Insmed Incorporated (NASDAQ:INSM) has released its first quarter financial results for 2024, highlighting significant progress in its drug development programs and financial standing. The company's lead product, ARIKAYCE, has demonstrated double-digit year-over-year growth and shows potential for label expansion to all patients with Mycobacterium avium complex (MAC) and nontuberculous mycobacteria (NTM).
The Phase 2 study of TPIP in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) has yielded positive results, showing high tolerability and safety, and paving the way for Phase 3 trials.
Furthermore, the Phase 3 ASPEN trial for brensocatib is on schedule, with results expected in the second half of the quarter. Insmed has also expressed support for the COPD Foundation's new care center network, aiming to enhance treatment for bronchiectasis and NTM patients.
Key Takeaways
- ARIKAYCE sales continue to grow, with potential label expansion.
- Positive Phase 2 results for TPIP in PH-ILD patients, leading to Phase 3 trials.
- The Phase 3 ASPEN trial for brensocatib is on track for results soon.
- Insmed is supporting the COPD Foundation's care center network.
- Financial guidance for the full year remains steady, with the company in a strong position.
Company Outlook
- Insmed maintains its full-year revenue guidance.
- The company plans to host a commercial day to discuss ARIKAYCE label expansion opportunities.
- Insmed expects to expand its sales force significantly in the U.S.
Bearish Highlights
- The improvement in six-minute walk distance with TPIP did not reach statistical significance.
- Higher occurrence of clinical worsening events was noted in the placebo group compared to the TPIP group.
Bullish Highlights
- ARIKAYCE has shown promising growth and market potential.
- TPIP has demonstrated a positive impact on patients with PAH, with a 19.9% mean reduction in PVR.
- Brensocatib aims for a treatment effect of around 20%, with significant market opportunity.
Misses
- Difficulty in interpreting the six-minute walk distance data due to unknown distribution of active and placebo patients.
- The trial may not be statistically significant due to the relatively small number of patients.
Q&A Highlights
- Insmed has a current U.S. sales force of 65-70, with plans to increase to 200-220.
- Management expressed confidence in the TPIP program and the potential for brensocatib based on data.
- The company is cautious about over-interpreting data before unblinding the ASPEN study.
This earnings call has outlined Insmed's commitment to advancing its drug development programs and expanding its market presence. With a strong financial outlook and promising clinical results, Insmed is poised to continue its growth trajectory in the competitive pharmaceutical industry.
InvestingPro Insights
Insmed Incorporated (INSM) has been navigating a critical phase in its growth trajectory, as reflected in the latest financial results. With an eye on the company's financial health and market performance, let's delve into some key metrics and insights from InvestingPro.
The company's market capitalization stands at a robust $3.83 billion, highlighting investor confidence in its long-term strategy despite its current financial challenges. The forward-looking PEG ratio, sitting at 0.24, suggests that the market may be anticipating growth that could outpace the earnings contraction, indicating potential for future value.
InvestingPro Tips reveal that while three analysts have revised their earnings upwards for the upcoming period, suggesting optimism in Insmed's future performance, there are concerns to be mindful of.
The company is quickly burning through cash and analysts do not anticipate it will be profitable this year, which is consistent with it not being profitable over the last twelve months. Moreover, Insmed does not pay a dividend to shareholders, which may be a consideration for income-focused investors.
For readers interested in deeper analysis, there are additional InvestingPro Tips available at https://www.investing.com/pro/INSM. These insights could be particularly valuable for evaluating Insmed's strategic decisions and their potential impact on the company's financial future. Use the coupon code PRONEWS24 to get an additional 10% off a yearly or biyearly Pro and Pro+ subscription, and unlock the full suite of expert tips and analysis.
With financial guidance for the full year remaining steady, and the company's support for initiatives like the COPD Foundation's care center network, Insmed's commitment to growth and patient care is evident. The InvestingPro Tips and data metrics provide a nuanced perspective on the company's performance and future outlook, essential for investors making informed decisions in the dynamic pharmaceutical industry.
Full transcript - Insmed Inc (INSM) Q1 2024:
Operator: 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's First Quarter 2024 Financial Results Call. [Operator Instructions]. I would now like to turn the call over to Bryan Dunn, Head of Investor Relations.
Bryan Dunn: 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; Gene 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 2 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. I will now turn the call over to Will Lewis for prepared remarks.
William Lewis: Thank you, Bryan, and 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 2 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 2 study in pulmonary arterial hypertension in a moment, Jim 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 3 ASPEN trial remains on track to readout in the second half of this quarter. Let me take one additional moment to touch on the detailed events and timelines 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 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 Eric has 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. I'm also pleased to report that the Data Monitoring Committee for the ongoing Encore trial held their fourth meeting in April, which resulted in a recommendation to continue the study unchanged. As a reminder, there are no interim efficacy analyses built into the ENCORE study. So this represents a best-case outcome from that meeting. With regard to securing agreement on the PRO we are now scheduled to meet with the team of patient reported outcome experts at the FDA in late June, after which we will settle on the final statistical plan for Encore we intend to provide you with additional updates once that work is complete. Finally, I want to take a moment to note the changing approach within the medical community to the treatment of NTM and bronchiectasis and the clear synergies that are being recognized by patient advocacy groups and physicians as they contemplate how to bring forward the best possible care to patients with these two diseases. This quarter, we signed on to be the founding sponsor of the COPD Foundation's new care center network for patients with bronchiectasis and NTM. Through this initiative, the CLP Foundation aims to create 150 multidisciplinary centers of excellence across the US. This will establish consistent standards of care coming from export-led academic centers and shared them with the broader community in an effort to bring more comprehensive care to patients with NTM and bronchiectasis as they strive to meet treatment goals. This effort recognizes the clear synergy that can be achieved by physicians treating NTM and bronchiectasis, and we will be structuring our medical support efforts to augment this new approach to patient care across the United States. We consider it an honor to be supporting this important work on behalf of patients. Now let me turn the call over to Gene to talk about the big news of the day. The results from our TPIP program.
Eugene Sullivan: 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 2 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 2 efficacy study of TPIP in patients with pulmonary arterial hypertension. Let's begin with PH-ILD. This study originally targeted and enrollment of 32 patients, but was overenrolled with 39 patients. The study utilized a three to one 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, the 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 TPIHP. 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 events that would lead them to discontinue the treatment with 13.8% of patients in the TPIPR. 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% percent of patients in the TPIP arm experienced any adverse events, 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 were judged to be related to 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 placebo arm. All deaths in the trial were related to disease progression or co-morbid causes, and none were attributed to study drug. What are the key reasons to conduct an initial safety trial in this population was to confirm that installation 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 over interpreting that exploratory endpoint in a study this small, as we have said many times in the past, six-minute walk distance often includes a substantial amount of variability as emphasized by the wide confidence intervals we see in this dataset as expected in a study, this small improvement in six-minute walk distance did not approach statistical significance on NT Pro-BNP levels. The TPIP arm showed a slight improvement from baseline in 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 to a cardiopulmonary indication, a lung transplantation or death from any cause for 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 small size. However, clinical worsening events were shown to be more common in the placebo arm with 50% of placebo treated patients experiencing such 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. And importantly, based on today's data, we intend to move this program forward to Phase 3, aiming to initiate a global study and 2025. Now let me spend a few moments providing you an update on our ongoing Phase 2 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. All those patients for discontinued the trial prior to completion, leaving 40 patients who completed the full 16 weeks of treatment. As a reminder, this trial is randomized two to one. 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 this study who experienced dramatic improvements in PVR. We are also excited by what we're 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, the improvement in six-minute walk distance from baseline was 43 meters. As I mentioned a few moments ago, six-minute walk distance 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 TPIPs effects. 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 one dose makes us very excited for the potential of this treatment. As a final reminder, we do not know which of these 41st 40 patients were taking TPIP and which we're 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.
Sara Bonstein: Thank you, Gene, 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 readouts. 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 US, net revenues for Q1 2024 was $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 US since the third quarter of 2019 when ARIKAYCE was in its fourth quarter of launch and ramping quickly. Positive impact of this increase in enrollment forms was partially mitigated, however, by temporary disruptions to the distribution of our case due to the changed health care 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 cyberattack. 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 aerospace 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 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 ASPEN 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 contributes slightly more than a fifth of each year's total sales due to the seasonal impacts in both the US 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 2024, our gross-to-nets in the US 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-nets 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 and 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?
Operator: [Operator Instructions]. Your first question comes from Andrea Tan from Goldman Sachs (NYSE:GS).
Andrea Tan: Sarah, Maybe I could start with you. I'm 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 air case, what assumptions underpin that with respect to how the drug would be used in the refractory versus the frontline setting?
Sara Bonstein: 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 three for you to 360. 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. And we feel if you look at the underlying patients, it's a three to fivefold 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 $1 billion opportunity pending regulatory approval for ARIKAYCE. We believe that the price that we charge today for and 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.
Andrea Tan: Okay. And then on -- Gene , maybe I can just ask you quickly on the blinded blended on PAH data. Just wondering if you're able to share what proportion of patients did see an improvement in PVR and of those what their average rate of improvement was? Just curious if it's still. And I guess maybe just curious if the magnitudes are still similar to the first cut of the data where the average PVR reduction in those patients was 47%. And there have been some commentary around on some patients seeing in excess of 65%. Thanks so much.
Eugene Sullivan: Yeah, sure. Thank you for the question. And as you said last time, we noticed that we could divide very clearly into those that improved and didn't improve and the income ratio, that was roughly mirrored our two to one randomization. And so we presented some data on if you looked at just those will improve now with increasing number of patients. If we use the definition of any improvement in PVR at all, we would capture some patients who had really negative or 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 have if you take that exact definition of any improvement of PVR, a matter how small it was more like 75% of the patients have that. But again, we wouldn't really want to call someone who would decrease 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 divided into three groups, which is sometimes done like groups that responded groups that got worse in group and a group that sort of stayed about the same. And then but we didn't want to sort of change the metrics that we were reporting from the last time. So we just didn't do that analysis. We do consider continue to see patients who have a remarkable decrease is remarkable in the sense that this shouldn't happen without the addition as a new therapeutic and our investigators are very impressed when you see a 50% reduction in PVR like that just doesn't happen. It's what you would expect. If anything would be a decline in patients who had not had a change in there therapeutic regimen because it's a progressive disease.
Operator: Your next question comes from Vamil Divan from Guggenheim.
Unidentified Analyst: Hi. This is Daniel on for Vamil. Thanks for taking the questions. I have a couple of questions on TPIP, if I can. So the first one for PH-ILD, you had about 38% of patients that show the kind of drug-related costs is fairly mild. But I guess are there any things that can be done clearly lower this cost for patients? And I guess I was kind of curious if that is it, it might be extra important, those patients that might be moving up to an even higher dose in the open-label extension and pH? That's my first question. Then the second question is more on the broader TPIP opportunities. It was previously at $2 billion-plus opportunity. I was wondering, could you maybe break down that opportunity between the different indications and NAV between geographies of US and the ex-US market. I'm just curious if the data I'm going to have may have any recent impact on your views on this?
William Lewis: Daniel, I'll just jump in and then I'll ask Gene and 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 continue to 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 we're striking there early. We want to emphasize the PH-ILD study is small, but the efficacy measures. And while they're 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. Gene, you want to take the question about cough?
Eugene Sullivan: Sure, yeah. The first point to make is that the PH-ILD population is different than the PAH population. In PAH, the lung parenchyma is essentially normal of the histologic abnormalities in the vasculature and cost really isn't a significant symptom of the disease. Where in interstitial lung disease, cough is a significant symptomatic diseases present at our most patients to some degree or another. So that was sort of the part of the reason to go in and do an initial safety study on in PH-ILD just to see how this drug would be tolerated in patients who have this underlying parenchymal disease. And until you point out that we did see an imbalance in terms of study drug-related adverse events, and that was particularly driven by drug-related cough. And what what that means is there was something about the cough in patients on active that made the investigator believe it was related to the to the drug and what that was was the temporal association with dosing. So it tended to be in discussions with the investigators, I tend to be a very mild cough right after taking that. And the drug and really wasn't problematic was graded as mild did not result in any one of discontinuing treatment and so forth. And the proof is in the pudding that they despite that, that imbalance in cough, they were able to titrate up to six because it has to the highest dose, the six 40 on. So we feel pretty good about it. On what we what we wanted to exclude was that in patients with underlying print from a lung disease, would this drug be somehow more exacerbate their underlying cough to a degree that was problematic clinically? And really, I think the data suggests that's not the case. And so we're really pretty pleased with that. And I think you raised the question of what happens when we go higher and we'll see, as we've said before the data on our more is better, if you will, with prostanoid is very clear with pulmonary arterial hypertension, no, with all of the routes of administration of treprostinil, it's very clear that the higher you can go, the more efficacy you can get. And so we definitely we are, as I mentioned, on amending the protocol to the open label extension to allow for these higher doses, just kind of see where we can go in PAH. We chose not to do that. And the open label extension for PH-ILD. in May primarily the data that more is better. It's not entirely clear in PH-ILD. There just is less clinical experience in that regard. So we weren't sure that it was necessary and also we'd like to get some clinical information on PAH. patients, how they start to tolerate higher doses. So hopefully that answers your question.
William Lewis: 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 and 13.8% in TPIP. So in terms of what it means for patients, as Gene said, continuing to be able to take the drug, it didn't seem to be an impediment.
Operator: Your next question comes from Jessica Fye from JPMorgan (NYSE:JPM).
Jessica Fye: 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 LTQ and those kinds of measures. And so basically, what would explain benefits that are measurable on exacerbations but not in 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 are say -- curious what they say if it may not be, you know, quality-of-life measures given the exacerbations are fairly infrequent and I'm not sure that would be the tip off. Hope that makes sense.
William Lewis: Yeah. So I'll take a shot of that, just given I invite Gene to comment anything further you'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 were hopeful we may be able to see one in on 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 on when 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 that 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 on not occurring or that they are feeling a greater degree of energy or perhaps the characterization of the sputum. And 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. I don't know, Gene, if you want to add anything further.
Eugene Sullivan: And I think I was very well said, I really don't have anything to add to that.
Jessica Fye: Can you just a quickie on TPIP and PH-ILD data on oxygen saturation? I don't know if it's just missed it somewhere, but can you give us the baseline oxygen saturation for each arm?
William Lewis: Gene, I don't know if we have that you want to address that if it's if it's handy, if not, we can circle back.
Eugene Sullivan: Yeah, I don't know that we've included that in the results. Is there something that you're getting at with that question. I mean, I just want to make sure that our lineup, yes, or we didn't include that in the in the baseline demographics mission, did we have that there was some indication on the TPIP group, we're a little sicker and their use of supplement option was a little bit higher. FEC was a little bit lower and done and frankly, during the six-minute walk test, they tended to desaturate at baseline a little bit more. So there were some evidence that they were a little bit sicker. So that's why we presented a change from baseline for each of the measures.
Operator: Your next question comes from Leon Wang from Barclays (LON:BARC).
Leon Wang: Thanks for taking my question and congrats on the data. So a couple on TPIP. One on slide 7, the six-minute walk distance was not available for the placebo arm. Can you just remind us on was just because of inability to collect data or just lack of data? And also any color on the time to response in PH-ILD, specifically looking to see if you can characterize the exploratory efficacy measures and how that change from week 12 to week 16.
William Lewis: Gene, you want to take those?
Eugene Sullivan: Sure. Yeah. The in that slide 7 and a refers to the fact that what we're what we're presenting here is the placebo-corrected change from baseline so the 30 that appears under week 16 is the placebo-corrected effect size. So there there's no comparable data point to put under the placebo arm. So it's a meaning not applicable more than not available if that makes sense. And so what we've included in that box is to emphasize that the point estimate is 30 with a point estimate, and that's remarkably similar to the point estimate of the effect size on six-minute walk that was seen in the pivotal trial for Tyvaso for PH-ILD, the so-called INCREASE trial was or it was comparable. However, we want to be very, very clear and we put two indicators of the variability. The confidence intervals are extremely wide and that in that Square (NYSE:SQ) and then the p-value is not doesn't even close to statistical significance. So that is up. I think that hopefully that responds to your question about what that any means and the other you asked about sort of the cadence of some of the improvement, and we have not released that yet. We haven't analyzed that closely to see how quickly we start to see a difference. I think that as well, this is data that will emerge as in the more fulsome presentations of the data. But since then, pivotal trial endpoints would be from change from baseline to the end. That's what we decided to focus the top-line results on.
Operator: Your next question comes from Joseph Schwartz from Leerink Partners.
Joseph Schwartz: Hi, and congrats on the very strong TPIP data. I was wondering how many patients in the Phase 2 study of TPIP and PAH have been enrolled in the 10 countries, which are allowing you to titrate up to 1280 micrograms. But are you still talking to other countries health authorities by doing so? We will just be and those patients when we have see that data. And then I have a follow up on brensocatib.
William Lewis: So we are talking the other countries. I can answer that part of it. I don't know, Gene, if you want to take the other one, if we if we know that.
Eugene Sullivan: Yeah, I don't have the specific figures because it's for the reason is that we don't think that the doors and closed in other countries. It's just that the back-and-forth is ongoing either with them. First, you have to go through the regulatory authority that you have to go through the ethics committee or IRBs. So those conversations are ongoing. So we haven't I it doesn't come to mind how many patients currently covered because I think we expect more of those countries to eventually allow on the expanded dosing.
Joseph Schwartz: That's helpful. Thank you--
William Lewis: Sorry, go ahead. Sorry about that. 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 only will be taking place in the PAH study, not the TPIP study.
Joseph Schwartz: Right. Okay. Thank you. That's helpful. And then on brenso, to what extent do you think the market opportunity could be influenced by the magnitude of effects, signs that we see in ASPEN? And what's the right way to contextualize the clinical benefit of something like a 15%, 25% or 35% reduction in exacerbations? How is your discussion -- physicians and payers gone in that time?
William Lewis: Yeah, I think what we've been tried to be very clear about is that on the clinical meaningful threshold. I think that everybody sort of agrees as a floor is about 15%. People would like to see 20%. And I think we certainly have tried to design the trial to capture that treatment effect. We have sort of oriented our entire thinking about this by saying that if we can get below 0.01 and a treatment effect of around 20% that we would keep for either dose. We would consider that a home run that we've got a drug and that we think will be a very successful outcome. And of course, we saw higher than that in WILLOW, and we certainly hope that is replicated in ASPEN. We have no reason to believe that it wouldn't be the baseline characteristics, the execution of the trial, all the design elements are in parallel to what was seen in WILLOW. So we're very hopeful, but that's sort of how we think about the threshold. As it goes up, it certainly would speak to the demand and the degree to of enthusiasm. I think that people will have in the physician community for calling their patients in, which is the fact that we've already heard that if this were to be find its way to meaning clinically meaningful thresholds of, call it 20% or more, I think patients will be called in to receive the treatment by physicians with enthusiasm. If that number goes up even more, it will probably affect the enthusiasm. I don't know that it's going to dramatically affect the way we think about the addressable market. But we're certainly going to reflect on the target product profile in its totality, which includes both efficacy and safety and some other reflections. But all of the education about this is already been underway with our medical group and indeed in our market access front as well. So we feel like we've got a pretty good understanding of how people going to react to this. And that's why we emphasize getting below 0.01 with one dose and a treatment effect of 20% or more.
Operator: Your next question comes from Nicole Germino from Truist Securities.
Nicole Germino: Hi. [Technical Difficulty].
William Lewis: I'm sorry, I'm having a hard time understanding the question. It sounds like your line is a little broken up. Could I just ask you to repeat it, please?
Nicole Germino: Sure. [Technical Difficulty] going back to the TPIP and PAH [Technical Difficulty] how does the drop in oxygen levels compared to [Technical Difficulty]--
William Lewis: Gene, did you hear that question? It sounded like how does it compare to Tyvaso?
Eugene Sullivan: How does -- which aspect?
William Lewis: TPIP on the PH-ILD side. Is that right -- did I get that right?
Nicole Germino: Yeah, that's right [Technical Difficulty] how does the drop in oxygen levels compares to the [Technical Difficulty] --
William Lewis: Well, I'm really having a hard time hearing there. I think it was the oxygenation levels in the PH-ILD. How does it compare to Tyvaso.
Eugene Sullivan: She's asking if the oxygen -- the drop in oxygen levels, how do they compare to Tyvaso? We didn't do a direct comparison because, again, this is a small study and we're not trying to make claims against today. So I think what we were looking for here was just to see that it didn't harm patients. So I think the one point I want to make is that patients with interstitial lung disease. They saturate when they walk that, that is a function of the disease. And we wanted to make sure that one, there was no negative impact of the drug on their oxygenation at rest or have a no negative impact on their desaturation during the course of exercise. And we think that's what we saw. The reason we were even looking for that -- the reason we are even considering that as a safety finding of interest, is that when you deliver a vasodilator to the lung where there is underlying lung disease. And there is a potential danger of diluting the vasculature in an area that's not ventilated and you get what's called shunt blood going past the lung, which is not getting oxygenated because the area of lung that's has delivered a blood to is not getting ventilated. And there have been problems when systemically administered vasodilators have been used to treat PH-ILD and in fact have led to some contraindications in the product labels for Rio SigmaQuad and for Amber Santana. The general understanding is that's not a good idea to deliver a vasodilator systemically orally or IV in these patients. But as the increase trial showed, the INCREASE trial is the trial. And for everyone's benefit of the time, though, in this population was that that wasn't a problem. And the theory behind that is that we're delivering the vasodilator primarily just to the regions that are actually being ventilated because you're delivering it by inhalation. So we just wanted to we they apparently did not see it in and with ide-cel, and we just wanted to monitor that in our trial as well. And again, we were we were pleased to see that come on at baseline three tests. There was no change in tack patients on placebo required a little bit more oxygen that patients on active drug had no change in their option supplementation. And then with exertion on there was really no significant decline compared to placebo.
Operator: Your next question comes from Graig Suvannavejh from Mizuho Securities.
Unidentified Analyst: Hi. This is Jerry on for Greg. Has taken our questions. Congrats on the TPIP data. I guess, first, the LNTPODTPIP, based on what you know now, what a Phase 3 study in PH-ILD look like? And then I do have a follow-up on brenso well after.
William Lewis: Yes, I'll take that quickly. We haven't really put any thoughts in the public domain about what that Phase 3 study will look like. We obviously want to have some interaction with the FDA and other regulatory authorities to ensure that what we produce from that trial will be adequate for full approval. I think today's data certainly suggests that there's going to be a clear path to being able to create such a trial. We'll rely on very likely on what has worked in the past, but it's difficult to commit anything further than that in the design centers because we're just obviously, the data is fresh and we're digesting it. And then we're going to want to have dialogue with regulatory authorities. But as soon as that is accomplished, we'll get that design out to everyone so that they can understand what is going to look like. Sorry, I can't be more specific. So if I had That's helpful on. And then for I guess, the upcoming ASPEN readout, since you know, you mentioned kind of the old patient that we have reached out to be two weeks of all the adults that time period. I'm wondering if I could gain more granular timing on the timing of data release. Well, I'd tell you that is the question of the day. I wish I could be more specific. We tried to narrow it down to the mid May end of June timeframe, which is 45 days that's pretty specific for a biotech company on. Let me just perhaps give a little bit more color on what is the sequence of events when you when you get to this point on a large trial. It's not simply the production of the top line results, as is often the case for something like a Phase 2 study. In this case, we not only need to produce the top line results, but we need, by the time we lock the database for every detail and quality issue to be resolved because this is a submission database. And what I mean by that is this is a database that's going to the FDA and the other regulatory authorities around the world. So if you will, there's an additional level of quality control and scrutiny to ensure that the database is submission quality, we would hate to snatched defeat from the jaws of victory by having good top line results and then a database that got rejected for some quality issues. So we're taking the necessary time to ensure that both goals are accomplished, that we can produce the data and that the database is in is in good shape, and I'm happy to report every aspect of that effort at the Company has gone incredibly well, and I'm incredibly proud of our clinical team for what they've been able to accomplish in that regard. But it will be within that 45-day window. We're confident of that. And that's as specific as we can get but those are the reasons that are sort of pacing when that database will be ready for review.
Operator: Your next question comes from Jason Zemansky from Bank of America (NYSE:BAC).
Jason Zemansky: Good morning. Congrats on the data and thanks for taking our questions. I was hoping you could provide some color on the discontinuation rates for TPIP. I'm appreciating these are small numbers, but about it 14%, it's twice what was observed for the Tyvaso BREEZE study. That said, the rate of treatment emergent AEs looks to be in line and it doesn't look like cough was the source of this. Was there something about the four patients who discontinued whether it was, I don't know, underlying disease severity or dose received or I don't know, was it early in the study, especially as you noted, the titration schedule was a little more aggressive? And then a follow-up, if I may.
William Lewis: Gene, do you want to take that?
Eugene Sullivan: Yes, sure. I think when we use the Tyvaso as the benchmark we don't so much look at the BREEZE study as we do the INCREASE study. And I think the discontinuation of treatment in our study actually compares favorably to the graph that you'll see in the publication that shows the discontinuations of treatment and the active arm with Tyvaso. So I guess I tried to point you to the INCREASE study as the better comparator than the BREEZE study. And then the second question was, but the second part of it was --?
Jason Zemansky: Was there something specific about these four patients? And like you said the titration schedule is a little bit more aggressive than what you normally see with Tyvaso. Is that when they dropped out or again, was there something about the dose that they received. I'm just curious if there was something consistent amongst the patients?
Eugene Sullivan: Oh, the actual dropouts from the study were not drug-related and nothing -- no signal of a ability to titrate the drug or anything like that in the PH-ILD study.
Jason Zemansky: Got it. Okay. And then just kind of thinking more broadly, when thinking about TPIP's potential in your guidance. How important is it that patients get to the 640 milligram or microgram dose or higher is the assumption that the drug will provide more benefit given the higher dose? Or is its value really in moving from four times daily to once-daily administration?
William Lewis: So I'll just jump in on that one and then ask Gene to comment. I think what you hear from treating physicians is the higher they can go the better from their point of view. Indeed, when we first developed the drug and we're working on the target product profile. We spent a lot of time with KOLs and asked them would they prefer a drug that had lower side effects and at a dose consistent with what's already being used or a drug that had perhaps some side effects but could go up in quantity of drug administered and the universal response I quite enthusiastic was go as high as you can because that's what we do with patients. We pushed them to max tolerated dose in practice. So we picked 640 micrograms for this study, which is 60% greater than what treprostinil is the equivalent of treprostinil. It's administered over four times and already. So it's quite a substantial step up. The physicians are very encouraged by that. They've now encouraged us in the PAH setting to double that yet again, based on the safety profile that they've seen, and we consider that to be a ringing endorsement, not only of what we've been able to accomplish so far, but what the future may hold given some of the improvements we've seen in PVR just getting patients to 640. So I think there's a lot of promise here for the clinical result that we expect to see from PAH as patients move from 640 to even higher levels. And that is a wonderful clinical objective that we have set for ourselves. And it's a very high bar, but being able to get to higher doses should produce that result to be able to do it with a once-a-day administration is the benefit of convenience as well as the clinical side I just mentioned. And the once-a-day piece was enough to get enthusiasm from treating physicians in and of its own right, even if the clinical profile is the same, the fact that we're able to suggest we may be able to get even better clinical outcomes and have the once a day is really sort of the Holy Grail. We're after why we think this will be on as some have said the potential go to a prostanoid of choice for the treatment of these patients. I don't know, Gene, if you have other reflections.
Eugene Sullivan: Yeah, I mean, I just the only thing to add to that, Tom, first of all, the basic assumption with prostanoid in PAH is that the more you can get in the better and generally patients and doctors tolerate a little bit of prostanoid related side effects to kind of match the efficacy. I will say that there tends to be a spectrum of tolerability like some patients tend to get just get who are more sensitive to the prostanoid-related side effects and others. So if you look at a population of patients on Remodulin, for instance, there will be patients had lower or higher doses depending on their individual sensitivity to the prostanoid-related side effects. So I don't necessarily think we need to get everyone up to the top dose. It's more a matter that there's the ability to keep going up. If the patient is tolerating it, the ability to keep increasing the dose. And you have that ability with Remodulin to just to keep increasing the dose. With Tyvaso, because of the peak systemic exposure immediately after dosing, you kind of don't you get up to the you titrate up to the target dose and then you stay there and you and label does not include continuing to dose escalate. I think that's probably related to that, you know, the pharmacokinetic pattern. So because of our lung kinetics, we hope to be able to dose TPIP in a mannermore similar to the way IV treprostinil is dosed. In other words, you can continue to increase the dose according to the patient's tolerability. We think that in addition to the once daily versus four times a day, that's a great distinction. But this is another distinction, you get the benefit of delivering the lung, the drug directly to the lung, but also the ability to titrate it in a manner that they do with the parenteral product interesting.
Operator: Your next question comes from Ritu Baral from TD Cowen.
Ritu Baral: Hi, guys, and thanks for squeezing me in and I apologize in advance. I still swear I hate biostatistics more than any of you, but often 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 0.04 to 0.1 and historicals work 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 on time or at the very end because it does seem to make an important difference in power. And this is a quick follow-up.
William Lewis: Yeah, I hate to disappoint, Ritu, because I know the work that you've put into this and I appreciate the the I'm focused on this particular aspect of the dataset, but that's not something we've talked about publicly other than to say, generally looking at everything in this study, we continue to feel very positive about what we're seeing on it. No one variable controls, but you note there really is nothing in this study that has given us pause or alarm with regard to what the expected results will be. We'll know it shortly enough, but I think we've seen remarkable consistency with WILLOW across many parameters, and that's about as far as unfortunately, I can go.
Ritu Baral: Fair enough. Just on discontinuation rates and ASPEN can -- have you tallied the final discontinuation rate, whether it stayed within expected parameters as per the last update?
William Lewis: Yeah, what we can say is that while we haven't given any update with the final data, the with the vast majority of data already in, we've been indicating that the safety is as good or potentially even a little better than WILLOW. We'll obviously see once we unblind by by various arms, et cetera. But the blended blinded data continues to look very favorable with regard to safety and just getting a lot of it.
Ritu Baral: Got it. And just one last in on the TPIP-ILD study, Eugene, I think you mentioned that cough was the main reasons to stop the titration upwards. Were there any other unusual symptoms that could be unique to TPIP that emerged either to impact titration or discontinuation?
William Lewis: Gene, you want to take the hit.
Eugene Sullivan: Yeah. And just to be clear, I think what I was commenting on before were the patients with study drug related adverse events and that and that, in fact, when they're worse cough, doctors tended to identify this study drug related, you know that it's tough to the investigator to decide do I think a 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. They had a lot of these patients have an underlying cause of that would be just representative of the disease. So just to just to clarify what I meant on that. But to your broader question, we are not seeing any particular safety finding that's that would be unique to TPIP something unexpected at all. And certainly nothing that's impinging upon I dose escalation because we're getting so many people up to really the maximum or we also release that the number of patients who got to the second second to the top dose and done. And that was pretty high, too, that if you if you go to that, it's 90% of patients. So we're not seeing problematic AEs that limit the dose escalation on and we're not seeing any novel safety events that would give us concern that something unique to TPIP.
William Lewis: And I would only add that I think you just have timeframe we have for that for that titration, Ritu, is five weeks. So in the real world, physicians could continue to dose escalate over perhaps a longer period of time and might find greater success. But backbone here is 80% of patients are getting the maximum tolerated dose of six 40 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.
Operator: Your next question comes from Jeff Hung from Morgan Stanley (NYSE:MS).
Jeff Hung: Thanks for taking my question. On particular, particularly based on the data, can you just comment if you see any evidence of disease modification? And then I have a follow-up.
William Lewis: Gene, do you want to address that?
Eugene Sullivan: Yes, by disease modification, I presume you're referring to on the underlying on pulmonary fibrosis, which I know that that was a was the observation made in the INCREASE trial that there may be some evidence of the effect on the pulmonary fibrosis and United Therapeutics (NASDAQ:UTHR) is currently conducting a large trial that trial to detect that on where we might see any effects on the underlying disease process would be lung function and we have not analyzed that data yet. However, it's extremely unlikely that we would see any evidence of that with such a small study and such a small placebo group. It's only 1010 patients, we really the three to one randomization was and intended because what we really wanted to do, it's just got some safety information to give this drug to patients with PH-ILD and make sure nothing untoward happened and that's what we saw. So we don't expect to see any information that could inform whether or not on treprostinil impacts the on the pulmonary fibrosis.
Jeff Hung: Okay, great. And then you started education efforts for brensocatib fairly early, but can you just talk about how far that's come in and how much more education you think is still needed for physicians for potential launch?
William Lewis: Well, I'm happy to report that we have that's the similar experience of being a first in disease drug and the first ever approved drug for the uricase were used in refractory MAC patients. So that experience forms our approach once again to the larger opportunity that would be represented by bronchiectasis using brensocatib into that medical education. It got underway with the American Thoracic Society really last year at this time and has been ongoing. And that will continue to read through our expected launch in the US, which would be the middle of 2025. In parallel to that, we are also I 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 has informed our experiences that by doing these things and people are at 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 and 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 US And then in Japan and Europe is also underway at the area director and regional director level on those critical promotions and hires have taken place. And 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 trying to gain access to the opportunity side of everybody feels what is coming is incredibly exciting and want to be a part of that appropriate disease education and ultimately that the commercial launch of the drug should everything go as expected by the middle of '25. Hopefully, that's helpful.
Operator: Your next question comes from Liisa Bayko from Evercore ISI.
Liisa Bayko: Hi, guys. Congrats on the TPIP data. Just a couple of follow-up questions on ASPEN. It kind of play out over to a saying, but in the more high level way. I noticed there was a lot of patients in your baseline paper from the Latin America region was, I think, more than a quarter of the population, which they seem to have milder disease. Can you talk about your comfort level, making sure like some specific large groups like that are well balanced across the arms that That's my first question. Then my second question relates to how we can think of a quiet period around the data. Are you planning on a kind of a couple of the quiet period a couple of days. Just wondering if we can now if we stop hearing from you guys, if we might think data is coming back.
William Lewis: I'll take the second question first, just to tell you that on when when the moment comes, I think that the certainly will be we'll be going quiet, but I think that is more a byproduct of us needing to take a step back and make sure that as I mentioned earlier, the quality of what we're doing is meeting the standard that the hierarchy here is very clearly and always has been quality first speed, second budget, third, in that order of priority in terms of making sure we produce of the best possible outcome here. So I don't know to be transparent how long it will take from the moment that we decide we're ready to lock the database to the moment that we're analyzing the data and interpreting the results. Obviously, some of that will depend on the results themselves. And but so it's hard to give guidance, Lisa, as to how long we would be quiet. It's just it could be any length of time. And most importantly, I would not interpret a longer period of silence as meaning that there is in any way something wrong. Indeed, we are very focused, as I said before, on the quality, and that may be of something that we just want to refine. And so so that would be my answer to that. With regard to the concentration of patients in different parts of the world. We remain very comfortable with the profile of what we have recruited into the study. There is remarkable, I would say, consistency in our experience with this trials so far based on our careful monitoring of regions on a weekly basis down to the country level and to ensure that there weren't significant deviations or aberrations from some other areas of the world. And so that's been an ongoing process that we've had. I think what we saw in terms of concentration from Latin America is not in any way on problematic or concerning. In fact, I think I don't know how to respond to the comment about milder disease because that that is not something that we would identify as being necessarily the case. But I can tell you we feel very good about the baseline demographics here and the distribution around the world. Hopefully that answers the question.
Liisa Bayko: Did you stratify for Latin America specifically or does that just go into rest of world through application?
William Lewis: We didn't stratified in that sense to the best of my knowledge. Nobody else can direct me if I'm wrong, but we do obviously track now where patients come from, and we can certainly cut the data that way should it become necessary to do so.
Liisa Bayko: All right.
Eugene Sullivan: Let me let me step in here for just a second. We actually did stratify based on region. Latin America is on the list, but other regions as well. Western Europe Eastern Europe, et cetera.
Operator: Your next question comes from Jennifer Kim from Cantor Fitzgerald.
Jennifer Kim: Hey, guys. Thanks for taking my questions. And congrats on the cheaper data, maybe to start with friends. So I think the answer is yes, but I just want to confirm, is it fair enough to say that the data is 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 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 looking at Japan, I know we saw in the paper there's a much higher use of that, for example,
William Lewis: So I'm not going to comment on the timing of the data anymore than I already have. We've given the window from mid-May to the end of June and sometime in that timeframe, we'll produce it in regard to the specific question about what we're monitoring on a on a country basis. I think there are a lot of things we look at. I don't go into the specifics of how we what we've seen or what we conclude or any that interpretation. I would just encourage everybody to not over-interpret comparisons from the past or or other studies. I think the simple answer is we're proximate enough to the actual data from ASPEN to just sort of wait for that data. I don't think it is possible and we have much better information than all of you to interpret what these results will really be until we unblind, we feel good about the direction of everything that is contained within the study. We see remarkable consistency with WILLOW. Those things are encouraging, the qualitative commentary from physicians, but the data will ultimately control as we all know and understand. I think at this point, the simple and most honest, answer is we need to just unblind the data and see what we have. I don't know, Bryan, if you want to add anything specifically about the question, just in light of the last one.
Jennifer Kim: No problem. Okay, thanks. And if I could ask a question on TPIP maybe for Gene, I wanted to confirm is Phase 3 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 intervals are wide, but can you say what the six-minute walk change was in placebo and PH-ILD and what the baselines were for both arms?
Eugene Sullivan: So the question is about Phase 3 and moving forward into Phase 3 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 on 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 PH data to inform key aspects of a design of a Phase 3 trial for PH-ILD. And I think your second question had to do with the six-minute walk test. We've given the delta right, that 30 meters placebo controlled. And so you were you asking what was the actual change from baseline in the group and the treatment groups? I was asking what the placebo six-minute walk change once I think you've given the placebo adjusted change and then after the placebo change and then also what the baselines were for both arms. So I'll just say broadly that probably the best way to do it is placebo-controlled. That would be the primary analysis. In general, it had to do it -- what we saw in the primary analysis was that there was a decline among placebo patients and a stability among active treatment patients. So that general pattern was what it resulted in. It's on the 30-meter delta between the two.
Operator: Your next question comes from Stephen Willey from Stifel.
Stephen Willey: Yes, good morning. Thanks for squeezing me in. Just a quick ASPEN question. So on the the manuscript detailing patient baselines suggests that there were about 20% of patients with elevated eosinophils. Curious as to whether or not you said anything about eosinophilic levels as it pertains to WILLOW and then just kind of curious as to your thoughts around the impact of brands. So in this elevated eosinophilic population where it may be inflammation, maybe not so neutrophilic image. Thanks.
William Lewis: Yeah, the short answer is I don't know the answer to that question, Steve. I can ask Gene, if you know offhand otherwise or Bryan, if someone else wants to comment otherwise we'll have to get back to you.
Eugene Sullivan: Yeah, the only comment I'd make is that when patients have elevated eosinophils in their secretions, either speed up or nasal secretions, it doesn't mean that all of this inflammatory cells RDS and of course, 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, it is still neutrophilic driven. So I think there's it's still a reason to expect a benefit even in those patients. That's why we didn't like exclude eosinophil patients. That's the only thing I want to clarify because sometimes and people think that when it's elevating EDO's, it's at the expense of the neutrophils. But in that milieu and the inflammatory milieu, there are plenty of neutrophils there as well.
William Lewis: We need to the specific numbers that we have and they're public. It was a follow-up.
Operator: Your next question comes from Andy Chen from Wolfe Research.
Unidentified Analyst: Hi, this [indiscernible] is on for Andy. Thanks for taking our question and congrats on the data. Just a couple of quick ones on our end. I guess how big is the existing arcade sales force? And then assuming brands are successful 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. As mentioned, it's a highly variable measure. So it's difficult kind of interpret this. But would you say this is a modest or big success? Was there kind of an internal bar.
William Lewis: Sara, do you want to take the question on sales force expansion and Gene, you can take the one on the six-minute walk on TPIP?
Sara Bonstein: Sure. Happy to. Thanks for the question. Our existing sales force in the US, we have about 65, 70 reps existing in the US and 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, calls on pulmonologists and ID docs brenso, primary call is a pulmonologist. So it's subject to very synergistic products that you don't necessarily see. And so we're really excited about being able to leverage the infrastructure. Gene, over to you.
Eugene Sullivan: Sure. So on the six-minute walk distance in the blended blinded of 43 meters, of course, we say this over and over again, it's a very variable measure. And more importantly, we don't know who's on active and who's on placebo. And so it's very difficult to interpret 43 meters, but we are happy to see improvements. We're seeing patients and improvements in those, you know, represent patients who were on active drug. That's great. And the 43 meters would be plenty of the other point I want to make, though is that even at the end of this trial, it's a larger trial than the PH-ILD study. But with 99 patients were not powered to see a statistically significant effect on six-minute walk distance even with the final unblinded data, we'll get a point estimate, we'll get a sense, but I just wanted to point out that even with 90, 99 patients or so, we know that it likely is not enough. If you look at the pivotal trial for Tyvaso in PAH that was over 200 I think it was 230 or so patients to show a statistically significant benefit. So we see the improvement in the blended population. We don't know who's on active and who's not, but we're pleased with it as a good number. And there are patients who are clearly improving, and we'll just have to wait to see the unblinded data.
Operator: And that concludes our Q&A session for today. And I would like to hand back to management for closing remarks.
William Lewis: Thanks very much, everyone, for joining us today.
Operator: This concludes today's conference call. Enjoy the rest of your day, and you may now disconnect.
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