Insmed Incorporated Price & Performance (INSM)

Good day, everyone, and welcome to today's conference call where we will discuss Insemed's fourth quarter and full year twenty twenty four financial results and provide a business update. I am joined today by Will Lewis, Chair and Chief Executive Officer and Sarah Bohnstein, Chief Financial Officer who will each provide prepared remarks after which they will be joined by Martina Flammer, Chief Medical Officer the Q and A session. Before we start, please note that today's call will include forward looking statements based on our current 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 for more information concerning the risk that could affect the company. The information we will discuss on today's call is meant 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 for prepared remarks. Thank you, Brian, and welcome everyone. 2024 was an historic year for Insmed.

While we celebrated the outcome of one major clinical trial, we also remain focused on laying the foundation for continued We believe we are just at the beginning of the realization of more than a decade's worth of work that has put us in a position to have several clinical and commercial catalysts all hitting major inflection points in quick succession. At the heart of our accomplishments in 2024 was the impressive Phase three data from the ASPEN study for brenzocatib in bronchiectasis. Historically, when a company is validated a new mechanism of action with the potential to address significant unmet needs across multiple indications This accomplishment has resulted in meaningful patient benefit and consequent value creation, sometimes in the tens of billions of dollars Often, the Phase three readout is just the beginning of the value creation curve. We believe this could be the case for brenzocada. With the Aspen readout representing just the beginning of the future potential for DPP-one inhibition. Aspen's success was only part of what made 2024 special. We also welcomed the first data from TPIP in PHILD, which began to reveal this compound's potential as a best in class treatment for pulmonary hypertension. We also drove steady enrollment across our ongoing mid to late stage trials for ARIKAYCE, brenzocatib and TPIP, all of which remain on track or ahead of schedule for readout.

Meanwhile, ARIKAYCE quietly and steadily produced the most impressive performance in its six year commercial history with record setting revenues Finally, in 2024, we took actions to deliberately strengthen our balance sheet positioning Insmed for success as we accelerate into the year ahead. In 2025, the expected U. S. Launch of brenzocatib and bronchiectinib in the third quarter is going to take center stage. But you can also expect Phase two data for TPIP and PAH in the middle of the year and Phase two data for brincocatib in CRS without nasal polyps which we estimate will read out by the end of the year. It is worth noting that this string of significant clinical and commercial catalysts does not end in twenty twenty five. In the first quarter of twenty twenty six, we expect our Phase three ENCORE trial for ARIKAYCE to readout, holding the potential to expand our label to include all patients with a MAC lung infection. Also in 2026, we expect to share updates from our Phase II trial of brensukATib in hidradenitis suppurativa. From several of our gene therapies including DMD, ALS and Stargardt disease and from our next generation DPP-one programs all while we launched brensocadab in Europe, The U. K. And Japan assuming we secure approvals in those territories.

I believe that our ability to execute on the many opportunities ahead will solidify Insmed's place among a small group of industry peers that have successfully advancing other programs in parallel. Now let me walk you through the progress we are making in pursuit of this ambition starting with brenzocatib. Earlier this month, we announced that the NDA filing for brenzocatib in bronchiectasis was accepted by the FDA under priority review with the PDUFA date of 08/12/2025. We are thrilled to be one step closer to bringing this important therapy to patients who have waited a long time for such a breakthrough. As of today, the FDA has not yet indicated whether it will convene an advisory committee as part of its review process.

The FDA can make that choice at any time during the priority review. Should they call for one, we will work to accommodate whatever topics the FDA may wish to As we learn more about any potential AdCom, we will share that information. Now that we know the likely timing for the FDA's decision, I'd like to spend a few moments revisiting our expectations for brensukadab's launch. Previously, we provided analogs of strong respiratory launches that we aspire to emulate with brenzocatib, including Dupixent, Vistenra, Ofev and TESPIRE. On average, these products recorded combined revenues two quarters of launch in the high double digit millions.

But note that most of these products benefited from approval dates that enabled their first quarter of reported sales to include nearly a full quarter In contrast, with a potential approval and launch in mid August, revenue generation for brenzocatib is expected to begin late in the third quarter due to the normal time it takes from commencing selling activities to recording sales. In the case of ARIKAYCE, it took nearly four weeks after we launched before the first sales were recognized. As a result of these dynamics, our expectation is that we will only have a few weeks of sales for brensukadib in the third quarter, assuming an approval on the PDUFA date. We continue to see tremendous excitement in the patient and physician communities for the launch with tens of thousands of patients actively engaging on our disease state awareness website, and more than ninety percent of surveyed physicians in The U. S. Indicating that they intend to prescribe brinsukadab to patients with two or more exacerbations upon approval. On pricing, we continue to expect Brensocatib's annual U. S. List price to be in the upper half of our original $40,000 to $96,000 range [indiscernible] This update is based on extensive pricing work conducted post Aspen that incorporated Brent Socatib's actual clinical profile to solicit feedback from payers, KOLs patients and others, giving us a more precise sense for what the appropriate price should be.

At the same time, our top priority in launching brenzocatib is to make access as frictionless as possible, both for physicians and their patients. Our plan will be to deploy a multifaceted market access strategy, which with the goal of achieving a simple and straightforward prior authorization process to get appropriate patients access to treatment and equally important, to get those patients seamlessly reauthorized We believe that this strategy will allow brenzocatib to reach more patients faster and will result in a smoother runway to achieving peak sales. [indiscernible] just a brief update on our CRS with nasal polyps study of brenzocatib. CRS without nasal polyps is a disease with a clear unmet medical need which brenzocatib could potentially address if it is successful. In The U. S. Alone, there are roughly two hundred thousand patients going in for sinus surgery each year and several million whose disease is not adequate controlled with steroids. Being able to offer these patients a once daily oral treatment to potentially help alleviate symptoms and avoid surgery would be a game changer for patients. Our ongoing Phase two BIRCH trial in patients with CRS without nasal polyps continues to recruit well. And we anticipate top line results from the study by the end of this year.

If successful, the BIRCH trial would provide proof of concept for the use of a DPP-one in this disease state and could represent a substantial opportunity that could be similar to or even larger than that bronchiectasis based on the number of patients who are steroid non responders progressing towards surgery each year. Addition, a positive result in Burch would serve to further validate the DPP-one mechanism as a pathway that can potentially offer benefits to patients with a variety of diseases caused by neutrophilic inflammation. Including Heidradenitis suppurativa for which we have a Phase two study that is currently recruiting patients Let me now turn to TPIP. The Phase II PAH data readout in the middle of this year is expected to be meaningful in multiple ways. First, it will be the largest study of TPIP to date with one hundred and two patients randomized two:one, so the results will be the best demonstration of And second, this trial is designed with a primary endpoint directly measuring the drug's efficacy in the form of reduction in pulmonary vascular resistance or PVR. Past studies of other forms of kerprosenil have shown PVR reductions in the mid teens to low 20%.

In our view, if treatment with TPIP leads to reductions in PVR that exceed those levels, that result would differentiate it from all other assets in the prostacyclin class solidifying TPIPs potential value. Before I move on, I want to briefly mention the full Phase two results from the PHILD study, which were presented earlier this month at the Pulmonary Vascular Research Institute's conference in Rio De Janeiro. In addition to the positive top line data that were shared from this study last year, we also showcased a lung imaging study conducted as part of the Phase two trial which demonstrated a consistent increase of blood volume in the small arteries of the lungs for patients treated with TPIP compared to placebo. While one might expect to see a transient benefit in the small arteries shortly after receiving a dose of propostinil, the images in our study were primarily captured long after dosing at a median of more than eight hours post dose and still showed impressive vasodilation of the small vessels. While patient numbers in this lung imaging study were small and should therefore be interpreted with caution, these data provide evidence that once daily dosing of TPIP can achieve important effects on the small pulmonary arteries even after a significant amount of time has passed after dosing.

This supports our conviction that TPIP may provide clinically meaningful benefits to patients with either PHILD or PAH. We remain on track and look forward to kicking off the Phase three trial in PHILD in the second half of this year followed shortly thereafter by a Phase three PAH trial. Finally, let me touch on ARIKAYCE. Continues to drive strong revenue growth across each of our geographic regions. I continue to be impressed with the performance of our commercial teams in The U. S, Europe and Japan, who are responsible for these extraordinary results. This is particularly remarkable given that the same team was recruiting, hiring and training 120 new U. S. Sales employees last year in anticipation of the BrentsoCannab launch.

And on top of all of that, they delivered a record setting year for ARIKAYCE sales while also positioning us for success in 2025. This track record of strong execution gives us us confidence to provide revenue guidance for ARIKAYCE of $4.00 $5,000,000 to $425,000,000 for 2025. Representing yet another year of strong double digit growth for the brand.

As a reminder, the strong commercial performance we have seen and expect to continue to see for ARIKAYCE is all within the currently approved refractory patient population. If the ENCORE trial readout in the first quarter of twenty twenty six positive, it could lead to an expansion of the current label to include all patients with MAC lung disease, addressing a significant unmet need and potentially propelling ARIKAYCE into a blockbuster brand. In short, I couldn't be more excited about our positioning going into 2025. Our commercial engine is humming. Our mid to late stage clinical programs are advancing and our early stage research is I will now turn it over to Sarah who will walk us through this quarter's financial results.

Thank you, Will, and good morning, everyone. Earlier today, we issued a press release detailing our financial results for the fourth quarter and full year 2024. I would like to highlight some details of those results now. As of year end, had over $1,400,000,000 of cash cash equivalents and marketable securities on our balance sheet. Which is relatively unchanged since the end of the third quarter. Excluding the impact of stock option exercises, and net proceeds received in the fourth quarter from the additional $150,000,000 term loan from Pharmacon discussed last quarter. Our underlying cash burn in the fourth quarter was approximately $191,000,000 which as expected was higher than recent quarters.

This figure includes the payment of the application fee associated with the filing of our NDA for brenzocastip in December as well as the impact of higher headcount and other expenses related to ongoing preparations for the potential launch of brenzlacab in the third quarter of twenty twenty five approved. We believe these investments have the potential to lead to future revenue growth offsetting the associated costs and potentially putting us on the pathway to sustained profitability. I will now walk you through our commercial performance in 2024. Last month at an investor conference, we disclosed that our global net revenue for $20.24 $363,700,000 reflecting 19% year over year growth Insmed exceeding the top end of our guidance range for the year. This result was driven by the highest quarterly sales for ARIKAYCE in its history in the fourth quarter of twenty twenty four. Representing the fifth quarter in a row in which we have seen double digit year over year revenue growth in each of our regions. Specifically, in The U. S, net revenue for 2024 was $254,800,000 up 14% compared to 2023. This growth was driven by strength in new patient starts, and continued efforts by our team to educate on the importance of remaining on therapy.

In Japan, 2024 net revenue was 87,700,000.0 up 33% compared to 2023. This outstanding performance was driven by the excellent execution of the commercial team, leading to higher new patient starts and a strong treatment continuation rate amongst existing patients.

A part of this strong performance also reflects the investment made earlier in the year to add six additional sales reps bringing the total number of reps in Japan to 32 which enhanced our ability to reach patients in need across the region. In Europe and Rest of World, net revenue in 2024 was $21,200,000 up 39% compared to 2023. This growth reflects continued strength in new patient starts particularly in Germany and The UK driven by the exceptional work of our European commercial team. In 2025, we continue to expect full year ARIKAYCE net revenue to be between $4.00 $5,000,000 and $425,000,000 As a reminder, this guidance range does not include any contributions from brenzlacathib.

Let me now turn to a few additional financial items. Our U. S. Gross to net in full year 2024 were 17% which was consistent with both our guidance and internal expectations. Looking forward to 2025, we expect gross to nets for ARIKAYCE to be in the high teens to low 20s, driven primarily by retroactive price inflation adjustments under the inflation Going forward, we expect this increase this to increase as more of the responsibility for catastrophic coverage for Medicare patients being treated with ARIKAYCE shifts to Insmed. [indiscernible] pricing and asset access dynamics will not be determined until the time of launch. So we are not yet in a position to provide specific gross to net guidance. However, based on a review of historical analogs for specialty launches, and the new responsibility of manufacturers to cover 20% catastrophic coverage for Medicare patients under the IRA we believe a twenty five percent to 35% gross to net at launch is likely to be a reasonable assumption in this environment. Moving to our operating expenses for 2024. Cost of product revenues for full year 2024 was $85,700,000 or 23.6% of revenues which is consistent with our historical performance. For full year 2024, research and development and SG and A expenses were $599,000,000 and $462,000,000 respectively.

Reflecting continued investment in our early and mid to late stage pipelines as well as investment in brenzl Cassib commercial readiness initiatives. In closing, we believe Insmed is in a unique position of strength both financially and operationally. We produced record setting revenue in the fourth quarter and issued strong ARIKAYCE revenue guidance for 2025. Additionally, we are currently well capitalized with more than $1,400,000,000 of cash on our balance sheet. We look forward to thoughtfully deploying that capital in the service of our patients and shareholders as we deliver on the upcoming catalysts in 2025 and beyond. We would now like to open the call to your questions. Operator, may we take the first question, please.

Thank you. Will now begin the question and answer Please be reminded that each analyst is allowed one question and one follow-up. Your first question comes from the line of Vamil Divan with Guggenheim Securities.

Okay, great. Yes, thank you for taking my question. Thanks for the information. On the call. So maybe just on Brenzo, we'll appreciate the comments you made just around the opportunity potentially in CRS without nasal polyps. So just maybe if you can just sort of level set expectations as we look forward to the Phase two data So what would you want to see from that data set and what would be considered good data and sort of move move that opportunity forward? I would agree with comments that people are not necessarily appreciating that indication yet. I'm just kind of trying to get a sense of what you're hoping to see before people start looking at it in their models? Thanks. First of all, thanks for the question, because I think you just put your finger on one of the larger opportunities that Insmed is coming up upon, and that is the a lot of reasons for enthusiasm for this indication and the potential of of brenzocatib to have impact. The study, I'm actually going to ask Martina maybe walk through a little bit of how we think about what we're looking for relative to other work that's been done in this space and also, just to think more broadly about the unmet medical need here to really put a finer point on this.

This is every bit as big and potentially bigger than bronchiectasis. And to remind everybody, if we're able to address successfully the patient populations that have already been diagnosed, we believe that that will produce a peak revenue number north of $5,000,000,000 So to talk about CRS as an interesting opportunity that is potentially larger than that, I think should place in context the importance of turning your attention to this where we'll have Phase two data we expect by the end of the year. Martina, do you want to talk a little bit about study? Yes, sure will. So what are we looking for in CRS? Without nasal bilex and ALBERTCH study? First of all, there's no treatment that is indicated for this patient population apart from ACE. Steroid inhaler that you may well be aware of. So this is a totally new mechanism with brand to cat of addressing the disease.

If you think about CRS without nasal polyps, this is a chronic inflammatory disease. It leads to changes in the paranasals in the sinuses and it changes here how the cells that produce the mucus exchange. That means more mucus production more inflammation and that leads to continuous increase of neutrophil cells migrating into the sinuses. That is the basic for this disease. So what do we need to do in order to truly impact the mechanism how this disease works? As you know, how barenzo catap works, it will do that. By impacting the neutrophil as it is maturing in the bone marrow. What do we want to see in BIRCH? We're using as a primary endpoint a measurement that's called the sinus total symptom score. This is a measurement that includes the three critical criteria for this patient. And this is nasal congestion, nasal discharge, facial pain or pressure. Insmed addition, what we will measure is something that is called the nasal congestion score, a snot or something that is the QLB, so a quality of life measurement validated in this patient population as well as a loss of smell. The study goes over twenty four weeks. We're looking at ten and forty milligram of branchedep versus 80% as an alpha level of 0.1 to show a difference as small as 0.9 of a unit change or a point change for the sinus total symptom score.

That is what we're looking for. We really only have one other measure and that is the as you are truly familiar with the Optinost studies that have done studies using a very similar score. The scores may have different Insmed. You see sometimes a comprehensive sign of score, but they all measure the same thing. Congestion, discharge and facial pain. And what they have shown was a treatment effect between one point seven and zero point nine in the ReOPEN two study. So that really the only one that you have as a comparison. We in the BIRCH study are looking for the effect of Frenzocatib on top of nasal steroids. So patients are already on a stable dose of nasal steroids for four weeks before they are being randomized. To brencocetib.

The only thing I'd add to that is when you think about this, the primary endpoint total symptom score, sinus total symptom score, patients coming into the study have to have a score of five or greater. So these are highly symptomatic patients that have already been exposed to best available treatment Many of them have had surgery previously and so the ability to have impact here will be very material for this patient population. And we're hearing that from the treating physicians as well. And I think that's part of the reason why you're seeing the trial enroll so effectively.

Okay. All right. Thanks for the information. Your next question comes from Joe Schwartz with Leerink Partners.

Please go ahead.

Great. Thanks very much and congrats on all the progress I was wondering beyond generating strong clinical data and assembling a solid sales force, what other factors are in your control and are you leveraging to ensure a strong launch for Bronzo in bronchectasis.

Well, if we think about The U. S. Launch and the PDUFA date of the August, I think, probably the thing that that keeps my attention more than anything else, I mean, we have to have it all running in parallel. So let's be really clear, medical affairs, the commercial preparation, all those things things. But really it comes down to market access in my mind as the one element over which we have control and which we really want to ensure we have the right strategy. And I am highly confident based on where we sit today that we're in a good position with that.

That relates not only to the selection of price, which is obviously driven by the impact we have on patients, but also the ability to work with the market access world to ensure a frictionless launch What we mean by that is verbal attestation by the physician to bring patients that are appropriate onto therapy and the reauthorization to ensure that they have continued access and benefit from the therapy once prescribed.

To accomplish that, we are willing to do some minor contracting We're not going to go into the details of what that will look like because that process is literally getting underway in the course of the next several months. But I will say that we sit in a very strong position with regard to the pricing studies we've done, the background that leads into the market access discussions and what we think those are going to yield that I think is the single most important thing that remains under our control that we want to ensure we get right.

And the other thing I would add though is the one other thing that's in our control is, as you know, last year, we augmented our sales organization and we brought in those additional 120 reps. As we mentioned last year, early this year, we'll be additionally augmenting to add more in the market access to field. Access managers and the case managers. So we have brought on list launch that Will was describing as well.

Very helpful. There's this might be a more difficult question to Insmed, but seems important to ask. So I will. There's been some signs that many government agencies could face some staffing shortages So I was just wondering how do you feel about the availability of adequate FDA staff remaining in place to review brentacadabine's on time. Do you have any insight into the folks who will actually be performing the review?

Yes.

So obviously, we're in the middle of the review now. We're This process kicked off at the end of last year when we put our submission in. And I would characterize our interaction as regular, steady and very encouraging. Consistent with all of our expectations. As we go one layer deeper in Insmed hypotheticals where government staffing becomes challenged for whatever reason, there is always an unpredictable element to this. It's important for everyone to remember that the staff that are involved in the review of an NDA are funded by the PDUFA fees from industry. So they should not be impacted in our estimation in the event of disruption to other aspects of that particular agency. We'll see what happens. Obviously, it's a there's some unknowns out there. But I would describe our current situation as extremely encouraging as evidenced by the granting of priority review and the pace at which our interaction has been taking place. Your next question comes from Jessica Fye with JPMorgan.

Please go ahead.

Guys. Good morning. Thanks for taking my questions. First one is, can you just remind me of your estimate of how many U. S. Bronchiectasis patients have had two or more exacerbations in the past year to the extent that could be key for patients being reimbursed for Renzo.

And second one is just what's the right way to think about the trajectory for SG and A and R and D this year? Thank you.

Sure. So I'll give the second question to Sarah. There was The short answer to the first one is about 50%, but to put a more refined description on that, currently, we know diagnosed from medical records that there are roughly five hundred thousand patients in The U. S. That have been diagnosed with bronchiectasis. Of those, we estimate about half have had two or more exacerbations in the last year, last twelve months. But it is important to note and you'll see this in many of materials that we produced, that we think of this as just the beginning of the potential address [indiscernible] time aren't reporting exacerbations in a way that would put them within the circle of potential eligible patients for treatment. Including those who have COPD and asthma as comorbidities, and are experiencing exacerbations, those patients, if they have a CT scan would be ended determined to have bronchiectasis would be eligible and on label. And that population could be quite substantial. We have more to do there to understand that, but it's our belief that there are many patients that will benefit from this therapy that fall within those categories.

And then Jeff on the question on SG and A and R and D, we haven't provided specific OpEx guidance as you know and we believe the early investment that we've made to support this launch will show to be fruitful with the revenue curve assuming approval and all those good things. I will say we don't expect that OpEx is going to decrease in the future, in the near term. We are continuing to invest and we think that's the right thing for shareholders on the R and D side as we're starting CRS, HS TPIP entering Phase three, commercial, the SG and A side specifically, I mentioned we are adding on some additional resources Insmed market access to ensure that the launch is as successful as possible. What I will say is, as as you think about once the launch curve starts to shape in 'twenty six and beyond, the percentage of SG and A to revenue that percentage will obviously begin to look much favorable.

Thank you. Your next question comes from Ritu Baral from TD Please go ahead.

Hi, guys. Thanks for taking the question. And Will, thank you for emphasizing market access guess Medicare is the new biostats in our conversations. So I have a Medicare question and then a follow-up.

Question on the June data.

Well, since you guys are specified small manufacturers by the IRA in that manufacturer discount program in the catastrophic phase. You've got this sliding scale of coverage picking up that 20% catastrophic over five years over, I guess, the next five years, if we're understanding that program correctly.

Can you talk about two things? Can you talk about how you may have to accommodate well, first of all, do you have to take that? Second, are you going to have to accommodate more In prior authorizations or what you're expecting prior authorizations to be and how that might [indiscernible] both the launch dynamics and also, Sarah, the 25% out of the gate doesn't imply this sliding scale for Insmed small.

Manufacturers. Yes. So a couple of points. First is we'll make a distinction between ARIKAYCE and BRENZOKATAB.

ARIKAYCE does benefit from the specified small manufacturers classification. And as a consequence, as you outlined accurately, there will be a phased in portion that we will have to cover. It starts at 1% of catastrophic coverage in 2025 and it ramps up to 25 pardon me 20% by 02/1931. So that's the and we can give you the actual year over year increases if you'd like them. As we think about Brent Catab, it does not have that benefit. So we get hit with that right out of the gate. And that is something that we are contemplating as we consider our market access strategy so that that [indiscernible] considered as we think about the cascade from gross price down to what the net price would ultimately be. Sarah, I don't know if you want to comment a little bit on the guidance we've given as we think about that and its implications for gross to nets in the setting of Brentso Cadab. Sure. So specifically on ARIKAYCE's Will mentioned, Beth obviously has the sliding scale. And in the prepared remarks, I was trying to point to that with the guidance for 25 of high teens to low 20s.

And then moving forward, will obviously have this sliding scale that will need to be adjusted within the gross net for ARIKAYCE. For Brento, the 25% to 35% at launch based on precedent and based on looking at other specialty Right out of the gate, as Will said, patients. So right out of the gate for Brantso, you have 1220% or 60%, 12% for gross to net.

And so we took that into account as we looked at precedent at 25% to 35% at launch seemed to be a reasonable analog. Got it. And then, a quick follow-up. [indiscernible] the PVR data, more specifically actually about the side effect data that may be coming out concurrently. Just given one of the big drawbacks of the current competition is the cost for dry powder inhalers.

Is there something in that dataset that would let you feature a potential reduction in cough or cough burden, whether it's a twenty four hour cough rate that's used in RCC studies or some sort of quality of life scale as it impacts patients, will we get something like that with the midyear data?

So a couple of thoughts there. The first is that obviously we track adverse events in detail. And so some element of of cough as represented in this population would certainly be captured. I do want to back up though and just highlight that the data we received in the PHILD study was quite encouraging in this regard And if we back up even further to the chemistry that's involved here, what we have is a prodrug that takes treprostinil and appends a 16 carbon chain with an ester bond. And that's significant in dry powder form because when in it means that the actual molecules in inert. So you're not breathing in the active Capricornil. We believe through guinea pigs studies we did early on, which are the gold standard in this arena, that there was a significant reduction in cough burden as a consequence of it being an inert molecule that was breathed in. We've seen this pull through in the small data sets that we have so far. We're encouraged by what we've seen so far and we're looking forward to seeing the actual data sets and we'll certainly dig in on this But once again, in the ILD setting, patients are particularly sensitive to this And so our ability to show some benefit there was really encouraging And I'd finally just punctuate the whole PAH side of the equation by observing that the scientific advisory group that observed this study was so impressed by the side effect profile that they encouraged us and we subsequently secured FDA approval double again the max dose that is targeted in this population.

So we have gone from six forty micrograms, which was the target max tolerated dose in the Phase II PAH study to twelve eighty micrograms which is now available for patients in the open label extension portion of the study. I don't know, Martina, if you want to add anything to these comments.

Yes.

So maybe related to one element that is always a good a good indicator of how the tolerability works and cough correctly, as you point out, is one of the reasons patients discontinue Our discontinuation rates that we observed in a blinded basis are very low. And very impressive in the PAH study. And when investigators, for example, describe a cough that they hear from patients, most often that is in the context of an immediately after after the inhalation, to have a quick of it's more a reaction, not really a cost that persists beyond the minutes after the inhalation at this point. We'll see, of course, exactly what the percentage of coughs will be. But it is described, I think, very differently than what you may have observed in other treatments.

Understood. Thanks for taking all the questions. Your next question comes from Andrea Newkirk with Goldman Sachs. Please go ahead.

Good morning. Thanks for taking our questions. Maybe I could also ask a follow-up here on TPIP and your expectations for the upcoming data. Outside of cost, but as you think about PVR reductions, if you frame for us what you would be considering clinically and commercially meaningful And as you think about the Phase three initiation of the PHILD study, what still needs to be done here? And where do you stand in terms of the final trial design?

Sure. So with regard to PVR reductions, I think if we look at the process prostacyclin class generally, what you've seen from all available data is a range of PBR reduction that starts in sort of the low teens and goes up into the very low 20s.

So about 20%, 22% at in terms of best available data for pulmonary vascular resistance percent reduction for the prostacyclin class drugs. We would expect that anything that is above the high end of that range would clearly position us as best in class with regard to prostacyclin's in use in PAH and PHLD patients And that would be extremely encouraging, particularly when it's coupled with the idea that this is a dry powder with as we discussed a moment ago, so far so good on the adverse event profile. The ability to provide much more drug and hopefully as a consequence some benefits. We can tie this down with a little bit of data from last year, needs to be interpreted with caution because it was a small study, but with thirty nine patients and a three:one randomization in the PHILD study, I'll just remind everybody that we saw a benefit in terms of time to clinical worsening and we saw a 30 plus meter, six minute walk performance. Now again, small numbers, we need to be careful. These are obviously very variable. But that coupled with the preclinical animal data where we saw some remodeling coupled with the imaging study that we've just presented in Rio, showing that vasodilation in the small arteries All of these things are sort of a mosaic.

And when you put them all together, it suggests that this program with PVR reductions in the sort of low to mid-20s would be a home run for populations, both PHILD and PAH. You asked about the Phase three progress for ILD that is well underway. The last remaining element here that we want to make sure we have is a single capsule administration for every dose strength that we propose to bring into commercial use And as a consequence, we're taking some time while we finalize the protocol and get ready for the launch of the study, to ensure that that is accomplished. That work has been underway and it's progressing very nicely. We have no concerns there, but we that's the final sort of piece of the puzzle And of course, we will benefit from interpreting the PAH data as well, even though it's a different disease state. Nonetheless, we think that will be something we want to reflect upon before we put our final Phase three protocol forward.

Your next question comes from Nicole Germano with Truist Securities. Great. Thank you so much for the question.

Congrats on all the progress. So as we think about the Brunsville launch from our survey, we're there is significant interest in prescribing Bremso to Bronchif patients with comorbid asthma due to TB, including in the community setting.

So as we think for what are the components for successful launch, How are you distributing your sales force between the academic and community settings And what are the hurdles with getting prescriber uptake in the community setting versus academic?

Thank you.

So the first thing I want to make sure everyone is clear on is that the addition of 120 sales reps last year to the original group that was calling on ARIKAYCE puts us in a position where we can call on every single pulmonologist in The United States. So we have access to all of the pulmonology community across The United States. That's academics and community level physician There are different dynamics that are relevant for both of those groups. Obviously, the KOLs in this field are on top of every piece of data and every aspect of the disease and the science behind it. At the community level, that becomes a little bit less an area of focus or expertise just by virtue of the fact that they have much more of a broad burden in terms of what they're trying to accomplish. So our efforts over the course of the last back to the American Thoracic Society meeting a couple of years ago, has been to bring that education to the community level physicians. About the importance of neutrophil driven inflammation in the setting of bronchiectasis and the way in which our mechanism of action may be able to impact that.

We think about these things and the vicious vortex as they use in the language of the description of this disease state as something that think the education has been very successful. Obviously, we're not talking about the drug itself. But this process of how inflammation is created and how it contributes to the worsening of the disease state has been very successful. And you can see that to date in the survey work that we've done where ninety percent of surveyed pulmonologists have indicated that they intend to write a prescription for patients who have two or more exacerbations.

Just turn it over to Martina to see if she has any other comments based on her interaction with physicians at in both communities.

Yes. I think what we know from physician, both communities and from patients is that they really don't at this time have an alternative. So patients at this point are waiting for a treatment that will address the underlying causes of their disease rather than only bring symptomatic improvement in these patients. Clearly, that is one element of it. But there is also a good recognition. If we look back two years two, three years ago, I think the we had to educate of what is truly driving the disease. The whole inflammation aspect of it was relatively new. Today, there is a good understanding even when we talk about the pulmonology community that it is inflammation that we need to address. Rather only than symptomatic improvements that patients really don't benefit and we continue then to deteriorate and get worse and worse. So the understanding of inflammation that leads to destruction of lung tissue has become at a much, much better level.

I have one quick follow-up. And based on the clinical trial sites, for bronchiectasis, what percent of the total patient population in The U. S. Does that represent? That have bronchiectasis.

If I understand the question correctly, what percentage of the population would be eligible for treatment with brensocatab, the two or more exacerbations that's half of the already diagnosed population in The U. S. Is five hundred thousand patients. That's those that are already diagnosed As you mentioned at the outset of your questions, there are those who are comorbid with COPD and asthma that also are experiencing bronchiectasis that may or may not fall within that population yet. And Insmed, that could make the addressable market multiples of what we are currently looking at. But there's more to learn there and more to to accomplish in order to diagnose and make those ensure those patients are appropriate for treatment.

Thank you so much. Your next question comes from Greg Sivanovia. With Mizuho Securities. Please go ahead.

Hey, good morning. Congrats on the progress. Thanks for taking my questions. I'm actually going to ask about the earlier stage pipeline.

I was curious about your gene therapy candidate for DMD and wondering how you think that might differentiate from other gene therapy approaches for DMD in the past?

Certainly gene therapy is very interesting as a modality, but wondering, what TPP here is and also on your ALS and Stargardt program, if you could share with us perhaps what the targets for your gene therapy efforts are there for each of those candidates? Thanks.

Sure. So the first thing I want to make sure everyone understands is that we have made tremendous progress under what has historically been referred to as the fourth pillar our research efforts. The fourth pillar contemplates several different platforms, which include gene therapy, but are not limited to [indiscernible] called synthetic rescue, which is out of our Cambridge operation in England.

We have a de immunized therapeutic proteins assisted by artificial intelligence. Which come out of our New Hampshire facility. And we have a number of small molecule candidates including the DPP-one inhibitor successors that are coming out of New Jersey.

If we turn to look at just what is coming out of San Diego at the moment, the next three that we've drawn attention to are DMD, ALS, and Stargardt. Each of these have preclinical data already in hand that is incredibly encouraging. We are now moving into the clinic for DMD. And I just want to clarify that the approach there that's novel we're using an AAV9 capsid and an MHC K7 promoter So we can produce microdystrophin using the transgene in this setting, these are well established in our mind as the best pathways to accomplish that. One of the things that's very novel here is [indiscernible] Would transduce into skeletal and cardiac muscle tissue, but indeed in preclinical models, that is in fact what we have seen. There's a lot of detail, devil in the detail that surrounds the assays we use, the specificity, the percent of empty capsids, that will combine to produce what we believe will be very good efficacy and very good safety, which is critically important for this patient population. This is just the beginning of our efforts here. I think most of what you can expect in terms of clinical data will begin to arrive in 2026.

And as we move our attention to other areas like ALS, we have seen very encouraging preclinical data in that setting and that includes both SOD1 and sporadic patients.

So, for those that don't know, ALS is a devastating nothing really available that is effective to treat these patients. And what we're bringing forward in this gene therapy is something that we think can address not only SOD1, but also potentially sporadic patients, which dramatically increases the scope of the patient population that could benefit should we show success there. The IND for that, we anticipate filing this year. And by the end of the year or by the beginning part of next year, the deployment of another novel technology coming out of San Diego, which is RNA end joining, which enables the construction of a larger transgene inside the body using two different viral vectors which then rejoin once inside the body to create a longer transgene that is then read for a longer length protein. Which could be helpful or even theoretically corrective to some of the diseases that that are monogenic that have this kind of profile that need a longer transgene. So that technology applied in the Stargardt ocular setting is one we're super excited about. Again, preclinical data there, very encouraging. And we'll look forward to advancing that through IND and into the clinic in twenty twenty six.

All three of these are just the tip of the iceberg coming out of the fourth pillar. We're not going to talk a lot about them this year, but I do want people to have some frame of reference that they can begin to expect our next layer, if you will, of candidate therapies to arrive in 2026.

Thanks, Juan.

Your next question comes from Jason Zimanski Bank of America.

Great. Good morning. Congrats on the quarter and thank you so much for taking our question. I appreciate it's still somewhat early in the process, but I was hoping you could provide some color regarding your expectations about Brenzo's potential label connecting the dots from some of your previous comments?

Mean fundamentally what are your expectations here in terms of restrictions whether it's pulmonary exacerbations or something else? Any feedback from the agency thus far? Think I'm just trying to get implications for prescribers and payers here. I mean, do you think we could see potential pushback where a payer might require multiple documented PEs for access? Yes. So I think there's a couple of layers in the answer to this question. The first is, what do we expect the label to be?

And there, I think we have ambition that there could be a broad label that doesn't actually make reference to the number of these exacerbations in the last twelve months. Whether that is true or not is really not controlling on anything we've shared by way of our intended commercial launch efforts, or indeed what our forecast peak sales numbers have been. Because we assume in the market access world separate from the label discussion, that there will be a restriction to patients who have had two or more exacerbations in the last twelve months because that was the entry criteria for the clinical trial and that's how market access often works. So, while the physician intention may be broader and certainly the label we expect be potentially broader, the market access is the the filter, if you will, that sets our expectations for peak sales. With that two or more exacerbation requirements, which we expect we are working on market access to ensure through modest discounting and contracting that we can secure the documentation, if you will, of that two or more exacerbations in the form of a verbal attestation by a physician. If we can get that, I think that will help goal of a frictionless launch.

That also with the hope that we can secure a pretty frictionless reauthorization process through that contracting. But to address your question, those are two sort of separate concepts. One is what is going to be utilized in terms of the appropriate patient, which is set by market access and the other, which is what is the label, which we think will be much broader. Got it. Thanks for the color.

Your next question comes from Lisa Baker of Evercore. Please go ahead.

Hi, thanks for taking the question. I had just another question on market access and that is, [indiscernible] Do you anticipate any requirements for say reauthorization or continued treatment would be based on certain markers of drug response And if so, what would some of those be, do you think? And how are you thinking about that? Thank you.

Yes. I think the direct answer to the question is part of our strategy for market access is to answer those questions, is to shape that policy prior to encountering that once we're in commercial launch. So that if we are successful in our strategy, we will have some minor discounting and some contracting that will provide assurance for verbal attestation both for the initial prescription and the reauthorization. So we don't anticipate specific limits or markers that will be necessary to be cleared in the reauthorization process And so far, our interaction, and I would just say we've spoken to more than 90% of covered lives, in terms of the groups that have access to them. Has been incredibly encouraging. So I think where we sit with a novel mechanism of first in disease treatment is a very strong position. And I should just clarify that as a result of that, we really don't need to do the contracting I'm making reference to. We could just push this forward. However, we think the smoother way to ensure wrap it up take and rapid reauthorization is to engage in a little bit of that contracting discussion Doesn't necessarily mean we're going to target getting on formulary, but it does so it is likely to be a medical exception as a process.

In terms of the pathway, but we do want that verbal out of state working on in terms of the negotiation. I think we'll have success with that, particularly as I said, because we would be the only approved therapy in the disease state.

Okay. Thanks a lot, Will.

Next question comes from Jennifer Kim with Cantor. Please go ahead.

Thanks for taking my questions.

Maybe to start with the readout later this year. I agree that based on our conversations with docs, they're really just looking for a positive trial. But in terms of powering assumptions for a study like this, there a way to think about the expected placebo rate in the twenty four week trial and then also very our standard deviation given it's a twenty eight day average STFS score.

You're referring to the CRS trial, just so I'm clear, Jennifer. Is it correct?

Yes, I'm asking Martina if you want to address that.

Yes. So Jennifer, if you look at placebo rates, I mean, as you know, placebo rates always vary widely. Even from trial to trial in similar population. We've looked at placebo rates of course, as we thought about BIRCH. And if you look at the OPTINOS studies, that have a little different treatment time, they have their primary endpoint that we four and then they are looking at up to week 12. So they have seen a reduction in placebo rates around one reduction of one to 1.5 points along along that their scale. If you look at and that is a different population, but I think we can also think about it because it's a related population and that is if you look at the CRS with nasal polyps population in the Dupixent they have shown placebo rates that range between the 0.2 to 0.4. If you look at all three items, congestion and obstruction, it's a little different cause they measure polyps. That maybe are ranging between the 0.4 to 0.6 on the scale. So there is always a placebo rate. We obviously look for twenty four week time period It is something that we take into effect right now.

What we look at from a blinded perspective is do we see a pattern and a trend as we would expect it and that's what we're seeing.

And the only thing I would add to that is a shout out to the excellent work done on clinical trial design, because here what we have is patients coming in, they're exposed to steroids and they're stable on that regimen. Both between screening and randomization. And the consequence of that is we can look at that interim period where there between screening and randomization and see are we seeing a blended blinded change in score during that time? And the answer is we're not. So that means that they're stable with the symptom score. They're highly evidentiary in terms of the score of a five or greater these patients are very symptomatic. And the fact that's not moving around a lot in that time between screening and randomization is a very encouraging sign that we can expect some stability within the trial. Obviously, we won't know till we unblind, but with reference to some of the ranges, Martinez said, I think we feel very good about the powering and whether or not we're going to see something directional here. I want to be clear for both TPIP and for CRS without nasal polyps, in neither one of these, these are Phase two studies.

We're looking for something directional. The presence or absence of statistical significance to me is far less significant than just whether or not we see something clear and directional that's supports our ability to design effectively a Phase three study for each of these programs. Okay, that's helpful. And maybe if I could ask one question on TPRP.

Other than PDR reduction, can you just remind us your thoughts on the importance of the six minute walk endpoint?

In the context of a Phase two should we frame our expectations with what we saw in the PHILB study or how should we think about that?

Thanks.

Well, my favorite measure here is the six minute walk test. It's highly variable, very difficult to predict. This is true across every study that's ever been done in PAH. So anything that comes through has to be interpreted with caution, which is what I said earlier, when we're looking at the ILD data. Encouraging though it is, and frankly stronger than most comparators, Nonetheless, we still would urge caution because it can be highly variable. And there are enough patients in this study that we hope once again to see something directional but certainly not statistically significant. And just to put it into context, I think Martina, I'm looking to you historic levels of six minute walk test improvement are right around 20 meters, aren't they? They're not that substantial. It is important to keep an eye on this though because it is the primary endpoint that FDA tends to look at for approval in this class.

Yes, that's correct. So anything above 20 meters is what you've seen in, for example, the INCREASED study. In PIA Child D and what you would see in in studies with prostacyclin. Anything north of 20 meters, I think is already a win. And certainly, in a study, the Phase two study, remember we're now powering on the six minute walk, we're powering on the PVR reduction.

So yes, as Will said, we look for directional improvement on six minute walk.

And that will inform us on the importance of powering for the Phase III study where the six minute walk will be the primary Your next question comes from Jeff Hung with Morgan Stanley. Please go ahead.

Thanks for taking my questions. For bronchiectasis, you've noted patients are motivated to act with about forty one thousand who have acted How do you define acting? And then how many of them are diagnosed already with bronchiectasis and had two plus exacerbations in the last year?

And then I have a follow-up.

Yes. So the bronchiectasis patients that are, as we describe, This means they're going to the website, they're downloading information, they're registering for more information, We have contact information for them. So if and when the day comes that the drug is approved, we can put them on notice of that effect.

And activate them to seek out treatment from their physician So I would tell you that relative to our expectations, that number is extremely high and it is growing by the thousands So we think this is going to create sort of repository of potential patients right at the time of launch. Which is very encouraging. It's consistent with what we've seen from the physician side. Where they are highly encouraged by the data set and want to draw patients in to treat them. So we think that the combination of both of these pieces of evidence is what gives us some conviction that the launch could be strong.

Great. Thanks. And then you talked about how you could reach out to these patients and let them know about the drug's approval and reaching out to their physicians. Can you talk about expectation on the timing and cadence for patients seeing their physicians and being prescribed Brantacatib over say like the first twelve months?

How does typically play out Yes. So it's the catch word in what you just said is typically and of course because there's nothing that's ever been approved here, there really isn't great precedent to know how both physicians and patients are going to behave. What we know from launches generally is that if you have motivated patients and motivated physicians and you run surveys to gain an index of their appetite, these scores are coming in very high. So physicians are motivated not only by the drug and their intent to use it, ninety percent of the physicians we surveyed indicated that they would put their patients who have two or more exacerbations on this drug. That's an extremely high number. The fact that we have tens of thousands of patients who've already registered and downloaded guides from our website, which is the actions they take are involved. It's not just visiting a website in clicking there. It's much more than that. And those are strong signs that there is interest among the patient and the physician community.

Whether that will translate into them seeing the the position in the first month or year, it remains to be seen. And that'll be part of the challenge of really trying to understand what the ramp will look like here is when do these patients and physicians actually follow through on those actions. We're trying to provide education now so that that happens as early as possible. We think patients will benefit from the drug and we want physicians to understand that. We also think that The more we can provide by way of education, the more this will become a circumstance where word-of-mouth will also lift interest and attention to this area.

This was described when the data came out after Phase two by someone at the American Thoracic Society as the holy grail of pulmonary medicine. A once a day pill to treat pulmonary condition. And for that reason, I think all signs point to positive.

Great. Thanks, Will.

Your next question comes from Stephen Stephen Willey with Stifel.

Please go ahead. [indiscernible] [indiscernible] follow-up on TPIP. So do you have any update on the percentage of PAH patients from the Phase two study that have chosen to participate in the open label extension portion of the trial. And then just wondering if you might have an opportunity to provide any of this data from the open label extension portion at the time of the Phase two top line disclosure, specifically given if it looks like you're achieving Specifically given if it looks like you're achieving an even greater PVR reduction at doses north of six forty.

Thank you. So we won't have the data for the open label trial participants. What we can say is that we do have some that have gone all the way to twelve eighty and many to nine sixty. So they are getting to higher doses in the open label portion. I don't know, Martina, if you have any of that data handy in terms of numbers and what that's looking like.

Yes. So what we what I can tell you is that we have the vast majority of patients continuing in the open label study. And there are a number of patients who are eighty percent up to the highest dose and the additional twenty percent, some of them are in between the six forty and all the way up to the twelve eighty. We have a couple of patients who are already up on the twelve eighty dose for several weeks.

And I guess what I would say about this is while we won't have that data at the time and we are not measuring PVR in the open label portion of the study, Nonetheless, we're tracking other biomarkers that we think will be able to correlate to what is seen in the clinical portion of the study where PVR is being collected And so there is going to be the ability to understand that whatever number we put out in terms of PVR percent reduction whatever benefits we may be able to demonstrate in six minute walk, if we're able to take the dose from that level to double that level, it would certainly follow logically that you could expect that the numbers we're producing in this Phase two study readout are indicative of only part of what could be accomplished. And to put this into a finer point as we turn to Phase three, it is our intention to have the max tolerated dose shifted from six forty micrograms to twelve eighty micrograms for the Phase three study participants.

Your next question comes from Trung Win with UBS.

Please go ahead.

Great. Hi, guys. Thanks for taking our question. In like you're in a quite strong financial position as you start 2025.

Dollars 1,400,000,000.0 in cash, but you've also got a lot going on. So you've got early stage trials starting, later stage trials starting, Brenzo launching, I'd love to get your thoughts on if there could be any incremental financing on the horizon. If it is on the agenda, how many of your key catalyst cards need to be turned over for you to start accessing that financing? Thank you.

I'll ask Sarah to respond to that.

Sure. Thanks for the question. Historically, it's not our practice to really talk about timing for future balance sheet augmentation, cash runway, all that kind of stuff. I can comment on is, as you mentioned, just really pleased with the strength of our financial position. A little north of $1,400,000,000 in the bank, gotten a ton of support from our shareholders. So thank you. So all listening for this support to get us here. What I will say is we do have a line of sight to becoming a self sustaining bio company. So that is our goal. That is our ambition. We are on that track. We are not currently funded through profitability. That is by choice. We believe it is in our shareholders' best interest and in patients' best interest to continue to invest in this pipeline, as you mentioned and to unlock these very meaningful future data catalysts that I think will be significant value creating opportunities. That's Insmed, when it is our time to augment balance sheet, we have a variety of ways we can do it. Equity is one of those paths. We may choose Sinato equity. We may choose royalty for ARIKAYCE or Brenso.

An example and R and D funding for TPIP as an an example, different sort of debt structures as an example, just to name a few. So sort of bottom line is we have ton of optionality, we have the ability to be patient and we have line of sight to becoming a self sustaining biotech company. And your last question comes from Andy Chen with Wolfe Research. Please go ahead.

Hi, team. It's Tugan for Andy.

Can you speak to your patient selection strategy for the chronic rhinosinusitis with nasal polyps trial.

How can how do you make sure you're picking the correct patients for the trial are there any baseline characteristics you can share?

Sure. So I appreciate the question. I think what is really useful about this is it once again frames out the enormity of the opportunity we're talking about here. So there are CRS without nasal polyps and there's CRS with nasal polyps. When we look at with nasal polyps, there are already several program up approved to treat that Humira, Dupixent, these are big products that are addressing that disease state. CRS without nasal polyps has nothing other than the inhaled steroid to treat it. There's nothing novel on the horizon that is available. So if we are successful with this, we are addressing a theoretical population in excess of thirty three million people in The United States. Now what we have done for this trial is to focus on the most severe patients where we think this drug has its greatest potential to show benefit and those are patients that are eligible or have already had surgery or those in every case who are steroid non responders. So much like our strategy with ARIKAYCE and refractory patients, let's assume that they've had access to or considered every available treatment option out there and then let's see what our drug can do to that challenged patient population so far feeling pretty good about the possibility that this drug is going to have an impact.

That selection strategy, as you point out, means that we are going to just the bottom end of that pyramid So it's 200,000 patients in The U. S. That are eligible for surgery every year. Is another couple of million that are steroid non responders So that makes this a very significant addressable population and why I said at the outset, that it could be as big if not bigger than the bronchiectasis population.

Thank you.

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