Good afternoon and welcome to the United Therapeutics Corporation Phase III TETON-2 Results Conference Call. My name is Drew and I will be your conference operator today. All participants on the call portion of this webcast will be in listen only mode until the question and answer portion of this earnings call. If you would like to ask a question during that time, simply press Star, then the number one on your telephone keypad. If you would like to withdraw your question, please press Star then the number two on your telephone keypad. Please note this call is being recorded. I would now like to turn the webcast over to Harry Silvers, Investor Relations Manager at United Therapeutics. Thank you, Drew. Good day everyone. It is my pleasure to welcome you to the United Therapeutics Corporation phase 3 TETON 2 Results Conference Call. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties. We assume no obligation to update forward-looking statements. Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products. These remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for the products is available on our website. Accompanying me on today's call are Dr. Steven D. Nathan, Chair of the Advanced Lung Disease and Lung Transplant Program at Inova Fairfax Hospital and Chair of the TETON steering committee, Dr. Leigh Peterson, Executive Vice President of Product Development and Xenotransplantation, Dr. Peter Smith, our Senior Vice President of Product Development and Lead for the global TETON program, and Dr. C.Q. Dang, our Senior Vice President of Biostatistics, Statistical Programming, and Data Management. Now I'll turn the call over to Leigh to begin our overview. Leigh, thank you, Harry, and good afternoon, everyone. We have slides available and I encourage you to review those when you have chance. Earlier this month, we were incredibly pleased to announce positive results from the TETON 2 pivotal study evaluating the use of nebulized inhaled treprostinil for the treatment of idiopathic pulmonary fibrosis, or IPF. The TETON 2 study met its primary efficacy endpoint of demonstrating improvement in absolute forced vital capacity, or FVC, relative to placebo. Statistically significant improvements relative to placebo were also observed in most secondary endpoints. Earlier today, we presented additional analyses from the trial at the European Respiratory Society Congress here in Amsterdam, which we will review during this webcast. These results mark a historic landmark in the landscape of IPF treatment. We believe these results not only demonstrate the efficacy of nebulized Tyvaso but also signal a turning point for patients who have had limited options and uncertain outcomes. These findings are more than an unprecedented statistical success in IPF. These positive results represent hope and progress, validating years of collaborative clinical research and patient commitment. At the heart of these positive results is the power of treprostinil, which we have long believed to be more than just a vasodilator. Through rigorous study design and thorough analysis, TETON 2 provides robust evidence that treprostinil's antifibrotic effects can improve key measures such as lung function as measured by FVC and quality of life. Importantly, the trial also reinforces the underlying mechanism of action, or MOA, demonstrating how targeting multiple pathways can bring tangible benefits to patients. This scientific validation of treprostinil's MOA highlights its promise and transformative potential to advance pulmonary medicine. We believe that the benefits truly extend beyond the data, offering patients the promise of better days and greater stability in their journey with IPF. Dr. Nathan will provide additional details, detailed analysis of the TETON 2 pivotal study. But first I'll turn the call over to Dr. Peter Smith who is responsible for running our global TETON program. He will begin with a brief review of the TETON 2 pivotal study trial design. Peter Great.. Thank you. Leigh Okay, so we'll take a look at the TETON 2 study design. TETON 2, the pivotal study, was a. 597-patient multicenter randomized double-blind placebo-controlled phase 3 study evaluating nebulized Tyvaso in IPF patients over 52 weeks and 16 countries outside the U.S. and Canada. Full enrollment was reached in July 2024. Participants in the study were randomized to nebulized Tyvaso or placebo starting at three breaths four times daily or QID and then titrated as tolerated up to 12 breaths QID. Participants who completed week 52 on study drug were eligible to then enter an open-label extension study. The primary endpoint was absolute change in forced vital capacity at week 52. Secondary endpoints included time to first clinical worsening event, first acute IPF exacerbation, overall survival, percent-predicted FVC, quality of life as measured by the King's Brief Interstitial Lung Disease Questionnaire, and change in DLCO. Safety was assessed via adverse events, labs, vital signs, and ECGs. Next slide please. So let's take a look at the eligibility criteria in terms of key inclusion criteria of note. We included subjects who were over 40 years of age, had a predicted FVC of 45% or more. Subjects should have been on a stable dose of nintedanib or pirfenidone if they were using one of those medications and diagnosed with IPF as confirmed by a high-resolution CT within the previous 12 months. Key exclusion criteria of note included evidence of obstructive disease, high supplemental oxygen use, use of drugs commonly used for PAH, recent IPF exacerbations or pulmonary infections. Next slide, please. On slide nine you can see the baseline characteristics for the TETON 2 pivotal study by treatment group. The study arms were well balanced across all criteria and no significant differences were observed between the treatment groups at baseline. Both treatment arms were representative of a typical IPF patient today. Now I'll turn the call over to. Dr. Nathan to walk us through the data in more detail. Steve? Thank you, Peter. And moving on to the next slide. Here you see the results of the primary, which as Peter mentioned is placebo-corrected change in FVC at 52 weeks. What's notable on the slide are a couple of things. First of all, patients were up-titrating their drug between 0 to eight weeks. Approximately in excess of 82%-85% of patients were on at least 10-12 breaths by eight weeks. So they weren't on really an effective dose for the first four weeks when you see that dip. But then at eight weeks the curves start to come apart and we hit statistical significance as early as 16 weeks and the curves look like they continue to come apart now towards the end. What we have here is the Hodges-Lehmann estimate of the difference between the two groups which came out at 95.6 mL, which was highly significant. What you see for all the time points along the way in circles is the observed mean data, mean FVC and you'll note a square plus the circles at the end at 52 weeks. The squares represent include imputed data and it's reported as the median. So we have the median difference at 52 weeks including imputed data of 95.6 mL. This is a forest plot which includes imputed data at each time point of change in FVC. And once again you see that we reached statistical significance at week 16 and the point estimates continue to come apart or move further from the line of unity up until 52 weeks. So it appears that there is ongoing improvement when we use imputed data in all these analysis at all these various time points. Moving on to the next slide here we have the change in FVC by background therapy. We'll start off on the left with no background therapy in the treatment arm, we have a change over 52 weeks of 54 cc's compared to the placebo arm where it comes in at 107 cc's. The placebo corrected difference using the Hodges-Lehmann estimate once again is just under 44 cc's. And this was not statistically significant. You can see the P value there at 0.33. Now there are probably two reasons for this. Numerically there is quite a difference in the two numbers, but the numbers were relatively small and the placebo group didn't deteriorate as much as expected as we'll see in the other groups as we move on to background antifibrotic therapy. If we move to the middle panel here, we see patients who are in background nintedanib. And this did reach statistical significance with the Hodges-Lehmann estimate of the difference being 97.6 mL. The treatment arm went down by 43 cc's over the 52 weeks versus a placebo arm at 115 cc. And then moving to the last panel to the right, we have changed based on background pirfenidone. And for the treatment arm there was a decrement of 52 cc's versus the treatment arm of just under 188 cc. Now, what's notable if you look at all the treatment arms, the dark blue. The treatment effect was very consistent across these three groups. 54, 43, 52, so almost replicate numbers, be they on antifibrotic therapy or not. Moving on to the next slide where we look at probably our most important secondary endpoint which was time to clinical worsening. This also met statistical significance with a 29% relative reduction in the risk of clinical worsening. I don't think we mentioned it, but clinical worsening was a composite, and I'll show you the components of the composite in the next slide. If you look at the absolute numbers, there were 27.2% of the patients on active inhaled treprostinil who had clinical worsening versus 39% in the placebo arm, hazard ratio 0.71. And once again, this met statistical significance with a P value as shown of 0.019, and here are the components of clinical worsening. It was the time to the first of these three events: death, respiratory hospitalization, or 10% relative decline in the predicted FVC. Most of these events were driven by change in FVC, which by itself favored inhaled treprostinil. Then we have respiratory hospitalization once again numerically favoring inhaled treprostinil, and death that was almost equivalent numerically. More total patients in the inhaled treprostinil arm met this endpoint as a first event, four to three, but as you'll see in a subsequent slide, there were actually more deaths during the course of the study on placebo versus inhaled treprostinil. Moving on to the next slide, one of our other secondary endpoints was time to first acute exacerbation of IPF, and this was adjudicated by a panel, and there was a 46% relative reduction in time to first acute exacerbation. But there weren't that many events so this didn't hit statistical significance. The number of events was 9 versus 17 or 3% versus 5.8%, so certainly numerically trending in the right direction. But this did not hit statistical significance. Moving on to the next slide, another of our secondary endpoint was overall survival at 52 weeks. Same story here. Numerically there were more deaths in the placebo arm versus inhaled treprostinil arm 19 versus 24 or 6.4% for inhaled treprostinil versus 8.1% for placebo 23% relative reduction but because of the small number of events this did not get statistical significance. But numerically this certainly favored inhaled treprostinil. Another of our secondary endpoints was change in percent-predicted FVC at 52 weeks and this slide looks almost a replica of the slide of our primary which was change in FVC and mL and you can see the same kind of thing here with the initial decrement in both groups as they up-titrated and then the curves start to separate at week 16 with the difference as shown of 2.7% at 52 weeks. Moving on to the next secondary endpoint which was our patient-reported outcome measure, the K-BILD. As Peter mentioned and here we had statistical significance again shown to the left for the overall K-BILD. The numbers are there, a p-value of 0.01 and the various domains that constitute the K-BILD are shown to the right. Most of the difference driven by the difference in breathlessness and activities domain and as well as psychological score. Both of these independently had statistical significance. The next secondary endpoint which was also positive favoring inhaled treprostinil was change in the percent predicted diffusing capacity and showing the difference here 1.91% and a P value of 0.04 favoring once again inhaled treprostinil. This is a busy slide. This is a forest plot of various subgroups and the major point to take home from this is that all point estimates are to the right of the line of unity. So there was no subgroup that didn't have a benefit. Some of these by themselves didn't have statistical significance because of the numbers, but all of them again were to the right of the line of unity, indicating a consistent effect across all the different subgroups. I will draw your attention to the top right last study drug dose less than. We dichotomized these by less than nine breaths. The patients are able to achieve only seven or eight breaths. The numbers are fairly small, 62 versus 30. But what you'll note underneath that are the patients who hit nine to 12 breaths per session and that was the majority of patients. And if you look at this higher dose group, the difference was actually 107.8 cc in terms of FVC. So this does raise the question of whether there might be some kind of a dose response. Moving on to our adverse events. This was an IPF study over 52 weeks. These are sick patients and it's no surprise that the majority of them, 91.89% had at least one adverse event. There were no adverse events that were a big surprise. Number of subjects with at least one study drug related AE. There was a difference there of 64.8% versus 42.4%, but generally the drug was pretty well tolerated. These are the major adverse events that were seen. Cough occurred most frequently at 48% versus 24%. I think the thing to bear in mind is that cough is a common symptom of these patients with IPF anyway. So how much of this cough was preexisting versus exacerbated by the medication is a little bit uncertain. The rest of the side effects, headache, diarrhea, are typical prostanoid side effects that we've seen in many of the clinical studies of inhaled treprostinil and that patients experience in the clinical trenches as well. So in conclusion, TETON 2 met its primary endpoint of change from baseline in absolute FVC at Week 52. The study also met statistical significance for several key secondary efficacy endpoints such as time to first clinical worsening, percent predicted FVC, K-BILD, and the diffusing capacity. Nebulized Tyvaso was well tolerated and the safety profile was consistent with previous inhaled treprostinil studies and known prostacyclin-related adverse events. So with that I will turn it back over to Leigh. Thanks a lot, Dr. Nathan, and for your trailblazing contributions in the field. We're really grateful to have you with us today and we appreciate the valuable perspectives you've shared. In summary, these data are a significant milestone for individuals living with IPF and I extend my heartfelt gratitude to all of the trial participants and their families, the dedicated teams at United Therapeutics, and the investigators whose commitment made this achievement possible. The robust and carefully executed TETON 2 trial has delivered persuasive evidence that treprostinil can meaningfully improve FVC for patients who previously faced limited treatment options, most of which offer only modest benefits and often come with difficult side effects. Equally, we observed benefits on several key secondary endpoints, all while demonstrating a well tolerated safety profile, and that's consistent with previous Tyvaso studies and known prostacyclin related adverse events. We consider these findings a decisive achievement and are committed to swiftly seeking regulatory approval for the IPF indication and advancing this important therapy to those patients who stand to benefit most. We look forward to providing results from TETON 1 pivotal study which evaluates participants in the US and Canada in the first half of next year, so now I'd like to open the call to questions. Operator. We will now b egin the question and answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time we will pause momentarily to assemble our roster. The first question comes from Olivia Brayer and Cantor Fitzgerald. Please go ahead. Hi there. Thank you guys for the question and congratulations on a really great result here. Can you talk about the decision to use Hodges-Lehmann in the TETON study and really what's driving that difference between the observed versus the imputed mean? I'm under the impression that HL hasn't necessarily been the standard method of choice in prior IPF studies. So just any thoughts there and then around the discontinuation rates? Is that something you guys have disclosed yet, both for the overall study but also across the different treatment arms? If I'm looking at this correctly, it looks like only about 203 and 212 patients were evaluable at 52 weeks, so any color there would be really helpful. And then I've got one more question if we've got time at the end. Thanks, Olivia. C.Q. will handle the stats question and then we'll kick it back to Dr. Nathan, for your question on discontinuations. Yeah, so for the statistical model initially we proposed parametric method using mixed model repeated measures. But you know, in all of these analysis, if you use a parametric model, you have to check the assumption for using that model, see if that assumption still hold. And in our TETON 2 study we, after you fit the model, we check the assumption. Essentially you check the normal distribution of that residual from that model, then the model indicates the result, indicate that the assumption is violated. So we then switch it to the non-parametric rank-based approach to analyze the data. But we did all these analysis parametric and non-parametric in both ways. So results are consistent. So but from a statistical standpoint, if your assumption for using parametric model is violated, you're supposed to switch it to the non-parametric method. Now I'll turn the question to Steve. Yeah, sure. Now that you did pick up that there were 203 and 212 patients at the end of 52 weeks who were continuing on therapy, and there were premature discontinuations. If you look at the 298 who started out in the treatment arm of inhaled treprostinil, 100 prematurely discontinued treatment and 50 of these were due to adverse events, another 32 due to patient decision. And then what we have coded is other. For the other 18 in the placebo arm there were 73 who prematurely discontinued treatment, 37 for adverse events, 22 was a patient's decision and 14 for other reasons. And there were 74 patients who discontinued before week 52 but still continued in the study. And so we had 224 versus 239 patients who completed the study at 52 weeks. I will have to say that this was a big ask of patients. We were giving them a medication that's nebulized four times a day. We were asking them to go 52 weeks and we were giving them a medication. And they didn't know if it worked or not. And they didn't know if they were getting placebo or the real deal. And so I think a component of this is really just nebulizer fatigue over 52 weeks. Once the drug is approved for IPF, I think there's added motivation for the providers as well as the patients to continue on therapy because now we know it works and now they will know that they're getting the real deal. So we might actually see, I would speculate we might actually see less discontinuation once it's in the clinical arena for IPF. The next question. Ready for the next question? Yes, thank you. The next question comes from Andreas Argyrides and Oppenheimer. Please go ahead. All right, thanks for taking my questions here and congrats on your impressive results across the board. Can you just... Maybe it may be hard to do so, but can you just speak to what you think is driving the magnitude of benefit? We've talked about the preclinical evidence of treprostinil's antifibrotic effects, so maybe a little bit of color there. And then looking at these results, is there any one particular endpoint that you'd find important for clinicians? And then just one more addition to that is looking at the results on the background medications. Any conclusions you can draw on why a more pronounced benefit? Let's just say background pirfenidone versus nintedanib. Thanks. Sure. That was three questions. I need some help remembering them. I'll start with the last one because. I remember that one. The three groups that we showed treatment naive on pirfenidone and on nintedanib. For some reason, the pirfenidone group appeared to deteriorate the most. The group that got placebo, and that's why we got that big difference. But I think an important point is if you look at the three groups who got treatment, they were all very replicate in terms of their response around the 50 cc loss of lung function over 52 weeks. To put it in further context, if you look at normal elderly individuals, normal elderly individuals over the course of 52 weeks will lose about 30 cc's of lung function. So you put the 50 cc's in that context and I think it's a pretty impressive result. Now, the second question is, is there anything else in the data set that will resonate with clinicians? I think a big one for me is quality of life. And I showed you that. And you know, if we can put patients on therapy that preserves or improves their quality of life, that's huge. That's going to resonate with patients, that's going to motivate them more to take the medication four times a day. And as you know, the agency, the FDA, is all about how patients feel, function and survive. Well, this gets to how they feel directly. And it's the first study in IPF, to my knowledge, that has shown an improvement in quality of life. So I think that's a pretty big secondary endpoint that we hit in the study. I'm going to ask one of my colleagues. Oh, the mechanism. Thank you. Yeah, I think as mentioned during this call, that prostanoids and treprostinil in particular have properties beyond their traditional vasodilatory effects. When we saw the signal from the interim study of the FVC change over 16 weeks, we went back into the literature and we did a deep dive, and in actual fact, there's a large body of evidence attesting to the antifibrotic properties of treprostinil. It engages at least four different prostanoid receptors that have downstream antifibrotic properties, and so it appears, based on biologic evidence, that it's a pleiotropic molecule in terms of its antifibrotic properties. Now, what I really like about it is we're giving it inhaled, a different route of administration. We're getting deposition of drug directly to where we want it within the alveoli. And if you think about the current paradigm of the pathogenesis of IPF, we talk about epithelial to mesenchymal transition. That's those lining alveolar epithelial cells that metamorphose and transition to fibroblasts. And now we're getting dragged directly down there where that activity is taking place versus giving systemic drugs. Currently available Pirfenidone and nintedanib gets into the bloodstream. We're not entirely sure where in the lungs it's going. So to attack this disease directly via the inhaled route makes a lot of sense and it's very gratifying to see that borne out in the results from TETON 2 The next question comes from Joseph Thome and TD Cowen. Please go ahead. Hi there. Good afternoon. Thank you for taking my questions. Congrats on the data and appreciate the presentation. Maybe for Dr. Nathan, can you discuss how you would incorporate Tyvaso into your treatment paradigm if it's approved? Would this be a frontline combination therapy? And earlier in your ERS session, the nerandomilast, the data were highlighted, but it does have that pirfenidone FVC, whereas Tyvaso looks to have about a 50 milliliter decrease no matter what. How would that impact your prescribing decision if both those are approved? And then anything different in the US and Canada that we should think about when we extrapolate these results into the expected findings for TETON 1. Thank you. Sure. If or when Tyvaso is approved for IPF, I think it will be nice to have different treatment options. I think we are in the era of multimodality therapy for IPF. That makes a lot of sense in all the different diseases that we've managed to chip away at, including pulmonary arterial hypertension. Now it's dual therapy, triple therapy, quadruple therapy. I think we probably going in that direction with IPF as well. And as I mentioned, giving an inhaled medication on top of a systemic medication makes a lot of sense to me. When I did the presentation this morning, I gave the analogy of attacking the disease from the front and attacking the disease from the rear. So to me it's a very attractive option to give multimodality therapy with an oral medication as well as an inhaled medication. How I might do this on a case-by-case basis is really going to depend on that patient interaction. But I would lean more to doing multimodality therapy in these patients. I will say that we started multimodality therapy in PAH before we knew it actually worked in PAH and so I think we might see the same kind of paradigm emerge in IPF. The answer is one versus two. What was the second question again? TETON 1 versus 2. Thank you. Yeah, we actually, I don't think that there's going to be a difference at least based on the baseline demographics of these two patient populations. There doesn't appear to be anything different in these populations. I know that folks had hypothesized that well, maybe more patients with PH ILD will get into TETON 2 because Tyvaso isn't available in many of these different countries. But we actually compared the baseline demographics of TETON 1 to TETON 2 and this was an abstract presentation at ATS this year and there really wasn't any difference between the two groups. The FVC was right about the same, the DLCO was right about the same. If anything there were more patients on supplemental oxygen from TETON 1 than there were from TETON 2. But overall the patient populations look very similar. Next question, operator. Thank you. The next question comes from Ash Verma with UBS. Please go ahead. Hey, good afternoon, this is Dee. On behalf of Ash, congrats on this data. So I have two questions. So the first one, just looking at the time course of FVC decline, the Tyvaso arm, what do you think drove this rapid decline after week 40 versus prior to that it was fairly stable. And then my second question is related to like competing in TPIP. Do you believe they would have to pursue head-to-head study versus Tyvaso to establish clinical differentiation? Thanks. I'll address the FVC and I'm going to ask C.Q. sitting there next to me to help me out with that. I think we see that in IPF studies. I think the imputation also helps drive that curve down because as you get further into the study, you're getting more dropouts and then you do the imputation, which generally is not favorable to the patient whose data is being imputed. But we see this in many different IPF studies where you tend to get a little bit more of a drop off towards the end. But if you look, if you think back to that graph that I showed of the primary, and you look actually at the imputed data, the squares that I spoke about, it looks like they are coming more apart than the lines would suggest. C.Q., do you have anything to add to that? Yeah. Essentially for patients who died before week 52, we have to apply that pretty conservative imputation approach. So for patients who died before week 52, we impute that using 2.5 percentile. In the very beginning, we actually even use a more strict rule to impute that. Then after we discussed with FDA, FDA suggests we use 2.5 percentile. So all of this imputation actually they drag down the mean value or median value for all of these submissions at the late time point. Yeah. Dee, thanks for the question on TPIP. We're happy to do some follow up, but I think today with respect to Dr. Nathan's time, we're going to focus on the results presented. Next question. The next question comes from Lisa Walter with the RBC. Please go ahead. Oh, great. Thanks so much for taking my questions and congrats on the data today. Just a couple for Dr. Nathan on the adverse events. Dr. Nathan, I wonder if you can comment on patient tolerability with using the nebulizer versus using an oral pill, and were there any dropouts specifically? Due to c osts in the study. And secondly, Dr. Nathan, just wondering if you were surprised by the slightly lower rates of diarrhea in the treatment arm. Was this mainly just driven by the fact that there was almost 2% less use of Ofev in the Tyvaso arm, or was there another factor at play here? Any color here would be helpful. Thanks. Yeah, I think that nebulized medication has a different adverse event profile to the oral medications. And certainly cough is a big one we worry about. When we reported cough, it was 48% versus 24%. What I would say is we don't have good granularity on the cough in terms of how sustained it was. Some patients I know from our own clinical practice will cough for five minutes after a treatment and then it will ameliorate. So we don't know how long the cough lasted. For a lot of this cough was in the up titration period. And once you get them through the up titration period, then generally it stabilizes out. So even though cough was reported as an AE, what we don't report is when cough gets more tolerable and becomes less of an AE and they get potentially back to a tolerable baseline cough. Now what I will say is that there certainly were patients who discontinued from the study for cough. I mentioned the number of patients who prematurely discontinued for an adverse event. It was 50 versus 37. And you know, between the two groups, a lot of that was cough. But what I would say is of those patients who discontinued for cough, there were only two who reported severe cough as an AE. So there were some other patients with mild cough, moderate cough who might have discontinued and maybe it was accumulation of gosh, I've been on this medication for so long, I'm coughing, I've had enough, I'm going to stop. So I think sometimes when patients discontinue, it's a combination of some AE, maybe with nebulizer fatigue and maybe not feeling much of a difference. This is also very different. This is an IPF study. This isn't like INCREASE where patients had pulmonary hypertension and some of them felt better, could do more with their six-minute walk test. This is an IPF study where the goal was and what we showed was slowing the rate of progression and preserving their quality of life. Next question. The next question comes from Jessica Fye with JP Morgan. Please go ahead. Hey guys, good afternoon. Thanks for taking my questions and congrats on the results for Dr. Nathan. I'm curious which of these clinical endpoints you think most convincingly makes the case for a direct antifibrotic effect for Tyvaso? And was total lung capacity also measured in this trial corroborating the FVC results? Second. Maybe I'll just close off the other one. The second one is just, you know, various papers suggest that a meaningful proportion of IPF patients eventually end up with pulmonary hypertension over time. And I guess recognizing that's not in the presentation today. Do the TETON trials capture and collect information around any IPF patients who might have received a PH diagnosis while on the trial? And then lastly, recognizing that right heart cath is the gold standard diagnostic for PH, and your earlier comments about the incredibly balanced baseline characteristics between TETON 1 and TETON 2 beyond the trials just being balanced, I'm curious if there are any inferences that you would make from the various baseline characteristics that we do have about the proportion of patients in the trials who might have also had PH. Thank you. Sure. Okay. A lot to unpack there, so I'll try and address as much as I can. Yeah. The study by purpose was totally agnostic to the presence or absence of pulmonary hypertension because our goal was purely to pursue an antifibrotic effect. Getting to your first question, which metric or outcome directly is most attributable to an antifibrotic effect? I'll have to say FVC. I think that clearly the 95.6 difference does attest to a direct antifibrotic effect. As CQ mentioned, we did multiple sensitivity analyses doing various imputations and they all came out at around 90-95 cc. So whichever way we looked at the data, whichever way we imputed it was pretty much the same result. I think that's a pretty impressive result, especially on top of ongoing antifibrotic therapy, as I showed you, for the pirfenidone and the nintedanib arms. Now you're quite right. I mean a lot of these patients, or some of these patients probably had PH that were lurking below the surface. If you look at some of the papers that are out there going back to an old study, Artemis-IPF, which was looking at another drug for IPF, all those patients got catheterized. The inclusion criteria were fairly similar, and about 15% of those patients had pulmonary hypertension, and that was under the guise of an older definition of pulmonary hypertension, so very likely that some of these patients did have pulmonary hypertension. The best surrogate, and perhaps one of the few surrogates we have for pulmonary hypertension, is the NT-proBNP, and you know, there wasn't a difference in the NT-proBNP in terms of their, their baseline values, so I think I answered your first question. I think most of your questions around pulmonary hypertension, so hopefully I address everything that you ask. The next question comes from Jason Gerbery with Bank of America. Please go ahead. Hey, thank you so much for taking my questions. Maybe for Dr. Nathan, just curious how you look at this group of patients that just cannot tolerate the existing antifibrotics. In this study, 25% of patients were not on background meds. We've heard anecdotally, maybe a third of IPF patients just can't take their Ofev or Esbriet for tolerability reasons. So does the data here inform in your mind that Tyvaso is an option as a monotherapy? Just kind of curious how you're thinking about that. And or maybe what you need to see from the pooled TETON 1 and 2 data as its approach as monotherapy would be helpful to understand. And then when you talked about polypharmacy, right, and you've got Tyvaso Nerandomilast, potentially Bristol's LPA, like, you know, is it the field's going to just be experimenting with this or is the catalyst for polypharmacy with triple or even quadruple therapy need to be really driven by registrational studies? Thanks. Yeah, I think how we use the drug when it's approved will really be on a case-by-case basis. And you're right, those patients who are intolerant of the current antifibrotics might be first up for monotherapy. And so I think this is a very nice alternative for them. And the numbers you mentioned, you know, if you read various registries and database reports, the number of patients who on antifibrotic at one year are even much lower. Some reports around 10% or 20% of patients who started on antifibrotics continue on them a year later. So certainly there's a large patient population who could or would be candidates for this and hopefully they would be much more tolerant of this versus the systemic side effects that we get with our current antifibrotics. I think how we use this drug in relation to what's approved will really be on a case by case basis. I think as clinicians in the trenches, we have been adopting dual therapy, triple therapy, quadruple therapy in the PAH field before that got proven, and I think it's based on clinical need. When you have patients who are deteriorating, you have limited options. Sometimes you have to use your best judgment before the clinical trials come out to prove that, you know, triple therapy or quadruple therapy works better than dual or monotherapy, so it's really going to be driven by how the patients do and each clinician's interaction with individual patients, how we use these drugs. All right, next question. Operator. The next question comes from Mazi Alimohamed with Leerink. Please go ahead. Thanks for taking our question. This is Mazi on for Roanna. Just kind of one really from us, which is what do you think drove the lower decline in FVC in the placebo group versus that on background standard of care. I'm recognizing that the treatment naive group had a smaller sample size, but just kind of seeing that there was a much larger difference there. What do you think was the primary driver there? You know, I can't be certain, and very interestingly, we've seen the same phenomenon in other IPF studies, including the Nerandomilast data set. For some reason, the treatment naive patients deteriorate less. I think folks have hypothesized that, well, you know, maybe these patients were stable and that's why they weren't started on antifibrotic therapy. And that's why we get less of a decline in these patients because they were predestined to continue to stay stable versus patients who are deteriorating and more likely to go on therapy. One thing that's made me think about, and this is entirely speculative, I have no data to support this, is do our current antifibrotics have a limited period of time where they might be effective? You know, the studies that got nintedanib and pirfenidone approved were 52-72 weeks. Maybe they're escape mechanisms that kick in three, four, five years later. We don't know. As I said, this is entirely speculative on my part. I don't know. But it's either that or patients who are predestined to stay stable who got included in these studies. But an interesting phenomenon that we've seen in other IPF studies as well. All right, operator, we have time for one more question. And that last questioner will be Roger Song with Jefferies. Please go ahead. Great. Thanks for taking our questions. This is Liang Cheng for Roger. So, kind of following on the placebo. arm in a population without background therapy, so just wondering with that delta seen. How does still warrant? Do you still see potential use of Tyvaso in the. First line without background therapies? Thank you Yes, I believe that it can and will be used as first line therapy. Because what I would say to you and to other providers is look at the treatment effect. And the treatment effect was consistent across all three groups at about -50 cc's in terms of loss of lung function. And so in the clinical trenches, you might be, or we might as providers be dealing with a different patient population versus those who came in treatment naive into the clinical trial. One other point I need to make is that if you look at the baseline demographics of the treatment naive patients compared to the rest, their baseline FVC was higher. So these patients might have also come in having milder disease and that's why they hadn't as yet been started on antifibrotic therapy. And if you take patients with more moderate or severe disease, that becomes an enrichment strategy for further deterioration. So that certainly could have also played a role. Thank you for participating in today's webcast. A rebroadcast of this call will be available for replay for one year by visiting the Events and Presentation section of the United Therapeutics Investor Relations website at ir.unither.com. You may now disconnect.