INSMED Inc Q1 FY2024 Earnings Call

Thank you for standing by. My name is Dee, and I will be your conference operator today. At this time, I would like to welcome everyone to the Insmed First Quarter 2024 financial results call.

Thank you, Dee. Good day, everyone, and welcome to today's conference call to discuss Insmed's first quarter 2024 financial results and provide a business update. I am joined today by Will Lewis, Chair and Chief Executive Officer; Eugene Sullivan, Chief Product Strategy Officer; and Sara Bonstein, Chief Financial Officer, who will each provide prepared remarks before we open it up for your questions. Before we start, please note that today's call will include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our filings with the Securities and Exchange Commission for more information concerning the risk factors that could affect the company. Also note that our call today will include blinded observations from our ongoing Phase II study of TPIP in pulmonary arterial hypertension. These observations may not be representative of results once the study is completed and all data is collected and analyzed. As a result, any future interim data readouts and the final data from this study may be materially different than the observations described today. Finally, the information on today's call is for the benefit of the investment community. It is not intended for promotional purposes and it is not sufficient for prescribing decisions.

Thank you, Bryan. Welcome, everyone. Today, we intend to review the progress from three of the company's main programs, ARIKAYCE, TPIP, and brensocatib. Let's begin with TPIP. The first of this quarter's two important data readouts came this morning with the announcement of the top line results from our Phase II study examining TPIP in patients with pulmonary hypertension associated with interstitial lung disease as well as an update of blinded data from our ongoing Phase II study in pulmonary arterial hypertension. In a moment, Eugene Sullivan will review these data in greater detail. But let me just say that we couldn't be more pleased with the progress and the clinical results that continue to come from this exciting program. Turning to brensocatib, the highly anticipated top line release of the Phase III ASPEN trial remains on track to read out in the second half of this quarter. Let me take one additional moment to touch on the detailed events and time lines relating to brensocatib. At the end of March, all adult patients in ASPEN have completed their 52-week visit, which is the point at which the primary and secondary efficacy endpoints are measured in the trial. As a result, we remain confident that the readout will come during the 45-day window from mid-May to the end of June that we have outlined previously. We look forward to sharing the top line results, which will include the prespecified primary and secondary endpoints as well as safety data across treatment arms once the work to clean, compile, lock, and analyze the data is completed. In regard to ARIKAYCE, we were pleased that ARIKAYCE delivered double-digit year-over-year growth across all three of our geographic regions, and 16% growth overall compared to the first quarter of 2023. We delivered this result despite minor headwinds that occurred in the quarter, which Sara will walk you through in her remarks. Notwithstanding those isolated events, our performance this quarter keeps us on track to deliver on our previously announced revenue guidance for the year. Turning now to the potential expansion of ARIKAYCE to all MAC, NTM patients, I'm pleased to report that our presentation of the full ARISE results has been selected for a plenary session at the upcoming ATS Conference in San Diego later this month, which speaks to the significance of that study and the excitement for it within the medical community.

Thank you, Will, and good morning, everyone. I'm pleased to share with you the data we have produced to date from each of our two programs that have been running in parallel for TPIP. I will start with the top line results from our recently completed Phase II safety study of TPIP in patients with pulmonary hypertension associated with interstitial lung disease, which were posted to our website this morning. I will then walk through the most recent blended blinded data from our ongoing Phase II efficacy study of TPIP in patients with pulmonary arterial hypertension. Let's begin with PH-ILD. This study originally targeted an enrollment of 32 patients but was over-enrolled with 39 patients. The study utilized a 3:1 randomization scheme and as a result, 29 patients were randomized to receive TPIP and 10 were randomized to receive placebo for the 16-week treatment period. The maximum TPIP dose allowed in the trial was 640 micrograms once daily. As a reminder, a TPIP dose of 640 micrograms contains roughly 60% more treprostinil as compared with the total daily dose of the current market-leading treprostinil dry powder product, which is dosed four times daily.

Patients were titrated up to their maximum tolerated dose over the course of the first three weeks of treatment with a final dose increase allowed at the five-week visit. Patients were not permitted to increase their dose for the remaining 11 weeks of treatment. Participant demographics and baseline characteristics were generally well balanced between study arms. However, a higher percentage of female participants were randomized to TPIP arm at 31% versus the placebo arm at 20%. Also, on average, patients in the TPIP arm of the study required one additional liter per minute of supplemental oxygen at baseline. The study's primary objective was to evaluate the safety and tolerability of TPIP in patients with PH-ILD, including assessments of oxygenation at rest and during exercise. Let's begin with tolerability. Among patients in the TPIP arm, 79.3% were successfully able to reach the maximum dose of 640 micrograms by week five compared with 100% of those taking placebo. If we look at the patients who were able to reach at least 480 micrograms by week five, nearly 90% of TPIP patients were able to achieve that threshold. This indicator of the tolerability of TPIP in this patient population is very encouraging, given the relatively short titration period included in the trial and considering the severity of the underlying disease process. Of note, while we adopted a titration period of five weeks for the purposes of this trial, in clinical practice, a more prolonged titration period could be applied, which may allow for even more patients to reach higher doses.

Additionally, we saw that patients taking TPIP were less likely to experience a treatment-emergent adverse event that would lead them to discontinue the treatment, with 13.8% of patients in the TPIP arm experiencing such an event compared to 30% in the placebo arm. We consider a higher treatment discontinue rate in the placebo versus treatment to be very noteworthy. In terms of overall safety, 93% of patients in the TPIP arm experienced any adverse event, which was similar to the 90% of patients on placebo, and 20.7% of TPIP treated patients experienced a serious adverse event compared to 40% of placebo-treated patients. Zero patients in either arm experienced a serious adverse event that could be related to the study drug. There were four deaths in the trial, including 6.9% of patients randomized to the TPIP arm and 20% of patients randomized to the placebo arm. All deaths in the trial were related to disease progression or comorbid causes, and none were attributed to the study drug. One of the key reasons to conduct an initial safety trial in this population was to confirm that inhalation of TPIP would not negatively impact oxygenation. Therefore, we were very pleased that we saw no worsening of oxygen saturation levels at rest, and no increase in the use of supplemental oxygen for patients taking TPIP.

Additionally, we also measured oxygen saturation continuously during and after the six-minute walk test to capture the lowest blood oxygen levels reached during that entire period of time, and found no meaningful differences between the TPIP and placebo arms on that measure, which is what we had hoped to see. I do want to note that we did see a slight decrease in oxygen saturation from baseline levels when measured after the six-minute walk test, with the TPIP arm showing an absolute decrease of 8% compared to placebo patients who saw an absolute increase from baseline of 1%. However, I would emphasize that there was no standardization in the trial regarding the timing for when that measure was recorded following exercise. So there is likely to be significant variability in that data point. As a result, we believe that the values reflecting the resting and the lowest oxygen saturation are the best indicators of the effect of the drug on oxygenation. Although we were previously not sure whether we would have any results from our exploratory endpoints in this study to share with you at the time of the top line safety readout, I'm pleased to report that we do have several of those data points available to share today.

Let me begin with the six-minute walk distance. We were pleased to see a 30-meter improvement compared to placebo at week 16 in patients taking TPIP using the study's prespecified analysis for that comparison. However, let me provide a note of caution on overinterpreting that exploratory endpoint in a study this small. As we have said many times in the past, the six-minute walk distance often includes a substantial amount of variability as emphasized by the wide confidence intervals we see in this data set. As expected in a study this small, the improvement in six-minute walk distance did not approach statistical significance. On NT-proBNP levels, the TPIP arm showed a slight improvement from baseline and the placebo group showed a slight worsening. However, the difference between groups was not meaningful which is to be expected in this small study. Finally, in this study, we measured events of clinical worsening, which was defined as a hospitalization due to a cardiopulmonary indication, lung transplantation, death from any cause, or a decrease in six-minute walk distance of 15% or more from baseline. To be clear, we did not expect to see a signal on this exploratory measure given the study's small size. However, clinical worsening events were shown to be more common in the placebo arm, with 50% of placebo-treated patients experiencing such an event compared to 10.3% of TPIP treated patients. This difference produced a nominally significant p-value of 0.0164. We are extremely encouraged and pleased with today's results and look forward to sharing more of the pharmacokinetic and additional safety and exploratory endpoints from the study at an upcoming medical conference later this year. Importantly, based on today's data, we intend to move this program forward to Phase III aiming to initiate a global study in 2025. Now let me spend a few moments providing you an update on our ongoing Phase II trial of TPIP in patients with pulmonary arterial hypertension. The trial is progressing as expected now with well more than half of the target enrollment achieved. In March, the second Data Monitoring Committee meeting was held to review the safety data from this trial, and the committee's recommendation was to continue the trial without any changes. In regard to dosing, among the first 43 patients in the trial to complete their five-week visit, 79% were able to reach the maximum dose of 640 micrograms or matching placebo, which is consistent with our last update and is very encouraging. We have already received the necessary regulatory approvals in 10 of 17 countries where the study is being conducted to amend the protocol in the open-label extension of this trial to allow for even higher dosing up to a maximum of 1,280 micrograms once daily. We are excited about what these higher doses could potentially mean for patient outcomes.

Today, I would like to share an update on the blinded efficacy data we have seen thus far in this trial. This update includes data from the first 44 patients randomized in the trial. Of those patients, 4 discontinued the trial prior to completion, leaving 40 patients who completed the full 16 weeks of treatment. As a reminder, this trial is randomized 2:1, so roughly two-thirds of the patients will be receiving TPIP and one-third will be on placebo. Starting now with the blinded data on pulmonary vascular resistance or PVR. Among the 40 patients who completed the study as of the data cutoff, the mean percentage reduction in PVR at week 16 compared to baseline is 19.9%. This observed reduction in PVR is comparable to the best clinical results produced with prostanoid treatments in the past, despite the fact that our result for TPIP is a blend of treated and placebo patients. What is equally encouraging is that we continue to see patients in the study who experienced dramatic improvements in PVR. We're also excited by what we are seeing on six-minute walk distance, which is another key efficacy measure for these patients. On average, across these 40 patients, including the TPIP and placebo arms of the trial, improvement in six-minute walk distance from baseline was 43 meters. As I mentioned a few moments ago, six-minute walk is a highly variable measure and especially difficult to interpret on a blinded basis, but we are nonetheless encouraged by what we have seen so far. It is worth pointing out that for both efficacy endpoints that I've described today, PVR and six-minute walk distance, these measures were taken at the end of the dosing interval or nearly 24 hours after the most recent dose. This was designed intentionally to highlight the potential durability of TPIP's effect. However, it makes these results more difficult to compare to the other key study of inhaled treprostinil, which reported hemodynamic measures obtained in the period immediately following the dose at the time of the drug's maximum effect. The fact that we are seeing profound effects in some patients in our study, nearly a full day after taking a dose makes us very excited for the potential of this treatment.

As a final reminder, we do not know which of these first 40 patients were taking TPIP and which were taking placebo. And the numbers I have shared today on PVR and six-minute walk distance will continue to change as more patient data is generated. However, we believe today's data supports our view that TPIP has the potential to be a best-in-class treatment for patients with PAH and PH-ILD, combining a potentially differentiated clinical profile with the convenience of once-daily dosing. Now let me turn the call over to Sara to walk through the detailed financial results from the first quarter.

Thank you, Eugene, and good morning, everyone. I'm happy to be with you to share some of the details of Insmed's financial performance for the first quarter of 2024. We ended the quarter with $596 million in cash and cash equivalents. This represents a cash burn for the quarter of approximately $185 million. As we have stated previously, our cash burn in the first quarter is higher than other quarters in the year due to the timing of our annual employee incentive compensation payout. In addition, this quarter was also impacted by larger payments for contract manufacturing services and inventory build for clinical and preclinical products than our usual cadence. When these items are excluded, the underlying cash burn was approximately $125 million, which is in line with recent quarters. Consistent with our statements on last quarter's call, we have not used our at-the-market equity offering since last year, and we do not intend to use this program between now and the ASPEN data readout. Turning to our commercial performance in the first quarter of 2024, global net revenues for the first quarter of 2024 were $75.5 million, representing 16% year-over-year growth compared to the first quarter of 2023. In the U.S., net revenues for the first quarter of 2024 were $56.3 million, up 15% compared to the prior year quarter. The growth this quarter was driven by the highest level of enrollment forms that we have seen in the U.S. since the third quarter of 2019 when ARIKAYCE was in its fourth quarter of launch and ramping quickly. The positive impact of this increase in enrollment forms was partially mitigated, however, by temporary disruptions to the distribution of ARIKAYCE due to the Change Healthcare cyber attack, which impacted the dispensing of medicines across the United States, particularly for patients starting a new treatment. That said, we are continuing to work to help patients gain access to ARIKAYCE who had difficulty starting treatment due to the cyber attack. In Japan, first quarter 2024 net revenue was $14.9 million, representing 13% growth over the same quarter last year. Although foreign exchange did not have a material impact on the overall business, the impact of changes in the foreign exchange rate on our revenue in Japan this quarter was notable. In fact, if average exchange rates this quarter were the same as they were in the first quarter of 2023, the year-over-year growth in Japan would have been approximately 27% or more than double the reported growth rate. I would also point out that the timing of inventory drawdowns led to a sequential decline in sales in Japan compared to the fourth quarter, which saw record-setting strength in ARIKAYCE sales volumes. Overall, our view on the opportunity in Japan continues to be very positive, and we look forward to the progress from this important region in coming quarters. In Europe and Rest of World, net revenue in the first quarter of 2024 came in at $4.3 million, up 42% compared to the same quarter last year and well ahead of our internal expectations as that region's collective efforts are paying off. While we continue to expect the relative contribution to global sales from Europe to remain modest, we are pleased to see their efforts gain momentum, especially as we round the corner to the potential launch of brensocatib assuming positive asset and regulatory approvals. Importantly, today, we are reiterating our full year 2024 global revenue guidance of $340 million to $360 million. As a reminder, the midpoint of that guidance range represents 15% growth compared to 2023, which is consistent with the 16% year-over-year growth that was delivered in the first quarter. Furthermore, as I mentioned on last quarter's call, the first quarter of each year historically contributed slightly more than one-fifth of each year's total sales due to the seasonal impacts in both the U.S. and Japan. By that same measure, our first quarter performance puts us squarely on track to achieve our guidance range for the full year. Let me now turn to a few additional financial items. In the first quarter of 2024, our gross to net in the U.S. were approximately 21%. As in prior years, we expect the gross to net in the first quarter of the year to be a bit higher before coming down in the remaining quarters of the year. We continue to expect gross to net will settle in the mid- to high teens range for the full year. Cost of product revenues for the first quarter of 2024 was $17.5 million or 23.1% of revenues, which is consistent with our historical performance. Turning to our GAAP operating expenses. In the first quarter 2024, research and development expenses were $121.1 million, and SG&A expenses were $93.1 million, reflecting continued investment in both our early and mid- to late-stage pipelines as well as launch readiness activities for brensocatib. In closing, Insmed's solid financial performance in the first quarter keeps us on track to deliver on our full year guidance. More importantly, we remain well positioned financially as we see double-digit growth from our global commercial efforts, positive top line results from the investment in clinical work and TPIP, continued progress across all of our clinical programs, and the imminent ASPEN data readout. With nearly $600 million of cash, giving us substantial optionality on the other side of that event.

Now we would like to open the call to your questions. Operator, can we take the first question, please?

Sara, maybe I could start with you. Just wondering if you could provide some additional color on what you're seeing that drove such a high rate of enrollment forms this quarter? And when you think about your estimated $1 billion peak sales for ARIKAYCE, what assumptions underpin that with respect to how the drug would be used in the refractory versus the frontline setting.

Sure. Happy to address that, Andrea, and thanks for the question. I continue to be so impressed with our commercial team and their performance. At the beginning of the year, we set out to have double-digit growth, and that's exactly what we showed in Q1, and we saw that across all three of our territories. So really gives us great confidence in reiterating the guidance of $340 million to $360 million. The commercial team continues to execute. And as you point out, Andrea, the medical team continues to execute as we are laser-focused now on the potential label expansion. We feel, if you look at the underlying patients, it's a three- to five-fold increase in the patients we think we will be able to attract with a potential label expansion, giving us a clear line of sight to a $1 billion opportunity pending regulatory approval for ARIKAYCE. We believe that the price that we charge today for refractory, we'll be able to carry forward into the label expansion. And as we've mentioned previously, we are planning on hosting a commercial day on the other side of ASPEN to do a deep dive across all of our pillars, including ARIKAYCE, to continue to educate on the broader label expansion opportunity.

Yes, sure. Thank you for the question. And as you said last time, we noticed that we could divide it very clearly into those that improved and didn't improve, and the ratio of that was roughly mirrored in our 2:1 randomization. And so we presented some data on. If you looked at just those who improved. Now with the increasing number of patients, if we use the definition of any improvement of PVR at all, we would capture some patients who had really negligible improvements, like very, very small, 2%, 3% reduction in their PVR. And so we didn't really feel like that was really representative. To answer your question directly, if you take that exact definition of any improvement in PVR, no matter how small, it was more like 75% of the patients have that, but again, we wouldn't really want to call someone who decreased their PVR by 5% as a real responder, and so we didn't do that analysis of like responders versus nonresponders. We did talk internally like would it make sense to then divide it into three groups, which is sometimes done, like groups that responded, groups that got worse, and a group that stayed about the same, and then we didn't want to sort of change the metric that we were reporting from the last time. So we just didn't do that analysis. We do continue to see patients who have fairly remarkable decreases, like remarkable in the sense that this shouldn't happen without the addition of new therapeutic, and our investigators are very impressed when you see a 50% reduction in PVR, like that just doesn’t happen, like what you would expect, if anything, would be a decline in patients who have not had a change in their therapeutic regimen because it's a progressive disease.

This is Daniel on for Vamil. I have a couple of questions on TPIP, if I can. So the first one for PH-ILD. You see guys about like 38% of patients that show like kind of drug-related cough. It seems fairly mild. But I guess are there any things that can be done to maybe lower this cough for patients? And I guess I was kind of curious if that if this might be extra important for those patients that might be moving up to an even higher dose in the open-label extension PAH. That's my first question. And then the second question is maybe more on like the broader TPIP opportunity. It was previously said a $2 billion-plus opportunity. I was wondering if you can maybe break down this opportunity between the different indications and then maybe between geographies of U.S. and the ex-U.S. markets. I was just curious if the data hasn't had any recent impacts on your views on this?

Vamil, I'll just jump in and then I'll ask Eugene to take the specific question on cough. I think with regard to the opportunity, stay tuned, we're going to go in a much deeper dive on the commercial day that Sara made reference to in the aftermath of the ASPEN data production into what the TPIP opportunity is. I will tell you this, our target product profile is completely supported, if not surpassed by the data that we've seen today. And if that continues, I think we feel very comfortable with the sort of peak sales at $2 billion plus. And certainly, based on what's been happening in PH-ILD and PAH generally, that is a comfortable target for us. These data today, I think, are striking. They're early. We want to emphasize the PH-ILD study is small, but the efficacy measures, while their exploratory are encouraging, I would say. And should they end up being the exact target product profile, the commercial profile we've suggested we feel very comfortable with, and we'll have more to say about that, Daniel, on the Commercial Day. Eugene, do you want to take the question about cough?

The PH-ILD population is distinct from the PAH population. In PAH, the lung tissue is mainly normal, with histological issues in the vasculature, and cough is not a major symptom of the condition. In contrast, cough is a significant symptom of interstitial lung disease and can affect most patients to varying degrees. This distinction was one reason for conducting an initial safety study in PH-ILD to assess how the drug would be tolerated in patients with this underlying lung disease. We did observe an imbalance with study drug-related adverse events, primarily linked to drug-related cough. This suggests that there was a connection between the cough and the medication, particularly regarding its timing with dosing. The cough reported was generally mild and occurred soon after drug administration; it did not lead to any treatment discontinuations. Additionally, despite the imbalance in cough occurrences, patients were able to increase their dosage to the maximum of 640 mg, which gives us confidence in the drug's tolerability. We aimed to determine whether this drug would worsen cough in patients with underlying parenchymal lung conditions, and the data indicates it does not. I'd like to address your inquiry about higher dosages. Previous data suggests that increasing dosages of prostanoids can enhance efficacy in pulmonary arterial hypertension, and this trend is evident across various administration routes. We are amending the protocol for the open-label extension to explore higher doses in PAH, but we decided against this approach for PH-ILD due to the unclear benefits in that population and the desire to first understand how PAH patients respond to increased dosages.

I'll just add one final punctuation on that, Daniel, which is a reminder that treatment-emergent adverse events leading to discontinuation were actually higher in the placebo arm than they were in the TPIP arm with 30% in the placebo arm, 13.8% in TPIP. So in terms of what it means for patients, as Eugene said, continuing to be able to take the drug, it didn't seem to be an impediment.

Sort of a two-part question on brensocatib. Thinking back to the WILLOW data, can you remind us why or what the hypothesis is behind not really seeing meaningful changes on quality-of-life, St. George's, SGRQ, and those kind of measures? So basically, what would explain benefits that are measurable on exacerbations, but not those domains? And the second part, kind of related to that is, I think you've talked in the past about doctors in the ASPEN trial kind of suggesting they can tell if patients are on drug or not similar to WILLOW. And I'm curious what they cite. I'm curious what they cite if it may not be quality-of-life measures, given that exacerbations are fairly infrequent.

Yes. So I'll take a shot at that, Jessica, and then I'll invite Eugene to comment anything further he'd like to. I think with regard to WILLOW and quality-of-life, I remind everyone that, that was a six-month study, and it takes about a month for drug to get the full pharmacodynamic effect. So really, it's not a lot of time for patients to be able to capture and express an impact on quality-of-life. So we didn't really expect to see one there. We're hopeful we may be able to see one in the 12-month study that we're conducting, which is the ASPEN study. But once again, I would turn attention to the key focus of the study, which is the exacerbations, that is the thing we're really trying to impact. And if we accomplish that, which is the primary endpoint of the study, then absolutely we are confident the drug will be adopted and utilized by patients and physicians alike with a lot of enthusiasm. I think when patients talk about their experience on the drug and convey this to physicians, it's a combination of different things that each patient feels. And of course, one always has to take with a huge grain of salt any qualitative characterization from a physician, but we did hear this in WILLOW and we are hearing it again in ASPEN, and that's why we mentioned it. I think typically, this is related to the patient's experience with exacerbations. And if they're feeling that those are not occurring or that they are feeling a greater degree of energy or perhaps the characterization of the sputum. All of these things are different experiences that patients have that collectively make them feel like they're experiencing a benefit. And so we're hopeful the QOL will capture that, but it's not certain. And of course, our primary focus is on the exacerbation impact. If we achieve that, then we will certainly have accomplished victory.

No, I think that was very well said. I really don't have anything to add to that.

Eugene, I don't know if we have that. Do you want to address that if it's handy? If not, we can circle back.

Yes. I don't know that we've included that in the results. Is there something that you're getting at with that question? Yes, we didn't conclude that in the baseline demographics information, did we? There was some indication that the TPIP group was a little sicker. Their use of supplemental oxygen was a little bit higher. Their FVC was a little bit lower. And frankly, during the six-minute walk test, they tended to desaturate at baseline a little bit more. So there was some evidence that they were a little bit sicker. So that's why we presented the change from baseline for each of the measures.

Congratulations on the data. I have a couple of questions regarding TPIP. First, on Slide 7, the six-minute walk distance data was not available for the placebo group. Could you clarify whether this was due to an inability to collect the data or simply a lack of data? Additionally, could you provide any insights on the time to response in PH-ILD, particularly regarding how the exploratory efficacy measures changed from week 12 to week 16?

Sure. In Slide 7, N/A indicates that we are presenting the placebo-corrected change from baseline. The 30 shown under week 16 represents the placebo-corrected effect size, so there’s no comparable data under the placebo arm. N/A means not applicable rather than unavailable. We included this to highlight that the point estimate is 30, which closely matches the effect size point estimate from the pivotal INCREASE trial for Tyvaso in PH-ILD. However, it’s important to note that the confidence intervals are very wide, and the p-value is not close to statistical significance. This should clarify the N/A meaning. Regarding the cadence of improvement, we haven't analyzed that yet, so we don’t have data on how quickly differences emerge. This information will come from more comprehensive presentations of the data, but we chose to focus the top-line results on the change from baseline to the end as per the pivotal trial endpoints.

Congrats on the very strong TPIP data. I was wondering how many of the patients in the Phase II study of TPIP and PAH have been enrolled in the 10 countries, which are allowing you to titrate up to 1,280 micrograms. And are you still talking to other countries, health authorities about doing this? Or will it just be those patients when we see that data?

Yes. So we are talking to other countries. I can answer that part of it. I don't know, Eugene, if you want to take the other one if we know that.

Yes, I don't have the specific figures because we believe the door isn't closed in other countries. The discussions are ongoing, as we need to go through the regulatory authority and then the Ethics Committee or IRB. We haven't tracked how many patients are currently covered because we expect more countries to eventually allow the expanded dosing.

I was just going to say, we haven't given out any specific data about patients that have progressed in the open-label extension. And just to note that will only be taking place in the PAH study, not the TPIP study.

Thanks for squeezing in, and I apologize in advance. I still square, I hate biostatistics more than any of you. But when we did the analysis on WILLOW and ASPEN for brenso, our statistical consultants basically said that it was the distribution of the data that mattered far more almost than the event rate. And then so looking back to the distribution constant between the arms and historical studies we noted that WILLOW obviously had very low variance of sort of 0.04 to 0.1 and historicals were in the 0.4 to 0.5 range. Have you been able to look at all at the ASPEN data and what distribution of data that has been seen either over time or at the very end, because it does seem to make an important difference in power. And got a quick follow-up.

Yes, I understand your interest in this area and appreciate the effort you've put into it. However, we haven’t addressed this publicly apart from our general positive outlook on the study results. There isn’t any specific factor that raises concerns for us regarding the expected outcomes. We're confident we'll have more clarity soon. We've observed remarkable consistency with WILLOW across multiple measures. Unfortunately, that's as far as I can go on this topic.

Fair enough. Can you provide the final discontinuation rate for ASPEN and whether it remained within the expected parameters from the last update?

Yes. What we can say is that while we haven't given any update with the final data, with the vast majority of the data already in, we've been indicating that the safety is as good, potentially even a little better than WILLOW. We'll obviously see once we unblind by various arms, et cetera, but the blended blinded data continues to look very favorable with regard to safety.

I think what I was commenting on before was patients with study drug-related adverse events. And that, in fact, when there was cough, doctors tended to identify it as study drug-related, it's up to the investigator to decide, do I think this study drug-related or not, and they tended to attribute cough to the drug more frequently in TPIP and did not attribute it to the placebo. And again, that's probably related to the temporal nature. As a lot of these patients have an underlying cough that would be just representative of the disease. So just to clarify, what I meant on that. But to your broader question, we are not seeing any particular safety finding that would be unique to TPIP, something unexpected at all, and certainly nothing that's impinging upon dose escalation because we're getting so many people up to really the maximum or we also released the number of patients who got to the second to the top dose, and that was pretty high too. If you go to that, it's 90% of patients. So we're not seeing problematic AEs that limit dose escalation, and we're not seeing any novel safety events that would give us a concern that's something unique to TPIP.

And I would only add, the time frame we have for that titration, Ritu, was five weeks. So in the real world, physicians could continue to try to dose escalate over perhaps a longer period of time and might find greater success. But backbone here is 80% of patients are getting to the maximum tolerated dose of 640 in this study, in the ILD study, and 90% of them are getting to the penultimate level, which is just a remarkable outcome from our point of view.

For TPIP, based on the data, can you just comment if you see any evidence of disease modification? And then I have a follow-up.

Yes. Eugene, do you want to address that?

Yes. I believe when you mention disease modification, you are referencing the underlying pulmonary fibrosis, which was noted in the INCREASE trial where some evidence regarding its effect was observed. United Therapeutics is currently running a large trial to investigate this further. We have not yet analyzed the lung function data, which could provide insights into the underlying disease process, but it seems very unlikely that we would find anything significant given the small size of the study and the limited placebo group of just 10 patients. The 3:1 randomization was primarily aimed at gathering safety data for administering this drug to patients with PH-ILD, and we did not experience any adverse events. Therefore, we do not anticipate finding any evidence that treprostinil affects pulmonary fibrosis.

Well, I'm happy to report that we have the similar experience of being a first-in-disease drug, and first ever approved drug for the ARIKAYCE use in refractory MAC patients. So that experience informs our approach once again to the larger opportunity that would be represented by bronchiectasis using brensocatib. And so that medical education got underway with the American Thoracic Society really last year at this time and has been ongoing, and that will continue to run through our expected launch in the U.S., which would be the middle of 2025. In parallel to that, we are also right now started at the end of last year working on the market access front to make sure that, that education on the disease state is handled appropriately and that everybody is informed. Our experience is that by doing these things, people are in a much better place to understand if there is a drug that is approved, and it has an effect. People know how to place that into context and what that would really represent for patient care. And that's the purpose behind all of it. But certainly, starting early when you're first in disease is crucial, and we've been doing that, and that's a critical investment we've been making. I'll also report that on the commercial front, the progress with regard to bringing additional resources in first in the U.S. and then in Japan and Europe is also underway at the Area Director and Regional Director level, those critical promotions and hires have taken place. I will say I am shocked at the degree of interest that is coming from the outside world for these positions when we indicate that there might be a position available, we are getting scores of candidates signing up to try to gain access to the opportunity. So I think everybody feels what is coming is incredibly exciting and wants to be a part of that appropriate disease education, and ultimately, the commercial launch of the drug should everything go as expected by the middle of '25. Hopefully, that's helpful.

Congratulations on the TPIP data. I have a couple of follow-up questions regarding ASPEN. In line with what Ritu mentioned, I noticed a significant number of patients in your baseline paper from the Latin America region, accounting for over a quarter of the population, who appear to have milder disease. Could you discuss your confidence in ensuring that specific large groups like that are well balanced across the study arms? That's my first question. My second question pertains to the quiet period surrounding the data. Are you planning a quiet period of a few days? I'm curious if we should interpret a lack of communication from you as an indication that data is forthcoming.

I'll address the second question first. At the moment we prepare to lock the database, there may be a period of silence, but this is mainly to ensure that, as I mentioned earlier, the quality of our work meets our standards. Our priorities are clearly defined: quality comes first, followed by speed, and then budget. I cannot precisely estimate how long it will take from when we decide to lock the database to when we start analyzing and interpreting the data, as some of it will depend on the results. Therefore, it's challenging to provide guidance on the duration of our silence; it could vary. Importantly, a longer period without updates should not be interpreted as an indication of any issues. We remain focused on quality, which might require refinement, and that would be my response to the question. Regarding the concentration of patients in different regions, we are very comfortable with the profile of participants in the study. We are monitoring the trial closely on a weekly basis down to the country level to ensure there are no significant discrepancies between regions. The concentration of patients from Latin America is not a concern for us. As for the comment about milder disease, that is not how we would characterize the situation. We feel confident about the baseline demographics and their distribution globally. I hope this answers your question.

Did you stratify for Latin America specifically? Or does that just go into rest of world stratification?

We actually did stratify based on region, so Latin America is on the list, but other regions as well, Western Europe, Eastern Europe, et cetera.

Congrats on the TPIP data. Maybe to start with brenso. I think the answer is yes, but I just want to confirm. Is it fair enough to say that the data isn't coming at ATS just given the timing of deadlines? And then also to follow up on the last question, when you're monitoring on a regional basis, on a blinded and blended rate basis, are you saying that the rates are sort of in line with what you would expect on a regional basis? And does that also take into account the differences in, I guess, macrolide background regimens and looking at Japan, I know we saw in the paper, there's a much higher use of that, for example.

So I'm not going to comment on the timing of the data any more than I already have. We've given the window from mid-May to the end of June, and sometime in that timeframe will produce it.

There are many factors we consider, but I won't get into the specifics of our findings or interpretations. I urge everyone not to overly analyze past comparisons or other studies. The straightforward answer is that we are close enough to the actual data from ASPEN that we should wait for it. We have more comprehensive information than anyone else to understand what these results might mean until we unblind the data. We are confident about the study's direction and have seen strong consistency with WILLOW, which is encouraging, along with the qualitative feedback from physicians. Ultimately, the data will determine everything, as we all recognize. The most straightforward and honest response at this time is that we need to unblind the data to see what we have.

If I could ask a question on TPIP, maybe for Eugene. I wanted to confirm if Phase III advancement in PH-ILD, still contingent on getting PAH top line data maybe to get a better sense of powering. And I know that the confidence intervals are wide. But can you say what the six-minute walk change was in placebo in PH-ILD and what the baselines were for both arms?

Sure. So the question is about Phase III and moving forward into Phase III. I think that will be primarily based upon the results of this trial as we analyze these results and the ones that will come in subsequently. And also on the experience of Tyvaso in this population. I think it's harder to extrapolate data on efficacy and data on a lot of things from a PAH population to PH-ILD, it's such a different disease process that I don't think we're going to be looking at the PAH data to inform key aspects of a design of a Phase III trial for PH-ILD. And I think your second question has to do with the six-minute walk test. We've given the delta, right, of 30 meters placebo controlled. And so were you asking what was the actual change from baseline in the treatment groups?

I was asking what the change in the six-minute walk test was for the placebo group. I think you've provided the placebo-adjusted change, but what was the actual change for the placebo group? Additionally, what were the baseline measurements for both treatment arms?

So I'll just say broadly that probably the best way to do it is placebo control. That would be the primary analysis. In general, it had to do with what we saw in the primary analysis was that there was a decline among placebo patients and the stability among active treatment patients. So that general pattern was what resulted in the 30-meter delta between the two.

Just a quick ASPEN question. So I know there are about 20% of patients with elevated eosinophils. I'm curious as to whether or not you said anything about eosinophil levels as it pertains to WILLOW. And then just kind of curious as to your thoughts around the impact of brenso in this elevated eosinophilic population, where maybe inflammation may be not so neutrophilic in nature?

Yes, the short answer is I don't know the answer to that question, Stephen. I can ask Eugene if you know offhand, otherwise or Brian, if someone else wants to comment. Otherwise, we'll have to get back to you.

Yes. The only comment I'd make is that when patients have elevated eosinophils in their secretions, either sputum or nasal secretions, it doesn't mean that all of the inflammatory cells are eosinophils. It just means there's a lot of them. And actually, there are a lot of neutrophils even in patients who have elevated eosinophils. A lot of the inflammation is still neutrophil driven. So I think there's still a reason to expect a benefit even in those patients. That's why we didn't like exclude eosinophils. So that's the only thing I'd want to clarify because sometimes people think that when it's elevated EOS, it's at the expense of the neutrophils. But in that milieu and the inflammatory milieu, there are plenty of neutrophils there as well.

We can get to the specific numbers if we have them in the public with a follow-up.

This is Eman for Andy. Congrats on the data. Just a couple of quick ones on our end. I guess, how big is the existing ARIKAYCE sales force? And then assuming brenso is successful, what's the target sales force size there? And that's one. And then on PAH regarding the average improvement in six-minute walk distance from baseline of 43 meters. How should we interpret this data point? I know during the call it was mentioned it's a highly variable measure. So it's difficult to kind of interpret this, but would you say this is a modest or big success? Was there kind of an internal bar?

Sure. Happy to. Thanks for the question. Existing sales force in the U.S., we have about 65, 70 reps existing in the U.S. We will look to expand that. What we've said publicly, 200 to 220 is what we've said publicly. We'll share more on those details on the commercial day that we've alluded to throughout the Q&A session. What I would like to comment on is the immense crossover between ARIKAYCE and brensocatib, and the synergies that we will have, ARIKAYCE, obviously, called on pulmonologists and ID docs. Brenso, primary call is pulmonologists. So it's two very synergistic products that you don't necessarily see. So we're really excited about being able to leverage the infrastructure.

Yes, sure. The six-minute walk distance in the blended blinded study was 43 meters. This measure is very variable, and it's challenging to interpret the significance of 43 meters, especially since we cannot determine who is on the active treatment and who is on placebo. However, we are pleased to see improvements and if these improvements are from patients on the active drug, that would be great, and 43 meters would be sufficient. It’s important to note that even with this trial being larger than the PH-ILD study, with 99 patients, we are not statistically powered to observe a significant effect on the six-minute walk distance, even with the final unblinded data. We will receive a point estimate and gain an understanding, but I want to emphasize that 99 patients is likely insufficient. For instance, the pivotal trial for Tyvaso in PAH included over 200 patients, approximately 230, to demonstrate a statistically significant benefit. While we see improvement in the blinded population, we cannot determine who is on active treatment, but we find the results encouraging. There are patients showing clear improvement, and we will have to wait for the unblinded data.

And that concludes our Q&A session for today. I would like to hand back to management for closing remarks.

Thanks very much, everyone, for joining us today.

This concludes today's conference call. Enjoy the rest of your day. You may now disconnect.