Study Result

Jan 19, 2021

Good afternoon, and welcome to the presentation of the increased study results in pulmonary hypertension associated with interstitial lung disease. I'm Dewey Steadman, Head of Investor Relations at United Therapeutics. Please note that our presentation today will include forward looking statements, and I encourage you to read the risk factors in our most recent quarterly and annual reports filed with the SEC for risks and uncertainties that may cause our actual results to differ. Today, we're pleased to have Doctor. Stephen Nathan, who the Director of the Advanced Lung Disease Program and Director of the Lung Transplant Program at Inova Fairfax Hospital in Falls Church, Virginia and a key INCREASE study investigator. Doctor. Nathan will dive into the increased results. Following Doctor. Nathan's presentation, Michael Vinkowitz, our President and Chief Operating Officer of United Therapeutics We'll provide an update on our commercial plan in PH ILD, assuming an April approval of the pending supplemental new drug application. Following Michael's presentation, we will host a Q and A session with Doctor. Nathan Doctor. Lee Peterson, our Vice President of Product Development Michael and James Edgmon, our CFO. Please note that if you've dialed in today's presentation and would like to ask a question, Please email me at irunitherd.com so we can identify you before you ask your question. And also given the opportunity to have 2 experts like Doctor. Nathan and Doctor. Peterson available for us, we ask that you limit your questions to the increased data in our increased specific commercial plans. Finally, today's slide presentation is available on the Events and Presentations page at ir. Unithur.com. And with that, I'll turn it over To Doctor. Nathan. Thank you, Dewey. It's a pleasure being here today and Thank you for the opportunity to present what I think is a very exciting and really groundbreaking study. It was a privilege for me to be part of the steering committee as well. And a lot of this data that I'm presenting today, I did present at the American Thoracic I'll let everyone speed read my bio, but suffice it to say, I've been Doing interstitial lung disease and pulmonary hypertension for the last, gosh, 25, 30 years. And this has been a particular interest of mine is The intersection of the 2 when pulmonary hypertension meets interstitial lung disease. I remember writing a State of the art or perspective for our blue journal in 2007, where I provided the literature at that time linking Attention with IPF in particular and one of the subtypes, the subtype to the perspective that I wrote was connecting the dots. And I think that this study is really the final dot to be connected now that we have a treatment which helps patients with Interstitial lung disease complicated with pulmonary hypertension. So let me see if I can advance. There we go. By way of further background, we have when we talk about pulmonary hypertension, there are 5 different groups. The group 1 Or what we refer to as pulmonary arterial hypertension are where all the PH medications are approved. There's only one that's approved outside group 1 And that's riociguet, which is approved for CTEF for chronic thromboembolic pulmonary hypertension and that's Group 4. The 2 largest groups really when it comes to pulmonary hypertension are group 2, which is pulmonary hypertension due to heart disease. Nothing has been shown to work there. And what we're going to be talking about today, group 3 pulmonary hypertension, where there's been nothing shown to work prior to the INCREASE study And which is a very large group as well. The 2 main subdivisions within lung disease are obstructive lung disease, primarily COPD And interstitial lung disease and that's where the INCRE study was focused. So nothing approved in Group 3 yet. Everything that's available approved in Group 1 and any one drug approved in Group 4. So if we look at Interstitial lung disease, it's a very broad group of different diseases, literally 100. And if you open any textbook, 150 to 200 Cause of interstitial lung disease. Once pulmonary hypertension supervenes and I think there's a lot of emerging data that as the disease progresses, as interstitial lung disease And invariably most of these do, then pulmonary hypertension supervenes. And what you can see in the graph to the right, this is from a registry out of Europe, the PARO registry is looking at the prognosis of idiopathic pulmonary arterial hypertension versus pulmonary hypertension related to IIP. As pulmonologists, we're very good with these different acronyms, which tends to confuse everyone, including ourselves. But IIP are the idiopathic interstitial pneumonias. That's one of the largest Subgroups of ILD, the idiopathic interstitial pneumonias, the prototypical illness under the IIPs is idiopathic pulmonary fibrosis And that's where a lot of the data comes from. So IIP, IPF, ILD, if nothing else, I'll confuse everyone by the end of the day. If one looks, this is generally an overview of epidemiology of ILD, so pulmonary hypertension complicating interstitial lung disease and you can see estimates there of cases annually. What's interesting if you look at ILD and you look at the actual incidence versus the prevalence, you can see that the if we look at Males to start 31.5 new cases per 100,000 and the prevalence 81 cases 100,000. When you have a incidence that's very close to the prevalence, that tells you something about the prognosis of the disease. And If you look at IPF in particular and look at the literature, median survival 3 to 5 years prior to the anti fibrotics. And what we do know is that once pulmonary hypertension Then patients fall to the left of the curve. Once patients develop pulmonary hypertension in the context of ILD, their prognosis is significantly worse. As you can see from what the slide says, most of the studies looking at this have been case series retrospective. And if one looks at the Incidents or the prevalence of IPF in particular, it's estimated anywhere from about 150,000 to 200,000 And IPF probably represents about 1 third of all the interstitial lung diseases. So if you look at the broad universe of interstitial lung disease, Probably 5000,000, 600,000 and that might even be an underestimate. I think we're seeing more ILD as we're dealing with an aging population. There's actually one study that has not shown here looking at incidental evidence of interstitial lung disease in various populations, various And it worked out that about 7% to 9% of patients who got CTs as screening for lung cancer had some evidence of interstitial lung disease. Some of those might stay stable, but some of those might go on to develop overt interstitial lung disease. So I think ILD is kind of emerging as maybe a higher incidence than what we previously appreciated. And you look at what's happening today with COVID in particular, And we're seeing a good number of patients end up with residual interstitial lung disease after COVID. So I digress a little bit. If you look at pulmonary hypertension and the incidence of pulmonary hypertension in ILD, that's very widely vary from anywhere from 15% Up to 86%. And it really depends when in the disease course you look for it. If you look for it early, it will be about 15% of the patients. If you look for it late At around the time of transplant, it's around 85%, 86%. So it seems invariable that as these diseases do progress and invariably they do, At some point, they're all going to develop some measure of pulmonary hypertension. What is the mechanism of the pulmonary hypertension? This is it's much more complicated than we previously thought. We used To think that well, very simple linear relationship, the more fibrosis, the more pulmonary hypertension, the more vessels that are destroyed, the more pulmonary hypertension. But it's much More complicated than that and there are probably a lot of interrelating factors involved. Sometimes the pulmonary fibrosis or the Lung disease is not that bad and the pulmonary hypertension is what we term disproportionate to the level of the underlying interstitial lung disease. I'm not going to get into this cartoon depiction. Suffice it to say there are probably many elements that exist that lay the foundation for pulmonary hypertension. What's interesting is a concept that I referred to as cytokine crosstalk. In other words, some of the same cytokines that are important in the genesis Of interstitial lung disease play a role in the genesis of pulmonary hypertension. So that might be another factor that's involved. Looking at some of the studies that have been done previously, we'll start off with at the top of here Sildenafil. Was studied through the NIH IPF network in a study called the STEP IPF study that was published in the New England Journal in 2012, this was a negative study based on the primary endpoint of a 20% change in the 6 minute walk test, although certain metrics Like quality of life, oxygenation, diffusing capacity, secondary endpoints did point in the right direction. So there was a suggestion of some efficacy But that hasn't been further validated. Now the endothelin receptor antagonists of which are 3 placentin, masotantin and bracentin Have all been studied in IPF in particular, but they were looked at for the anti fibrotic effects and not for their pH effects. So these Studies invariably were agnostic to the presence of pulmonary hypertension, although ambrisentan was looked at in pulmonary hypertension in particular, That was the ARTEMIS IPF study, the ARTEMIS PH study, but the ARTEMIS PH study was stopped early when ARTEMIS IPF was clearly a negative study. Riociguet has been studied in a very similar patient population to what we're going to be talking about. This was the RISE IP study. I was privileged to be the global PI for the study. And unfortunately, not only was it a negative study, but it was a harmful We actually got a call from the Data Safety Monitoring Committee saying we think you should stop your study. So rheocigarette is actually contraindicated In idiopathic interstitial pneumonia is in interstitial lung disease because of the RISE IAP study. I was also privileged to be the co chair of the task force that wrote the last guidelines for group And these were published in the European Respiratory Journal early in 2019, so exactly 2 years ago now. And we came up with this algorithm to try and help people work their way through Group 3 pulmonary hypertension. This is going to be Much more of a hot topic is when do you suspect it and when do you look for it and when should you go seeking it? Previously, I think folks were a little bit nihilistic about pulmonary hypertension complicating interstitial lung disease because the invariable response was, well, if I'm going to find it, What am I going to do about it? Well, now there's going to be something to do about it, namely using inhaled treprostinil. So I think the ante has been raised in terms of screening for pulmonary hypertension and looking to find it so that we can help these patients. This gets to the construct So the trying to differentiate Group 1 from Group 3 pulmonary hypertension, I'm not going to get into that, because Clearly now we have something that works for Group 3. So whether it's Group 1 or Group 3 is not so important in interstitial lung disease anymore because we have a drug that works for both group 1 and group 3. This at the bottom over here, and I remember sitting with my Fellow task force member saying, hey guys, we've got to say something more than this, but there was really no data to support saying more than this other Individualized care, we couldn't be more prescriptive, even though I wanted us to be, but there's nothing to say because there's no evidence to And if we had to rewrite this algorithm and flowchart today, I think it would be quite a bit different. So let's move on to the INCREASE study, which was a multicenter randomized double blind placebo controlled study to evaluate the safety and efficacy of inhaled in patients with pulmonary hypertension due to interstitial lung disease, Group 3PH. These were it was a one to one design. These were the inclusion criteria. Patients had to have various forms of interstitial lung disease and I'll show you which forms Qualified for the study. They had to have pulmonary hypertension documented by Ryan Hart Kath By the old definition, so mean PA pressure greater than 25, wedge less than 15 or equal to 15, so no group 2 disease and a PVR of at least 3 or more. They had to walk at least more than 100 meters, so we didn't want them to be Totally limited by the underlying lung disease. For those patients with IPF, they could be on one of the anti fibroids either nintenum or profenidone. And we did include patients who had connective tissue disease. Now connective tissue disease can give you group 1 pulmonary hypertension Or you can have interstitial lung disease due to connective tissue disease giving you group 3 pulmonary hypertension. So if they were included with connective We wanted to make sure that they had significant interstitial lung disease. So for this group in particular, their forced vital capacity needed to be less than 70% predicted. I'm not going to read through all the key exclusionary criteria, but they couldn't be on any other PH medication, they couldn't have any significant heart disease. Couldn't be on too much oxygen, couldn't be actively engaged in pulmonary rehab or have a recent pulmonary embolism. This slide can be a little bit overwhelming. I warned you about interstitial lung disease and all the various subgroups And I'll just focus on a few over here. So here we have interstitial lung disease. What's in green is patients who could qualify for the clinical trial. The idiopathic interstitial pneumonias of which IPF is the most common. Then we have its Less evil cousins NSRP has a better prognosis. RBILD, DIP, these are respiratory bronchiolitis, interstitial lung disease, Desclamat of interstitial lung disease, these are significantly more rare than these other 2, so very few patients who came in with these diagnoses. One condition that can be very difficult to differentiate from IPF and was included in the study is chronic hypersensitivity pneumonitis. So Patients breathe something in, usually an antigen in bird poop is the major culprit for this Moles can be a culprit for this, but this isn't idiopathic, there's a known cause, chronic hypersensitivity pneumonitis. We did include CTDs, Connective tissue diseases, occupational lung disease and then CPFE is the shortened acronym for combined pulmonary fibrosis and emphysema. So that's a distinct subgroup that could be included as well. The primary endpoint was a change in the 6 minute walk distance measured at peak exposure from baseline to Week 16, so 16 week study and the walk had to be done between 10 to 60 minutes after the most recent dose of the medication. Secondary endpoints include a change in the NT proBNP, so that's our biomarker between baseline and week And then we had a composite endpoint of time to clinical worsening. And this composite was composed of The Other secondary endpoints included change in the peak 6 minute walk at week 12 and change in the trough 6 minute walk at week 15. All right. This gives you an idea of the time course of the clinical trial, screening, randomization 1 to 1, Half the patients got inhaledraprostenal, the other half placebo, it's given 4 times a day. Patients were targeted to get 9 breaths Four times a day and could take as many as 12 breaths 4 times a day, but we try to get everyone up to at least 9 breaths 4 times a day. Try to come up with an app description for these little, What it looked like hanging chairs to me. I don't know what a hanging chair looks like, but that's the best description I could come up with. And they're color coded. The blues Endpoints and when they were measured, the yellows are the secondary endpoints and the green is the primary endpoint at week 16, which was changed in the 6 minute walk distance. Looking at the baseline characteristics of the study population, they were well matched. The mean age was 65 to 67, there's a little bit of a difference in gender distribution, more males In the placebo arm actually as more females in the active treatment arm, but that really didn't impact the study one way or the other. Looking at the etiologies of PHILD gives you an idea of the different prevalence of these different underlying disorders. So most of these patients had 1 of the idiopathic Interstitial pneumonias seen over here 40% versus 50%. Most of these were the most common form of death and that's idiopathic pulmonary fibrosis. CPFE, 25%, 25%, CTD, 25% versus 20% and then other less common conditions, chronic hypersensitivity, 6 5.5%. Most of these patients were on supplemental oxygen. Once you have pulmonary hypertension, you tend to have a little bit more severe disease, 73%, 70%. And then there were some who came in on anti fibrotic therapy. These were mostly the IPF patients and you can see the distribution here at the bottom between pifenadone and nintenumab. They were a pretty sick group of patients Based on the underlying 6 minute walk distance 254 versus 265. If you look at most of PAH studies, mostly if you look at the baseline 6 minute walk is generally around 320, 340 meters, so a little bit more sick than that. They did have significant pulmonary hypertension with the PVR in the 6 range, the NT proBNP was also elevated, NPAP, mean pulmonary pressure 37, 36 And the wedge pressure was 10% to 9%. So well matched in all regards in terms of functional ability as well as the hemodynamics. Just looking at their PFTs now, we'll focus on the FVC because these are restrictive disorders, 62%, 63%, a little bit more severe than what we've seen in typical IPF studies where most patients most studies, the FEC of the group is around 70 And the deal, which tends to correlate with pulmonary hypertension was also on the low end at around 30% 28%. This shows you the screening randomization and follow-up. I'm not going to go through all of this. What I will say is that they were a sick group of patients, so there were some dropouts, but that appeared to be equivalent between the two arms. So that at 16 weeks, we had 130 patients who completed in the Tyvasa arm and 128 who completed in the placebo arm. Coming to the primary endpoint and remember now it was 16 weeks and we look at the change in the 6 minute walk distance, It came out at 31 meters favoring inhalediprostinil. If we look at week 12, it was also around 31 meters. That remember was one of our secondary endpoints. Another of our secondary endpoints was the trough at 15 weeks, which was 22 meters. So we know that Tyvaso is given 4 times a day. There are going to be peaks and troughs. So even at the trough, there was a difference favoring inhaled treprostinil, so 31.12 meters. To put this in perspective, when inhaled treprostinil got approved for PAH for group 1 pulmonary hypertension, That was a TRIME study and that was published in 2010. And the difference there was, I believe, 19 or 20 meters. So at least numerically more than that. And right in the range of what we see in most of the clinical trials for Group 1 pulmonary arterial hypertension in terms of the difference in the 6 minute walk distance. This is a graphic depiction over time. What we saw the groups tended to separate out pretty early. So you saw a difference as early as 4 weeks certainly by 8 weeks and then by 16 weeks. And this just represents different statistical methodologies in terms of working out the difference. But whichever way we looked at it, I think it favored treprostinil significantly. Well, actually what's also interesting, which I should also point out is a lot of this difference was driven by improvement In the treprostinil group versus deterioration in the placebo arm. And I think it's important that a lot of this difference was By improvements. So it served to not only be different to the placebo arm, but actually there was a numeric increase in the walk distance for this group of patients. This is a forest plot looking at different subgroups And I think the bottom line message is that everything is to the right, everything favors treprostinil if we looked at it by age, By 6, by baseline 6 minute walk distance, by baseline diffusing capacity. The one thing that you'll note here is that The higher the PVR, the more robust the response. But what I would also point out, which was very nice to see is an apparent dose response For those patients who couldn't get up to the maximal number of breaths, you see less of a response. Then once patients get to 10 to 12 breasts, you see a greater response and those on the highest dose got the best response. So that kind of validates The robustness of the underlying primary was at this dose response that we could see from these analyses. In terms of secondary endpoints, we met pretty much all of the secondary endpoints, Improvements in NT proBNP, reduction in time for clinical worsening. I showed you the data for week 12 as well as week 15 in the 6 minute walk distance. Many things we didn't hit which was further down on the list were differences in our patient reported outcomes, the St. George's Respiratory Questionnaire And the distant saturation product, which is gained from the 6 minute walk distance, looking at the distance in relation to the oxygen saturation. The one thing I will say, which is always a concern with invasive dilate in patients with underlying lung disease is that there was no worsened oxygenation, there was no evidence of increased EQ mismatch. That was one of our safety endpoints. This slide can be a little bit confusing when you look at it initially. I will walk you through it. This gets to the NT proBNP and let's look at baseline first. So you can see at baseline that the Treprostinil group had a higher NT proBNP than the placebo arm, 550 versus 420. And what happened over time to the treprostinil group, it went down 550 to 485 to 454. The placebo arm that started lower started at 420, Went to 528590. So it appeared that there was I apologize, I have background noise in my office at the hospital. So unfortunately, they tend to repeat that three times and then they tell you that it's a false alarm the 4th time. Anyway, so hopefully I made the point about the NT proBNP. So we had our biomarker going in the same direction, which was gratifying to see as well. Actually, it's a good time to take a water break for me until the operator gets through the announcement. All right. Well, let me try and talk through that. Kaplan Meier plot of time to first clinical worsening event. Once again, this favored the inhaled treprostinil group. You can see the Kaplan Meier plot here. There was a 39% risk reduction. If you look at the absolute risk, 22.7% in the inhaled treprostimal group versus 33% had clinical worsening over 16 weeks. So that's quite a difference over a relatively short period of time. Now the next question we always got to ask ourselves, See if we have that on the next slide is what drove this difference in clinical worsening. Remember, it's a composite. So what were the components of the composite that drove this? And here we see the numbers again, 22.7% versus 33.1%. Hospitalization, there was a difference, 18 hospitalizations versus 24 Cardiopulmonary hospitalizations, difference or change in the walk distance of greater than 15% from baseline. This is Decrease 13% versus 26%, 8% versus 16%. Mortality was the same in the 2 arms, 44 in both arms And then there were 2 lung transplants in the inultraprocessional arm. As a ratio shown over here, 0.61, 39% reduction and this was significant The p value has shown of 0.02. Whenever we give an inhaled medication, We have to be sure that we are doing no harm. So one of the safety measures was exacerbation of underlying lung disease. We wanted to make sure that those So who got in alteprostinil didn't have increased exacerbations of the underlying lung disease. And in fact, and indeed, it went the other way That there were less exacerbations in the intraprostenal arm versus the placebo arm. So even though this was a safety measure, It went in directionally favoring treprostinil in terms of reducing exacerbations of the underlying lung disease. Can see the numbers over here, 26% for enalteprostinil, 38% for the placebo patients. This was not centrally adjudicated. This was as determined by each shouldn't be oral treprostinil, it's inhaled treprostinil, sorry for the typo. And 8% of the placebo patients prematurely discontinued due to an AE, so equivalents there. Serious AEs occurred in 23% of patients receiving inhaledriprostenal, 25.8% of placebo patients. Everything gets reported as an AE and this is This is a summary of the AEs. The ones that are bolded are actually favorable AEs, if you want to look at it that way. Dyspnea increased shortness of breath, less in the inhaledraprostenal arm versus the placebo arm. NT proBNP was also captured as an AE And an increase in this was less 5.5% in the treatment arm versus 15.3% in the placebo arm. Other things like cough are to be expected in patients who have interstitial lung disease and you always have to look at placebo corrected, So 43% versus 33%. So placebo corrected, that's more like 10% of the inhaledroprostinil arm at increased Cough, headache, not unexpected. This is aprostinoid 27% versus 19%, so 8% placebo corrected And the rest of these, I'll let you read for yourselves. Now, this was very interesting. Another safety measure was looking at their lung function. We're giving them an inhaled medication that interstitial lung disease. We wanted to make sure that this Didn't have deleterious effects on their lung function. So I'll focus you on the right first and here we have inhaled treprostinil and here we have placebo and much like Acute exacerbations of the underlying lung disease, it went in a directionally favoring inhaled treprostinil. You can see a significant difference when expressed as Percent predicted between inal treprostinil and the placebo arm. So that was a very pleasantly surprising finding that came out of the study. This is how we typically look at differences in forced vital capacity. And as most of you are probably aware, forced vital capacity Has been the primary endpoint in pretty much all the IPF clinical trials and ILD clinical trials and that's what's gotten pifinidone and nantinib approved. And if you look at it for the group as a whole expressed in MLs, there's a difference numerically between the treprostinil arm and the placebo arm, but the error bars across. So this wasn't statistically significant, but if you express it as percent predicted, it was and that's probably a function of the tighter standard deviation around the percent predictive versus the numbers in MLs. But this is where it gets even more And this is a busy slide and a busy table, but I'll point you to the subgroup analysis of the IIPs, the idiopathic interstitial pneumonias And looking at the difference between the treatment arm in alteprostinil and placebo and Let's go to MLs and let's look at 16 weeks. And here you can see a difference favoring in alteprostinil of 108 cc's At 16 weeks in the subgroup with idiopathic interstitial pneumonia. And we'll make it even more interesting by going to the IPF group over here At 16 weeks, looking at the difference in MLs between the placebo and inhaledeprostanol arm, 168 cc's At 16 weeks of inhaledriprosinil and the P values for all of these subgroup analyses At 16 weeks was significant, 0.01, 0.01. So a very nice safety signal that perhaps Suggest efficacy of inhaledeprostinil as an anti fibrotic. This was a safety endpoint. So what I'm saying is perhaps somewhat speculative, It will be studied in a pivotal study to look at the potential anti fibrotic effects of analtriprosmol. Additional safety measures or safety endpoints, no clinically relevant treatment related changes in pulse ox or supplemental oxygen use were noted in the study period. PFTs, I alluded to no safety signals there. Median improvements in percent predicted FEC at week 16 in the Prostinil group I mentioned already. And then I mentioned as well these numbers over here, I didn't get into too much Detail for the group as a whole. I think what was exciting in particular that I alluded to were the IOPs, idiopathic interstitial pneumonias and especially the IPF patients 100 and 68ccs at 16 weeks and a sizable group of patients as well that demonstrated this difference. So in conclusion, INCREASE is the largest and most comprehensive study of this patient population to date. Patients experienced significant improvements in exercise capacity as early as 8 weeks with effects sustained throughout the 16 week period of the clinical trial. Patients also demonstrated improvements in other clinically meaningful outcomes including the NT proBNP, a decreased Risk of clinical worsening as well as a decreased risk of exacerbation of the underlying lung disease, the treatment was well tolerated. There was no evidence Worsening oxygenation or increased VQ mismatch and there was evidence a signal of an improvement in the FVC, especially in the IP population and the IPF population and the results support an additional treatment avenue And might herald a shift in the clinical management of patients with interstitial lung disease. So with that, I'd like to conclude and have to acknowledge all my co investigators around the country All the patients who enabled the study to be positive, all the clinical coordinators who worked on enrolling these patients. And I think I'd like to thank United Therapeutics to be quite honest, taking on this big study, taking the risk of this big study and coming up with a new treatment for With this devastating complication of the underlying interstitial lung disease. So at this point, I'll hand it over or back to Dewey. Thank Thanks, Doctor. Nathan. Josh, our operator, can you put the presentation back up on the screen? I'm sorry, I Knocked it off the screen. But next up will be Michael Benkowitz, UT's President and COO, He will discuss our commercial plans for increase in PH ILD. Great. Thanks, Dewey. And thanks, Doctor. Nathan, for that excellent presentation. I'd also like to thank you and your fellow INGRED steering committee members, Doctors Waxman and Tapson, For your leadership in this trial. I too would also like to thank all the investigators and patients that participated in CREASE. We at UT are very excited about the results of this trial and that we are on the verge of being able to bring a treatment to the estimated tens of thousands of patients with PHILD who have up till now had no approved treatment option. We're also very pleased that the results The trial has been well received by the academic medical community, so much so that the data were published in the prestigious New England Journal of Medicine. This is the first time in UT's history that we've been honored to have one of our clinical trial results published in the New England Journal. So it's very exciting for us as a and especially those in the company that contributed so much to designing and running this trial. So as Dewey said, I'd like to spend the next few minutes providing an overview of The PHILD commercial opportunity, our launch readiness and expectations. And I was trying to buy you guys some time to get the presentation up. Josh, do I have control? No. All right. Give us one second, guys. All right. There we go. Okay. So let me start off by framing things at a macro level and this may be helpful for those of you that are on the call that We are new to or unfamiliar with United Therapeutics. So we're a company focused on providing life extending technologies to patients in early two core areas. The first is pulmonary arterial hypertension or PAH and the second is interstitial lung disease or ILD. We have 3 primary medicines in the prostacyclin class of drugs approved for PAH generating about $1,500,000,000 in revenues each year. We expect those PAH sales to grow each year through continued promotion and education about the benefits of our products, along with newer more convenient delivery devices, formulations and novel therapeutics that are in development. So today our focus though is on our first foray into ILD and specifically pulmonary hypertension associated with ILD, an indication we expect to receive an approval for in April. Tyvaso would be the 1st product approved for these patients' pulmonary hypertension. But this is just the beginning of our work in ILD. We have 2 more active Phase III trials in this area. 1 is in pulmonary hypertension associated with COPD and the other as Doctor. Nathan mentioned is in pulmonary fibrosis without pulmonary hypertension, which we believe will be the 1st disease modifying drug in this indication. Our deep pipeline also includes using Xeno technology and 3 d bioprinting to create an unlimited supply of transplantable kidneys, hearts and lungs. Okay. So we're talking about Tyvasa today in the context The PHILD, but really this is a product that is positioned to significantly advance our growth in the near term. Tyvaso was already approved in PAH, which as you can see at the sort of top left of the circle here is a market of approximately 45,000 patients. As I said, we believe there are opportunities to grow Tyvaso in this market even though PAH is a crowded market through continued education about the efficacy of prostacy cyclone therapy along with a new more convenient dry powder inhaled form of Tyvaso that we expect to be approved and ready to launch by the end of the year. Moving to the right into PHILD, which is the focus of today's discussion. Here's a market with conservatively 30,000 patients with no approved therapy. On the strength of the increased data, we're confident that we're going to be able to bring Tyvaso to many of these patients. As we move to the bottom right, we move into Pulmonary hypertension associated with COPD, which I mentioned a minute ago. This is another 100,000 potential patient population that currently has no approved therapy. And then finally, if we go to the bottom left, we move to the 100,000 patient IPF market. Based on the improvement in forced vital capacity and reduction in underlying lung disease data that Doctor. Nathan described from INCREASE, we have launched a Phase III trial in IPF And Ernie, where as I said, there is no disease modifying therapy. So that's a virgin market opportunity of approximately 230,000 patients in ILD In addition to the 45,000 patients in PAH. There we go. Okay. So let's drill down a little bit on the PHILD opportunity. So here we show the epidemiology of PHILD. I think Doctor. Nathan covered this brilliantly in his presentation, but to state again, I think the data suggests that would point to approximately 200,000 to 250,000 ILD patients in the U. S. And that an estimated 15% to 86% have or could develop Pulmonary hypertension. It is difficult to establish precise prevalence since most of these estimates come from case reports and retrospective data. As we know, pulmonary hypertension is confirmed with a right heart cath. And frankly, the vast majority of these patients have not had a right heart cath because without an approved therapy, there's really no sense in putting the patient through this procedure. Finally, we point out here as Doctor. Nathan that as ILD advances, the frequency of PH continues to rise. So we anchor and continue to anchor to the 30,000 patient population figure for Child D, but I think this information clearly suggests that this could be a very, very conservative figure. Okay. Here, this Kaplan Meier curve on the left, I find fascinating. We can see that the prognosis difference of ILD patient with pulmonary hypertension as compared to one without pulmonary hypertension is quite significant. And I'll say that this has been a Pretty powerful chart with the healthcare providers that we've shown this to in our market research and testing. They told us that this creates a strong and compelling case If a therapeutic option is available to evaluate ILD patients for pulmonary hypertension and hopefully change the course of these patients prognosis. And that evaluation is really going to be key to our launch, come in April. Okay. So let's talk about that. How do we identify these patients? Doctor. Nathan talked about the suspect, support, confirm framework and we have already started discussing this framework with ILD With treaters with an emphasis on screening early. In the suspect category, you're looking for some of the signs and symptoms listed here that are out of proportion to the underlying lung disease and or signs of RV strain or failure. From there you support the suspicion with an echo And then based on the results of the ECHO, we finally confirm with a right heart cath. Over time, we expect that we'll fine tune these criteria as we gather more data and work with physicians. But as Doctor. Nathan indicated, this is we believe this is a sound rubric for identifying these patients now. So as I said, we have started the process of raising awareness around both the severity of pulmonary hypertension in these ILD patients and how to identify these patients As early as possible. Okay. Next, let's talk a little bit about physician reaction to the increased Yes. Obviously, I think you hear Doctor. Nathan's enthusiasm with the data and its potential to help patients. I think the headline here really says it all. He's not alone. These physicians that see these patients, as Doctor. Nathan said, they're very, very sick patients. They're eager for a treatment that can improve their patients' outcomes and are excited about the potential for NIDAYSO to be doing that to be that drug. Since unblinding the study last year, we've engaged in multiple investigator meetings, advisory boards with physicians And market research activities. And I think what you can see here on the slide are the key themes that we hear across all of these channels of input. So the kind of the key things we're hearing is that physicians believe that the increased data will have a positive impact. They are motivated to screen more. Like I said, that's incredibly important to our launch and beyond. The data suggests that PHILD treatment will be augmented with a new safe effective treatment option. I think generally the Physicians that have had an opportunity to see the increased data are impressed with the data set as a whole, but in particular, they find the 6 minute walk distance, the time to clinical worsening and the reduced risk of exacerbations of underlying lung disease to be the most impactful of the data. They believe that Tyvaso does have the potential to help these patients improve their condition. They found that the etiologies of the patients in the INCREASE study match what they're seeing in their clinic. And importantly, very importantly, they believe the data is Okay. So with that, let's change gears a little bit and talk about our launch prep. So an important factor in a successful commercial launch It's obviously understanding who your customers are. And here we're really talking about a group of physicians that is new to us. In PAH, there are about 2,300 physicians plus or minus who are Main PAH doctors and in ILD there are about 4,700 physicians, but about 1700 of those are what we call our top decile doctors. For those of you that are not familiar with the concept of deciling, we place our doctors into deciles based on the number of patients they see. So The higher decile doctor you are, the more patients you see and the lower decile doctor you are, you see fewer patients in the disease area. And so what you can see here by the chart on the left is that you've got an overlap of about 1300 physicians between PAH and ILD, Yes, which is about 30% of the ILD docs. But in reality that actually overstates things. Of the 1300 overlap physicians, I would say most of those are primarily PAH docs For lack of a better word, dabble in seeing ILD patients. So they would be, we would consider low decile ILD doctors. And so there are not that many physicians relatively speaking that are both high PAH and high ILD treaters. So as I said, we're really talking about a new base of doctors that we need to call on. Now with our efforts to educate on the severity of pulmonary hypertension in these patients And the availability of a treatment option. Some of these doctors may decide to refer their, PHILD patients to PH doctors and that's fine. But many have also indicated that they will treat these patients themselves. Either way, our commercial and medical teams need to access these new Physicians to make them aware that there is a treatment available or will be available and advocate that they screen for pulmonary hypertension so that the patients have the opportunity To benefit from TIDEASO. Okay. So to pull this off effectively, we have to expand our commercial and medical organization for PHILD. We've expanded our field based staff comprised Sales representatives, nursing specialists and medical science liaisons by about 40%. And then we've restructured the team to provide more focus and reduce Execution risk. So we now have a team dedicated to promoting Orenitram and Tyvaso and PAH. We have another team focused on detailing Remodulin and PAH. And then you had a 3rd team that will focus exclusively on promoting Tyvaso and PHILD. We started these expansion efforts last summer and have effectively completed our hiring. The new employees are on board and have gone through or are currently undergoing training right now. They're out starting to meet These new physicians in an appropriate and compliant way and we'll be ready to hit the ground running at launch. Okay. So lastly, we get a lot of questions about how we think about uptake. As we said last week at the JPMorgan conference, our goal is to have at least as many patients on Tyvaso and PAH ILD as we do in PAH within about 18 months post launch. I'm not sure it's going to be a linear journey between here 18 months. In fact, I'm pretty sure it won't be, but We know the patients and the opportunity are there for us. Obviously, this comes with the usual caveats around, obviously, they have to receive FDA approval in April There being no additional COVID related delays or impacts in the spring and later this year. So in summary, the key takeaways here Yes, are outlined here. Upon approval, we're entering a PHILD market with at least 30,000 patients and no other approved therapy. Physicians find the increased data impactful. They're excited to have a treatment option and plan to use TIDESO. The staff expansion we need to support the launch Complete. We started the process of increasing awareness around the impact of pulmonary hypertension in these patients and the need to screen early And we're looking forward to working toward our goal of doubling the number of Tyvaso patients within about 18 months of launch. And just as a reminder, this is a really busy and exciting year for UT. While we spent today talking about our launch into PHILD, this is just one of 4 potential launches this year. The others being RemUnity, our new subcu device for Remodulin, which will launch imminently also the implantable system for Remodulin, a new intravenous device launching in the second half of twenty twenty one and finally Trae T, our dry powder inhaled form of FIDESO, which is currently on track to also launch by the end of the year. And by the way, we expect that with the approval of TRY T will apply to both our PAH and PHI LD indications That's offering a more convenient delivery system for Tyvasa to both groups of patients. So with that, I will turn things back over to Dewey and we can move into the Q and A portion of the call. Thanks, Mike. So today for the Q and A, we'll be hosting it through the webcast itself. So if you have a question to ask, feel free to hit The raise hand button. If you're on the phone, Josh from Zoom, how do people on the phone ask a question? So we have a couple of people in the queue already. I guess the first question would be from Hartaj Singh with Oppenheimer. Sorry, can you hear me now? Yes. Great. Thank you. So this is a question for Doctor. Nathan. In one of the slides, Michael had mentioned, the doctors really like the significantly fewer lung exacerbations. It's almost by a third that Tyvaso is decreasing lung exacerbations. I know that lung disease as diverse as COPD, asthma, cystic fibrosis, That decrease in lung exacerbations is actually considered a pretty important event. I mean, I guess lung exacerbations are considered a sentinel event. Would you agree with that, Doctor. Nathan? How important do you think that is for Tyvaso and PHILD? Thank you for the question. Sure. I think that's very important. As I mentioned, it was an unexpected, very pleasant surprise finding. But if someone has an acute Subtation, it has a lot of ramifications for the patient. They feel worse for whatever reason. They're more short of breath. They're coughing more. It's increased healthcare resource utilization, doctor visits, ER visits, maybe hospital admission. So they require more medical attention. So I think it's meaningful to everyone, the patients, the payers, everyone. And we know Certainly, if patients are admitted to the hospital with interstitial lung disease, and I don't know how many of these were admitted, we don't have that data. Well, we do have that data, The mortality over time is more and their prognosis is generally significantly worse. So how many of those acute exacerbations over time, is that Precursor, other bad events happening further on down the road, it's quite possible. So I think it is a pretty big deal. The one caveat I would say is when we look at acute exacerbations in many clinical trials as a primary endpoint, then typically they are adjudicated. These The investigator reported that if it was important enough to the investigator, then it was certainly important enough and was meaningful to the patient and was truly an event. Let me leave it at that. Great. Thank you, Hartaj and Doctor. Nathan. Our next question will come from, I think it's Liana Moussatos, but she's showing up as Shpata Dinghy. And I've got to allow her to talk. And if you could just unmute and ask Can you characterize the physicians who treat PHILD versus PAH? And despite the unmet knee, Do you anticipate initial sales to be slow in a COVID environment? So we can't we are able to characterize Those physicians or at least identify those physicians as compared to PAH and have done that. And as I said, we're out For forming those relationships, engaging with those doctors, I think one of the interesting things will be, as I said, We're going to rely on those physicians to certainly screen these patients. Whether they decide to actually treat the patients or refer them to their colleagues over PH clinic, I think remains to be seen. I think it's still a little bit of an unknown right now in terms of like how that's going to break out. I mean, as I said, we've A lot of the IL docs just said they feel like they're going to be perfectly comfortable treating these patients. Others have said, No, I'll probably refer them over to their PEA. So we're covering both basis. And we'll leave it up to the doctors and To figure out how that gets managed within the institution. But as I said, we're covering both basis. I don't know about the COVID impact right now. I mean, I think one again gaining issue right to getting Approve will be is typically you need to have a right heart cath in order to confirm diagnosis and get that approved for reimbursement. CMS, I think back last maybe April or May instituted a temporary waiver on right heart At procedures for patients at PAH and as we read the language that is actually not limited to PAH and would extend to Patients with pulmonary hypertension associated interstitial lung disease. So that gives us at least some comfort that doctors will be able to STAR patients on therapy in lieu of having done a right heart cath. They will eventually at some point have to come back and do the right heart cath to confirm But that waiver, it continues to exist and it's being reviewed I think on an every 90 day basis. And so that we expect that Probably through at least the first half of this year, that will stay in place. So if I may comment, because See the COVID question come up in the chat box as well. And I think it's very hard to have any kind of Medical conference or talk at this point without talking about COVID, especially to a pulmonologist because it's affecting us all. But this is an emerging issue, no doubt, as we There are a number of patients, the numbers remain to be defined who come into the hospital, Languished in the hospital and are left with residual fibrosis. What the natural history of these patients will be is unknown. I think that this we're getting data Every day on these patients, I just saw a paper I think this week that said, well, the incidence in patients who come into the hospital and That being meeting oxygen is 5%, 10%. Whether that holds out or not, whether 1 year into the pandemic, What's the natural history of these patients? Will they resolve over time or will they be left with permanent injury to their lungs? I think a Significant number will be left with a measure of fibrosis. We've had a number of patients who've been referred to us already for lung transplants post COVID who have advanced fibrotic Lung disease. But I think it's still a little bit of a black box in terms of how many patients might be affected by this. Thanks, Doctor. Nathan. Our next question will come from Joe Thome from Cowen and Company. Thank you for taking my question. Just one for Doctor. Nathan in terms of usage patterns. As soon as you sort of confirm PHLD in your patients, would you use Tyvaso early on if you're in course? And maybe on the flip side of that, Is there a patient subtype or any sort of characteristics where you wouldn't consider intervening with treatment? I think for patients I document pulmonary hypertension. It's certainly something to consider and that I will use. And in my experience so far, these patients have been Very willing to try it and use it and be compliant with it. As opposed to say PAH patients, sometimes these PAH patients have mild disease Or not that symptomatic, let me say that, I'm not on oxygen. For the most part, as you saw in the numbers, about 3 quarters of these patients are on oxygen. They're limited already and they're prepared to try anything that's going to help them in terms of their functional ability and quality of life. I think an important point is if you Compare and contrast this to say the anti fibrotics. The anti fibrotics slow the rate of deterioration. They don't make the patients feel better necessarily. And this is a medication that potentially will make the patients feel better and enable them to do more. And I think you could see that in the walk distance, which was mostly driven by an improvement in the treatment arm. What's also very interesting to compare and contrast When I showed you that FEC data, if you look at pifinidone and entininib, both the slopes go down and the difference is driven by The rate of decrement in FVC over time, what was very interesting with inhaled Tyvasa is the difference between inhaled Tyvasa and the The placebo arm was driven a large part by improvement in the FVC. Now that's speculative and that will be tested and trialed in the TETON study, But that was also a very nice neat surprise to see was that there appeared to be actually a measure of improvement in the FVC in the treatment arm. Thanks. Our next question will come from Sara Girdarazzi of Jefferies. Sorry, this is Yuna Yang. I don't know why I stated her name, Kei Lo. I think she registered for the data, I think. So I have a couple of questions for Doctor. Nathan and I have questions for Michael. So Doctor. Nathan, so the 30,000 Child patients that you first cited could be very conservative. I mean, it could be up to over 100,000 patients. So question to you is that once the patients are identified and diagnosed, based on Phase III study criteria, What percent of patients would be eligible for Tyvaso? That's question number 1. Number 2 is that You mentioned the patient's willingness to take it. So what percent of a patient would be willing to take a Tyvaso In addition to oxygen supply, and then once the patients get on The drug, what would be the Adherence rate? Let me take them one at a time. I missed the last part of the question. But I think that, Yes, certainly. These are patients who their prognosis is pretty poor and anything that might help them in terms of doing more the quality of life, I'm going to offer it to the patients and because they are feeling their disease, they are symptomatic. Most of them in my experience will elect to go on the medication, especially when they know that this could potentially result in improvement Patients who are tethered to their oxygen and are compromised already are very willing to try things that might help them. So I think the uptake should be pretty good. I think you're right. I think the estimate presented are conservative and Michael did allude to that. I think there There are many of these patients out there. And you mentioned 100,000, it could be 100,000, could even be more than 100,000. We'll have to wait and see. If you look at that number, That 85% of them will eventually at some point develop pulmonary hypertension. It's just a question of discovering these patients and getting the education Physicians out there, but I think physicians are hungry for this. If you look at ILD and what we have, For some ILDs, we can treat them with immunosuppressive therapies for the fibrotic conditions we have natinib and peprazanidine, but those aren't home runs. They help They delay disease progression and there's data to suggest that they improve survival. The way the analogy that I think about with all these different things and dealing with patients Various advanced forms of lung diseases, we put various scaffolds in place to catch patients. We put them on oxygen and put them on antibiotics. We put them into pulmonary rehab. This is another scaffold further down that we can help to catch patients and delay their disease course. So I think Because these patients are on the more severe end of the spectrum and these are patients that have been typically neglected in the clinical trials, I think my viewpoint is that there should be good uptake of the medication both by physicians as well as patients who are prescribed it. Now I apologize, I can only take one Tom, and I forget if I address everything you asked. I think there was another aspect to your question. Yes, I was just muted. And the last question is when patients get on the drug, what would be the compliance rate? But if you think about next 3 years. Yes, I think that compliance in this patient population will be quite good. That's my anticipation. Sometimes there can be cough and a little bit of intolerance. You saw that some patients settled out at a lower dose, but they're still despite a lower dose, they did better. But I think patients who are symptomatic With lung disease tend to be quite motivated. So I'm anticipating that compliance will be very good. I think if you look at, say, IPF clinical Trials, we have very mild patients, and you have to talk them into taking anti fibrosis. That can sometimes be difficult because they say, well doc, I'm feeling okay. Why should I take this medication? Well, these patients aren't feeling okay. They're all symptomatic. Their walk distances are 260. They want to be able to do more. So The pay theft compliance should be good, especially if the medication makes him feel better and do more, that's just going to enhance the compliance. And that's been my experience. And I have a question for Michael. So when you guys are targeting ILD specialist, How aware are they of pulmonary hypertension? And what percent of ILD specialists that you're going to be targeting Are currently actively diagnosing pulmonary hypertension? I don't have exact percentages. I think they're I would say they're generally aware of pulmonary hypertension. I think the diagnosis rate and the treatment rate is extremely low, but That's what we have been trying to address since, frankly, last fall and we'll continue to address between now and launch and beyond. I think as Doctor. Nathan alluded to, it's really going to be a process of continuing to educate these physicians about how to screen and diagnose these patients so that they can get the treatment they need. Thanks, Michael, and thanks, Eun. Our next question will come from Jessica Fye from JPMorgan. Great. Thanks, guys. Maybe, Selvar, to Yoon's question, Just trying to hone in on the kind of addressable population here. What proportion of the PHILD population resembles Study population, given some of the comments made, I think, by Doctor. Nathan that the patients tend to be More sick than in PAH studies? I think the inclusion criteria Captured it cost a pretty wide net in terms of the diseases that were included. And pretty much Anything they needed was to have Rytard cathprobe in pulmonary hypertension to get into the clinical trial. So I think it is reflective of Population out there, I think the question that we'll all have to ask and which I ask myself every day is when do you do the right heart cath? And what if you do the right heart cat and the PVR is 2.8 and the mean PA pressure is 24. We know that this tends to be progressive over time. So the concept will be to do more right heart caths, But sometimes we might not be able to show or document pulmonary hypertension. It might only manifest 6 months later or 12 months later. So that's what we're going to have to be prepared for as well. Okay. And is the 30,000 patient estimate an estimate of those who have a Those who have a confirmed PH diagnosis per Bright Heart cat? Yes. And I think that that's going to be conservative at the end of the day. I think we see more ILD. And if you look at those numbers in terms of the incidence and prevalence, starting out at 15% and going as high as 85%. It seems like it's almost invariable depending on when you look for Clinical course, you're going to find it. So unless something else gets these patients and some of them are elderly and some of them might succumb for other reasons, Many of them will develop pulmonary hypertension at some point in their course. Getting it's actually interesting this paradigm between PH docs and ILD docs. PH docs are either cardiologists or pulmonologists. ILD docs are all The cardiologists are not that aware of ILD, but if you but now they'll have to be. And I think where we're going to find these Patients are in the ILD clinic. That's where they're going to present first. And so I think that's where the education is going to become very important. It's very rare that someone will get Tend to cardiologists for pulmonary hypertension and the cardiologist says, well, you have interstitial lung disease and that's why I have pulmonary hypertension. That's Extremely rare. It's going to be the ILD docs. And I think as soon as you have a treatment to offer these patients with more advanced disease, I think the education is not going to be that difficult in terms of at least convincing them to go to the next step and get a right heart cath. A right heart cath These days it's kind of bread and butter for any cardiologist. It's a same day procedure. It's not a huge procedure with a lot of morbidity or mortality. What's interesting to me, and this is a question I posed to some of my ILD colleagues, would you much rather send the patient for a biopsy or right Which one is going to help more? And arguably, the right heart cath would help more in many of these cases rather than subjecting into a surgical end biopsy to get a tissue diagnosis. Okay, got it. And maybe just the last one, you've kind of talked about how these patients have very Pneumatic disease and clearly there's a benefit for the drug here on a number of these disease measures. But the paper does say that there was no significant between group difference in patient reported quality of life. So how do you reconcile that, I guess? What does that and ultimately, you guys, what does it mean commercially, right? Yes, I think that's an important point. The first thing I'd say is that if you look at the anti fibroids in interstitial lung disease, none of them have been shown to impact quality of life. And if you look at The pivotal pifenadone and entinative studies, those were 52 weeks, much longer and there was no measure of a PRO difference. Quite honestly, I think the St. George's respiratory questionnaire is not the best questionnaire for this patient population. I think we need better instruments And it is difficult to show a difference in quality of life metrics over a 16 week study. If you look at some of the questions that St. George's gets It says something to the effect. I don't remember, I haven't looked at it in a while, but how do you feel now compared to say 2 weeks ago or something like that? Some of the questions go to wheeze and cough, which might not be relevant in patients with ILD. So in terms of disease specific Questions, I think the St. George's, which was initially designed for COPD population is not the best instrument to be using in these patients. So I think sometimes when you have short to intermediate studies like this one was, I call it intermediate 16 weeks, it doesn't fully Capture the benefit of the drug that we might see over time. And the analogy I'll use and I'm not going to speculate too much, but if you look at the Antifibrotics that showed a difference in FVC at 52 weeks, well now we're seeing that patients on antifibrotic therapies are living much longer. We can't do the 3 or 5 year study to show that difference. It wouldn't be feasible. If you look at some of the drugs that were approved initially for PAH, Bozentan, Ambrisentan, tadalafil, those were 12 or 16 week studies as well. What was the primary? The 6 minute walk. And what we know now is that patients with PAH are living significantly longer. I put Remodulin into that category as well. I think the original Treprostinil study showed a difference in the 6 minute walk of 14 meters. And there's a lot of controversy when subcu Remodulin first got approved, but clearly the benefits of subcu Remodulin IV Remodulin are far are superior to what we saw with those relatively initial short term studies. So I'm being kind of a little bit speculative in this regard, but to the point that sometimes What we see in the context of a clinical trial doesn't fully capture the long term benefits down the road. Thanks, Jess, and thanks, Doctor. Nathan. Our next question, Josh, it will come from the 646 number. That's Jason Zymanski with Bank of America. Jason, you can hit star 6 to unmute there. Hi, team. Can you hear me now? Yes. Perfect. Thanks so much. Jason Zimansky with Geoff Meacham's team. Congratulations on the study. I was curious, is there a breakdown of the results based on disease severity? Were the outcomes Kind of more concentrated on those with more severe disease or did you see the effect on kind of the earlier stage patients, Maybe those with an MPAP closer to 25 millimeters of mercury? I think that Now that the primary paper has been accepted and published in the New England Journal, that's one of the spin off papers that we are actively going to be Looking on is looking at the different subgroups. So expect that hopefully to come out and I don't know, it depends on quickly we can get that together. But I think that if you might remember that Forest Plus I showed along the way, There did appear to be a bigger difference in the patients with a higher PVR. But I think that's I wouldn't speculate too much around that because that wasn't subjected to a multivariate analysis to know if there were more patients with Yes. And I appears in that group that showed the greater benefit. What we what I can say is a cursory look at the various subgroups doesn't appear that There is one distinct subgroup that didn't necessarily have a response. I think that those forest spots I showed you everything was at least on the line or to the right of that line suggesting a favorable benefit. But now we're going to do a deeper dive into the subgroups Thank you. That's very helpful. I was just one of the limitations of the study, at least mentioned in Paper was approximately 21% of those enrolled didn't complete the course. And if they're Earlier stage patient, what's the likelihood for a longer duration of therapy? Yes, I think that there were patients who dropped out, but the caveat there is that this is a sick group of patients And the dropout rate was very equivalent between the placebo and the treatment arm. And there might be some criticism of, well, this was only 16 week study. Well, that's a problem when you're enrolling a sick group of patients. How do you keep these patients in a study for a longer period of time? So I think that 16 weeks was kind of right on the mark. Otherwise, we would have risked potentially having more dropouts and not seeing the positive benefit that we did. But to your point, we only study patients once they had documented pulmonary hypertension. Could we have more benefit if we get them Forehead, now that wasn't the study design and probably won't be in the label. But to me, that's something that perhaps Makes intuitive sense. If someone's mean PA pressure is 24, do you deny them therapy and wait for it to be 26 before you put them on therapy? So this is something we're going to have to wrestle with as we move forward. Got you. Thank you so much for the color. Really appreciate it. Thanks, Jason. Our last question is a write in question for Doctor. Nathan. Could you share your thoughts on how important The dry powder inhaler version of Tyvaso will be for adoption. Do you expect it to increase the oiliness of ILD docs to manage Tyvaso patients themselves? Yes, I think it's really exciting and I was excited to hear that apparently if you guys or when UT gets approval for this that It will extend beyond PAH and will apply to this patient population as well. I haven't seen the device myself. You guys probably can give further insight into that, but I Understand that it's like a metered dose inhaler, you can put it in your pocket. That's not a is that it right there? I can barely see it. So yes, I think it's a huge difference to patients. It's like albuterol inhaler, you put it in your pocket and you walk around with it. And To use it 4 times a day becomes much less cumbersome to be quite honest and is much more conducive to Quality of life, getting out and going to the shops and hopefully we can all go to the shops again post COVID at some point, but going To wherever you're going to go and socially distance and get out your little inhaler and give yourself ahead of it during those times, Four times a day, when is that? It's when you wake up at lunchtime, early evening and bedtime. It just makes it so much easier and I think the adoption will be so much Better if this therapy hasn't been adopted beforehand, I think it's going to be very good and very nice and convenient for the patients. Thank you so much, Doctor. Nathan, and thank you to the UT team for taking the time to share our thoughts on the INCREASE trial. We're looking forward to speaking with everyone again at our Q4 earnings call at the end of February. In the meantime, if you have any questions, feel free to reach out to me, dsedman. Unithird.com and also slides from today's presentation are available now on our website at ir. Unithird.com under the Events and Presentations tab. Once again, thank you for joining us and have a great afternoon or evening.