Q4 2024 Earnings Call Transcript

Thank you for standing by. My name is Pam, and I will be your conference operator today. At this time, I would like to welcome everyone to the Insmed Fourth Quarter and Full Year 2024 Financial Results Call. [Operator Instructions] Thank you. I would now like to turn the conference over to Bryan Dunn. You may begin.

Thank you, Pam. Good day, everyone and welcome to today’s conference call where we will discuss Insmed’s fourth quarter and full year 2024 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 after which they will be joined by Martina Flammer, Chief Medical Officer, for the Q&A session. 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 for more information concerning the risk factors 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, Bryan 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 success in 2025 and beyond. 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 3 data from the ASPEN study for brensocatib in bronchiectasis.

Historically, when a company has 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 or more. Often, the Phase 3 readout is just the beginning of the value creation curve. We believe this could be the case for brensocatib with the ASPEN readout representing just the beginning of the future potential for DPP1 inhibition. Aspen’s success was only part of what made 2024 special.

We also welcomed the first data from TPIP in PH-ILD 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, brensocatib 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 6-year commercial history with record-setting revenues that came in higher than even our own internal projections. 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 brensocatib in bronchiectasis in the third quarter is going to take center stage, but you can also expect Phase 2 data for TPIP and PAH in the middle of the year and Phase II data for brensocatib and 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 2025. In the first quarter of 2026, we expect our Phase 3 ENCORE trial for ARIKAYCE to read out 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 2 trial of brensocatib in hidradenitis suppurativaa, from several of our gene therapies, including DMD, ALS and Stargardt disease and from our next-generation DPP1 programs, all while we launched brensocatib 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 pioneered an entirely new mechanism of action while successfully advancing other programs in parallel. Now, let me walk you through the progress we are making in pursuit of this ambition, starting with brensocatib.

Earlier this month, we announced that the NDA filing for brensocatib in bronchiectasis was accepted by the FDA under priority review with a PDUFA date of August 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 explore 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 brensocatib’s launch. Previously, we provided analogs of strong respiratory launches that we aspire to emulate with brensocatib including Dupixent, Fasenra, OFEV and Tezspire. On average, these products recorded combined revenues for the first 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 brensocatib 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 4 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 brensocatib 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 90% of surveyed physicians in the U.S. indicating that they intend to prescribe brensocatib 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 at launch. This update is based on extensive pricing work conducted post ASPEN that incorporated brensocatib’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 brensocatib 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 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 to maintain that access.

We believe that this strategy will allow brensocatib to reach more patients faster and will result in a smoother runway to achieving peak sales. Now, just a brief update on our CRS without nasal polyps study of brensocatib. CRS without nasal polyps is the disease with a clear unmet medical need, which brensocatib could potentially address if it is successful. In the U.S. alone, there are roughly 200,000 patients going in for sinus surgery each year and several million whose disease is not adequately 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 2 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 DPP1 in this disease state and could represent a substantial opportunity that could be similar to or even larger than that of bronchiectasis based on the number of patients who are steroid non-responders progressing towards surgery each year.

In addition, a positive result in BiRCh would serve to further validate the DPP1 mechanism as a pathway that can potentially offer benefits to patients with a variety of diseases caused by neutrophilic inflammation including hidradenitis suppurativa, for which we have a Phase 2 study that is currently recruiting patients. Let me now turn to TPIP. The Phase 2 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 102 patients randomized 2:1, so the results will be the best demonstration of the clinical profile of the drug.

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 treprostinil 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 were differentiated from all other assets in the prostacyclin class, solidifying TPIP’s potential value. Before I move on, I want to briefly mention the full Phase 2 results from the PH-ILD study, which were presented earlier this month at the Pulmonary Vascular Research Institutes Conference in Rio de Janeiro.

In addition to the positive top line data that were shared from the study last year, we also showcased a lung imaging study conducted as part of the Phase 2 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 treprostinil, the images in our study were primarily captured long after dosing at a median of more than 8 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 PH-ILD or PAH. We remain on track and look forward to kicking off the Phase 3 trial in PH-ILD in the second half of this year, followed shortly thereafter by a Phase 3 PAH trial. Finally, let me touch on ARIKAYCE, which 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 brensocatib 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 confidence to provide revenue guidance for ARIKAYCE of $405 million to $425 million 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 2026 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 accelerating and showing promise. I will now turn it over to Sara, 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, we had over $1.4 billion 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 million term loan from Pharmakon discussed last quarter our underlying cash burn in the fourth quarter was approximately $191 million, 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 brensocatib in December as well as the impact of higher headcount and other expenses related to ongoing preparations for the potential launch of brensocatib in the third quarter of 2025, if 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 2024 was $363.7 million, reflecting 19% year-over-year growth and 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 2024, 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 $254.8 million, 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 $87.7 million, 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 6 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 $21.2 million, up 39% compared to 2023. This growth reflects continued strength in new patient starts, particularly in Germany and the U.K., driven by the exceptional work of our European commercial team. In 2025, we continue to expect full year ARIKAYCE net revenue to be between $405 million and $425 million.

As a reminder, this guidance range does not include any contributions from brensocatib. Let me now turn to a few additional financial items. Our U.S. gross to nets 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 Reduction Act.

Going forward, we expect this increase to increase as more of the responsibility for catastrophic coverage for Medicare patients being treated with ARIKAYCE shifts to Insmed. For brensocatib, pricing and 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% of catastrophic coverage for Medicare patients under the IRA, we believe a 25% 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 $85.7 million or 23.6% of revenues, which was consistent with our historical performance. For full year 2024, research and development and SG&A expenses were $599 million and $462 million respectively, reflecting continued investment in our early and mid to late-stage pipelines as well as investment in brensocatib 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 $1.4 billion 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. [Operator Instructions] Thank you. And your first question comes from the line of Vamil Divan with Guggenheim Securities. Please go ahead.

Okay, great. Yes, thank you for taking my question and thanks for the information on the call. So, maybe just on brenso, I will 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 2 data sort of what would you want to see from that dataset and what would we consider good data and sort of move that opportunity forward?

I would agree with your comments that people are not necessarily appreciating that indication yet. So I am just kind of trying to get a sense of what you are hoping to see before people start looking at it in their models? Thanks.

Well, 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 this opportunity in CRS without nasal polyps. We have a lot of reasons for enthusiasm for this indication and the potential of brensocatib to have impact. The study, I am actually going to ask Martina to 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 are 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 billion. 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 will have Phase 2 data we expect by the end of the year. Martina, do you want to talk a little bit about the study?

Yes, sure, Will. So what are we looking for in CRS without nasal polyps in our BiRCh study? First of all, there is no treatment that is indicated for this patient population apart from a steroid inhaler that you may well be aware of. So this is a totally new mechanism with brensocatib 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 change. That means more mucus production, more inflammation, and that leads to a 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 brensocatib 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 are 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 these patients and this is nasal congestion, nasal discharge, facial pain or pressure. In addition, what we will measure is something that is called the nasal congestion score. It’s not or it’s something that is the QLB so the quality of life measurement validated in this patient population as well as a loss of smell.

The study goes over 24 weeks. We are looking at 10 and 40 milligram of brensocatib versus placebo. What are we power to show, we are powering this, this is a proof-of-concept study, 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 are looking for.

We really only have one other measure – and that is the – as you are truly familiar with, the Optinose studies that have done studies using a very similar score. The scores may have different names. You see sometimes a comprehensive sign of score, but they all measure the same things: congestion, discharge and facial pain. And what they have shown was a treatment effect between 0.7 and 0.9 in their ReOpen2 study.

So that is really the only one that you have as a comparison. We, in the BiRCh study, are looking for the effect of brensocatib on top of nasal steroids. So, patients are already on a stable dose of nasal steroids for 4 weeks before they are being randomized to brensocatib.

And 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 5 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 are hearing that from the treating physicians as well. And I think that’s part of the reason why you are seeing the trial enroll so effectively.

Okay. Alright, 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 brenso in bronchiectasis?

Well, if we think about the U.S. launch and the PDUFA date of the middle of August of this year, I think probably the thing 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. But really, it comes down to market access, in my mind, is 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 are 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 on to 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 are 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 have done the background that leads into the market access discussions and what we think those are going to yield. And that, I think, is the single most important thing that remains under our control that we want to ensure we get right.

And the only 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 will be additionally augmenting to add more in the market access to field access managers and the case managers. So we have brought on additional field access managers and that will help with that frictionless launch that Will was describing as well.

Very helpful. There is – this might be a more difficult question to answer, but it seems important to ask. So I will. There has 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 brensocatib on time? Do you have any insight into the folks who will actually be performing the review?

Yes. So obviously, we are in the middle of the review now. We are – 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 and consider hypotheticals where government staffing becomes challenged for whatever reason, there is always an unpredictable element to this. But 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, there is some unknowns out there, but I would describe our current situation is extremely encouraging as evidenced by the granting of priority review and the pace at which our interaction has been taking place.

Thanks again.

Your next question comes from Jessica Fye with JPMorgan. Please go ahead.

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

Sure. So I’ll give the second question to Sara. The response – and 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 500,000 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 12 months. But it is important to note and you’ll see this in many of the materials that we produced that we think of this as just the beginning of the potential addressable market. There are many patients who either fall off diagnosis codes or over 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 and 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&A and R&D, we haven’t provided specific OpEx guidance, as you know, and we believe the early investments 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&D side as we are starting CRS HS TPIP entering Phase 3, commercial on the SG&A side, specifically. I mentioned we are adding on some additional resources and market access to ensure that the launch is as successful as possible.

What I will say is, as you think about once the launch curve starts to shape in ‘26 and beyond the percentage of SG&A to revenue that percentage will obviously begin to look much more favorable.

Thank you.

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

Hi, guys. Thanks for taking the question and well, thank you for emphasizing market access because I guess, Medicare is the new bio stats 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 the sliding scale of coverage picking up that 20% catastrophic over, I guess, the next 5 years if we are understanding that program correctly? Can you talk about two things? Can you talk about how you may have to accommodate – first of all, do you have to take that? Second, are you going to have to accommodate more in prior authorizations or what you are expecting prior authorizations to be and how that might impact both the launch dynamics and also, Sara, the 25% out of the gate doesn’t imply this sliding scale for the small manufacturers?

Yes. So, a couple of points. First is we’ll make a distinction between ARIKAYCE and brensocatib. 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 2031. So that’s the scale and we can give you the actual year-over-year increases if you like them. As we think about brensocatib, it does not have that benefit. So we get that – 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 elements can be considered as we think about the cascade from gross price down to what the net price would ultimately be.

Sara, 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 brensocatib.

Sure. So specifically on ARIKAYCE as Will mentioned, that’s obviously 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, we will obviously have this sliding scale that will need to be adjusted within the gross to net for ARIKAYCE.

For brenso, the 25% to 35% at launch based on precedent and based on looking at other specialty right out of the gate, as Will said, we believe the mix of patients will be about 60% Medicare patients. So right out of the gate for brenso, you have 12% – 20% or 60%, 12% for gross to net. And so, we took that into account as we looked at precedent at that 25% to 35% at launch seemed to be a reasonable analog.

Got it. And then a quick follow-up on the PVR data, more specifically, actually about the side effect data that maybe 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 data set that would let you feature a potential reduction in cough or cough burden, whether it’s a 24-hour cough rate that’s used in RCC studies or some sort of cough 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 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 PH-ILD 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 pro drug that takes treprostinil and appends a 16-carbon chain with an ester bond. And that’s significant in dry powder form, because when inhaled, it means that the actual molecules in inert. So you are not breathing in the active treprostinil. We believe through guinea pig 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 datasets that we have so far. We are encouraged by what we’ve seen so far. And we’re looking forward to seeing the actual datasets 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 to double again the max dose that is targeted in this population. So we have gone from 640 micrograms, which was the target max tolerated dose in the Phase 2 PAH study to 1,280 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 led to one element that is always a good indicator of how the tolerability works in 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 they inhale – make – after the inhalation to have a quick – it’s more a reaction not really a cough that persists beyond the minutes after the inhalation at this point. We’ll see, of course, exactly what the percentage of cough 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 could frame for us what you would be considering clinically and commercially meaningful?

And as you think about the Phase 3 initiation of the PH-ILD study, what still needs to be done here? And where do you stand in terms of the final trial design? Thanks so much.

Sure. So with regard to PVR reductions, I think if we look at the prostacyclin class, generally, what you’ve seen from all available data is a range of PVR 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 prostacyclins in use in PAH and PH-ILD 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. It needs to be interpreted with caution because it was a small study, but with 39 patients and a 3:1 randomization in the PH-ILD study, I will 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 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 PH-ILD and PAH. You asked about the Phase 3 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 are 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 3 protocol forward.

Your next question comes from Nicole Germino with Truist Securities. Please go ahead.

Great. Thank you so much for the question and congrats on all the progress. So, as we think about the Brenso launch from our survey work, very significant interest in prescribing Brenso to bronchiectasis patients with comorbid asthma and COPD, including in the community setting. So, as we think for what are the components for a 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 physicians. 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 are trying to accomplish. So, our efforts over the course of the last really almost 2 years now, going back to the American Thoracic Society meeting a couple of years ago, has been to bring that education to the community level of 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 I think the education has been very successful. Obviously, we are 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 have done, where 90% of surveyed pulmonologists have indicated that they intend to write a prescription for patients who have two or more exacerbations. I will just turn it over to Martina to see if she has the other comments based on her interaction with physicians in both communities.

Yes. I think what we know from physicians in 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 2 years, 3 years ago, I think 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 in inflammation that we need to address, rather only than symptomatic improvement that patients really don’t benefit and be continue then to deteriorate and get worse and worse. So, the understanding of inflammation that leads to a 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 brensocatib, the two or more exacerbations that’s half of the already diagnosed population, which in the U.S. is 500,000 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 indeed, that could make the addressable market multiples of what we are currently looking at.

But there is more to learn there and more to accomplish in order to diagnose and make those – ensure those patients are appropriate for treatment.

Okay. Thank you so much.

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

Hi. Good morning. Congrats on the progress. Thanks for taking my questions.

I am 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 the 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 gene therapy. We also have a technology called synthetic rescue, which is out of our Cambridge operation in England.

We have 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 DPP1 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 have 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 are using an AAV9 capsid and an MHCK7 promoter, so we can produce micro-dystrophin 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 that we are using intrathecal delivery. It is non-obvious that intrathecal delivery into the cerebral spinal fluid would transduce into skeletal and cardiac muscle tissue.

But indeed, in preclinical models, that is in fact what we have seen. There is 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 disease with nothing really available that is effective to treat these patients. And what we are 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 was 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 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 are super excited about.

Again, preclinical data there are very encouraging, and we look forward to advancing that through IND and into the clinic in 2026. All three of these are just the tip of the iceberg coming out of the fourth pillar. We are 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 a lot.

Your next question comes from Jason Zemansky with Bank of America. Please go ahead.

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 Brenso’s potential label, connecting the dots from some of your previous comments.

I 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, I think I am just trying to get implications for prescribers and payers here. I mean do you think we could see a potential pushback where a payer might require multiple documented PEs for access?

Yes. So, I think there is 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 exacerbations in the last 12 months. whether that is true or not is really not controlling on anything we have 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 12 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 to be potentially broader, the market access is 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 at a station by a physician. If we can get that, I think that will help our 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 Liisa Bayko of Evercore. Please go ahead.

Hi. Thanks for taking the question. I have just another question on market access, and that is for data [ph] of that do you think any – 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 things 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 are 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 have 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 am making reference to. We could just push this forward. However, we think the smoother way to ensure rapid uptake and rapid reauthorization is to engage in a little bit of that contracting discussion, doesn’t necessarily mean we are going to target getting on formulary, but it does – so is likely to be medical exception as a process in terms of the pathway, but we do want that verbal attestation both for the initial prescription and reauthorization and that’s really what we are working on in terms of the negotiation.

And I think we will have success with that, particularly as I have said, because we would be the only approved therapy in the disease state.

Okay. Thanks a lot Will.

Your 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 are really just looking for a positive trial. But in terms of assumptions for a study like this, is there a way to think about the expected placebo rate in the 24-week trial and then also variability or standard deviation given it’s a 28-day average STFS score.

You are referring to the CRS trial? Just so I’m clear, Jennifer, is that correct?

Yes.

Yes. I mean I will ask Martina, if you want to address that.

Yes. So, Jennifer, if you look at placebo rates, I mean as you know, placebo rate is always very widely even from trial-to-trial in similar population. We have looked at placebo rates, of course as we thought about BiRCh. And if you look at the Optimal studies that have a little different treatment time.

They have their primary endpoint at week 4 and then they are looking at up to week 12. So, they have seen a reduction in placebo rates around reduction of 1 point to 1.5 points along 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 because they measure polyps that maybe are ranging between 0.4 to 0.6 in on the scale.

So, there is always a placebo rate. We obviously look for 24-week time period. It is something that we take into effect right now, what we look at from a blended perspective is do we see a pattern and a trend as we would expect it. And that’s what we are seeing.

And the only thing I would add to that is a shout-out to the excellent work done on the clinical trial design because here what we have is patients coming in, they are exposed to steroids and they are stable on that regimen both between screening and randomization. And the consequence of that is we can look at that interim period where they are between screening and randomization and see, are we seeing a blended blinded change in score during that time. And the answer is we are not. So, that means that they are stable with the symptom score.

They are highly [indiscernible] in terms of the score of five or greater, so these patients are very asymptomatic. And the fact that 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 are on blind, but with reference to some of the ranges Martina said, I think we feel very good about the powering and whether or not we are 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 2 studies. We are looking for something directional. The presence or absence of statistical significance to me, is far or less significant than just whether or not we see something clear and directional that supports our ability to design effectively a Phase 3 study for each of these programs.

Okay. That’s helpful. And maybe if I could ask one question on TPIP, others on PDR reduction, can you just remind us your thoughts on the importance of the six-minute walk endpoint in the context of a Phase 2? Should we frame our expectations with what we saw in the PH-ILD 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 are 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 am looking to you at the historic levels of six-minute walk test improvement or right around 20 meters, aren’t they, they are 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 about 20 meters is what you have seen in, for example, the INCREASE study in PH-ILD and what you would see is in studies with prostacyclin anything north of 20 meters, I think is already a win. And certainly, in a study, the Phase 2 study, remember, we are not powering on the six-minute walk, we are powering and the PDR 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 3 study where the six-minute walk will be the primary endpoint.

Your next question comes from Jeff Hung with Morgan Stanley. Please go ahead.

Thanks for taking my questions. For bronchiectasis, you have noted patients are motivated to act with about 41,000 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 active, this means, they are going to the website, they are downloading information, they are 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 a sort of repository of potential patients right at the time of launch, which is very encouraging. It’s consistent with what we have 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 to let them know about the drug’s approval and reaching out to their physicians. Can you talk about your expectation on the timing and cadence for patients seeing their physicians and being prescribed brensocatib over, say, like the first 12 months? How does that kind of typically play out?

Yes. So, the catch word in what you just said is typically. And of course, because there is 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, 90% of the physicians we surveyed they had 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 have already registered and downloaded guides from our website, which is the actions they take are involved. It’s not just visiting a website and clicking there.

It’s 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 physician in the first month or a year, it remains to be seen. And that will 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 are trying to provide education now. So, if that happens as early as possible because 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 2 by someone at the American Thoracic Society is 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 a lot.

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

Yes. Good morning. Thanks for taking the questions. Just a quick follow-up on TPIP, so do you have any update on the percentage of PAH patients from the Phase 2 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 2 top line disclosure, specifically given if it looks like you are achieving specifically given if it looks like you are achieving an even greater PVR reduction at doses north of 640. Thanks.

Yes. 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 up to 1,280 and many to 960. 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 have – what I can tell you is that we have the vast majority of patients continue in the open-label study. And there are a number of patients who are 80% up to the highest dose. And the additional 20%, some of them are in between the 640 and all the way up to the 1,280. We have a couple of patients who are already up on the 1,280 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 are 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 are 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 are producing in this Phase 2 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 3, it is our intention to have the max tolerated dose shifted from 640 micrograms to 1,280 micrograms for the Phase 3 study participants.

Got it. Thanks for taking the question.

Your next question comes from Trung Huynh with UBS. Please go ahead.

Great. Hi guys. Thanks for taking our question. It looks like you are in a quite strong financial position as you start ‘25, $1.4 billion in cash.

But you have also got a lot going on. So, you have got early-stage trials starting, late-stage trials starting, Brenso launching. I would love to get your thoughts and if there could be any incremental financing on the horizon. And 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 will ask Sara 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. But I can comment on is, as you mentioned, just really pleased with the strength of our financial position, a little north of $1.4 billion in the bank.

It’s gotten a ton of support from our shareholders, so thank you, so all listening for the support to get us here. What I will say is we do have a line of sight to becoming a self-sustaining biotech 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 I have said when it is our time to augment balance sheet, we have a variety of ways we can do it. Equity is one of those pads. We may choose equity. We may choose royalty for ARIKAYCE or Brenso, as an example, and R&D funding for TPIP as an example, different sort of debt structures as an example, just to name a few.

So, sort of bottom line is we have a 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 Chan with Wolfe Research. Please go ahead.

Hi team. It’s Keegan [ph] for Andy. Can you just speak to your patient selection strategy for the chronic bronchiectasis with nasal polyps trial, how can – how do you make sure you are picking the correct patients for the trial? And are there any baseline characteristics you can share. Thank you.

Sure. So I appreciate the question. I think what is really useful about this is once again, frames out the enormity of the opportunity we are talking about here. So, there are CRS without nasal polyps and there is CRS with nasal polyps.

When we look at with nasal polyps, there are already several program – products 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 is nothing novel on the horizon that is available.

So, if we are successful with this, we are addressing a theoretical population in excess of 33 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 in refractory patients, let’s assume that they have 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 and we are, so far, feeling pretty good about the possibility that this drug is going to have an impact.

That selection strategy, as you pointed out, means that we are going to just the bottom end of that pyramid. So, its 200,000 patients in the U.S., that are eligible for surgery every year. There is another couple of million that are steroid non-responders. So, that makes us a very significant addressable population and why I have 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.