Thank you for standing by, and welcome to the Insmed 12-month results from ongoing open- label extension study of TPIP in PAH patients conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you'd like to ask a question during this time, simply press star, followed by the number one on your telephone keypad. If you'd like to withdraw your question, again, press star one. Thank you. I'd now like to turn the call over to Bryan Dunn, Head of Investor Relations. You may begin. Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss the 12-month results from our ongoing open- label extension study of TPIP in patients with PAH. Before we start, please note that today's call may 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 SEC filings for more information. I'm joined today by Will Lewis, Chair and Chief Executive Officer, and Gene Sullivan, Chief Product Strategy Officer. The call will begin with some opening remarks from Will before turning it over to Gene to walk us through the study results in detail. After Gene's remarks, we will welcome Dr. Raymond Benza, who is the George M. and Linda H. Kaufman Academic Chair of Cardiology at Sentara Health. Dr. Benza will share some of his thoughts on these data. After Dr. Benza, we'll turn it back over to Will to share some closing remarks. When we open it at the end for the Q&A session, Martina Flammer, Chief Medical Officer, and Sara Bonstein, Chief Financial Officer, will also join us. The slides we will review today were furnished with the 8-K we filed with the SEC this morning and can also be found on the Events and Presentation section of our website. Now, let me turn the call over to Will Lewis. Thank you, Bryan, and welcome everyone. I'm thrilled to announce the exceptional results from the first 12 months of our open- label extension study of TPIP in patients with PAH, which continue to validate our conviction in this transformative potential for patients with PAH. Let me step back and remind everyone why TPIP could represent such a meaningful advancement in the PAH treatment landscape. TPIP is a prodrug of treprostinil that our research team specifically engineered to unlock the full therapeutic potential of prostacyclin therapy. We designed TPIP to address three critical treatment challenges: efficacy, safety, and convenience. On efficacy, TPIP's inhaled delivery targets the lung tissue directly, which has demonstrated efficacy advantages over other delivery methods. TPIP is unique even amongst other inhaled options due to its ability to release the active drug slowly once it reaches the lung. This creates higher drug availability exactly where patients need it most. With consistent 24-hour coverage, including overnight protection. On safety, we also believe that the slow conversion of TPIP to active drug within the lung may reduce systemic side effects from high peak exposure. In addition, because patients aren't inhaling the active drug itself, TPIP may also improve cough. Our preclinical cough models show that TPIP only induced a cough response when the dose was increased to approximately 7x the dose which induced a cough response with active treprostinil. On convenience, TPIP requires just once daily dosing versus the typical 4x per day dosing with other inhaled options. A single breath delivers up to 640 mcg of TPIP, which contains nearly 60% more active drug than the highest labeled dose of TYVASO DPI. Doses of up to 1,280 mcg would require only two breaths, once per day. Additionally, this less frequent dosing may have the advantage of improving patient adherence. Before we move into the OLE results, it is important to ground the discussion in the randomized phase II-B study in PAH that preceded it. Those results showed a highly statistically significant 35% placebo-adjusted reduction in pulmonary vascular resistance, which far exceeds the numerical reductions shown for any other prostacyclin treatment of which we are aware. Treatment effects across other efficacy measures were similarly impressive, with a placebo-adjusted 35.5 m improvement on six-minute walk distance and a 60% placebo-adjusted reduction in NT-proBNP at week 16. What makes these results even more compelling is that they were measured roughly 24 hours after the most recent administration of TPIP, demonstrating TPIP's sustained therapeutic effect. Safety was equally encouraging, with 90% of patients completing the study and no unexpected safety signals observed. Importantly, all incidences of cough in the trial were mild or moderate, with more than 85% classified as mild. As you will see, all of these efficacy results for TPIP are numerically superior to the published results for other forms of inhaled treprostinil, both nebulized and dry powder. They are also comparable to the results that have been published for sotatercept. Given the strength of the data produced in the randomized lead-in trial, our desire was to see those efficacy measures sustained over the longer OLE period. I am pleased to report that patients in the continued TPIP group were able to sustain those demonstrated improvements on six-minute walk distance and NT-proBNP through the first 12 months of the extension study. Additionally, those patients saw further improvement in Functional Class from the end of the randomized trial and saw clinically meaningful reductions in their risk of morbidity and mortality, as assessed by the REVEAL Lite 2.0 score. Patients who were randomized to placebo in the lead-in trial saw a clinically meaningful response once switched to TPIP, with overall improvements in six-minute walk distance, NT-proBNP, Functional Class, and REVEAL Lite 2.0 risk scores catching up with those in the continued TPIP group by month 12. Equally important, over 90% of patients completed the first 12 months of the OLE with no new safety signals being identified at doses up to 1,280 mcg or double the highest dose in past trials. This is a remarkable result for patients and one that we believe will drive additional interest from investigators and patients for our phase III trials. I will turn it over to Gene to walk us through the data. Thank you, Will. Good morning, everyone. I am very pleased to be with you today to share the 12-month results from our ongoing open-label extension trial of TPIP in patients with pulmonary arterial hypertension. First, I will provide a review of the study's design. The PAH open-label extension study is a 24-month study allowing patients to continue on treatment with TPIP and to move patients receiving placebo in the lead-in study onto treatment with TPIP. The study was designed to allow up titration to doses as high as 1,280 mcg, which is double the maximum dose that was allowed in the lead-in phase II study. Using a blinded double-dummy approach during the first three weeks of the trial, patients who had received TPIP in the lead-in study were able to remain on the dose that they had achieved in that study, and patients who had received placebo in the lead-in study underwent up titration to their individual maximum tolerated dose of active drug. During the open-label period, investigators were permitted to titrate patients to the level required to optimize clinical benefit, up to as high as 1,280 mcg. This means that patients who were doing well could remain on a stable dose, while patients who may not have achieved optimal clinical status or who showed signs of disease progression could be further up titrated during the course of the study. The ability to increase the dose of TPIP over the long term is one of the more important differentiating features of TPIP. There is wide variability between patients in terms of their sensitivity to prostanoids, meaning that the initial safe and effective dose will differ across patients. We saw this in the lead-in study where the safety and efficacy of TPIP were demonstrated as the drug was titrated to each patient's individual maximum tolerated dose rather than to a specified dose. Another important aspect of prostanoid dosing is that patients will typically require increasing doses over time as the disease progresses. With parenteral prostanoid treatment, for example, the patient's dose is typically gradually increased over time. However, with the currently available inhaled prostanoids, there is a limit to the ability to titrate the dose up over time, and therefore, patients often have to come off of inhaled therapy in favor of parenteral therapy. As a result of its pharmacokinetic profile, the dose of TPIP can be increased over time in a manner similar to the approach taken with oral or parenteral prostanoid formulations. With this in mind, in this study, physicians were not encouraged to increase the dose. Rather, they were given the opportunity to do so if they felt that a patient's condition warranted it over time. In that sense, they were able to utilize TPIP in the same manner that they are accustomed to utilizing oral or parenteral prostanoids. The primary endpoint of this study focused on the safety and tolerability of TPIP during long-term use. Secondary efficacy endpoints include change from baseline and six-minute walk distance, NT-proBNP, WHO Functional Class, and the REVEAL Lite 2.0 score, which is a validated measure of the risk of morbidity and mortality in PAH patients. Finally, it is important to remember as we review these data, that all efficacy measures in this open- label extension study were taken at trough exposure or roughly 24 hours after the most recent dose of TPIP, consistent with the timing of the efficacy assessments in the randomized trial. On this slide, you can see the baseline characteristics of the patients who participated in this open- label study. It is important to note that all baseline characteristics reflect the measurements taken at the start of the lead-in trials, not at the start of the OLE. We chose that approach so that we could assess the performance of the patients who had initially been randomized to placebo in comparison to those who were randomized to TPIP. The baseline characteristics were comparable between these two groups with only minor imbalances, most notably in the number of background medications. Note that these baseline data describe the open- label study population of 91 patients, not the entire phase II-B lead-in study population, which was 102 patients. This open- label extension study was fed by two prior phase II studies. The first was a randomized, placebo-controlled trial that enrolled 102 patients randomized two to one. A total of 95 patients, 62 treated with TPIP and 33 treated with placebo, completed that study. It is that study that was a major source of patients who rolled into this OLE. Some of you may remember the second lead-in study shown here, which was a single-dose, 24-hour PVR monitoring study that we initiated around the time of the COVID epidemic. We enrolled only one patient in that PVR study and chose to give that patient the opportunity to receive TPIP in the OLE once it was initiated. We were very pleased that 95% of patients who completed those phase II studies chose to enroll in this open-label extension. Of the 91 patients who entered the OLE, 83 patients, or 91%, completed at least 12 months of treatment in the OLE. Of the eight patients who discontinued, four were due to death, none of which were considered study drug-related, three were due to an adverse event, and one was lost to follow-up. For reference, a typical mortality rate for patients resembling this population is around 8%, versus the 4% incidence of death described here. Only one patient, or about 1% of the total, discontinued TPIP due to cost in the first 12 months. TPIP was generally safe and well-tolerated with no new safety signals identified. 89% of patients experienced a treatment-emergent adverse event, the vast majority of which were mild or moderate. 19% of patients had a serious AE, which we believe is in line with what one might expect in patients with serious diseases like PAH over a 12-month period. Only one serious AE was considered related to the study drug by the investigator. That one was a case of orthostatic hypotension, which did not lead to discontinuation or dose reduction of TPIP. The patient was hospitalized and subsequently discharged after a precautionary workup was completed. The most common events observed in the OLE were headache, cough, nasopharyngitis, and diarrhea. Importantly, all TEAEs of cough were mild or moderate, with over 85% being mild. Given that this study is the first to report the clinical experience of patients who received TPIP at doses higher than 640 mcg, we've included some safety information specifically for those patients. Among patients who titrated up to doses greater than 640 mcg, there were no deaths or TEAEs leading to discontinuation. Only 10.5% of these patients experienced an SAE, compared to 18.7% overall, and only one patient experienced a TEAE of cough, which was categorized as mild. There were no new safety signals observed among these patients. Before I walk through this slide, I want to remind you again that the placebo-adjusted six-minute walk distance benefit reported in our phase II-B trial was 35.5 m, which is by far the largest improvement we have seen from a prostanoid in a randomized trial. This figure shows that over the following 12 months, patients in the continued TPIP arm maintained and even slightly improved their six-minute walk distance. PAH is a progressive disease, meaning that you might expect this measure to gradually decline over time, which makes this outcome even more impressive. Patients who had crossed over to TPIP from placebo had a similarly positive outcome on six-minute walk distance. In fact, these patients essentially caught up with the continued TPIP group by month 12, with both groups showing around a 55 m improvement in six-minute walk distance from baseline. This figure illustrates the changes from baseline in NT-proBNP, an important biomarker of cardiac stress. We were very pleased to see that the continued TPIP group maintained its improvement in NT-proBNP during the OLE period after an already impressive result during the randomized trial. Perhaps even more striking, the placebo cross group had completely caught up to the continued TPIP group's result by month six and maintained that benefit through month 12. Both groups showed approximately 60% reductions from baseline at month six and month 12. Now let's discuss the impact of TPIP that we saw on WHO Functional Class. The WHO Functional Classification system categorizes patients according to the magnitude of the limitation that the disease places on their physical activity. Patients in Functional Class III experience marked limitation in their physical activity. While they are comfortable at rest, even less than ordinary activity triggers symptoms, and this can have a significant impact on a patient's quality of life. At baseline, all patients were in Functional Class II or III. By month 12 in the open-label extension, more than 25% of patients in both groups had achieved Functional Class I status, meaning that they no longer had any limitation on their physical activity. And 80% of patients in both groups reached either Functional Class I or Functional Class II. Also encouraging is that 50% of patients in the continued TPIP group and 42% of those in the placebo cross group saw at least a one-category improvement in Functional Class by month 12. Let's move to the topic of risk stratification. REVEAL Lite 2.0 is a validated instrument that has been shown to predict the risk of mortality and morbidity in patients with PAH. This type of risk stratification is commonly used in clinical practice, with many large centers requiring an assessment at every visit. The score is often used in treatment decisions with the aim of achieving low-risk status for the patient. The REVEAL Lite 2.0 score incorporates BNP or NT-proBNP, Functional Class, six-minute walk distance, systolic blood pressure, resting heart rate, and renal insufficiency. High, intermediate, and low scores are associated with a mortality risks of greater than 10%, between 5% and 10%, and between 1% and 5%, respectively, at one year. Beyond mortality, low and refined low-risk scores have been shown to predict improved morbidity as compared with higher scores. Based on the excellent work by Dr. Benza, who we will hear from in a moment, we know that a one-point reduction in REVEAL score corresponds to a 23% reduction in the risk of mortality and a 21% reduction in the risk of clinical worsening. This is important context for the study results on the next slide. On this slide, you'll see the results of REVEAL Lite 2.0 scores. I'd like to note that risk stratification was not one of the pre-specified efficacy endpoints in the phase II-B lead-in study. However, it is a pre-specified endpoint in this OLE. Because we collected all of the necessary elements to calculate the score at baseline time point in the lead-in study, we can now show those data here alongside the OLE data. On average, both the continued TPIP and the placebo cross groups began the randomized trial with intermediate risk scores. While the average score for patients taking placebo remained roughly flat during the 16-week trial, patients on TPIP saw a meaningful drop in score, bringing their average into the low-risk category. Within just six months in the OLE, the mean score in both the continued TPIP and the placebo cross groups had dropped below four into the refined low-risk category. As discussed in the previous slide, this means that at the start of the trials, the average mortality risk for these patients was 5% to 10% at one year. By the end of 12 months in the OLE, their average mortality risk declined to less than 5% at three years. In fact, patients in the continued TPIP group saw about a two-point average improvement, and patients in the placebo cross group saw a 1.4 point average improvement in their REVEAL scores. This is very encouraging, particularly in light of the data that I mentioned previously, which showed that a one-point improvement in REVEAL Lite 2.0 score has been shown to result in a 23% reduction in the risk of mortality and a 21% reduction in the risk of clinical worsening. It is also notable that 65% of patients in both groups were able to reach the refined low-risk category by month 12 of the OLE. Looking at the current PAH treatment landscape, we see established inhaled treprostinil like TYVASO, which have offered meaningful advances but remain constrained by tolerability concerns, dose limitations, and 4x daily dosing. More recently, WINREVAIR has provided another step forward with its potentially complementary mechanism of action, yet clear need remains for improved prostanoid therapies. We believe TPIP could represent the next major advance in the treatment of PAH. While cross-trial comparisons require caution due to differences in patient populations, trial designs, and how and when endpoints are measured, among other things, we are excited by what we have seen from TPIP so far and its potential impact. This slide provides some examples of what we mean. Let me just walk through the first two of them. TPIP's 35% PVR reduction matches the best result we've shown for WINREVAIR's clinical program. On six-minute walk distance, TPIP's placebo-adjusted 35.5 m improvement in the randomized trial and 55 m improvement in the OLE compares favorably to TYVASO's 20 m improvement in the 12-week trial and 25 to 38 m in the OLE at 12 months. WINREVAIR showed a 41 m improvement in a randomized trial and 47 m as the top improvement in its OLE, both of which are relatively comparable to TPIP's results. Similar patterns are shown across other endpoints shown on this slide as well. Once again, I want to emphasize that each of these individual comparisons across trials should be noted with caution. However, it's not the individual data points, but rather the totality of this data that we find so encouraging. Today's results suggest that TPIP has the potential to become the prostanoid of choice and may deliver benefits that could be seen as comparable to those of WINREVAIR. Combined with favorable safety, tolerability, and once-daily dosing, we believe that TPIP would be well-positioned for an expanded role in the modern PAH treatment, assuming future clinical and regulatory success. With that, I'm now pleased to hand the call over to Dr. Raymond Benza to share his thoughts on these data. Dr. Benza? Thank you so much, Gene. It's a real pleasure to be here this morning and to speak with all of you about this open- label extension trial and its fairly impressive results. I'd like to remind everyone on this phone call that pulmonary arterial hypertension is a disease that we treat as clinicians, is probably one of the most devastating diseases that I've treated in my clinical practice. The results of this open- label study really give us genuine reason for optimism. The results, just to put in perspective to the various people on the phone call, were probably the most impressive results I have seen, not only with an inhaled product, but really across the entire landscape of medicines that we use to treat this devastating disease. The impressive efficacy improvements that we're seeing with an inhaled treatment are really quite remarkable. Going back to what we saw in the phase II-B study, both the reductions in PVR and the improvements in six-minute walk test are both well within what we consider the minimally important treatment difference to push our patients in the right direction. What I mean by that is that patients who achieved an improvement in walk distance greater than 30 m not only have improved functionality, but improved quality of life. This is really the measure that we hold all our drugs against because we want people to function better and feel better at the same time. In addition, that reduction in PVR that you noticed is at the accepted range that we need in order to ensure appropriate right ventricular remodeling. Remember, right ventricular remodeling is really the essence of predictability of patient outcome with this disease. Having a reduction that significant ensures that we will have right ventricular remodeling and improved outcome. This is seen very impressively through the very robust changes in the REVEAL risk score. In fact, a two-point reduction is probably the largest reduction in REVEAL risk score that I have seen throughout many of the clinical trials that I've participated in. Achieving ultra-low risk, which we defined as a REVEAL score less than four, not only ensures that our patients are going to survive more, but they're going to survive better because they're not going to have morbidity events, which is really the major thing that we fight now, given the improved overall survival rate with the current landscape of current medications. It does all this with a really great safety profile. The most important thing being the lack of systemic side effects, particularly a systemic hypotension, which we always want to avoid in patients with high pulmonary vascular resistance. I think one of the other points to really stress is that more than a quarter of patients by month 12 received Functional Class I status. This means that people do not even recognize that they have the disease anymore. That is really impressive. In fact, most of our patients always get stalled in Functional Class II, which means they're still symptomatic. Having a large proportion virtually asymptomatic is a really unique finding to this study. The results to me are impressive enough where it will probably change my clinical practice once this drug becomes approved. As I have always considered inhaled products, particularly inhaled prostacyclins, as an edge drug. If I needed to push a person a little bit more in a favorable direction, that was the drug I've used. This changes the entire landscape with TPIP, which is now going to be a major contender for additional therapy when we want to move people from intermediate- risk to low- risk with, I feel, efficacy signals similar to what we're seeing with remodeling therapy like sotatercept, but without the significant side effects that we see with that injectable drug. I just can't tell you how enthused I am with the results of this particular study and very much looking forward to seeing if we could reproduce these results in our upcoming studies. I'd be happy to answer any questions that the audience might have. Thank you, Dr. Benza, for joining us today and for sharing your valuable insights with our audience. Today's compelling results strengthen our conviction that TPIP has the potential to become the prostanoid of choice. Let me summarize the key takeaways that reinforce this belief. First, patients who were initially randomized to TPIP in the prior lead-in trial were able to sustain those best-in-class improvements over 12 additional months of treatment, and patients who switched from placebo achieved comparable benefits. In addition, patients experienced meaningful reductions from baseline in their average REVEAL Lite 2.0 scores, a validated measure of morbidity and mortality risk. Importantly, TPIP demonstrated a favorable safety and tolerability profile even at higher doses with low rates of cough, which was predominantly mild. Given the strength of the results we have shared, we are incredibly excited for what is to come for TPIP. This slide illustrates our TPIP clinical program that is currently underway in four large indications. Our phase III PH-ILD study initiated in December last year, it is currently progressing well. Our phase III PAH study opened its first trial site in April of this year, sites are now screening patients. Our phase III trial in PPF is on track to initiate later this year, our phase III trial in IPF is expected to begin in the first half of next year. Finally, keep in mind that this current OLE study is still ongoing. We expect the 24-month data readout from this trial to be available around this time next year. We are energized by TPIP's potential to transform treatment across all four conditions. Our team remains committed to advancing this program with urgency, knowing that each milestone brings us closer to potentially changing lives for patients who need better options. Before we turn to your questions, I want to personally thank the patients and investigators whose continued participation makes this progress possible. We will now be pleased to take your questions. Operator, may we take our first question, please? Thank you. If you would like to ask a question, please press star one on your telephone keypad. We ask that you please limit yourself to one question. You may reenter the queue for follow-up questions. Your first question today comes from the line of Joseph Schwartz from Leerink Partners. Your line is open. Great. Thanks so much, and congrats on the exciting data. I was wondering if you could talk some more about how TPIP's efficacy compares for the PAH patients who were titrated to higher doses versus those who weren't. Is there as much rationale to believe that higher doses of TPIP could be more beneficial in the other indications you're pursuing? Gene, you want to start off on that question? Yeah. I'm glad you brought it up because this is a topic that comes up fairly often. It brings up the whole topic of how prostanoids are dosed in the clinic and how that differs from how most other drugs are dosed. I tried to address a little bit of this in the introductory comments. I'll make a few comments here. I'm probably going to ask Dr. Benza to give his perspective. It's important to remember how prostanoids are dosed, particularly the oral and parenteral prostanoids. As I mentioned in the opening comments, the inhaled prostanoids have a limitation that they can't continue to be titrated. Parenteral and oral prostanoids are dosed to the individual's sensitivity to prostanoid, meaning trying to achieve the best therapeutic effect while maintaining optimal tolerability. There's a wide variability between patients in terms of how sensitive they are to prostanoids. You may get an equal therapeutic benefit at one dose, but need a higher dose for another patient to achieve the same therapeutic benefit. There's just some intrinsic differences in the sensitivity. With oral and parenteral prostanoids, doctors tend to titrate the dose up, limited by tolerability, to try to achieve best efficacy and land wherever they land for that patient. We saw that in the randomized trial, where we allowed patients to go up to 640 mcg, but some patients stopped before getting to 640 mcg. They were getting good effect. We saw the outstanding hemodynamic effects and six-minute walk distance effects that were shown in that trial. Another point about prostanoids is that over time, patients tend to require more. As we talk to the doctors, and among them, the doctors would like the opportunity in an individual patient to be able to keep titrating up the way they titrate up the, say, Remodulin. That's why we opened up in the longer-term study, we saw it might be necessary. Doctors might want that opportunity. They wouldn't necessarily need it, but they might want that opportunity in an individual patient in order to maximize that benefit. As you saw, the outcomes of these patients were dramatic. If you can achieve a patient in Functional Class I or even II in a low REVEAL score at a certain dose, there's no need. The physician wouldn't necessarily increase the dose. I just want to emphasize that the increase in the ceiling to 1,280 mcg was just to give doctors the ability to respond to any individual patient. It really wouldn't make sense to look at the effect of a patient who the doctor decided to go to greater than 640 mcg and compare that to a patient who was doing well and the doctor decided to stop at a dose at 640 mcg or lower. That's the general background on prostanoid dosing and how to think about dose escalation. Again, in my mind, and Raymond, I'll stop in a minute and ask you to comment on this, but in my mind, one of the problems with the existing inhaled prostanoids is that you get to this maximum dose, and you can't respond to that need by increasing the dose. With TPIP, you can dose it the way you might increase the dose of Remodulin. If a patient came in on parenteral prostanoid, and you thought they could achieve a better efficacy, and they were tolerating it fine, you might increase the dose. We wanted doctors to be able to use TPIP in that same manner. Raymond, maybe I'll ask you to comment on that approach to prostanoids in clinical practice. You've been dosing prostanoids for a long time. Almost 40 years. Having a titratable prostacyclin is really the holy grail of prostacyclin therapy. Not only for all the reasons that Gene mentioned, because some patients do have tachyphylaxis to those and require dose adjustments every now and then. Having the first really titratable inhaled product that improves significantly hemodynamics, opens the window for countless additional opportunities to really push right ventricular remodeling and normalize hemodynamics to achieve complete remission. I am totally excited about the ability to really titrate this drug given the known baseline significant improvements in hemodynamics, so that I can challenge patients when they get at low- risk and try even to push for remission using a titratable product like this. Your next question comes from a line of Jessica Fye from JP Morgan. Your line is open. Hey, guys. Good morning. Thanks for taking my question. I wanted to ask about some potential differences between phase II and phase III in PAH for the clinician, and just the potential implications for the phase III results. The three things that I'm thinking about are, I think in phase III, I want to say six-minute walk is being assessed like one to three hours after dosing compared to trough that was used in phase II. I think the primary endpoint is being assessed at 24 weeks instead of, was it 16 in phase II? Lastly, I know sotatercept is allowed in phase III. I was curious what proportion of the patients might be expected to be on sotatercept at the time they initiate prostacyclin therapy with TPIP, and what implications that could have? Thank you. Thanks, Jessica. Well, Gene, you want to run through the response on that? Yeah, sure. Thanks for the question. Those differences you've identified are right on target. In the phase II study, I think we held TPIP to the highest standard. We knew that we were introducing a drug that would be dosed once daily and wanted to make sure we had evidence that it was maintaining its activity throughout the dosing interval. If we had measured, for instance, the hemodynamics at what might be peak exposure, I think there would've been legitimate questions in everyone's mind, is there still an effect at the end of the 24-hour dosing interval? We chose to kind of actually handicap TPIP in the phase II-B. Some people at the time asked us, "You could probably get better numbers if you measured hemodynamics and six-minute walk at the peak exposure." We decided that wasn't what we needed. What we needed was real evidence to feel confident going into phase III that we were doing the right thing for patients, and that a once-daily administration was, in fact, ideal. That's why we did it at the trough during the phase II study. We recognize that there's cross-study comparisons and effect sizes and so forth, and we also recognize that FDA has allowed the primary endpoint to be at the peak exposure. We've chosen to kind of now put the best face. Now that we know for sure that this is a once-daily drug, let's explore what the maximum benefit is shortly after dosing. That's the intention behind that change. In terms of the duration of the study, right, the phase II-B was 16 weeks. The phase III will be 24 weeks. I think that we are really impressed by the ability to maintain patients in the study. For instance, in this 12-month study, 91% of patients stayed in the study for that time. Often, you worry, and at least I did in the old days of PAH trials, that if you make them super long, you're going to end up with more missing data, and missing data is hard to handle statistically. Maybe we should use a modest treatment duration. We felt so confident that we wouldn't have that degree of missing data, and we also see that patients continue to get better with continued exposure beyond 16 weeks. We've shown some of that data here now, where there's continued accrual of benefit in some of these endpoints. With the phase III, we'll give a longer period for patients to have been on drug, and hopefully, that might translate into even more dramatic findings at least for certain endpoints than we had already seen in phase II. I think your third question was about sotatercept. Obviously, sotatercept wasn't approved at the time of phase II study, so we don't have patients that began the trial on sotatercept. We recognize that that's a new player in the field, and physicians are going to want to know how do these interact? Does it work on top of sotatercept? How should we think about them? Dr. Benza may comment after me. I might bring him in to talk about that. One of the questions will be, when should you move to a prostanoid versus sotatercept? If a patient is on one of these two, what's the benefit of the other one? We think it's important to inform clinical practice to include patients on sotatercept in the phase II trial. We plan to do so, knowing that we don't really know what the added benefit will be. We just don't have that data yet. We're making some cautious assumptions about the effect size that we might see in patients who are already on sotatercept to inform the powering of the trial. We're going to limit the number of patients who are on sotatercept, who are allowed to be on sotatercept as background. We'll get some information, but we don't think we're jeopardizing the end result of showing efficacy because we'll have plenty of patients who are much like the patients we've seen in the phase II study. We hope and expect that there will be added benefit on top of sotatercept, although we're not counting on it. Let's see. That's it. Maybe, Raymond, you had some comments about when we spoke about this data, about sotatercept and its role, and how you might use a drug like TPIP if we continue to show the type of effects that we've seen so far. I think it's going to be a really interesting decision tree point. As we use sotatercept more and more, we're continuing to see additional issues with this product that we hadn't seen in the randomized clinical trials. Including the increasing number of patients we're seeing with exercise-induced hypoxia due to the development of AV malformations in the lung and intrapulmonary shunting. Not to mention the pericardial effusions and other potential side effects that we see with sotatercept. In my mind, having an inhaled product with a safety background that we have demonstrated could make it a very close competitor with sotatercept in the decision tree when you're on someone with dual upfront combination therapy, and you're looking for a third medication to push them to low- risk. I think TPIP, if it continues to show these type of favorable effects, will be a competitor to sotatercept in that area. Jessica, just to clarify, on six-minute walk, we are measuring primarily at the one to three hour after administration, but we are also taking measurements 24 hours after administration. We will have that data to compare to what we saw in phase II. It's worth noting that the 24 weeks versus the 16 weeks also will permit a longer period of uptitration should the physician conclude that for that individual patient. They want to go to a higher dose to try to achieve some of these in what has been characterized a remarkable reduction to refined low- risk categories in the REVEAL Lite 2.0 score or Functional Class reductions, which is certainly the goal of therapy. It also gives us an opportunity to really look for true right ventricular remodeling, because that doesn't happen overnight. I actually like the longer observation period to determine if that's something we can actually achieve. Your next question comes from a line of Ritu Baral from TD Cowen. Your line is open. Good morning, guys. Thanks for taking the question. I think that some of the client focus I've been getting this morning, guys, around the higher doses is less Gene comparison across patients, understanding that they can get to different required levels of treatment, and more about how these patients fared intra-patient as they dose escalated. I believe at one point you had mentioned that seven patients were able to get up to the 1,280 mcg. As you followed these patients, did they have continued improvement in six-minute walk or proBNP as they dose escalated? As they tolerated that dose escalation, were there any patients that had to then dose reduce because of the cough that was triggered after a certain dose? Thanks. Gene, go ahead. Yeah, thanks for that. These become very complicated to try to assess over the course of time whether the increase in dose that a doctor decides to go to has resulted in a benefit. We haven't done those kind of analysis. I think they have to be very fraught. I think that the main point here is that we're giving the doctors the ability, if they so choose, to maximize the benefit in those individual patients. The end result is an assessment of what that strategy achieves. That strategy of allowing patients to go wherever they need to go, achieves the results that we've shown here. The number of patients that achieve a Functional Class I and the reduction in REVEAL scores and so forth. It's that strategy, rather than looking at the individual patients I think we have in the deck that in terms of the safety as we continued, of course, to me, that's the main question. It's not should you compare the efficacy, how they were doing before and after, because presumably the doctor made the decision to increase the dose for a reason. Ultimately, we see the results that we've seen. My focus really was on, are we going to start to see the emergence of any new safety signals as we got higher? That really wasn't the case. I think in the slide deck, we show that in those patients who went above, because a lot of attention is paid to cough. We feel like cough has not been extremely problematic. We don't have a lot of dropouts due to cough. If you look, which we did look at the patients who received greater than 640 mcg, there was only one TEAE of cough, didn't lead to discontinuation or anything. We felt like there was nothing that emerged in terms of safety. It was the typical, the same pattern that you might see at lower doses in patients who are more sensitive to prostanoids. Your next question comes from the line of Vamil Divan from Guggenheim Securities. Your line is open. Great. Thanks for taking the questions. Congrats on the data. I do, again, on the titration question, a couple of follow-ups I could. One, it sounds like there were 19 patients that got over 640 mcg, seven that got to the 1,280 mcg. What was the reason or limiting factor in terms of why your patients were not able to get all the way to the 1,280 mcg? Maybe you can just share that. What is the plan in phase III in terms of how dose titration is being managed? Is there specific criteria or is it more left to the investigator's discretion? Any details there would be helpful. Just to clarify, in all of our phase III studies, we are permitting patients to go as high as 1,280 mcg, which is a remarkable opportunity for physicians to get to those higher doses. It is important to understand that many of these patients, as demonstrated by the fact that we're able to get 65% of patients in both groups to the refined low- risk category by month 12. In some of these cases, the physician's making a decision they don't need to go any higher because they're getting the patient to the asymptomatic goal, which is a remarkable accomplishment and outcome. Gene, do you want to comment on this question? I think you put it just right. For that reason, there isn't like a CRF in the case. There isn't an entry of, "Hey, this patient isn't at 1,280 mcg." Why aren't they? Because that's not really a clinically relevant question. We're not intending or expecting every patient to get to that dose, nor are we wanting to imply to physicians that they should. Physicians dose these medications, and in certain circumstances, add another medication in clinical practice in order to achieve what the clinical outcome they desire in that patient, hopefully to move that patient to as low- risk as can be. If a patient is at a low- risk status, the patient is doing well, there would be no reason to keep dose escalating, we wouldn't really query the doctor, "Hey, why haven't you?" If you have a patient with a REVEAL score of 2 and a Functional Class I, there's no reason to ask them, "Why haven't you increased the dose any further?" Raymond, this is really, to me, kind of challenging, and it reflects the prostanoids themselves, how they're dosed in the clinic, and because they're dosed differently than other drugs. This sort of goal-oriented treatment which has emerged over the last decades, where the goal is to improve patients into a low- risk category, and be happy when you're there. I can see from these questions that it's a little bit confusing. I think it's best maybe to hear from Dr. Benza, his perspective on these issues. In other words, why wouldn't you, if you have a patient on parenteral treprostinil, just turn the knob all the way to the right, rather than being guided by their clinical circumstance. Raymond, can you help with this kind of complex topic? The decision to titrate parenteral prostacyclins or any prostacyclin really revolves around several central issues, and they're all related to achievement of various goals. Obviously, we want to achieve low- risk. In most patients, we will continue to titrate parenteral prostacyclins until we achieve low- risk status. That is probably our primary goal and the primary reason for titrating actively prostacyclins when they're first initiated on patients. The second thing is really to achieve secondary goals. Once we've achieved low- risk, we look to determine whether, one, we can achieve hemodynamic remission, meaning normalization of PVR, cardiac output, and right atrial pressure. Secondly, we determine whether there's a further need to restore right ventricular function to normal. Those are two other reasons, once low- risk status is achieved, to continue to titrate prostacyclins in any form. The ability to do that with an inhaled product is now opened with TPIP. We've never been able to do this with our other inhaled prostacyclins, and the fact that we can almost double the dose and achieve levels similar to what we see with parenteral prostacyclins is very impressive with a once-day inhale product. This really opens the door for not only our standard titration schemes but also these alternative titration schemes that are ultimately very important. The last thing to note is that as we've mentioned several times before, many patients who are on stable doses of prostacyclins need a little tweaking now and then. Not only because they can tachyphylaxis to prostacyclins at certain doses, that doesn't happen with everyone, but in a small minority of patients, this tachyphylaxis is a real phenomena, you have to increase doses to make sure that you continue to keep someone at low- risk. Your next question comes from the line of Olivia Brayer from Cantor Fitzgerald. Your line is open. Hi. Good morning, guys. Thank you for the question. Another follow-up from me on higher dose levels. Have you seen anything from the OLE that maybe changes how you're thinking about the potential to see a dose effect in your phase III programs? Had we planned to actually look at dose response in the phase III as you try to measure the different titration schemes? If I could ask a question on cough. Maybe just what do you make of that 15% cough rate? It looks like you're maybe just looking at new onset of cough. Is that reported number lower just because it's a bigger denominator of patients? Or is there maybe something else that you're seeing around a better cough profile? Just trying to get a better understanding of where that number comes from and whether patients who previously reported cough were excluded, even if they did have a lingering cough. Thank you so much. Sure. Let me just make it very clear. There is nothing in this study that does anything other than encourage us to believe that our phase III data will be nothing short of impressive. These results, getting many of the patients to an asymptomatic status is, to the best of our knowledge, without precedent in this quantity. To do so with the mild safety profile that's presented here, I think is what we find to be most compelling. Now we will apply that to broader groups of patients with different conditions. Giving the physician the ability to go all the way up to such a high dose level affords many benefits, one of which is that you can continue to increase the dose to achieve the best possible outcome for the patient. As Gene and Dr. Benza have mentioned, over time, should the need to increase the dose present itself, that opportunity will remain for the patients that aren't already at 1,280 mcg. This opens the door to a usage of this drug in a way that is without precedent at the moment. That's one of the things we're very encouraged by. Gene, do you want to go through perhaps some of her points directly? Yeah, sure. Again, this gets to how prostanoids are different than other drugs. For other drugs that are being developed, you need to do a phase II dose ranging. You randomly assign patients to two, three, four different doses, and you see the dose response. Prostanoids are not dosed that way. If you look at the oral prostanoids, the parenteral prostanoids, there wasn't a selection of a particular dose. It was an accepted dosing strategy, and it's obviously accepted by the FDA and accepted in terms of our phase III trial design, that we're not doing a dose response. We're testing that if you administer prostanoids in this way with an individually maximum tolerated dose approach, what's the safety and what's the efficacy? There's no comparison of how people that got to one dose compare to people that got to another dose because those aren't randomly assigned. Those are defined by individual patient biology. I think it's in keeping with a lot of the discussions today, and I'm really glad we're having these conversations because it is complex. We shouldn't look at phase III, nor phase II. We didn't do a dose response trial because that's not what's done with prostanoid therapy. We're testing the strategy of if you take this drug and you administer it in an individually maximum tolerated dose, what's the ultimate safety and efficacy of that approach? I think I just want to make that point in terms of dose ranging and such to keep in mind that this is different. We obviously agreed with the agency on this. We came out of phase II, and they said, "Fine, go to phase III." The designs of the other parenteral and oral studies reflect the same idea that it's an IMTD dosing approach rather than a specified dose. I think your second question was about cough and noting that the incidence of cough overall was 15%, I think it was higher in the phase II in the active, maybe 40%. I think these AEs are AEs that are new after entering the study, so there may be doctors who didn't continue to report cough in patients who came into the study on a cough. Probably the best way to do kind of apples to pears is to look at the data in the open- label. What's the incidence of cough among patients who crossed over from placebo? I don't believe that's on the chart, but I can say that that's about 26%. If patients came in on placebo and then were obviously not randomized, they began on active drug, cough was about 26%. That's roughly, it's a little bit lower than what we saw in the phase II trial, but I think within the realm of noise. Importantly, of those 25%, I think it was eight patients, all of them but one were mild, and I think there was one that was moderate. None of those caused, I think ultimately the test is the cause problematic such that you come out of the trial. None of them led to discontinuation. That may help to put into context why you're seeing on the slide that we showed a percentage that's 15% went in the randomized trial. It was higher in the active group, and I think all those factors come into play. Your next question comes from the line of Leonid Timashev from RBC Capital Markets. Your line is open. Hey, guys. Thanks for taking my question. I just want to stay with the safety topic for one minute. There were a couple of AEs of anemia and then some of nose bleed. I don't necessarily recall these earlier, I was wondering if that's a new signal, if that's somehow related to the underlying disease? Or if that was in any way correlated to the higher dose? Thanks. Gene, do you want to take that? Yes. I'm pulling up the chart in front of me to see. I think these are kind of background adverse events that one might see in any population and maybe in the PAH population. We have not looked at this and said this is any new signal at all. I'm very clear about that these kind of background low rates over the course of a year. There are going to be some differences in terms of the frequency that you might see any random adverse event in a study that's 16 weeks compared to one that's done over a year. And over a year, almost all patients are going to have some AE, and that's what we've shown in the high 80s, almost 90% had any AE. Over time, you're going to start to see things. There's nothing that we're concerned about in terms of, I think you mentioned anemia. There's no suggestion that prostanoids could cause anemia or that it's a drug-related phenomenon. I think I'll leave it at that. Your next question comes from a line of Matt Phipps from William Blair. Your line is open. Thanks for taking my question. Congrats on good to see durability here with longer follow-up. Just wanted to clarify on the dose again. The 19 patients who achieved greater than 640 mcg dose, was that at month 12 or at any point throughout the OLE? I guess, were there other patients there that got above but then went back down? Thank you. Gene? Yeah. This is the output that comes from statistics. I'm not 100%, I'm pretty sure this is anyone who got to that level, and I don't have the data on anyone who got to a particular dose who went back. Frankly, that could have happened anywhere along the line. I'm not that interested in finding it out because if a doctor decides, "You know what? I'd like to go up a little higher. Oops, you're having something that you don't like. Let's drop back down." That is typically the way things happen with prostanoids, so it's not something that I paid a lot of attention to. I can't say for sure whether anyone in the 12-month period reached 1,280 mcg and then dropped down a little bit. Again, I don't find it all that clinically important, but I don't have that information at the tip of my tongue. Sorry. Matt, we can find it up for you and get it to you. Your next question comes from a line of Faisal Khurshid from Jefferies. Your line is open. Hi, guys. Thanks for taking our question. Wanted to ask how is the phase III enrollment going, and to what extent is the availability of two commercial therapies a gating factor to enrollment? Thank you. The enrollment is, I would say, ahead of schedule, and I suspect that with these data in circulation, we may find additional attention and excitement for bringing patients in. I don't know if, Gene, you want to comment, or anyone else, frankly, from the Insmed team on the other question with regard to the other therapy and the availability and that impact. We have not had that as a point of concern, but I don't know if there's any more specific commentary anyone wants to provide. Yeah, what I can provide is that- Go ahead, Martina. I think you're the expert on that too. What we can say is we've received a lot of interest from sites to be part of that study, and that is actually what we've seen across from the U.S. as well as on a global level. The progression of sites initiation is going well, and I think with additional data such as this becoming available will further fuel the interest, but on the patient as well as on the physician side and the investigators to enroll in this study. Maybe just going back to the question that was asked before, because as you know, in the 12 months data, we had three participants who reached the 1,280 mcg before month 12, and none of those patients required a dose reduction. Just to follow up on that one. Your next question comes from a line of Maxwell Skor from Morgan Stanley. Your line is open. Great. Thank you very much. Is there anything in the OLE data or given the high-dose tolerability that's changed your enrollment or dropout assumptions for the phase III study? Just one more question on dosing. Do you just think, or could you give us some guidance on whether the lion's share of patients in the phase III you think will be dosed above 640 mcg? Any color around that would be helpful. Thank you. Yep. Nothing that we've learned from this study has changed any of our assumptions driving our approach to phase III, other than our obvious enthusiasm for the outcomes we've seen here today. I can't recall the other question. Maybe Gene, you can take it. Yeah. This is our expectation of what kind of spectrum of doses that we will see in the phase III. As was mentioned before, it's 24 weeks, there will be more opportunity for doctors to increase the dose. I would predict maybe that compared to phase II, which was a little bit shorter, there will be more patients that reach 640 mcg and want to go higher. It's a little hard to look at the 12-month study and say they will reach the same dose that the patients that have 12 months to keep increasing the dose. In the phase III, patients will be able to dose range throughout the bulk of the study, toward the end, there will be a period where we sort of lock in on the dose and want people to be at a stable dose for the last certain period of the trial. That's what we did in the phase II trial as well. I think that the bottom line is we have this ceiling of 1,280 mcg now, and there may be some who get that high. I would expect not the majority by any means. Again, if patients are doing well in a low-risk status at 640 mcg or even below 640 mcg, I would expect they would stay there. The point is that we just want to give the doctors the opportunity to manage the TPIP in the way that they manage parenteral. I think the one thing I would just emphasize is that this was a safety study. Its primary goal was to establish safety. I do think that this study clears the path and provides some comfort for physicians in all the phase III studies that should they wish for whatever reason to go to a higher dose, they can expect these data to inform what the side effect profile would be. I think that's probably the most compelling part of this is that you can go higher and the side effect profile doesn't really change. That is a remarkable opportunity as physicians think about the trade-offs for trying to achieve that lowest- risk score for these patients, returning them to an asymptomatic status for patients with this condition. That range of opportunity now presents itself and gives them a lot more incentive, I think, to explore pushing patients to get to that more favorable outcome. That's really what the goal of the introduction of this therapy is all about. Can we get these patients to this asymptomatic profile? These data suggest that indeed, for many of them, we can. Your next question comes from the line of Jason Zemansky from Bank of America. Your line is open. Good morning. Congrats on the data, thanks so much for taking our questions. Gene, to follow up on an earlier point you brought up, have you observed any difference in the degree or timing of the tachyphylaxis between TPIP and native treprostinil? Appreciating it may be somewhat early, but beyond improved efficacy, are there any signals the prodrug could support a more stable or durable treatment effect? Then real quickly for Dr. Benza, I was hoping you could provide some quick qualitative feedback on the patient experience and the side effect profile looks improved over the native molecule, but just wanted to get a better sense of how that was translating into terms of treatment burden? Thank you so much. Over to you first, Gene, then Dr. Benza. Yeah, sure. The first part of it had to do with tachyphylaxis. As Raymond mentioned, that's one of the elements that can come into play in terms of why doses are slowly increased over time in certain patients, but not others. Also, there is the possibility of disease progression that would require higher doses. It's kind of a complex thing as to why and when a dose would be increased to push for maximum benefit, to drive down the REVEAL score, for instance, to deal with any tachyphylaxis that's happening at a molecular level, to deal with progression of the disease and so forth. All those things are interplayed. I can't think of a reason why the prodrug formulation would alter that overall dynamic. In other words, like a molecular tachyphylaxis, because the prodrug itself is inert, and it's really just a slow release of the active drug. Biologically, it's the active treprostinil that would have its biological effect. I'm going to think about your question, but at the moment, I don't think of a reason why the TPIP formulation would particularly impact molecular mechanisms of tachyphylaxis which are a number. This is a G protein-coupled receptor which can be subject to that. I'll say that about your first portion of the question and maybe turn it over to Raymond for the second portion. Pardon me, this is the operator. Dr. Benza has disconnected. He had to see a patient. Sorry about that. He warned us that a patient was coming. Sorry about that, Jason. Yeah, no, obviously. Jason, we'll track down Dr. Benza for the answer to your question. Your next question comes from the line of Ellie Merle from Barclays. Your line is open. Hi, this is [Jasmine] on for Ellie. Thank you for taking our question. It seems like the time to benefit from TPIP is very rapid. When looking at this data, do you think there's room for continued improvement beyond 12 months? At 12 months or even six months, patients are kind of reaching near their maximal treatment benefit? Thank you. Gene, over to you. It's always interesting to hypothesize about what would happen. We don't have, obviously, data to inform it. When we look at the patterns of achieving, for instance, six-minute walk distance benefit and seeing that maintained, there's probably a ceiling. We have 55 m of improvement compared to the baseline. I wouldn't expect necessarily that to go to 60, 70, 80, 90, 100 over time. I think more important in this disease is showing that benefit and then showing stability. You point out there are some other endpoints, like the BNP happens pretty quickly. If you look at the curves, it looks like that sort of predates a little bit of the six-minute walk distance benefit, and that makes sense to us, showing initially a decrease in right heart strain and then temporarily that turns into a benefit in six-minute walk. The more comprehensive assessments like WHO Functional Class or REVEAL, you're right, there does seem to be some continued improvement. It's hard to know after, I'm looking at the WHO Functional Class and the large number of patients who are Functional Class I, 25%. I don't know whether to expect after month 12 into month 24, whether we'll see even more. That would be wonderful, but I think I'm just tempering my expectations because this is a bad disease. This is a progressive disease. It's just hard to know how much we can prevent, ultimately, things getting worse over years. Seeing the stability. I'm really excited about this data because we showed that the 16-week data, that was fantastic. The question is: how will people be after a more prolonged use? We're showing this, in some cases, continued improvement and stabilization in a progressive disease. I just think it's great. Although, of all open label studies, in a disease like this, looking at year-long data really makes you think you can see the effect of the drug. You would not have patients becoming asymptomatic without an intervention. I don't know what to expect. My ultimate would be that you'd see this level of benefit continue beyond month 12. I suppose it could be possible there could be continued accrual of more patients in Class I and so forth. Your next question comes from a line of Andy Chen from Wolfe Research. Your line is open. Hi, this is [Jason] taking it for Andy. Congrats on the results. I just wanted to ask in terms of titration. I know that you guys are doing titration for both this trial and for phase III? I just wanted to see what you guys expect for real life dosing and how that would play into pricing? In terms of what are your plans for PH-ILD and if this trial kind of guides this PH-ILD trial towards a different direction? Thank you. We haven't made any decisions as it relates to pricing. As we get closer, we'll have more to say about that, obviously once we see the data from phase III. The other question I'll flip over to Gene if he has any commentary or anyone else. In terms of real world dosing, I would expect the physicians who are participating as investigators in this trial are generally well experienced PAH physicians, and they're using it the way they will likely use it if and when it gets approved. I would think it would be a similar pattern where doctors would be informed by the label as to what we did in this trial. It would be this initial kind of more rapid uptitration to a level that they feel like the patient tolerates and is achieving something in terms of clinical benefit. Over time, as Dr. Benza mentioned, this ability to continue to titrate a prostanoid that's inhaled, I think will be very welcome. I think I would expect the real world dosing to be reflective of what we're seeing here and what we'll continue to see in the remainder of this open label study, which goes for another 12 months. Your next question comes from- Just to add on the PH-ILD. Sorry, I think you asked about PH-ILD and the other trial. We allow and encourage in the protocols dosing as high as patients tolerate, so they can, in all of the trials, go up to 1,280 mcg. I see. Thanks. Your final question comes from a line of Sam Lee from Mizuho. Your line is open. Hi, this is Sam on for [Graig]. Thanks for taking our questions. Sorry for the noise. Maybe for the patients that didn't achieve the low-risk category, are there any theories or trends that could explain why those patients didn't reach that low-risk profile? Another question on potential commercial side. Assuming approval, what would you say is the strongest argument for patients that are on WINREVAIR that would compel physicians to switch or add on TPIP? Thank you. Go ahead, Gene, on the low-risk profile. Yeah. That's a good question. I understand where it's coming from in as much as doctors are trying to adjust medications to achieve the lowest- risk possible in any individual patient. Some of these patients were very severe to start with and had late-stage disease. So that would be the doctor's judgment of, what do I do? I have a patient on a certain dose of TPIP. Do I want to increase it? They also had the opportunity, if they thought there was room, then they needed to add other drugs. They generally did not do that. I think there was one patient where a drug was added. For the most part, they were for the constellation of clinical reasons, and it's too bad Raymond is no longer here to talk about the complexity of the decision-making. They were comfortable sitting on the patients, for instance, in WHO Functional Class II. Maybe they dropped from WHO Functional Class III, and they felt like that was a good outcome, and they've done what they can, and they didn't want to be more aggressive in terms of either increasing the dose of TPIP or adding another drug and so forth. It's a little hard to put yourself in the mind of each individual doctor about why they made the decision they made for a particular patient who is not in the, for instance, the reveal refined low category. Why aren't they being more aggressive? It's a really complex clinical decision. In regards to your question about WINREVAIR and why might they choose to add Arzone or WINREVAIR and how is that calculus decided? Building off of Gene's comments, it's obviously going to be specific to each patient. It is worth noting that I think what today's data presents is the opportunity to achieve lowest- risk status in a large number of patients, which I think is very exciting. I would also observe that the side effect profile that was mentioned by Dr. Benza is part of his calculus as he thinks about WINREVAIR versus TPIP. In a perfect world, our ambition is that all the patients get to that lowest- risk asymptomatic category, and some of the calculus that will go into which drugs to choose, it's going to be different for every physician. I was struck by Dr. Benza's comment that he would be, in fact, thinking of this versus WINREVAIR as he's making his own treatment decisions. One could theorize that they might be used together to achieve that outcome, or the third drug that's added in the usual repertoire might, in fact, be TPIP. What we've heard is that physicians do think that these data, if they are sustained in phase III, really change the way that they will use this prostanoid in the treatment paradigm. That's probably the most disruptive and exciting dimension or conclusion from the data that are presented today. This concludes today's conference call. We thank you for your participation, and you may now disconnect.