going back to your ideal ARISE scenario, Will.

In the event that you validated PRO, but you don't see what you'd like to on culture conversion, how do you see the program moving forward from that perspective? And is the opposite possible that you'd seen the culture conversion but not validate the PRO?.

Yes. To be totally transparent -- first of all, I think that's the heart of the question for ARISE. Like the -- what we're trying to convey in this quarter and the last quarter is look, success with this program is clear and simple.

As complexity increases, it just -- it affords us the opportunity to make changes for ENCORE, but we're just going to have to walk people through that if that's necessary. So, I'm as anxious as anyone to see these data.

I think on both measures, the PRO, let's remember, is designed to inform us what we can learn about these PROs and their applicability in this setting. No one's ever used them before in the frontline setting. We have some data from the refractory setting that we think guides us. And of course, we have five years of commercial experience.

So, we think we know how patients' symptoms change. But these are going to be quantifications of those patients, and we're going to learn a lot from this study. I'm convinced of it. Success is a PRO that shows that patients get better. And home run success is a PRO that shows that patients on our drug get better than those on the control arm.

For culture conversion, I think it's really two measures. It's overall culture conversion relative between the two arms and time to culture conversion, both of which are trends we've typically seen positive in favor of ARIKAYCE in the past in other settings.

So, I think there's a lot of variables here, and I'm hoping that we'll have a clear answer for you in about a month's time..

Okay. And just a quick one on the refractory setting. It's been probably a couple of years now, we've been talking about pent-up demand or under diagnosis for refractory MAC patients as we've gone through, but it sounds like things are normalizing globally.

Are you seeing evidence of that under diagnosis or pent-up demand in the refractory patients?.

I don't know how to characterize it, Judah. It's just clear anymore. We're back in growth mode, and I think everybody feels really good about where things are right now with the refractory patient populations really around the world.

Our expectation, and that's why we raised guidance today is that that's going to continue, that momentum will carry into Q3 and Q4. I'm finally relieved to not have the unexpected happening in the quarter for this commercial opportunity. The team has done incredible work during one of the most challenging times, we're past that now.

And we're now back into an era where it feels not only normal, but that there's opportunity there..

Thanks..

Your next question comes from Vamil Divan from Guggenheim. Vamil, please go ahead..

Great. Thanks for taking the questions. Maybe just a couple. I appreciate all the insight around ARISE. As you've been talking to investors a couple of questions that have come up, but I just want to get your updated thoughts. And I know you've given sort of peak sales for ARIKAYCE plus brenso.

I'm wondering if you have any thoughts -- if you could just kind of give your perspective on ARIKAYCE alone, especially just the refractory setting, if the frontline opportunity doesn't sort of come about, what do you see as the sort of longer-term growth opportunity just in refractory MAC? And then, do you see any risk to accelerate approval if the frontline study do not read out positively? Thank you..

Yes. Thanks for the question. I think we haven't given guidance on MACs peak sales on refractory alone. I will just observe that we remain in a growth mode there. We see patients in the field that will benefit from this medicine. They are appropriately on label. And that's our focus.

I think what you've seen in the last couple of quarters is that those patients are interested in receiving treatment. And so, we're going to continue to chase down that opportunity. And I think you're going to see that growth continue into next year.

When we talk about accelerated approval and the probability of success based on ARISE, ARISE is a learning study. It's not powered for statistical significance, but it's powered for us to learn how to ensure that ENCORE is a success.

And I think we have a lot of levers to pull once we see the data in terms of what we're going to need to do to ensure ENCORE'S success.

I don't see a lot of risk to the refractory market in a world where some parts or some aspect of ARISE goes sideways because we still have ENCORE before we have to answer ultimately to the success or pillar of the trial in the U.S. and Japan. And I'll remind you that there are separate primary endpoints for each of those regions. U.S.

is PRO, Japan is culture conversion. So, somewhere in there, I have a high degree of confidence we're going to find a path to expanding the addressable market for this compound. And I think the community is excited about that as well.

And finally, I would just observe that I think FDA is approaching the assessment here from a very different perspective than it did when it first gave approval to our drug conditionally for refractory MAC. And that is that we have now five years of experience on the market as a commercial product without any major issues.

And indeed, we've had full approvals in Europe and Japan with very successful launches in those regions and a lot of patients helped. And I think that collection of data does bear on their assessment of the viability of this product to help patients who are just a little earlier in their development of the disease..

I would just also add and remind folks of the inclusion of the international treatment guidelines with a strong recommendation for use of ARIKAYCE in the refractory setting..

Okay. Thank you..

Your next question comes from Jennifer Kim at Cantor Fitzgerald. Jennifer, please go ahead..

Hey. Good morning. Thanks for taking my questions and congrats on the quarter. I have two questions here. The first is post Adrestia acquisition. I'm wondering what is your appetite or potential need for further BD? And then going back to ARISE.

I'm just curious, is the sizing of ENCORE determined by culture conversion rates alone? And so, if it gets to the lower end of that 10% to 20% culture conversion, what would the potential impact on enrollment size be? Or if it fall below that, but the improvement in time to conversion is meaningful, what potential adjustments, would you have room to make? Thanks..

Yes. Thanks. On the Adrestia front, super excited about that acquisition. I think what you see with this acquisition is, in many ways, the completion of what we refer to as our fourth pillar in terms of the components needed for a truly robust engine that will be able to produce multiple INDs.

Strategically, what we have done at Insmed, and I think we'll always look at other opportunities. I don't feel the need to do anything more necessarily to get to a state where we have an adequate capacity. We have that now. We will always look and be opportunistic.

I want to be clear about that, but I feel very good about what is inside our fourth pillar. We now have capabilities that are second to none in terms of IND production that will have a major impact on patients and in an accelerated fashion.

What do I mean by that? These technologies we've acquired, the strategy behind them, it's not just that they're novel and interesting and exciting. They are, but they also allow us, in my mind, to introduce productivity to the biotechnology equation. We are looking for ways to get drugs on the market faster that are more impactful to patients.

And that ambition directs us towards therapies and therapeutic approaches like gene therapy and synthetic rescue and be immunized by design that allow us to design and advance programs that with a successful Phase 1/2 program, clinical trial can apply for conditional approval. That's really what we're trying to do here.

So, there's a world where many of these programs that, while they seem early today could get to commercial relevance in a shorter period of time for the clear benefit of patients by demonstrating a significant impact in Phase 1/2 trials. So, that's the reason why we built the fourth pillar.

It is the answer to the question of what's coming next in Insmed, and it is now in a place where we'll answer that question for many years to come with multiple INDs. And I would draw anyone's attention who wants to learn more to the recording of our Research Day back in May.

On the ARISE study, in particular with regard to culture conversion and how we think about that informing the ENCORE study, we're going to learn from ARISE on many different fronts. We'll learn about culture conversion, we'll learn about the PRO and the information we collect from that will inform the ultimate size we decide for ENCORE.

It may be that it's adequate as it is, it may need to be increased. I don't lose sleep over any of those two outcomes. To me, the important point is ENCORE must succeed. One theme you've heard from us over and over again is you find out what you think is an adequate powering and then you add a few bit more patients because you must win with the trial.

That's the theory behind the bronchiectasis study. It's why it's 1,700 patients. We want to give our drugs the best chance to demonstrate their impact, and we'll bring that same theory to our ultimate sizing of ENCORE..

Okay. That's helpful. Thanks..

Your next question comes from Leon Wang from Barclays. Leon, please go ahead..

Hey, and congrats on the quarter. Thanks for taking my question. I have one on the PRO readout. So, there was a recent article that came out CHEST that talked about doing a PRO and this response in NTM MAC.

And basically, they gave some baseline in both the two drug and also the three drug regimen and patients kind of responded with around a 7 to 8 point improvement.

So, with that kind of -- can you talk about how this plays into your thinking in terms of expectations on ARISE? And also, any thoughts on the two and three drug regimen as well? And I have a follow-up for -- on ARIKAYCE..

Sure. So, I don't -- I have to confess, I'm not familiar with the details of that article.

But what I can tell you is that the -- when we think about the PRO that we're using, the quality of life bronchiectasis PRO, that PRO in the setting of bronchiectasis, it has been established or believed that an 8-point intra patients change constitutes a clinically meaningful improvement.

So as a frame of reference, an 8-point change on a scale of 100 is considered clinically meaningful for bronchiectasis using the QOL-B PRO. That may or may not be relevant to NTM. And one of the things we're going to answer with ARISE is what point change do you need to see that to constitute a clinically meaningful improvement.

So that's what ARISE is going to answer. And then, we're going to see what improvement we actually saw in each of the arms.

So, we don't have that question today, and I'm not familiar with that article, but I suspect that, that is making reference to the bronchiectasis experience and applying that to NTM and suggesting that, that may be what is needed. That would not be uncomfortable to us in any way.

But we'll know more in a month and certainly share with you our learnings. I'm not sure -- I'm sorry, I don't recall the second part of your question..

The second part was on ARIKAYCE. So, for ARIKAYCE, in terms of ex U.S.

growth, and I guess more specifically in Japan, with the onetime price discount happening this past quarter, can you characterize the volume growth that you see over there? And do you think any of the volume growth could have been because the price discount it's known that going to happen.

So, payers in Japan are people who buy ARIKAYCE in Japan would kind of hold off until there is a price discount? So, do you see any stocking effect in essence?.

Yes. I appreciate that question. We don't think that's the origin of what's going on in Japan. I want to remind everybody we've had some additional leadership capabilities brought to bear in Japan as part of Team Insmed. We're super excited about them.

This builds on an already strong team and allows us to get ready for what's to come, both in terms of frontline, for ARIKAYCE and hopefully, if all the trials are successful and regulatory approvals cleared, the launch of what would be the first ever drug for bronchiectasis. So, we needed that horsepower for what's coming.

This most recent quarter did include the price discount. It wasn't that substantial. So, I don't think it would have caused a massive change in behavior, of far greater significance was the lifting of the restrictions due to COVID. It's hard for people to remember. But it's actually in Japan.

It wasn't until May that they lifted all restrictions on COVID that opened up access to physicians, and our activity volume, our outreach has increased significantly since that time.

And I would attribute the early signs of success that we're seeing in Japan to a combination of that, the energy flowing from the leadership changes, coupled with the lifting of restrictions in that territory.

And that's why we've said all along that we think the second half of this year is really when Japan is going to do its best, it looks like it started early and we're super encouraged by that. And hopefully, we'll continue to see that as we go forward..

Great. Thanks and congrats again on the quarter..

Thank you..

Your next question comes from Jason Zemansky from Bank of America Jason. Jason, please go ahead..

Perfect. Good morning and congratulations on the quarter. Thanks for taking our questions. A couple on the pipeline, if we may. We certainly agree with your comments regarding TPIP's potential. But that being said, the landscape of trepostinil and PH ILD is changing. There's been uptake of a DPI formulation. There's another DPI waiting in the wings.

And of course, there's a potential launch of sotatercept, as you mentioned, which could be disease-modifying.

Obviously, there's still some derisking ahead and it’s a bit early, but as you think about these upcoming shifts and the potential that a product like TPIP may be able to add, could you maybe discuss where you think it could fall in the evolving paradigm? And then a follow-up on ASPEN. Thanks..

Yes. So, I'm going to steal a line from an investor that we heard. I won't attribute it, but someone who is talking to a strategic that is in this space, shared with us that from their perspective, TPIP could be a category killer.

The reason they say that is because a once-a-day treprostinil formulation that covers patients all day and all night at higher doses than what can be achieved with any of the formulations you're referencing right now would be best in class. So, what we see for this product is this becomes the cornerstone of prostanoid therapy.

This is the go-to product for anyone who is reaching for a prostanoid to treat a PH-ILD patient. This is where you go. And in that world, I think products like sotatercept incredibly encouraging as they are and a new mechanism of action, I see this as something that sotatercept may well pair with to produce even better results for patients.

As you know, this is a combination therapy market, at least in the PAH Type 1 patients, and we're encouraged to think that we can be the prostanoid of choice. It is very important for people to understand that our dry powder formulation is fundamentally different than every other dry powder out there. This is not just treprostinil in a dry powder.

The 16 carbon chain formulation is the key to unlocking the full potential of the underlying drug because what happens is that 16 carbon chain means that the molecule is inert when you inhale it, that's particularly relevant for PH-ILD patients because it means, and we demonstrated this in repeated animal studies under the excellent work of our scientist, Dick Chapman, that the cough is reduced substantially.

This is a major issue for PH-ILD patients and the reason why many of them cannot tolerate Tyvaso so, we see ourselves going there very successfully. We see ourselves going into PAH as the prostanoid of choice and very likely being paired with some of the other molecules you made reference to.

In the end, the key metrics that drive improvement in these patients and that get people excited about potential disease modification are looking at things like sustained improvement in pulmonary vascular resistance. And when you see reductions as was seen with sotatercept that get up as high as 33% on average, that's very exciting.

All I'm suggesting to you right now is though while it's early and our patient numbers are small, I would describe what we're seeing as very exciting..

Got it. And then, I believe the update regarding the DSMB's May review of ASPEN is new.

Any additional color you can provide here and how does that factor into your optimism over next year’s readout?.

Yeah. I mean, I think every time a DSMB meets and nothing happens, it's a reason to get encouraged. I think what is most important about this study is that it continues to behave exactly as we expected and wanted it to. We aren't seeing anything changing within the broad analysis and metrics that we watch and we do so in a detailed fashion.

This is a very substantial study. It's more than 50% larger than every other study that's ever been done previously. So, the volume of data we're going to generate from the study is very significant. Why is that relevant? Because it tends to address any of the outlier effects that can sometimes cause headaches for studies.

Just to remind everybody, our Phase 2 study, which was statistically significant at both doses on the primary endpoint was 80% powered to show a 40% treatment effect. The Phase 3 study is 90% powered to show a 30% treatment effect. So, we have more power in this study to show a more modest impact.

And the study is behaving and the baseline characteristics of the patients are almost identical, there's every reason to believe that this study will look just exactly as successful as WILLOW did. And that will unlock the first ever potentially approved therapy for bronchiectasis.

It will validate the mechanism of action of DPP1 inhibition as a neutrophil-mediated disease agent, and that unlocks a series of additional therapeutic area possible indications, including the next one we're going to be launching here shortly, which is the Phase 2 study for chronic rhinosinusitis without nasal polyps. Just a footnote for people.

We anticipate at the launch, assuming everything goes well for bronchiectasis, we could be addressing as many as 1 million patients, up to 450,000 in the U.S. and the balance in Europe and Japan. CRS without nasal polyps, the population in the U.S. is 26 million, and there are no approved therapies for this indication.

And we do not intend to address all 26 million. I want to be very clear about that. We're going to go to the severe end of the spectrum, those who are scheduled for or eligible for surgery or who have already had repeat surgeries to fix this condition. We think because it's a neutrophil-driven condition that the DPP1 will be very effective.

And that opens a second very substantial opportunity and that trial will be underway by the end of this year.

So, there's a lot going on in the bronchiectasis -- pardon me, the brensocatib world of DPP1, the DSMB giving another clean bill of health continues to build on the safety track record of this molecule, and that is encouraging for not only bronchiectasis, but all the other disease conditions we're examining where it may be potentially applicable..

Great. Thanks for the color..

Your next question comes from Stephen Willey with Stifel. Please go ahead, Stephen..

Yeah. Good morning. Thanks for taking the questions and congrats on the quarter. Maybe just a couple of ARISE related question.

So, I guess the first is, I'm just curious how you think about current efforts to characterize disease severity and NTM MAC beyond just the presence or absence of cavitary disease? And I guess where you would expect ARISE patients kind of based upon the baseline characteristics that you've seen thus far to sit on that proposed spectrum of either lower versus higher risk?.

Yes. So, I think the way I would describe it is these patients have to be diagnosed with MAC and they have to be symptomatic, right? So that there's an instinct to treat these patients on the part of the physicians. And this is a definition broadly that I'm describing that we arrived at in close consultation with the physician.

The North Star of the company is always how can we benefit the patient. So, let's describe the patient with the KOLs, understand where they think treatment is needed and then go there.

The interesting thing about our trial design here for ARISE and ENCORE, we actually didn't propose to the FDA that we go after these broader patient populations, they proposed it to us for validation of the drug in the refractory market, right? You remember we were conditionally approved for refractory MAC.

The FDA directed us to go after frontline for full approval of both refractory and that broader indication.

At the end of the effort here when ARISE and ENCORE are done, if they are successful as we hope they will be, we will have a drug that is valid for the treatment of NTM MAC patients, and that is 3x to 5x the size of what you're seeing in refractory right now. It's a very substantial market.

And currently, there isn't anyone else who has a drug that has been approved. There are a couple as you know, that are now trying to pursue this indication. The FDA has been very clear. You have to have a PRO that shows improvement. You have to have -- culture conversion is nice, but it's not controlling.

And that's why we're so keen to see the results of the upcoming study..

Okay. And then, I guess just a second question is how tightly correlated do you think the culture conversion data between ARIKAYCE and placebo in the ARISE and ENCORE trials might be just given the differences in time off therapy at which culture conversion is being measured? Thanks..

Yeah. So, I want to be clear, the culture conversion is measured separately from the PRO. The correlation between those two measures is not something the FDA is looking for. I'm sure if we see it, it's a nice to have, but it certainly isn't something that's necessary.

When we talk about culture conversion between ARIKAYCE and placebo and the measurement of time, we're thinking about it through two broad lenses. One is time to culture conversion and consistently with the application of our drug in sick patients, we've seen patients convert faster on our drug.

And we've seen more of them convert than in any control arm that we've been looking at or studying, we would expect that to continue here. We expect a range of 10% to 20% improvement in our arm versus the control arm.

The one month off drug, we also -- although we won't be measuring it here for purposes of this report, but we've also seen much more durable results from our drug, and we saw that very distinctly in the refractory setting. So, we would expect that, that will carry forward here.

If that weighs on at all, it would only be that one month off, we don't have any concerns about a waning effect in that 30-day off time frame when the measurement is taken..

Great. Thanks for taking the questions..

Your next question comes from Graig Suvannavejh from Mizuho. Please go ahead..

Hi, good morning. This is Richard on for Graig. Congrats on the quarter, great beat and right in guidance. So, two questions for me and consistent with the theme here on the PRO for ARISE. I know that the company has talked about the 8 point change on the KOL for bronchiectasis, but any expectations for the fatigue PRO? And then I'll follow up..

Yes. It's interesting that we don't have any specific guidance on the fatigue PRO.

If you think about the way the disease progresses and between these two PROs, the quality of life bronchiectasis measures the actual experiential condition of the patient in terms of cough and sputum production and those sorts of things and fatigue is sort of the next derivative of that as a consequence of the disease you are fatigued.

And so, there's less data out there measuring this. But nonetheless, we know that it is one of the symptoms patients experience, and we wanted to find a measure that could quantify it.

So, we don't have any guidance on what we expect to see here, but we will know for the fatigue and the quality of life bronchiectasis questionnaire in a month, we'll know both. And we'll see what the cards show us.

If ARISE gives us the information we need to ensure ENCORE is successful using either of these PROs, then we will secure, we believe, approval for this drug for all MAC-NTM in the U.S. So it's exciting to be only a month away from that answer..

And on clinical trials, right, you have seven primary endpoints and two of them are on CDF and PDFs that are measured at different time points from the Promise scores and the Bronchiectasis score.

Can you talk a little bit more about those?.

Well, what I would say is these are two different PROs. And what we're trying to do in ARISE is learn what degree of change is needed for a patient to clinically improve using either of those PROs. And then do we see a difference given that degree of change in the two arms of the study.

And without going into the details of the nine different questions in the quality of life bronchiectasis questionnaire or the different questions in the fatigue, suffice it to say that each PRO is well designed to capture those changes if they are evident. And so, we'll know the answer to does either PRO work, hopefully, in the month.

And if they do, then we win, and we have a path toward ensuring that ENCORE is going to be a success and approval expanded in the U.S. It is worth noting that culture conversion alone is the primary endpoint in Japan. They're not particularly focused on the PRO.

And while we are very excited to see the results of the PRO, it's also worth highlighting that neither the clinicians nor the market access world are particularly focused on the PRO. Don't get me wrong.

If we see success with either of the PROs, I think that's going to be very well received and would be something we would seek to include in the label, of course. But the driver here is the eradication of the infection that gives rise to this condition.

And while the FDA is not aligned with that as the primary endpoint, Japan is, and we think it's important to remember that because there are really two trials going on here, one for Japan and one for the U.S..

Thank you. And if I could sneak in one more question about DMD, right.

How are you positioning your product versus Sarepta's or other program?.

Yes. I appreciate that question. I can tell you, as we said in May, we expect this program to be the best. The intrathecal delivery, we think is going to improve efficacy and safety for these patients. Better results, better transduction, better outcomes overall at a lower amount of drug required to be delivered.

And while there is still some biology to be learned about why there is such good transduction through intrathecal delivery, it is very clear from the preclinical animal model work that we have done, which is extensive and which we shared a lot about in May that we are getting excellent transduction in all kinds of muscle as well as including the cardiac and diaphragm which are critical.

Probably 90% of what is dosed in patients in IV is lost in the liver in most cases. Intrathecal delivery avoids that unfortunate circumstance. And could be really a game changer, we think, for these patients.

We'll have our first human biopsy data, we hope in the first half of next year and ideally before ASPEN data, and that would put us in a position where we could validate all of these beliefs, which are generated from the preclinical data..

Great. Thank you and congrats again..

Thank you..

Our next question comes from Liisa Bayko from Evercore ISI. Liisa, please go ahead. Liisa, you are live..

Hi, there. Sorry about that. I just have a couple of questions across different programs.

So just starting with ARISE, how are you thinking about the change in PRO, the kind of sustainability of culture conversion, one month after therapy, that's kind of a bit of a missing link when you look through the literature? So just curious about how you're thinking about that and yes..

So for the PRO, the one-month off drug is ideal, right, that when the FDA saw the wisdom of that, that was a real win from my point of view because it allows us to give the full effect of the drug and then step away from the side effects that are associated with the delivery of the drug.

Physicians often liken this to chemotherapy, and it's an unfortunate parallel because it just speaks to the severity of what these patients experience.

But the way to think about this is you have to take a medicine and it's not as bad as chemo, I would submit, but certainly, but it is difficult to take, right? This regimen of drugs that these patients have to take are very challenging and they create their own side effects.

So, checking in on patients one month after they're off all drugs is key to understanding how do they feel now that the drug cocktail has had its effect. And so, I would expect that, that will be a positive for us and an important one to reflect the impact of the medicine.

When we think about culture conversion, we've shown durable culture conversion going out well past the year in refractory patients. So, I don't have any concerns about checking culture conversion of one month off drug or even much further beyond that.

In fact, I think the durability of culture conversion is going to increasingly become one of the strong selling points of this medicine as it continues to find use, hopefully in broader patient populations..

Okay. Great. And then with respect to TPIP, you talked about much greater exposure if you titrate up to 640 micrograms.

Can you talk about any -- like is there a ceiling effect here in terms of efficacy? Are you -- would you expect greater efficacy with increased dose up that high in that range? Or are we kind of at the plateau part of the curve? Can you just talk to that?.

Yes. So, I think what we have heard from KOLs, it's a very interesting question because it gets at the heart of how we were strategically thinking about the drug.

When we were originally designing it, we were doing a combination of the ability to titrate higher while -- and get good dose strength in patients, in their lungs while also mitigating the side effect profile.

And what we heard loud and clear from the physicians is the key to having benefit to these patients is getting as much of the prostanoid into the patient as you possibly can, and they are willing and patients are willing to manage through side effects to the greatest degree possible.

So, all of these trials are actually MTD trials, max tolerated dose. And so, what we did in Phase 1 was to establish doses as high as 640 micrograms. With an MTD approach, that's one of the reasons why we think it will be interesting to share that data at the end of the year.

How high are we getting with these patients? Are they hitting side effect profiles that are preventing them from getting to 640 micrograms and how high do they get? And how does that compare to Tyvaso? When we went over the data today, if we're able to get to 640 micrograms, that is 60% more treprostinil in these patients than any other dose that's approved right now on a daily basis.

So that is a substantial increase in the amount of drug getting to these patients. Is it possible to go above 640 micrograms? I'd like to see if we get to 640 micrograms first, but maybe it is possible to go higher. I don't know I haven't put a lot of thought into that. But the goal is certainly to get as much drug into these patients as possible.

And the single most important point that people should take away in terms of the predictability and likelihood of this drug having an effect that is positive for patients is the more drug you get into these patients, the better they do. That is clearly already established away from us.

So, our ability to get up to 640 micrograms should result in significant improvement in these patient outcomes. And while it's early and there are small numbers and all the other caveats, I can summon the hints that we're seeing in the blended blinded data are suggesting that, that may indeed be happening..

Interesting. Okay. And then just a question on brensocatib. Have you done any market research Will looking at kind of what kind of uptake you might see? I actually starting to get this question, which I love because we're skipping ahead of data. But I've just been getting some questions because there's a lot of patients have bronchiectasis.

-- well, they have bronchiectasis because they have other diseases that have gotten them there. And so there will be a lot of, obviously, treatment already on board for treatment of other diseases comorbidity.

So just curious on what the feedback has been on that?.

Yes. It's -- the question is well timed because we just came from the world bronchiectasis meeting in New York City. And I would describe the physician community as giddy over the possibility of brensocatib's approval in bronchiectasis.

We are hearing from physicians that they are intending to -- assuming that the data is good, it looks like WILLOW, let's put it that way, they will put all of their patients on this drug. I expect the uptake to be very strong. And I would say that the work we've done -- we've done market research, we've done quite a bit.

We will continue to do more, especially as we get closer and closer. But our disease awareness campaign has already begun. It was at the American Thoracic Society. It was at World Bronch. It's going to be at ERS in Milan in September. It's going to continue full force until we have an approved drug.

And it is very clear that there is an unmet medical need here that is substantial. We talked about comorbidities. I sized the market for you earlier, we think patients that are diagnosed today with exacerbations, documented, number 1 million, up to 1 million between the U.S., Europe and Japan.

So, the markets where we have commercial infrastructure, this is 1 million patients at launch that are on, would be appropriate for immediate use of the drug. What we are learning as time goes by is that beyond that, there may be other patients in comorbid diseases like COPD and asthma who are exacerbating and may indeed be bronchiectatic.

There was a lot of data that was thrown around and the ranges are very wide. I won't go into the details. I'll just say that if you consider that there are 20 million patients in the U.S. with COPD and some portion of them are also bronchiectatic and experiencing exacerbations.

And as -- if they were to get a CT scan and diagnosed because that is the definitive way to diagnose a bronchiectasis patient, they would be eligible for use of our drug. They would be on label. It is a massive potential opportunity with this drug. So ASPEN is a very exciting data set. I'm glad people are looking beyond that already.

I think that's appropriate. Our current stock price suggests to me they aren't looking too carefully beyond that. But when they do, I think we're going to be in a very different world. This is, in my opinion, all the caveats about data and regulatory path approval needing to be in place.

If we clear those hurdles, which I expect that we will, this is a blockbuster drug..

Thanks, Will..

You bet..

Our next question comes from Andrea Tan from Goldman Sachs. Please go ahead, Andrea..

Hi. Good morning, and thanks for squeezing us. And Sara, can you speak a little bit more to the assumptions that underpin your updated guide? Is this being driven more by, what you're seeing in the U.S. versus Japan? And then, any updates you could provide on what you're seeing with re-treatment with ARIKAYCE would be helpful? Thanks so much..

Go ahead, Sara..

Great. Thanks for the question. So, our guidance, we were very excited to obviously increase our guidance this morning to increase its $295 million to $305, while we haven't given a breakdown from a regional perspective, what we saw in Q2 was strong growth across all three of our regions.

And as we mentioned earlier, Japan's growth happened a little bit earlier than we had expected. So really encouraged by the performance in Japan in Q2.

As we said during the prepared remarks, we almost doubled our opportunity to interact with health care professionals this quarter versus last quarter, mainly driven due to the restrictions being reduced from a COVID perspective. So, really encouraged by that. The new leadership in Japan, building on that U.S.

We are back in growth mode, back into pre-COVID levels, so really encouraged there. Europe, while small, again, saw a very sizable percentage growth quarter-over-quarter.

So really encouraged and hopefully see that in us increasing our revenue guidance and just the overall health and opportunity that the ARIKAYCE refractory alone opportunity can yield us, let alone the opportunity with the broader with a 3- to 5-fold increase with the broader label. And then specifically on retreatments.

We haven't provided specific details there. We see retreatments, which is wonderful. I think that speaks to the need for this drug and the fact that patients have successfully had a course of therapy, we're able to show success, culture convert.

And unfortunately, with the disease being ambiguous in the air, in the pipes in the water, they get a new infection and wanted to come back on therapy, I think, is probably one of the -- a great confidence boost to the brand that it is successful and patients have a need for it..

Thanks, Sara..

Yeah. Thanks, Andrea..

Our next question comes from Joseph Schwartz from Leerink Partners. Please go ahead..

Hi. Thank you for the updates and congrats on all the progress. A couple of questions on brensocatib. How much subjectivity is there in the definition of pulmonary exacerbations that you're using in ASPEN? And with such a wide-ranging study, I think there's 40 countries, almost 500 sites.

Is there anything that you can do to try to harmonize the definition and avoid seeing any untoward heterogeneity? And then, second question on brensocatib would be, we noticed that the age inclusion criteria skews lower or extends lower to include 12 people, age 12 and up and ASPEN versus 18 and up in WILLOW.

But I also heard you say that the baseline characteristics on a blended basis are almost identical. So, I was just wondering, is there any difference in disease characteristics or the way younger patients could handle the drug in ASPEN or is this not even an issue because of who is actually enrolled? Thank you..

Yes. So, on the definition of exacerbation it's really important. First of all, we're using the same definition we used in WILLOW. And one of the lessons learned from the other companies that have done bronchiectasis studies, albeit in their case, in all cases, they were using inhaled antibiotics. So, our mechanism and approach is totally different.

Nonetheless, the variability of what constitutes an exacerbation is an important point. So, to overcome that, we created a -- used a very strict definition of an exacerbation.

This has to be something that is not just defined by the patient but has to also be agreed upon as an exacerbation by the physician and had to result in a change in clinical treatment. So, they have to put the patient on additional medication, admit them to the hospital.

So, it's a high hurdle and one that is not subjective in any way, right? They have to make that judgment that this patient had a severe enough experience that they need additional clinical care. So, that is a high hurdle. The one we used in WILLOW; the same one we're using in ASPEN.

As we think about the global heterogeneity, which is true for all studies, we're very sensitive to that. We have many different ways that we watch that carefully. One of these is that WILLOW was quite a broad-ranging study.

ASPEN is far more range, wide ranging, but we look for the same kinds of controls, including a review of what constitutes an exacerbation if there's some debate about that. We can look at a country level, how many patients are being enrolled, what the characteristics are of that country.

We do that on a regular basis down to a weekly basis to make sure that the behavior going on is not unexpected. And I would say, for those reasons, we feel extremely confident that the performance of the patients in the study will be not dissimilar to what was seen in the WILLOW study.

The question about lower age group, we did go a little bit younger. It's a handful of patients that are going to be in that category. I have to double check on this one, Joe. It may well be that, that was a specific regulatory request. The vast majority of patients who get bronchiectasis are older.

And so, I don't think it in any way has impact on the trial or what direction it might travel or age or that sort of thing in the DSMB clearing most recently, certainly supports that. I would be surprised if it was more than a handful of patients that are below the age of 18. And I think it may be specific to a regulatory request.

But let me get that information and get back to you to confirm.

Unless, Sara, you know offhand?.

Yes. So, there was a pediatric requirement, but it will not be related to the analysis for the main study. So, the 18 or older, completed enrollment, that's the primary. The pediatric is obviously a regulatory requirement, as Will mentioned..

There you go..

Very helpful. Thanks for the color..

Yep..

I will now turn the call back over to Will Lewis, Chair and CEO for closing remarks..

I just want to thank everyone for joining us today. It's an exciting time at Insmed. We look forward to talk to you hopefully within about a month. Have a good day..

Ladies and gentlemen, that concludes today's call. Thank you for joining. You may now disconnect..