Liquidia Corporation (LQDA) Earnings Call Transcript & Summary

Well, great. Thank you, everybody, for being seated. Welcome. I'm Roger Jeffs, CEO of Liquidia, and welcome to our first ever R&D Day. We're really excited about what we're able to share with you today. I also want to recognize that we have a large number of our leadership team here. And I think if you have questions after the event and you'd like to speak with them individually, please do. So today's presentation, as you know, will include a number of forward-looking statements that may include risks and uncertainties and thus are not meant to guarantee future results. We refer you to our filings for a more complete listing of the associated risks and uncertainties. So our goal at Liquidia is to revolutionize the care for patients with challenging respiratory and vascular diseases through precise innovative therapies that restore health and hope. By improving drug delivery, using proprietary formulation technologies to reduce the burden of administration and help patients live and breathe longer. To level set, as we look at all markets, both current and future, the ideal product profile for inhaled treprostinil delivery is optimized for 5 key elements, and you'll hear this repeatedly today in the other speakers' presentations. First, targeted lung delivery to reduce the off-target effects and toxicities from oral and IV and subcu delivery like GI toxicities and site pain and erythema or risk of septicemia. Another element is that the therapy should be affordable for convenient and easy use to support compliance by the patient. It should be tolerable, so it's customizable and not dose limited. Critically, it should be titratable across a wide dose range to extend time on treatment. And the dosing frequency should be easy and a simple regimen. So those are the 5 elements that if you were to produce an ideal therapy, you would check the boxes for all of those. YUTREPIA in particular, addresses the first 4 elements. And it's the current best-in-class inhaled treprostinil option by the virtue of meeting these 4 elements. And as such, clearly has tremendous opportunity within the currently approved indications, pulmonary arterial hypertension and PH with associated lung disease. If you look at it, it's targeted lung delivery, but targeted in a unique way through the print formulation technology and that it discretely gets to the lower airway. It's portable with a low effort, trustable, reliable and robust device, tolerable as you've seen from the original INSPIRE study, and as you'll hear more about today from the ASCENT trial, titratable, and we're going to share more and new data from the ASCENT trial to show you a continuing titration over time. And the only thing where it may fall a little short is it's still 4 times a day, which is where the incumbent brand therapy also is. L606, our liposomal sustained release formulation takes this the one step further and aims to address all 5 elements by reducing the dose regimen to twice daily, and thus would represent the next major advance in inhaled therapy of treprostinil delivery and patient care. So as you can see, retains all of the things that you would want, targeted delivery using a liposomal formulation, which we'll dive deep into today, both at the science and the results from the L606 48-week study. It's portable with a rapid breath-actuated nebulizer. Rajeev will go into detail on it, but this is it here. It's tolerable with -- and actually, what we feel it will further improve the tolerability that we already observed with YUTREPIA because it lowers the Cmax while sustaining the exposure over twice daily administration. You'll see readily titratable because it's well tolerated. And the dosing frequency, we now check that box as a twice-a-day therapy. The real important people here today are sitting here. These are invited guest speakers. Dr. Richard Channick. He's the Endowed Chair in Pulmonary Arterial Hypertension, Co-Director of the Pulmonary Vascular Disease Program and Professor of Medicine and Critical Care Division at the David Geffen School of Medicine at WCLA (sic) [UCLA]. Rich and I have worked together since the early '90s on the first-ever trial of Flolan and on many subsequent trials over the past 3 decades. So welcome, Rich. At UCLA, Rich's acumen is complemented by Dr. Rajan Saggar, who along with his brother, Rajeev Saggar, our CMO, were the original innovators for the use of treprostinil to treat PH in patients with associated lung disease with publications dating back as early as 2009. And as you can see, the titles that Rajan holds at UCLA. Rich and Rajan are truly a dynamic duo and have created one of the leading practices in the world at UCLA, both in terms of expertise and volume of patients that they treat. And finally, a true rising star in the pulmonary field is Dr. Ricardo Restrepo. He's a leading clinical investigator in almost all of the major studies, is one of the leading enrollees in our L606 study, which he'll review with you today. So here's today's agenda, and we'll cover the following topics. Rich will take a deep dive into the diagnosis and treatment of PAH and PH-ILD and the critical role that inhaled treprostinil can play, with special emphasis on the differentiated product benefits of YUTREPIA. Rajan will then provide for the first time, exciting 24-week data from our ASCENT study in PH-ILD. We'll then turn to a review of the formulation science and PK that underpins our liposomal sustained release suspension by our CMO, Rajeev Saggar. And this will be followed by the first-time presentation of week 48 data from the 28 patients that have participated in the ongoing open-label L606 study by Dr. Restrepo. With that, I'll turn it over to Rich, who will address the unmet needs for patients with pulmonary arterial hypertension and PH-ILD. Thank you, Rich.

Thank you very much, Roger, and thanks, everyone, for being here. I'll try not to distract you from the view, which I'm looking at. But as Roger said up, yes, I've been involved in this field for 34 years. So I think I see the perspective from the era of no therapies whatsoever, back in the late '80s, early '90s, when I started doing this, to now. So I think that perspective gives me a lot of ability to see where we're headed, what we need, where are the gaps. And I hope to kind of give you that perspective from a really personal point of view, having dealt with this condition and these therapies for so long. As you know, and I done enough of these to know that this group is probably very sophisticated in this disease state. So we're not doing a basic review. And as you know, when we're talking about treating pulmonary hypertension, the first step is to diagnostically categorize a patient correctly. One of the big mistakes of not getting adequate therapy to patients is not treating the right patient, either not making the diagnosis or making the wrong diagnosis. So we use this category of classification groups from 1 to 5 based on a pretty standard workup that every clinician should know, and which we spend our time teaching about. Today, as we're talking about the drugs that we have are approved for Group 1 or what we call PAH. So this is pulmonary arterial hypertension, and that can be idiopathic or associated with a lot of diseases. Or Group 3, which is pulmonary hypertension associated with lung disease. And when it gets to drugs like YUTREPIA, we're talking about pulmonary hypertension associated with interstitial lung disease, one form of lung disease. So that's obviously what we're going to focus on when we're talking about the treatment today. So the next thing to set this all up for what we're going to be hearing about later is how common is it. And the prevalence of pulmonary hypertension, whether it's Group 1 or PAH or Group 3 PH associated with ILD, is a changing target because one of the problems is, of course, underdiagnosis and lack of diagnosis. And the more you look for it, the more you find. So when I -- when you see all these numbers on here, we always have to take them with a little grain of salt, like the 48 per 55 cases per million for PAH makes it obviously a very rare disease. It's a lot less rare than that, in my opinion, having done this for a long time. And many, many patients are not diagnosed with PAH when they have it. Even more so, when we're talking about PH associated with ILD, you see these kind of percentages depending on what kind of ILD from up to 86% with IPF. We're not going to go through every form of interstitial lung disease, but it's complicated, right? And so we have NSIP, we have connective tissue diseases in pulmonary hypertension. We have hypersensitivity pneumonitis, CPFE. So these are all sub forms of ILD. And you can see the numbers there in terms of the percentage that will develop PH in those diseases, pretty darn high, ranging from 20% up to over 80%. So this really sets up the importance of looking for pulmonary hypertension in a patient with interstitial lung disease. And again, this is what we spend a lot of time hitting home. The other point related to that is that if you do have pulmonary hypertension in the setting of interstitial lung disease, it significantly and negatively affects survival. And there are data from a number of recent registries. This is one called GoDeep, but there are several others showing that, in fact, on the curve on the left, patients with PH-ILD do have a significantly worse outcome survival than even patients with PAH. And importantly, and this gets to how big the market is for these patients, even in the setting of mild, what we might call mild pulmonary hypertension in the setting of ILD, as shown on the right-hand graph, that still has a pretty poor survival. You can see there with a wood unit. That's a measure of the resistance or PVR, less than or equal to 5, maybe pretty mildly elevated. Greater than 5 is more severe. But you can see poor survival in both of those groups. So the take-home message is that even with relatively mild, and there are some studies showing even with very mild PH with ILD, outcomes are worse, another call to action for recognizing and treating early. One of the problems, however, is making a diagnosis. And as a clinician who sees thousands and thousands of these patients, one of the problems, and this more gets to the clinicians, is that the symptoms of pulmonary hypertension overlap the symptoms of interstitial lung disease. So they're short of breath, they're lightheaded. There are a number of symptoms. So in the trenches, when a doctor is looking for pulmonary hypertension, it can be hard to unmask it in a patient who has a lot of underlying lung disease. But the vigilance required for repeated testing and the high index of suspicion for finding PH, again, is a critical part of the messaging and the education that experts like myself spend our time doing to try to teach these clinicians to find it and routinely screen for pulmonary hypertension, again, now that we have effective therapies for these patients. And even going a step further, when we're talking about how mild is mild, we have these hemodynamic definitions. I don't know how familiar you are with these, but the hemodynamic definitions change, and they keep getting lower and lower. In other words, the level of pulmonary artery pressure and the level of resistance, that we call abnormal now, keeps decreasing. And the reason why that is, and you can see that laid out here in these different guidelines, is that there's pretty good data, and that's shown on the right, that mortality goes up even when you have mild, and some would say even borderline pulmonary hypertension. And this is just a study showing that inflection at a PVR of like 2 wood units, which 10 years ago, we would have said it was completely normal. It doesn't look like it's normal and an increase in mortality at a PVR above 2 wood units was actually a surprise to me, and I think really, again, indicates why it's important to diagnose this early. Well, why do we diagnose it early? Because we now have effective therapy. And now we're going to turn to the prostacyclin pathway, which is obviously what we're talking about today with the therapies you're going to hear about. So again, I've been doing this as long as Roger, and he was involved in the very first study with the very first drug for pulmonary hypertension, which was Epoprostenol or Flolan. That's a prostacyclin that was developed to augment what was deficient in patients with pulmonary arterial hypertension. And we know, even 35 years later, that prostacyclin is a critical pathway in the development and progression of this disease. And that replacing prostacyclin, targeting prostacyclin, we believe, is very critical and will remain critical in the future. The prostacyclin that we're delivering, it does a lot of positive things like relaxing the blood vessel, preventing proliferation of the blood vessel wall, preventing things like platelet aggregation. So there's a number of effects that prostacyclin has that will be desirable in a patient with pulmonary hypertension. So the prostacyclin pathway continues to be critical. And this is just a brief timeline showing how this developed from the early days of the early '90s when, again, we came on the scene, so to speak, when we had IV epoprostenol approved in 1995. Then you had a longer-acting treprostinil formulation delivered as continuous parenteral therapy in the late '90s, early 2000s. You then had the oral prostacyclin pathway drugs. And then the inhaled drugs, starting with inhaled iloprost, inhaled treprostinil, given as a nebulized form is TYVASO, followed by a DPI formulation of TYVASO. And we'll talk a little bit about some of the challenges with that drug related to cough and irritation. Now to the latest formulation, which is YUTREPIA, recently approved. And I'll give you my own personal experience with this evolution and what we've seen. Clearly, when it comes to inhaled therapies, there's some theoretical benefits. It doesn't take a genius to figure out that if you have a disease in the lungs, getting a drug directly to where the disease is and not delivering it systemically seems to make sense. And so the ability to reduce systemic side effects, deliver a drug directly to the lungs, maybe have less specificity, higher local concentrations, maybe improving what we call the ventilation perfusion matching and then importantly, in a way that patients will be willing to do. The worst treatment is one that the patient throws out the window because they don't want to do it. And that's a critical part. Drug can be really effective, but if they don't use it, it doesn't help. So let's turn then to the inhaled treprostinil. And that's where we're going to really go with the rest of this day today. So one of the things we know, and there's a few general themes that I've observed over many decades working with prostacyclin, one of them is that dose seems to matter. And I can unequivocally state that if you can get a patient to higher doses, higher exposure of prostacyclin, and they tolerate it without dose-limiting side effects, you'll likely get better benefit, and the patient will do better. One of the challenges, frankly, with the previous form with TYVASO nebulized, and this is shown here, is the ability to get patients to high enough doses. And this is just study showing that only 28% of patients could get above 9 breaths. And we'll talk a little bit about the breath equivalents with the other speakers when you look at some of the other data. And you can see here that, that seemed to make a difference. So the less you could get on with that drug, the less effect it seemed to have on something like exercise capacity. And that's a problem. And it's an opportunity for a new drug to come on to hopefully get those doses higher. Another issue, real-world issue -- and I'll get it a little bit into sort of the real world. So this is a paper presented by the National Jewish Group that looked at actually a dry powder formulation of TYVASO, the TYVASO DPI, and showed a problem with it in patients with PH-ILD. And I will certainly attest that this is likely a real problem, like the tolerability as it relates often to cough with patients with significant lung disease who are delivered that particular DPI. And this particular study, presented for the National Jewish Group, a significant majority of patients discontinued the drug, whether they were naive to prostacyclin or were transitioning from the nebulized form. You can see in the circle there that very high discontinuation rate. And it happened pretty early, like within 40 days or so. So it seems to be a challenge and again, an opportunity to develop a DPI, maybe specifically in patients with PH-ILD, but maybe other forms of PAH that's tolerated in terms of the local effects on cough. And I think we're seeing that benefit with YUTREPIA. That's been my experience at least. So we're not going to go into detail on the drug and the delivery of it. But based on the way these particles are made, you get this deep lung delivery, you have what's called a low-resistance device because the particles don't aggregate and can get deep with very little patient effort. And it appears that we can get to significantly higher doses with the drug, with YUTREPIA. So that's a good thing. One of the things that there was some data was the INSPIRE study, which looked at PAH patients who are transitioning from TYVASO to YUTREPIA, and you may have seen some of this in patients who are naive to prostacyclin. And this just shows some of the local side effects. We don't want to get into the weeds on this. We certainly can answer it during the question and answer. But the two things that were looked at that are reported here were cough and throat irritation. And one can see here that in both populations, the naive patients and the transition patients, cough did occur as throat irritation, but it actually seemed to decrease over time and was rarely a reason for discontinuation of the drug. Patients almost never had to discontinue YUTREPIA due to those local effects, which is a reassuring finding. So again, I didn't show you that much data. We can talk a lot more about it. You can hear a lot more data. What I wanted to do in the last slide is to really give my perspective, again, as somebody who's done this for 35 years, as to where I think this field is going, and what I think this drug and maybe the drugs to come are allowing us to do in a center like ours and others that see thousands and thousands of patients. I think the issue of dose is clearly critical. And many of our patients up until now have been dose limited due to side effects. The ability to deliver inhaled prostacyclin at those adequate doses, and we're seeing it with YUTREPIA for sure, has allowed us to in some cases, completely avoid and in other cases, certainly delay the institution of a parenteral prostacyclin. I can tell -- and this isn't just me, I can tell you, others have the same experience that the number of patients we're starting in real world on parenteral prostacyclin is clearly decreasing as we're using this drug more and more. Maybe even more excitingly, it's allowed us to start to transition patients off parenteral therapy. And we have a series of patients who were actively or have already transitioned off of the pumps to YUTREPIA at high doses. We think that the addition of the drug sotatercept, that I'm sure you're familiar with as well, the subcutaneous activin signaling inhibitor has helped facilitate that. I don't know if it's 100% necessary, but that's been -- we have a written protocol for adding sotatercept and then eventually transitioning patients off of parenteral therapy now to YUTREPIA. And I think even broader, when we talk about the treatment algorithm in our practice, in our large center and others, this question of when we should start a prostacyclin now in the era with all these other drugs is something that we talk about all the time. And I think, again, having a convenient form of inhaled prostacyclin that can get to higher doses and is well tolerated, has pushed it earlier. So I personally will start a prostacyclin a lot earlier than I would have when it was more worried about side effects, route of delivery, convenience of delivery. So that's also, I think, pretty exciting real-world experience. I think, again, the dosage that we're getting to are much higher than we've been able to deliver with other non-parenteral formulations like oral formulations or other inhaled. And I believe, and this is hypothesis, I say, that over time, giving a drug like this in high doses will give a patient a better exposure to higher dose of prostacyclin, which I believe and hypothesize will give them better long-term effects, not just acute effects on how far they walk, but actually cumulative effects on their disease course. That's what we hope, and that may, may replicate what we've seen with parenteral therapy in the past. So very exciting stuff. And we're doing it also transitioning from the oral prostacyclin to the inhaled formulation. So lots of exciting things happening in the field. I think I've sort of set it up for you by talking about how common this is more than we think, how severe it is, the importance of looking for pulmonary hypertension in the setting of all forms and certainly PH-ILD and then the importance of prostacyclin and the potential/prudential convenience of inhaled prostacyclin and why our experience with YUTREPIA to date has been so positive, and then looking towards the future, where we think this might all be headed. So with that, I'll stop. And we'll go on to the next speaker. Again, plenty of time for questions afterwards. So now I'd like to introduce my partner and colleague at UCLA, Dr. Rajan Sagger, who's going to present data from the ASCENT study.

All right. Got it. All right. Thank you. Thank you for -- Dr. Channick, nice talk. So I'm Dr. Rajan Saggar. I'm at UCLA, a pulmonologist. We are a program -- I'm specifically a professor of medicine. I actually have a keen interest in pulmonary vascular disease. I co-direct the program with Dr. Channick at UCLA. And we have about 2,000 patients that we follow with pulmonary hypertension. I think a conservative estimate would be about 10% to 12% of those patients have some form of interstitial lung disease. We're also a certified center for pulmonary fibrosis and for scleroderma. Scleroderma, you might know, is the most common autoimmune cause of PH-ILD. We've had a very keen interest, as Roger mentioned earlier, in the molecule of treprostinil and how it affects patients with PH-ILD. And that goes back about 20 years. We have used it in all its forms, including parenteral delivery. So it's very exciting to see this field in PH-ILD sort of manifest with inhalational therapies. And as Dr. Channick mentioned, it makes a lot of sense to deliver the drug directly to the lungs. So I'm here to really talk to you about YUTREPIA and look specifically at this very exciting data that's out from the week 24 data in the ASCENT study. And just to remind everyone, the ASCENT study was an open-label randomized multicenter study really to look at primarily at the safety and tolerability of YUTREPIA in patients with PH-ILD. There were 54 patients in this study who all had right heart catheterization proven, pulmonary hypertension, precapillary pulmonary hypertension. And these patients all had some form of interstitial lung disease or combined pulmonary fibrosis and emphysema on a CAT scan, okay? And all of these patients had a baseline walk distance of greater or equal to 125 meters. What's important is the dosing strategy in this study. And as Dr. Channick mentioned, we were informed initially by the INSPIRE study, which Dr. Channick mentioned earlier. And the dosing in the INSPIRE study allowed us to really challenged the concept of the idea that doses need to be higher or could be higher when treating patients with PH-ILD and PAH. So it brought up this concept that, hey, maybe we're able to get patients on much higher doses of inhaled treprostinil and maybe even do it faster. We were also informed by post-hoc analyses of the INCREASE study. Remember in the INCREASE study, it's very clear that more is better. Getting to 10 to 12 breaths per session or higher is really what led to the primary and secondary efficacy endpoints. In addition, there's also data from post-hoc analysis from INCREASE showing that treatment delay, which is really a theme in pulmonary hypertension. If you delay therapy, the placebo arm never catches up or never does as well. So the idea is, can we get to higher doses, and can we do it faster? And if you can do those two things effectively and maintain tolerability, I think you've really met the burden of an ideal drug, in this case, inhaled treprostinil. So here's the dosing strategy on this slide, which was prescriptive to the investigators, and we weren't investigator in this study. We enrolled about 10% of the patients in the study. And you can see here at week 8, week 16 and week 24, the investigators were asked to try to get to this peak dose, okay, or that dose, that specific dose at those weeks. How they did it was up to them. They could titrate as fast as every 3 days. So 132.5 micrograms of YUTREPIA at week 8, 159 at week 16 and 185.5 micrograms at week 24. These are -- the comparable doses of TYVASO here would be 15, 18 and 21 breaths QID. If you talk to multiple practitioners today that manage PH-ILD, you'd be hard-pressed to find people using those types of doses with the other inhaled treprostinil. We did have exploratory endpoints. I'll talk to you today about the 6-minute walk distance. I won't get into the other ones, but they did look at some quality of life metrics or dyspnea 12 index as well as the emPHasis-10, which is actually a validated questionnaire, quality of life questionnaire in PAH, not in PH-ILD necessarily. But we will look at the 6-minute walk. And the other thing we're going to talk about is cough. This was actually the first study that I'm aware of using inhaled treprostinil that looked at some quantitation of cough going into the study and not just treating cough as a binary sort of issue like yes or no, but actually, okay, how much cough did you have going into the study and did it really change during the study? And I'll get more into that in the future slides. So out of the gate, we can see that at week 24, the majority of patients, over 70% of them were still in the study. There were 15 discontinuations. None of them were related to the actual therapy. There were no discontinuations related to the treatment itself. This was a 27.8% discontinuation rate. And to be fair, this is the same discontinuation rate. If you look there at week 16, the discontinuation rate in this study was 18.5%. In the INCREASE study at 16 weeks, the discontinuation rate was around 24%, fairly comparable using nebulized treprostinil. But actually in stark contrast to what we saw at least in the real-world experience that Dr. Channick mentioned from National Jewish, where the TYVASO DPI -- the discontinuation rate in the naive patients that went on to TYVASO DPI with PH-ILD, the discontinuation rate was 70% at a median of 40 days after starting the medication. So we want to make that parallel there. The other thing you can see here is the adverse events here. The patients came out of the study discontinued for -- remember, this is an aged population, mostly in their late 60s. They have other comorbidities. Two of these patients had lung cancer, one had chronic pancreatitis, one had coronavirus. Three of the patients got transplanted, one of them after an acute exacerbation of the interstitial lung disease. So this is all kind of real-life cohort. And one of the main messages here is that ASCENT, among other studies that we're going to talk about today, really represent what we see in real life and real clinical practice, and this is that. So let's move on here. So let's talk about the demographics. So as mentioned, these were aged patients mostly in their late 60s. I guess it depends who you talk to when you say aged. These were mostly males. They mostly have prevalent ILD. So these are patients who had established interstitial lung diseases. However, they were newly diagnosed with pulmonary hypertension. The interstitial lung diseases really ranged much like INCREASE did. There were multiple etiologies of interstitial lung disease. So you have idiopathic interstitial pneumonias, of which IPF is the most common. You have autoimmune interstitial lung diseases. I mentioned scleroderma as the most common cause of that. And then you had other more uncommon stuff like hypersensitive pneumonia. And then also as with INCREASE, combined pulmonary fibrosis and emphysema was also enrolled. As you know, PH-ILD has the word ILD in there, and we have antifibrotic therapies that are also on the market. And as with INCREASE, these patients were on background therapy, but the rate of background therapy here with antifibrotics was twice as much as it was in INCREASE. About 40% of patients here were on antifibrotics background, about 20% in INCREASE. And most of the use in the U.S. here is with nintedanib. But what also distinguishes this study, and I want to point this out, unlike in INCREASE, these patients were allowed to be on background therapy, specifically with the PDE5 inhibitor. either sildenafil or tadalafil. And that's really important because sildenafil is a medication that is used in the United States and frankly, in other countries as a therapeutic for PH-ILD. It's just a fact. It's easy to get and many patients will benefit from it. And there is data that suggests that there may be a subgroup of patients with PH-ILD that do benefit. The drug was -- YUTREPIA was studied over a broad range of peak inspiratory flow rates, and it worked beautifully. Just to point out here that there was a broad range of peak inspiratory flow rates. Dr. Channick brought up the low-resistance circuit in the inhaler device itself. This worked beautifully as anticipated. The hemodynamics in the study, you can see that the pulmonary vascular resistance was 6 wood units on average. Keep in mind that the definition of severe PH complicating ILD, 5 wood units is sort of that threshold. So above that is considered severe. So on average, most of these patients had severe pulmonary hypertension complicating their ILD. Most of these patients based on pulmonary function tests were moderately restricted. They had severe loss of diffusing capacity. These are typical features of pulmonary hypertension associated with ILD. And just a few things on clinical characteristics. The walk distance at baseline in the study was just below 300 meters. This is a little bit higher than you might expect for a PH-ILD population. We explained that in the context of -- in this study, we actually did enroll patients who had a milder PH phenotype. I sort of forgot to mention that. So patients who had a mean PA pressure of 21 or higher were also included in the study, which is a little bit different from the INCREASE study. So there was a milder population, which probably increased the baseline 6-minute walk. The other thing is we did allow for background therapy with PDE5 inhibitors, as I mentioned earlier, that also probably brought up the 6-minute walk at baseline and hence why you see a little bit higher than what you might anticipate. I mentioned the simplified cough score here as well, which we're going to get into in a future slide, but this was that semi-quantitative scale that I'm going to get into in a future slide. So this is really -- let me just set the slide up for you. So on your right is the YUTREPIA dose on the Y-axis. And opposite of that is the comparable nebulized treprostinil dose, okay? And you can see here, it's broken up by week 8, week 16 and week 24. And what you can see in the red lines there are the median dose of YUTREPIA and the comparable dose of nebulized treprostinil. And at week 8, week 16 and week 24, the median doses in this study are 132.5 micrograms of YUTREPIA, 159 micrograms of YUTREPIA and 185.5 micrograms of YUTREPIA, which correlate to comparable doses of nebulized treprostinil of 15, 18 and 21 breaths per session, okay? So I think the bottom line here is that we were clearly dosing this drug at comparable doses of nebulized treprostinil, which are very high. And we were able to get to such doses in a very fast manner. And I'll remind everyone that at week 16 in the INCREASE study using nebulized treprostinil in PH-ILD, the median dose was 12 breaths of nebulized treprostinil QID. In this study, the comparable dose was 18 breaths of YUTREPIA -- sorry, 18 breaths of nebulized treprostinil equivalent of YUTREPIA at the week 16 median dose. So well, that's all great. You can get the drug high, you can get the drug high fast, meaning quickly, all novel thing or all very noble things that get done here in the ASCENT study. But if that's at the expense of tolerability, you got a problem, which we did not see in this study. So here, you can see week 8, week 16, week 24, you can see the median doses just beneath that, okay? And those correspond to the 15, 18 and 21 breaths of nebulized treprostinil breaths per session. The most common adverse event was cough, not surprisingly. About 40 -- somewhere in the mid-40s to high 40s of the patients had cough. But what's really important is the investigators were asked to label the cough as mild, moderate or severe. Almost all of the cough was mild. There were no discontinuations in the study related to cough. I mentioned that earlier as well. Nothing -- no discontinuations related to the medication at all. And importantly, the second most common adverse event was headache. And this is a common prostacyclin side effect. It was about 13% to 18% as you go from week 8 to 16 to 24, and the other side effects there were minimal. So very well tolerated. And really, it looks like the cough as you go through time, week 8, 16 and 24 sort of stays relatively stable, right? Now we're going to talk a little bit more about that cough. So the cough scale here was a simple -- it's a non-validated scale, but I think it's the first time that someone has taken a look at quantitating the amount of cough that someone enters the study with PH-ILD. So here, you can see the scale is 0 to 3, 0 is no cough, 3 is frequent cough. And you can see at baseline, the patients had cough. And as we go from week baseline to week 8, week 16, week 24, as sort of was intimated in the last slide, there's really no change in the report of cough as we go through the study. And as I mentioned, all of the cough that was reported or almost all of it was mild in nature. So I think that's important to keep in mind and really a big, big deal in terms of tolerability and really brings this home nicely. So let's talk about the exploratory endpoint. This is one we're going to speak about today, which is the 6-minute walk distance. And you can see, just to set it up here, this is the walk distance changes, okay? These are -- there's no placebo arm here. So this is just straight up walk distance changes at week 8, 16 and 24. In black are the median values by the bars. And then if you want to see the mean values, to the left of your screen -- sorry, to the right of your screen. So at week 8, you had a 21.5 meter; at week 16, 31.5 meter; and week 24, 41-meter improvement. Well, that's just a lot of numbers. What does it really mean? Well, in pulmonary vascular disease, one of the critical numbers you need to remember for significant walk distance improvements is actually 30 meters. It's a very important threshold. In PAH or Group 1 pulmonary hypertension, this has been validated and anchored to patient-reported outcome measures of improvement -- improved quality of life. So 30 meters or above is the magic number where at least in PAH, it's considered to be clinically relevant for that patient, okay? We don't know what that number is for PH-ILD. But again, these patients are being treated for PAH. We feel that this is still a relevant number. We'll keep in mind, these patients are much thicker. The number may actually be less. But the point is that by week 16, the median change in walk at 31.5 meters surpasses that threshold. And certainly, at 24 weeks, it's even more past that threshold of 30 meters. So just to get more granular, these are the 37 patients at the end of 24 weeks that actually were able to walk. And you can see here that more than half the patients walk 40 meters or more at 24 weeks. And in fact, over 40% of them walk 50 meters or more. And again, 30 meters being that magical threshold for clinical relevance, at least in the field of PAH, okay? So in summary, I mentioned this earlier, but UCLA enrolled about 10% of the patients in the ASCENT study. I want to second what Dr. Channick said and echo what he said. We have a long-standing experience with inhaled treprostinil prior to YUTREPIA. And this was -- we certainly dealt with a significant amount of cough and other side effects, throat irritation, et cetera. In this study, and again, this is an open-label study, so you have to take it with a grain of salt. We had anecdotal experience from this study that this was in some ways, different, very different for us. We didn't have the patient calls. We weren't -- they weren't being bothered. We weren't being bothered. Everyone was happy. And there was clinical efficacy at doses that were much higher in terms of comparable nebulized treprostinil doses with YUTREPIA than we had seen before. If you go around the country today and ask people how much inhaled TYVASO they use standardly in their practice for PH-ILD, they're not going to tell you 15 breaths or higher. That just doesn't happen. It's just not a thing. And that's usually because of lack of tolerability. The other thing is we saw this 6-minute walk improvement. I think we talked about this 30-meter threshold. So that's very important. This drug was approved, as you know, in May of 2025. So we have about 5 months of experience. We've used this drug extensively since our experience with ASCENT, and Dr. Channick can attest to this as well. We've seen the ongoing experience that we anecdotally saw in ASCENT has continued gloriously since then, and we're very happy and so are the patients, most importantly, with the medication. So I want to thank everyone for their attention, and we'll move on to the next talk here. So I'm going to introduce another Saggar, my brother, Dr. Rajeev Saggar, who is the Chief Medical Officer of Liquidia.

I want to thank everyone for coming here today. It's an honor to be present and speaking on behalf of Liquidia about our next-generation formulation program to take treprostinil to the next level. This is known as L606, which is our liposomal sustained-release formulation. Before I start here, I think it's an honor. It's the first time I'm speaking actually with the very people who mentored me, my trainer Dr. Channick, when I was a fellow, and then underneath my brother, when I was a senior fellow to a junior attending. So it's fantastic. I also want to thank Roger Jeffs for giving me this opportunity to take my passion from clinical medicine and drive it into drug development. We proposed treating patients with PH-ILD and, my brother and I, as early as 2006 to Roger saying that this molecule is magic. And it shouldn't just be positioned in Group 1. It's going to change how we manage patients even in Group 3 and I think beyond. And we looked forward to leading that charge here as Liquidia advances forward. I think Dr. Channick set up the concept so eloquently. In the late '90s to probably the first decade of the 2000s, the concept of delivering prostacyclins was game-changing for patients with pulmonary arterial hypertension. It took the prototypical young female who had less than 3 years to live to completely revolutionizing their life in terms of quality and longevity. And it was known at that time that if you can dose the patient continuously 24 hours, 7 days a week, clinically, it was impressive results that you saw. People who were short of breath, literally walking to the bathroom to normalizing relatively their lifestyle. It's all relative to their disease state. But that came at a cost. And the cost was being hooked on to a pump and all the complexities that occur with that, and also the complexities of every time you increase the dose, it rechallenged the patients with classic prostanoid side effects: headaches, jaw pain, leg pain, diarrhea, nausea, et cetera. But what was very clear is that in clinical practice, the anecdotes, the case reports, the publications started coming in at unbelievable rates that patients with severe pulmonary hypertension lo and behold when they repeat the catheter after months or years on continuous therapy showed almost relative normalizations of their pulmonary pressure. So the take-home message was that if we can develop a drug that is very tolerable and can maintain 24-hour exposures, I think you've hit sort of the best ideal formulation for these patients. This was followed with the construct of trying to use oral therapy, but what can never be fixed with oral is the intolerability to the very side effects of the prostanoid therapy, leaving it to be less used. And that's where inhaled came in. And Dr. Channick and Rajan eloquently already showed you why delivering to the lungs has tremendous advantages for a field that is a pulmonary-driven disease. We know with COPD and asthma, you don't give pills, you don't give infusions. You give inhaled medications. And while this formulation, I think, is incredible for today, I think we have to do better because we know we don't take the medicine at night. And when you don't take the medicine at night, how can you continue on with that antiproliferative process? How can you continue to remodel disease? I would argue you actually allow it to maybe reappear to some degree, right? So we must do better, and we must cover both the daytime and the nighttime experience. And we think the answer to that is actually going to be a twice-a-day drug. And the reason why is because we need to establish an AUC profile in the first half of the day, which is very synonymous to what you're going to see in the second half of the day. And while convenience matters with a once-a-day play, I think the pharmacokinetics may tell you a different story. And these are hypothetical simulations. But if we can establish this in some form, some way, prove its efficacy, showcase incredible tolerability, this next-generation opportunity for patients, I think, is going to be fantastic. So how do we get there? Well, we think the answer is with L606. And before we get there, I want to acknowledge that we did in-license this molecule from our partners, which is Pharmosa, which is a Taiwanese-based company, which is led by Dr. Pei Kan, who is a scientific expert in liposomal formulations and technologies. And we're very confident and hopefully, I can convince you that the science that we're bringing is going to allow us to believe that the efficacy that's going to result from our Phase III study is going to be robust. Liposomes have been known since the 1960s. These are lipid nanoparticles. And in the case of L606, we size these particles, and I'll explain to you why in the next few slides. We size them around 100 nanometers to 140 nanometers. And this optimizes them to be deposited into the alveolar epithelial membrane, which I'll explain to you why that's purposeful. The design of a liposome, specifically L606 is purposeful. They are a closed bilayer lipid membrane. And these are typically designed in aqueous membranes, liposomes tend to be amphophilic. That means that we have a phosphate head that is hydrophilic on the exterior, and we have a hydrophobic fatty acid tail on the interior. This creates a closed system that creates a central cavity that is free of water that can allow the molecule, in this case, treprostinil to be inserted. Depending on how you want your molecule to be released, the beauty about treprostinil is that it actually is amphophilic. It's both hydrophobic and hydrophilic. And I'll show you why it specifically is released in the alveolar regions of the lung and not the upper respiratory tract, and that's going to be critical to offset the very side effects that the last two speakers had spoke about, cough and throat irritation. The key part of why we're so excited about inhaling L606 is that we're trying to design a formulation that not only can deliver the drug to the targeted area, but we can do so in a slow controlled release format. We know that liposomes have been approved in intravenous formulations, transdermal depots as well as inhaled anti-infective agents, but it's never been used in rare pulmonary conditions such as pulmonary hypertension. Specifically with L606, as I noted, we use particular concentrations of phospholipids, and we stabilize the liposome with cholesterol. We also enhance the physiochemical properties of our liposome such that it avoids certain pulmonary barriers because as you know, our lungs are full of mucociliary elevators. We have macrophages we need to avoid. And it does so by avoiding those barriers, and it also is designed to interact with pulmonary surfactant. What is most unique is the size. The size embeds itself in the alveolar epithelial membrane. And I will talk on the next slide because the alveolar is a site where gas exchange occurs, we take advantage of the high carbonic acid level inside this tissue to allow treprostinil to diffuse across the liposome and directly into the site of action into the capillaries and hitting the bloodstream directly. Of course, once the liposome has released the treprostinil, the standard at that time, it is removed with alveolar macrophages through phagocytosis as well as mucociliary clearances, we cough it out or we swallow it. I think what is exciting about this slide is it shows a high level of science in the design of the liposome. Unlike the upper respiratory tract, the lower respiratory tract, i.e., the distal alveolar regions contain -- where the gas exchange actually occurs, contain a very prescriptive level of carbonic acid and bicarbonate buffers that maintain a very tight pH balance within this area. And those of you that practice medicine, we study this all the time about acid-based disorder and how the lung is involved with keeping that pH balanced in our blood. It just shows that we have a high level of carbonic acid in the distal alveolar fluid, and inside the liposome contains a deproteinated treprostinil. The carbon -- high level of carbonic acid through osmosis diffuses into the liposome, hydrogenates the salt, in this case, treprostinil, that allows it to selectively diffuse out of liposome in a very systemized release kinetic profile as you see in the simulation on the right side of that curve. But what is really remarkable is that we have virtually no release of treprostinil from the liposome in the upper respiratory tract. And the reason why is because there's no involvement with gas exchange, and therefore, there is a low concentration of carbonic acid. And as such, there's trivial release of treprostinil. And that would tell you, and we can hypothesize when we license this drug that as a result, we think and we should see that we have minimal amount of throat irritation, and we have minimal amount of cough, and we maximize our tolerability profile of the drug. And Dr. Restrepo will share the data about the results of that. But how do we inhale the drug? And we've spent, I would argue, the last 1.5 years really optimizing the device to our formulation to maximize and improve deliverability of the drug and to ensure that the patient has a good response, and this is very easy to use. And I'm proud to say that we have partnered with Phillips Medisize to bring forward with you what I believe is a very novel and exciting nebulizer, which is known as the FOX Vibrating Mesh Nebulizer. This is breath actuated. It's handheld, as you can see in this picture. It's battery powered, and we are convinced that it's the best device to maximize the performance of L606 in patients both with PAH and with PH-ILD. You can see the older technology to the right. And let's just be honest, there's no comparison here. This device here, if you look at it in my hands right now, the base unit is about 2/3 the size of your iPhone. This weighs about 128 grams or a little less than 0.3 pounds. You can hold it with 3 fingers. It contains 4 different parts. It contains a base unit. This is a plastic disposable mouthpiece. This is the actual mesh nebulizer that sits on top, you set it in. You can't see here, but there's a little hole or like a neck. And we use what's called blow-fill-seal ampules to deliver treprostinil -- our L606 formulation of treprostinil. As you know, every eye dropper of that ampule has a little neck. You stick the neck right into the hole, you squeeze it in. You cover the cap, and you turn it on. There's no liquid in here. So you'll see two lights. The first light you'll see is a green light that tells you it's on. And then when it finishes, it will turn orange and beep and say, "There's no more liquid." Now some will argue, well, why do you have such a long nose, not my Indian nose, but this nose here. This actually is very purposeful. This is because in order to see the light, you need to have a distance from your eyes to the actual frequency of the light. This is very important that the patient gets positive affirmation that they're taking the drug. The device will sense the patient's inspiratory flow and will guide them on how to breathe in and to set them at a continuous inhalation time, and then they will exhale into the ambient air. As you can see, we use a very high concentration of L606, where our volume are less than 0.5 milliliters or 500 microliters. Now the total nebulized time is going to be around 1 minute, inclusive of inhalation and exhalation. Now I've been a practicing pulmonologist since 2005. I've never seen a nebulizer that can deliver so efficiently and effectively and in a manner that we allowed for portability as well. This obviously can be put into your pocket and taken where you need to. So let's get into the kinetic profile of our drug. So we did a Phase I healthy volunteer crossover study using single ascending dose. We first treated the patient with 54 micrograms of TYVASO, and then we cross it over to 51 or a comparable dose of L606. And you see two things. One, our AUCs are comparable with the single dose. But you see one key signature here, and that's our Cmax. And our Cmax is sevenfold lower than what you would get with a single dose of TYVASO. And why is that important? Because we know the systemic side effect profile of virtually most drugs is based on your Cmax. And while it's -- while the liposomes, we believe can protect the throat and throat irritation, we want to further offset headaches, diarrhea, jaw pain because we want to titrate this drug even higher. So we needed two things. We needed great tolerability in the oropharynx and the throat and the upper respiratory tract, and we also needed the systemic tolerability to be robust. And what was really remarkable about this study is that we right away knew we had the right tolerable drug because in a healthy volunteer with a single dose, 66% of the patients with TYVASO complained of a cough, and 1% or 8% of the patients with L606 complained of a cough. So we already knew there was a tolerability profile difference. But how does this look when you actually take it twice a day? As you know, 4 times a day inhaled treprostinil short-acting is in the market, both with -- inclusive of YUTREPIA, and we understand the pharmacokinetics very well. And as Roger said, we solved many problems, but one thing we haven't solved is dose frequency. And again, creating that twice-a-day profile is so critical. You can see here, we used 102-microgram L606 twice a day in the simulation. And when we look at this from a 0- to 12-hour AUC and a 12 to 24 AUC, this is the signature that I talked about. We talked about creating a steady-state kinetic profile similar to what you can do with an infusional and do it in such a way that the patient doesn't feel the ebbs and flows of the drug, leaving their system or adding on to their system, minimizing the peak and trough, limiting the cross tolerability as you go up higher, okay? This is what we're aiming to do. So it's a pleasure to give the next speaker introduction. This is Dr. Ricardo Restrepo from the University of South Florida. He will tell you about our open-label study with L606.

Okay. Here we go. So thanks, Rajeev. Good try with rolling the hours. Roger, the same. My name is Ricardo Restrepo, pulmonary doctor at the University of South Florida, Director of the Pulmonary Vascular Disease Center for the last 11 years. So my experience is not as robust as my prior speakers. But I think those 11 years have allowed me to see a little bit more than 1,000 patients currently in our center with the forms of pulmonary hypertension and our certified ILD center carries more than 2,500 patients currently, which allow us to participate on most of the studies with all the type of prostacyclin and lately on all the studies with inhaled treprostinil. So I can say that it's very honoring to be witnessing the evolution of inhaled treprostinil. And I need to thank Roger, Rajeev, Jason and the Liquidia team for bringing me here to present to you the clinical data from the U.S. open-label study using treprostinil liposomal inhalation suspension. So this was a prospective open-label study to assess safety and tolerability on patients with PAH or patients with PH-ILD. To do that, we enrolled patients on 2 cohorts. The Cohort A were patients with PAH or PH-ILD were transitioned from stable doses of TYVASO to a compatible dose of L606. Cohort B were patients with only PAH who were naive to prostacyclin, and they were initiated on the compound of L606. The primary safety endpoint was defined as any incidence of treatment-emergent adverse event at week 48. And we also wanted to explore some exploratory endpoints defined as the change at the peak and trough of the 6-minute walk at week 48. And we wanted to hear the satisfaction of patients who were transitioned from TYVASO using the treatment satisfaction questionnaire medication also at week 48. Most of the patients were able to be evaluated at 48 weeks. We enrolled 28 patients initially. 4 of those patients needed to be excluded from the study, one of them due to protocol violation, due to the use of illegal drugs. And the other 3 were secondary to adverse events that I'm going to explain a little bit better in a later slide. So we were able to complete the analysis at week 48 for 24 patients. Here, you can see the basic description of the demographics, and we are pretty well versed reading statistics or numbers like this. But I just want to point a few key information of these baselines. And the first one is the age. In our overall population, the age was 61. And 61 seems to be a little bit on the higher side of the age on the newer studies with inhaled treprostinil, but it's consistent with what we see in our center, and which has been reported on the major registries for pulmonary hypertension and pulmonary hypertension in ILD. The vast majority of them were female. And I have to say that it's really important to note that these patients were prevalent diagnosed with pulmonary hypertension or pulmonary hypertension in ILD. That means that they were diagnosed with a median of 6.5 years of diagnosis when they were enrolled in the study. And this is going to be important in a subsequent slide that I'm going to talk about. It's also important to mention that the vast majority of patients in PAH on the Cohort A, 17 out of the 18 or 94% were pretreated with 3 therapies. One was the inhaled TYVASO that they were transitioned from, and the other 2 were therapies with PDE5 or endothelin receptors. Out of the patients with PH-ILD that were transitioned from TYVASO, 80% were on dual therapy. They inhaled prostacyclin or the TYVASO and PDE5 inhibitor. And as Rajan mentioned, we have evidence that PDE5 is a medication that have a positive impact and clinical impact on patients with PH-ILD. As far as the functional class, we saw basically what we saw in all the studies. Overall, patients were functional Class II, 55% of them when compared with 44% in functional Class III. Again, this is a spot with all the data that has been reported for patients with PH or PH-ILD. Here, I'm going to point to really something important in the clinical base characteristics on our population. And it is that overall, the patients who were able -- at baseline were able to walk 395 meters. Remember, these were patients that were prevalent, and these were patients that were treated with 3 therapies for PAH and 2 therapies for PH-ILD. The mild elevation on the proBNP of 168 in the overall population speaks itself of the same. They were prevalent patients, and there were patients that were treated with multimodal therapies as a baseline, which is very common to see on patients who are well treated and in prevalent disease. If I can reinforce something really important measures today is this slide. L606 was very well tolerated with no treatment-related severe adverse event. That means that in overall population, 89% of them report any treatment-emergent adverse event. This is pretty common. We see this. All the studies report very similar numbers of treatment-emergent adverse event. But only 10 of them or 35% of those patients were treatment-related TEAEs. Also, it's important to note that there was no treatment-related severe adverse event. Only one patient on the group of PAH from the Cohort A lead to the -- treatment-related adverse event lead to a diminution of the dose. There was no death on the overall on the group of that we study. And there, I can explain the treatment discontinuation of those -- the 3 patients that I referred before. One patient on the group of PAH from the Cohort A developed shortness of breath, which was mild in nature, and it was stopped around 28 days from the initiation of the L606. One patient on the Cohort A with PH-ILD after 259, and this one was my patient, 259 days after the introduction or the treatment with L606, the patient developed hypoxic respiratory failure that was severe. It was felt to be related to a worsening or an acute exacerbation of the interstitial lung disease and that exacerbation lead the patient to lung transplant. As a consequence, he was excluded on the study. Only one patient on the PAH Cohort B was excluded, and it was associated to a chest tightness sensation really soon after 8 days after initiation of the L606. And we believe was associated with bronchospasm. The patient had history of asthma and it's pretty well known, even though it's rare, but it's a very well-known side effects of any of the inhaled treprostinil. And as I said, no deaths were reported on our group of study. This slide is to analyze the doses that the patients were able to be reached when they were medicated with L606. Remember, for patients on the Cohort A, those patients who were transitioned from TYVASO, there was no specific instruction to titrate the medication. That titration was done solely on the estimation from the principal investigator depending on efficacy and tolerability. For patients in the Cohort B naive to prostacyclin, they started on L606 and the titration was done based on efficacy and tolerability. So on the left of your screen, you can see the numbers at week 12. And as [ Ray ] can explain, at the left of the graph, you're going to see the median dose -- sorry, the median dose of the L606, and on the right, the comparable dose of the TYVASO nebulized given 4 times a day. So at week 12, our patients were able to reach 169 micrograms, which is equivalent to 13 breaths 4 times a day of the TYVASO nebulizer. On the right, our patients were able to reach 229 micrograms of L606, which is comparable to 19 breaths per session of the TYVASO. What is really more striking about this graph is the fact that on week 12, you have 31% of those patients reaching more than the comparability of 19 breaths of the inhaled TYVASO 4 times a day. And on the right, you have close to 30% of those patients reaching more than 25 breaths per session of the inhaled TYVASO. So very significant higher doses than what was recommended at the point of the study of 9 to 12 breaths per session of the TYVASO, very significant higher doses. L606, you can see here, was very tolerable. Out of the whole cohort, 9 patients developed a cough, 32%. Remember, when we are talking about inhaled treprostinil or inhaled prostacyclin, we are talking about cough like it's not going to happen, but when. With L606, that seems not to be the rule. Only 9% -- only 9 patients or 32% of those patients report cough as a side effect. And only 4 of them for 14.3% was thought to be related to the therapy. This is a very significant lower number to what we are used to see on the research studies and what I see in my practice. Out of those 4 patients, all of them were described as a mild. Again, this is a very low number to what we are used to our practices treating patients with PH-ILD or PAH that are treated with inhaled treprostinil. And I have to point here as well that there was no reports of systemic prostacyclin side effects like headaches, diarrhea, muscle aches. And that probably was explained because of the 7-fold lower Cmax that Rajeev eloquently speak before. So that lower Cmax concentration is allowing us to see that there was no systemic side effects associated with the use of this inhaled prostacyclin. When we went to analyze our exploratory endpoints, most of the patients were able to maintain or improve the 6-minute walk over the 48 weeks of therapy out of all participants. So 24 at week 12, there was an improvement of 17.2 meters. And at week 48, it was 22.5 meters. I want to remind again, these were prevalent patients. These were patients that were treated with multimodal therapies for PAH, 3 therapies, for PH-ILD, 2 therapies. So showing efficacy, showing improvement on the 6-minute walk is way more difficult on this type of populations that patients that are not treated. When we analyze patients on Cohort B, patients who were naive to prostacyclin and were given the L606, at week 12, there was an improvement of 29 meters of median change from the baseline. At week 48, it was 22. Again, stating that even on this prevalent population pretreated, we are still able to -- and capable to show an improvement on the 6-minute walk from the baseline. When we analyze that endpoint between peak or the difference between peak and trough walk distance, we found that at week 48, the trough change on the 6-minute walk was 24.3 meters, and peak was 22.5. This is probably a function of that steady state over 24 hours that Rajeev explained in the prior slide. That steady state of exposure over 24 hours is what is making no difference -- virtual no difference between the trough and peak 6-minute walk difference. Remember that TYVASO was approved based on a peak difference, placebo-controlled peak difference of the 6-minute walk. But when they analyze and when we analyze the peak trough difference, there was a numerical gap there. There was a difference between peak and trough. Again, probably related to the pharmacodynamics of the TYVASO. Here, we are showing the individual data of all the patients with PAH in the right and PH-ILD on the left. 80% of them had any degree of improvement. 80% had that magical number that [ Rajan ] showed of 30 or more meters on the 6-minute walk, which has been associated with positive outcomes. There were a few outliers. As any study, there is always a small cohort of patients that aren't going to show improvement on the 6-minute walk. One of them on the PAH, that one that decreased the 6-minute walk by -- a little bit more than 100 meters was a patient that had a knee surgery weeks prior to the 6-minute walk. On the patients with PH-ILD, 3 out of 4 show an improvement more than 60 meters over 48 weeks. And again, the small number of patients that are going to show no improvement. But this is the individual data. So you can see that at least 80% of them show any improvement or maintain that difference on the 6-minute walk. Then we went to analyze the satisfaction scores. And it's not surprising that almost all the subjects have a global satisfaction because they went on the transition -- remember, this was done only on the transition patients from TYVASO. But when you go from 4 times a day to 2 times a day, you are going to find -- it's not surprising to find an improvement on the satisfaction score. They were positively influenced by the effectiveness given the increase on their 6-minute walk. There was definitely a less presence of side effects. So that's why this questionnaire is not a surprise for anyone. There's an improvement when the patients were switched to the L606. And then here, you can see the summary. You can see the conclusions of my presentation. To be honest, to me, it's very exciting to see and witnessing firsthand the evolution of inhaled treprostinil. The redefinition of inhaled treprostinil is put in here with this study where we went, as we said, from a continuous IV infusion for patients with PAH to have the availability to provide an inhaled treprostinil formulated only twice a day. And that twice a day, allowing us to maintain levels 24 hours, constant levels 24 hours, minimizing the gaps between the walk distance at trough and peak is very exciting. And it's more exciting to see a signaling towards efficacy at 48 weeks with improvement on the 6-minute walk with minimal side effects. Only 14% of the patients were having cough associated to the therapy. Remember, cough on our inhaled therapies is not if they're going to happen, but when. With L606, that seems not to be the rule. And this is my personal opinion, a pharmacology, a medicine with this pharmacokinetic profile, this safety profile and this efficacy to me, seems to be the perfect companion to the new anti-proliferation medications that are being developed in Liquidia. And with this, I'm going to end my talk and reintroduce Dr. Saggar to talk about the new study.

Thank you, Ricardo. So it's my pleasure. As you can see, a lot of work has been done at Liquidia to not only advance YUTREPIA to approval for patients with PAH and PH-ILD, bringing what I truly believe is a revolutionary PRINT formulation to maximize and set a new standard for how we treat patients with inhaled treprostinil, higher doses, earlier onset and to get to levels that I think historically since 2009 has never been done before. And as Dr. Channick pointed out, the results of that will have to be shown with long-term data, but I think we're taking the right steps forward. The next steps that we're taking in this frontier is to initiate the Re-Spir pivotal study, which is our global placebo-controlled Phase III study in patients with PH-ILD using L606 or our liposomal suspension formulation for inhalation. To get there, I've already shown you that we've completed our Phase I study. We have plenty of ongoing safety data, as Dr. Restrepo just showed you from our U.S. open-label study, highlighting, I think, a world-class tolerability profile. And the next step is now to show how this drug performs in patients specifically with PH-ILD on a global basis. This will be a parallel design study, and this will be performed in at least 20 countries or more. As you know, YUTREPIA and other forms of inhaled treprostinil are only approved in the United States. Some countries do have approvals for TYVASO. But in general, across the globe, there's a significant unmet need, and we have spent at least a year, if not longer, talking with practitioners, explaining them about the study. And I can tell you the demand is tremendous. It's going to be wonderful for patients to showcase this drug. The Phase III design, as I stated, will be a one-to-one randomized placebo-controlled double-blind parallel group study. We will enroll approximately 344 patients in over 120 sites across the globe. The patients will be given L606 twice a day or placebo twice a day. The primary endpoint will be a change from baseline in peak 6-minute walk at week 16. But the secondary endpoint is critical. We need to show durability of that response. It's something that is lacking in the literature. It's lacking in TYVASO. We try to show it with YUTREPIA with an open-label format with ASCENT that Rajan Saggar just showcased as well. But we want to prove our durability. We will also look at a change in -- from baseline in trough 6-minute walk also at week 16. I think we feel extremely confident given our pharmacokinetics that, that gap will have narrowed to a minimal gap, but we will showcase this. And of course, it is very important to show a time to clinical worsening in the benefit of L606 during this randomization process. Those endpoints are the long-term portion of the 24-week study. After 24 weeks and the blinded portion, patients will be allowed to enter into an open-label extension period as you see in the diagram below. We will look at exploratory endpoints, including hemodynamics. So one thing I think there is a paucity of data is in the inhaled treprostinil world is in terms of before and after hemodynamics, specifically in PH-ILD. I think this is a high priority for the study. We need to understand that the drug not only works on exercise capacity, we need to know that it actually improves time to clinical worsening, but we need to explain how we're getting there in terms of the hemodynamics to the practitioners so that they can put the whole story together. We'll also be looking at several other data points as we point out over here. To better explain our stratification methodology, patients will be stratified using three methods. One, we will be allowing PDE5 therapies as stated above. There is real-world use of this. We've come to know that in certain areas of the world, this is the only option. And of course, we understand that and the patients can be on a stable dose of background PDE5 inhibitors. This is, for the most part, sildenafil. We will put a cap on the amount of patients that have this. We will also stratify for baseline 6-minute walk between 300 meters greater or less than that number. And finally, we will stratify it based on CPFE and PH-ILD etiology. You can see here is that in the black shows at what point the patient will be either contacted by the site or come into clinic. And you'll see two very -- you'll see three points that are early, 2 weeks, 4 weeks, 6 weeks. The 2 and the 6 represent phone calls that we are calling patients -- not we are, the sites will be calling patients to determine their AE profile to remind them of dose titration. We will be providing guidance, which is critical. And to ensure that they're not having any unmet adverse events and also to remind them about their upcoming visit and to make sure they're otherwise in good health. This is really key. When we designed the study, we do not only seek opinion of key opinion leaders throughout the globe, but we also spent an exorbitant amount of time with the very coordinators and nursing staff that manage these patients in a clinical study to ask them how to make sure the study is run robustly, is easy and fast for them to do and to do it with a high-quality standard. And I can tell you, this is going to be one of the main reasons why the study will, without a doubt, in my mind, will be very successful. Some of the key eligibility criteria is the CT scan of the chest. All patients will be required to have a high-resolution CT scan of the chest. That will be performed at within at least 12 months of screening. People can ask, well, why don't you just get a new CT scan on everyone. There's actually very rigorous rules in certain countries about radiation safety. But as long as we can access that scan through a virtual portal and review the scan, that would be okay. I anticipate that the majority of patients will actually have a new scan coming into this study. That scan will be blindly reviewed by a minimum of two expert ILD thoracic radiologists and a third if there's a discordance in their opinions. They will have to have evidence of fibrotic interstitial lung disease, first and foremost. The second thing is that emphysema plays a big role in this disease. As you know, in the INCREASE study, our lessons learned is that the combined pulmonary fibrosis and emphysema patients may have a robust effect, but they're complicated and they're heterogeneous. And we wanted to make sure that the total lung emphysema must be less than or equal to 15%. This will be adjudicated by the blinded thoracic radiologists who are blinded to the clinical diagnosis and any history of the patient. So this is very critical in the study. Finally, we do allow background antifibrotic therapy. And when we designed this study, we did anticipate that the PDE4 inhibitor that was recently approved would likely have been led to approval. We actually brought that in. So that would be allowed in as well. So the anticipation is that there will be patients based on real-world data, depending on where they are on the globe that are likely to be on antifibrotics. And as I already stated, they will -- they can be to a limited degree with a cap on background PDE5 inhibitors. So at that time, I appreciate your time. I think that's the end of our presentation, and we'll move on to a question-and-answer discussion session.

Thanks, Rajeev. So we're going to ask our guests and Rajeev to take a seat. I'm going to play a little bit of the MC. I'm Jason Adair, Chief Business Officer. We have some other people around the room that will allow you to ask some questions. But if you saw our press release, our earnings call is next Monday. So we are not answering questions around revenue today. We're going to focus on the R&D Day that we just did. And some of you have asked some legal questions. If you have those, you can ask me after. We're not going to answer those today. We do have the call next week. The last thing I'll say is we're going to take some time. The questions are free to be asked by anyone. At the conclusion of this, we will have a nice social, and we also have access to the balcony outside on this nice beautiful day on this building. So with that, to get the questions going, I'm just going to call out a few people, Julian Harrison from BTIG, if you have a question.

With YUTREPIA down the market for about 5 months, I'm curious if you could talk a little bit about the real-world feedback as it relates to, let's see, titratability, cough profile, also the presence of company-sponsored data in PH-ILD informing use.

Rich?

Yes, the titratability, and I don't have a number count, but we have a lot of patients on it right now. I could tell you that certainly in the PH-ILD, I can give you kind of an arc of how it went. So we had, obviously, TYVASO nebulizer and then we had -- we had a number of patients on TYVASO nebulizer with PH-ILD. Then when the TYVASO DPI came out, we tried switching a bunch over. And -- I mean, nothing is 100%, but the vast majority really had trouble with it even at low doses. And 100% kind of attest to the cough. Another is -- I mean, they had to stop. They said, I can't do this. And so it's gotten to the point then where then we would go to -- then we had YUTREPIA DPI and it was clearly better tolerated. So to the point where before we had YUTREPIA, I don't even start TYVASO DPI on ILD PH patient. If you'll either go a nebulizer or now with YUTREPIA they'll get that. And our ability to titrate up has actually been quite simple. I mean I haven't -- and Raj can attest personally haven't really had issues with titratability in our -- either our PAH or our PH-ILD group with the drug. Sort of right and right up pretty quickly. I don't agree.

I completely agree with Dr. Channick. In our program, in our center, we have studied a significant amount of patients on YUTREPIA. And to my knowledge, I don't have any of the patients that have been stopped of the therapy because of side effects or cough. Remember, as I said, with these therapies, cough is not if they're going to happen, but when or if they are going to be severe enough to stop the therapies. I haven't stopped any of the therapies with YUTREPIA. And I say anecdotical case that I call my colleagues, I had one patient that by mistake, went from the initial dose of 26 micrograms, he jumped all the way to 105 micrograms, skipping the middle doses, by surprise. And this is a patient with PH-ILD middle 60s, no side effects, only mild cough after the therapies. Anecdotical case, but I think it represents how tolerable the medication can be.

Excellent. And then a follow-up, if I may. I heard a few times the potential benefit of YUTREPIA delaying the progression of disease in PAH, the need of parenteral treprostinil. Before YUTREPIA, how achievable was that? And also just curious how easy is it to identify those patients where you could say, okay, this patient would have progressed most likely if they want something else.

Yes, it's a great question. I think that the real-world data from that Shelley Shapiro paper where they looked at that specialty pharmacy data of those 5,000 patients, I think drawn over about 9 years. What they were really asking there was this was a nebulized treprostinil. If you look at the patients who got to the higher doses, did that in real-world data, again, with all the caveats of real-world data, 5,000 patients, they really showed in that study, right, that there was a mortality advantage that was significant for patients who got to higher doses and that they had a delay in their transition, having the need for parenteral therapy. And I mean that was pretty -- I mean, again, real-world data. This is not blinded, it's not placebo-controlled, et cetera. But it really brought to the light that the molecule works. The question is, can we get it up and can we do it and can we get to the doses that need to be gotten to? And if you can do that, I think it's pretty clear that you can avoid or at least delay going to parenteral therapy. And I say that because I think some of the patients we have now are doing quite well. Does that mean that they'll never be on parenteral therapy? I don't know. Now we have sotatercept. So there's that playing into all this. But the fact of the matter is that we certainly see the delay. And the only reason we can see that now with YUTREPIA is because we're actually able to get to comparable doses of nebulized treprostinil that are much higher. And I just want to echo what everyone else said, I think I really -- in a sense, obviously, it was an open-label study, but this titration -- up titration was seamless. I mean it was very different. And it wasn't me saying that our staff, right, our study coordinators and our staff and everyone that runs the study and even the specialty pharmacy, everyone that's interacting with these patients, it's a consensus, right? I mean it's anecdotal, but it was a consensus in ASCENT. And that only got propagated once the drug became available and FDA approved. And as mentioned earlier, in the last 5 months, we've used this product, YUTREPIA in a considerable number of patients. I think our experience is very skewed to PH-ILD because we see a lot of PH-ILD. So we can be really very confident in our experience over the last 5 months, which only, I think, sort of upholds what we saw in ASCENT.

Julian, one thing I'd add, TYVASO was always viewed as treprostinil, that was used as a sort of temporary bridge until you needed something that was more burdensome but could be titrated even with severe consequence. So I think what YUTREPIA is doing now is really changing -- flipping that script completely to say you can now start on an inhaled formulation that has durability and longevity because you can titrate it to effect. What really pleases us is now we're seeing oral transitions. We're seeing sotatercept added. And as they de-intensify or deescalate the parenteral therapy, they're keeping those patients on a prostacyclin because it's a critical pathway to maintain. And they're using YUTREPIA to do that because they can titrate up, take them off of the parenteral and move them up on an inhaled. So kind of the thing that Rajeev and I dreamed about when we -- when we talked -- when I talked to Rajeev about hiring him was could we have a one-size-fits-all kind of therapy that was really a game changer. And I think what you're starting to see in the field in the commercial space is that's actually turning out to be true.

Julian, I just want to add one thing to that. The -- we have recent experience, Rich and I with 2 patients, which -- I come from our program with the PH-ILD patients because we're transplant bound, is really -- was really aggressive in using parenteral therapy. This is what we've been doing for years and years. The idea that we could take a patient who, let's say, with PH-ILD ended up in the hospital decompensated, let's say, because of their pulmonary hypertension, they would go on parenteral therapy because they were sick enough to require that, and they were very sick in the hospital at an ICU. We have 2 patients recently who we actually did that protocol with because they were sick enough to be in a hospital. We initiated the parenteral therapy. We had recovery. But in the transition to going home, we actually transitioned 2 patients recently acutely from parenteral therapy after we had salvaged them with parenteral therapy and transitioned them to YUTREPIA for discharge. And we were successfully able to do that in 2 patients. I mean, honestly, I would -- I have never -- I would never have imagined that we could do that, but we were able to make that transition successfully. And we've only tried it in 2 patients, but we're 2 for 2. So...

It's my idea.

It was his idea. And I was skeptical. I was.

I don't think it will hurt.

I was very skeptical and it worked, and it worked beautifully. I mean we only have about 3 to 4 months out from both of these patients, but really everything looks quite good. And we're still able to titrate up the YUTREPIA as an outpatient, obviously. So that was very exciting for me because we've had this -- it's really a shift in our sort of a -- paradigm shift in our program, hopefully, the beginning of one, which is really great for the patients.

Thanks, Dr. Saggar. I think, Cory, you had a question.

Historically, we've seen this negative stigma around nebulized formulations primarily due to the treatment burden of carrying around and using and cleaning this very large nebulizer device. Thinking about the new handheld nebulized device with L606, how amenable do you think your patients would be to a more modern approach versus some of the DPI options that are available or might be coming available?

Yes, it's a great question. I mean it's all relative. So -- and we're all lung doctors, so we use a lot of nebulizers, not just for this disease, but there's a whole group of patients maybe that actually prefer the feeling of a nebulized treatment. I mean we have like asthma patients, COPD patients that are convinced that they're not really getting the drug unless they're nebulizing it in there. And like -- and we hear that all the time, and they're almost insisting on a nebulizer. It's a different story because there, they're just sort of plugging it in. It's not a thing you put together. So I think nebulized by itself is actually -- patients kind of like it in a way. So if you can sort of mesh, pardon the pun because it's a mesh. But if you can mesh -- the feeling of a nebulized treatment along with a convenient device, that's not a big pain to put together, then I think it would kind of be perfect. I mean I don't know a lot about this device, but it looks pretty simple and like small. And so I think -- I don't think that, that device is going to limit the convenience for patients, but we'll see.

And I think the time to administer is important.

Yes, that too.

A minute or less, and I think hopefully, we can improve upon that over time.

So if I can echo what Dr. Channick is talking is we all know those connotations of the nebulized therapy. But in the United States, the population of PH and PH-ILD is an older population. So in my experience, in my center, we haven't found much difficulties with the nebulizer. Actually, when we were enrolling patients on the BREEZE study, transitioning from the nebulized TYVASO to the DPI powder, I had a lot of difficulties transitioning patients from the nebulizer where patients will come to me -- actually, one of the dropouts on the study was one of my patients that was not feeling the medication going in with the inhaled powder and he wanted to come back to the nebulizer. And this is the big -- I can say, a substantial number of my patients are very reluctant to switch to the inhaled powder because of that reason.

Yes. But just to add to that, having said that, I mean, the BREEZE study pretty clear that patients were very happy to transition from a nebulized therapy to a DPI. So -- but the reason is why, right? Is it because is it nebulizer versus DPI? In other words, that's the advantage? That wasn't the advantage. If you talk to the patients, it's very clear that this was a convenience. It was the ability to carry it around, the inconvenience of all that. That's really what drove the satisfaction piece, if you will, in that transition study. It had nothing to do with, oh, I really prefer getting a dry powdered inhaler as opposed to a nebulized device. In fact, I would echo what Rich said earlier. I think when patients -- in the world of COPD and asthma, nebulization, they love nebulizing. When they're not feeling well, everyone uses the nebulizer. Why is that? You could argue about why exactly that is. But there -- it's not -- the nebulization piece itself -- in and of itself, the nebulizer versus the DPI is not the -- it's not that DPI is better. It just is more convenient. I actually think when I talk to patients about nebulization just in the world of pulmonary hypertension, that was -- they actually enjoy or they're comfortable nebulizing treprostinil. That was never an issue. And certainly, in PH-ILD, this is why we had so many -- so much difficulty transitioning to the DPI. It was just a convenience factor.

Maybe I can just add a little bit. I think we have to be careful not to compare COPD and asthma. There are COPD and asthmas here in New York City that are walking amongst you all day long, and you would never know that. The average patient with PH-ILD, about 75% are pulling a tank of oxygen. The majority of patients with pulmonary hypertension, even the prevalent ones are on multiple different drugs. They are short of breath. They're functional classes, for the most part, impaired. It's always going to be 5% that are extremely functional and active. So take those apart. These are -- this is not about convenience for a patient. This is about efficacy and tolerability. However, to your point, the nebulizers of the past that have been brought forth in pulmonary hypertension have been limiting. There are multiple parts. They're not portable. They're complex. They take a long time. And when you have to do that 4 times a day, that's a problem. We strongly believe that we're solving that issue. We've spent a lot of time trying to figure out the best device that's associated with L606 to maximize performance. As I showed you, it's effectively 4 different parts if you include the cap. Maybe that takes 20 seconds to assemble. You push the button, it turns on, it takes you 1 minute. So in general, you wake up in the morning, you reach over, 2 minutes later, you've taken your med, you go to sleep, you reach over, you go to -- you take it -- you take your meds and you're done. If you can do that in a manner that is -- limits the side effect profile, but maximizes efficacy, you have the winner.

Thanks, Rajeev. Before we take our next question, I'll just remind we have people listening. So if you're on the webcast, you can also ask a question through the platform. So I think we'll go back to Serge right there with the next question, right behind you.

Thanks for hosting us at this great venue. Dr. Channick, in your presentation, you talked about that these new delivery methods like DPIs and the next-gen inhalers would allow for better compliance and higher dose levels, which should eventually lead to improved cumulative effects. If you can just expand on what those outcomes you'll be looking for, for improvements? And whether you're already seeing them now with YUTREPIA usage?

Yes. That's a really great question, very, very insightful and something I thought about for a while. I think we all have. So I'll set up really quickly with sort of from the beginning, actually. The very first drug approved, ostensibly, some people think it's still the most effective drug, which is continuous infusion of epoprostenol. And maybe continuous treprostinil is similar. Having done this for 30-some years, I think my colleagues would have attest that we still have felt that there's something about a continuous infusion of a prostacyclin over years. So it never stops, that gives an efficacy that we haven't really been able to replicate. And that's why in every algorithm, if you're failing everything else, you go on to parenteral prostacyclin. Why is that? I mean why is the same molecule given a different way, the most effective therapy? And I don't have an answer to that. I have some hypotheses. I mean, maybe you all thought about this. It's -- if you're giving it continuously, why is it so much -- why is it seem to be better than giving it intermittently? And that could be a couple of reasons, and my colleagues alluded to this. It could be the exposure and the levels that you're getting, the exposure over 24 hours, even when you're sleeping. Not over hours, days or weeks, but years that can have effects that go well beyond just like being able to walk further on a 6-minute walk test. We've all seen, for instance, that patients who get continuous parenteral prostacyclin over weeks, months and years can, in some cases, normalize their hemodynamics, normalize their echos, even to the point where you can deescalate therapy. And that's something that we haven't really been able to replicate. And so what I hope is as we develop, and it's a hope, but I think there may be a reality there, as we develop, let's say, a non-parenteral drug that's given intermittently but has a pharmacokinetic profile that one gets exposure similar to what you might see from a continuous infusion and you can get to a higher enough dose that maybe we will see those cumulative effects and we'll start to see this so-called normalization that we see in so many of our sickest patients who get continuous infusions of prostacyclin. That's, I think, where we all went ahead and want to head, and I'm optimistic, and Rajeev with L606, for instance, that, that will get us closer to that point.

Thanks, Dr. Channick. We have a question, just go right there behind you, Wilson.

This is Pavan Patel filling in for Jason Gerberry from Bank of America. Just two questions from us. First, can you help us quantify and speak to what the skew towards PH-ILD over PAH has been with YUTREPIA in your clinical practice? And do you see scaling up to a higher treprostinil dose equally beneficial in both indications? Or is it more pronounced benefit in one patient segment over another? And then on the L606 pivotal trial design, can you help us understand the rationale behind the 3 patient stratifications? And how you think that can help differentiate L606 from nebulized TYVASO? Will this one trial be approvable for both PAH and PH-ILD? And what feedback have you gotten from the FDA so far?

Okay. So I wrote some notes down because that was a long question. So I think the first question was around how they're using YUTREPIA in the split between PAH and PH-ILD.

Yes, that's correct.

Yes, I kind of alluded to that earlier. Our experience, to be honest, is mostly in the PH-ILD space. That's where the bulk of our experience is. In the PAH realm, we've -- as I mentioned earlier, we just transitioned 2 patients with parenteral therapy to YUTREPIA, as I mentioned earlier, and we've had some oral transitions as well. And then with our sotatercept starts, we've sort of started sotatercept and then attempted to wean off the parenteral and then cotton off the parenteral by using YUTREPIA in that context as well.