Ladies and gentlemen, thank you for standing by and welcome to the Insmed TPIP phase I data call. At this time, all participants are in a listen-only mode. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during that time, please press star one on your telephone keypad. I would now like to hand the conference over to your speaker today, Eleanor Barisser. Thank you. Please go ahead. Thank you, Megan. Good morning and welcome to today's conference call to discuss our phase I top-line results for treprostinil palmitil inhalation powder. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Such statements represent our judgment as of today and may involve risks and uncertainties that may cause actual results to differ materially from the results discussed in the forward-looking statements. Please refer to our filings with the Securities and Exchange Commission, which are available through the sec.gov website or from our website for information concerning the risk factors that could affect the company. Joining me on today's call are members of the Insmed Executive Management Team, including Will Lewis, Chair and Chief Executive Officer, Dr. Eugene Sullivan, Chief Product Strategy Officer, and Dr. Martina Flammer, Chief Medical Officer. Let me now turn the call over to Will Lewis to begin the prepared remarks. Upon completion of those remarks, we will open up the call for your questions. Thank you, Eleanor. Good morning, everyone, and thank you for joining us to discuss top-line results from our phase I study of treprostinil palmitil inhalation powder or TPIP. We are very pleased with these top-line results and appreciate the opportunity to provide some additional color around the data. At Insmed, we are fully committed to transforming the lives of people with serious rare diseases. I'm proud of what the team has accomplished across our pipeline, and the progress we've made with TPIP builds upon our prior successes with both brensocatib and our commercial ARIKAYCE franchise in the U.S. and Europe. We believe TPIP is a product candidate that sits directly within the mission of Insmed because it has the potential to transform the lives of patients suffering from the serious rare disease, pulmonary hypertension. The phase I study results exceeded our expectations. While all drugs are subject to the outcome of future studies in patients, these results demonstrate the potential for TPIP as a once-daily administered drug, potentially at dose levels exceeding 600 mcg. This is a dose level considerably greater than what can be achieved with Tyvaso, one of the most widely used inhalation therapies for the treatment of PAH, placing us one step closer to unlocking the full potential of the prostanoid pathway. TPIP may also have utility in the treatment of Group 3 PH-ILD and IPF patients, and we look forward to advancing this program. Let me now turn the call over to Gene, who will walk through these phase I results in greater detail, followed by a clinical development update from Martina. Gene? Thank you, Will, good morning, everyone. I'd like to begin on slide four. Previously, treprostinil palmitil has demonstrated promise in non-clinical models as a potentially paradigm-changing advance in the prostanoid class for the treatment of pulmonary arterial hypertension or PAH. Today, we report the top-line results of a phase I single ascending dose and multiple ascending dose study of TPIP in healthy volunteers. The highest dose tested as a single dose was 675 mcg, and the highest dose tested in seven-day repeated dosing was 225 mcg once daily. To put these doses into context, the product label for Tyvaso states that dosing should begin at 18 mcg four times a day, with the dose being escalated as tolerated over a period of two to four weeks to reach the target maintenance dose of 54 mcg four times a day. The data from our trial demonstrate that TPIP was generally well-tolerated. Adverse events were generally mild and were consistent in nature with those that might be expected with an inhaled prostanoid drug, despite nominal doses that were well in excess of the recommended maintenance dose of Tyvaso. Also consistent with the experience with other prostanoid drugs, tolerability was improved by utilizing an uptitration approach. The pharmacokinetics that we observed were consistent with our expectations based upon preclinical experience as well as the prior single-dose healthy volunteer study that we conducted using a nebulized inhalation solution formulation. This prior phase I study of treprostinil palmitil inhalation suspension, or TPIS, included a Tyvaso comparator arm. These results suggest that TPIP may be safely dosed at doses far in excess of Tyvaso and support moving forward with once-daily dosing. Turning to slide five. Prostanoids have long been considered to be the cornerstone or gold standard therapy for PAH. However, this class of drugs has also been plagued by challenges related to rapid metabolism and dose-limiting tolerability issues. These factors may have hindered the ability to harness the full therapeutic potential of prostanoid drugs. We believe that TPIP has the potential to address the shortcomings of the existing prostanoid therapies by providing prolonged local exposure and pharmacodynamic activity with fewer systemic prostanoid-related side effects. In addition, animal model data suggests that the prolonged local exposure in the lung may allow for potential disease-modifying effects. Let's now turn to slide six. First, a few words about the product candidate TPIP, which is a dry powder formulation of treprostinil palmitil. Treprostinil palmitil is a prodrug consisting of treprostinil linked by an ester bond to a 16-carbon chain. The prodrug is itself inactive. In vivo, endogenous lung esterases gradually cleave off the 16-carbon chain, resulting in the active moiety, treprostinil. The dry powder is formulated for use in a simple, palm-sized, capsule-based inhalation device manufactured by Plastiape. Before proceeding to the next slide, I'd like to refer you to the extensive materials that we discussed at our R&D day last September. That presentation is available on our website. The team at Insmed has done extensive preclinical work to develop and evaluate treprostinil palmitil. For those who may be interested in even more detailed information on that work, I suggest searching the literature for papers by Dr. Richard Chapman. Dr. Chapman has been one of the key researchers driving the work on this compound here at Insmed. If you search his name, you will find rich information on treprostinil palmitil. In fact, Dr. Chapman is the lead author on a comprehensive review article on treprostinil palmitil, which has just become available online in the journal Pulmonary Pharmacology & Therapeutics. Let's turn now to slide eight to review some data from preclinical experience comparing treprostinil palmitil to treprostinil when administered to rats by nebulization. The figure on the left shows that while straight treprostinil rapidly leaves the lung, treprostinil palmitil had a very prolonged lung residence time. These kinetics impart two important characteristics shown on the right. Prolonged lung residence time translates into a prolonged duration of pulmonary vasodilatory activity, as shown in the figure on the top right. Also, as might be expected, the prolonged lung residence time impacts the systemic exposure. As shown in the figure on the bottom right, inhalation of treprostinil resulted in an immediate high systemic treprostinil plasma concentration. Whereas inhalation of treprostinil palmitil does not. We believe that this difference in the pharmacokinetics may have important clinical implications regarding systemic adverse reactions. Turning to slide nine. This slide summarizes experiments conducted in two species, the rat and the dog, and shows that the exposure response curve of inhaled treprostinil palmitil was shifted to the left of the exposure response curve of IV treprostinil. This implies that at any given plasma treprostinil level, the vasodilatory effect is greater if the drug was administered by inhalation than if it was administered intravenously. These data provide evidence that in these animal models, treprostinil is at least in part a locally acting drug when administered by inhalation. This is potentially very important because it implies that a portion of the pharmacologic activity of treprostinil can be achieved locally before the drug reaches the circulation, where it contributes to systemic adverse effects. This phenomenon makes the prolonged lung residence time that we've seen in animals potentially even more important. Moving to slide 10. This slide illustrates data from a widely accepted animal model of PAH, the rat Sugen/H ypoxia model. In this study, in addition to TPIP, we included inhaled, oral, and intravenous prostanoids as comparators. This spider graph visually depicts the various readouts from the Sugen/H ypoxia model, including indices of hemodynamics, right ventricular hypertrophy, and vascular remodeling. In the graph, the individual parameters are represented on separate axes, radiating out from the center of the figure. Each parameter is normalized between the normal healthy state, a score of zero at the center of the figure, and the vehicle control Sugen/H ypoxia injury, a score of one at the periphery of the figure. The findings for each compound are depicted in various colors. In this type of a figure, the closer that the lines are to the center, the more efficacy they demonstrate. Here you can see that the high-dose TPIP in dark green demonstrated a superior overall profile. With that background, let's move to the top-line results from our phase I study with TPIP. As shown on slide 12, this phase I study was intended to assess the safety, tolerability, and pharmacokinetics of TPIP in healthy volunteer subjects. The intent was to verify the systemic pharmacokinetic properties of our new inhalation powder formulation and to characterize the safety in the setting of single-dose and seven-day multiple-dose administration in healthy volunteers. The intention was to explore the upper end of the dose range in order to understand where adverse events would begin to occur. In this study, serial cohorts of subjects were enrolled. In the first cohort, subjects were randomized to receive single doses of 112.5 mcg, 225 mcg or 450 mcg of TPIP in a blinded fashion. In the next cohort, subjects were randomized to receive single doses of 675 mcg of TPIP or placebo. The next cohort was the first multiple dose panel in which subjects were randomized to receive 225 mcg once a day for seven days or matching placebo. The final cohort incorporated a placebo-controlled up titration approach, in which subjects began at 112.5 mcg once a day for four days, then advanced to 225 mcg once a day for three days. Let's now turn to slide 13. This table shows the adverse events that were seen in the single ascending dose cohorts of the study. Included here are all adverse events that occurred in more than two subjects, as well as others that were considered to be of interest because we believe they might be related to the prostanoid pathway or the inhalation route of administration. Most of the adverse events were mild in severity. The few moderate events are noted in purple text. There were no severe or serious adverse events. As we approach the highest single doses, we began to see more adverse events. In terms of the potentially prostanoid-related AEs, it's important to remember that patients generally tolerate a particular prostanoid dose better if it is achieved through an up titration approach than if therapy is initiated at that dose. Thus, in a clinical setting, prostanoids are generally administered in an up titrating fashion. While we explored a wide range of doses in this single ascending dose or SAD study, in future studies, we would not anticipate initiating dosing at doses as high as 450 mcg or 675 mcg. Turning to slide 14. This table provides the subject disposition and shows the adverse events that were seen in the two multiple ascending dose cohorts of the study. Consistent with the previous slide, this also includes adverse events that may be related to the prostanoid pathway and/or the inhalation route of administration. One subject in the 225 mcg once a day for seven days cohort chose to discontinue treatment after dosing on day two due to chest discomfort. As was seen in the SAD cohorts, most of the adverse events were mild. One patient in the 225 mcg once a day for seven days cohort experienced syncope that was temporally related to a blood draw eight hours after dosing. This subject continued in the study with no further episodes of syncope. The key takeaway from this multiple dose experience is that tolerability was notably improved in the up titration cohort. The patients who began at 112.5 mcg and progressed to 225 mcg showed better tolerability than those who started at 225 mcg. This learning will be incorporated into future development. We believe this up titration approach may allow us to reach much higher doses. Let's turn to slide 15. This slide shows the pharmacokinetic profiles of the SAD portion on the left and the MAD portion on the right. First, in regard to the single dose PK, the Cmax and AUCs were dose proportional across the range of doses, and treprostinil was detected in the plasma at 24 hours at all doses. In regard to the multiple dose kinetics, the green line represents the subjects who received 225 mcg once daily for the entire period, whereas the pink line represents the subjects who received 112.5 mcg once daily for four doses, followed by 225 mcg once daily. Turning to slide 16. Here, the PK curves for the SAD cohorts in the current study are reproduced. For comparison, I will now overlay the PK curve that we previously saw in the Tyvaso cohort in the phase I single ascending dose study that we conducted with TPIS, our first clinical formulation of TP. Keep in mind that the Tyvaso dose depicted here is the labeled target maintenance dose of 54 mcg, which is to be achieved after gradual dose escalation over two to four weeks, according to the product label. The differences in the Cmax profile are notable. First, the Cmax for Tyvaso is higher than the Cmax demonstrated by TPIP, even at a dose of 675 mcg. Second, the plasma half-life of treprostinil with TPIP administration was considerably longer than that of Tyvaso. The plasma concentrations of treprostinil fell below the lower limit of quantitation after the four-hour time point with Tyvaso. Treprostinil was present in the plasma out to 24 hours at the lowest dose and throughout the 48-hour sampling period for the two highest doses. Moving on to slide 18. We are very pleased with these top-line results from our phase I study and a few of our takeaways are listed here. First, the safety data showed adverse events consistent with an inhaled prostanoid, and the events were primarily mild, despite the fact that there was no uptitration phase in the single-dose cohorts. Along those lines, and consistent with prior clinical experience with prostanoids, the tolerability of TPIP was improved with an uptitration approach. We plan to incorporate such an approach in our further clinical development. We believe that the findings from this study suggest that TPIP may be safely administered at doses far in excess of Tyvaso, and TPIP showed substantially lower Cmax and longer half-life when compared to Tyvaso. Finally, we believe that the PK supports the continued development of TPIP with once daily dosing. Let me close on slide 19. As we move to the next phase of clinical development of TPIP, it may be worthwhile to consider these data on the pharmacokinetics and pharmacodynamics of inhaled treprostinil, which were published in the Journal of the American College of Cardiology in 2006. In a series of clinical trials, these investigators characterized the PK and PD of various doses of inhaled treprostinil in patients with moderate to severe PAH. It should be noted that these academic investigators did not utilize the currently marketed Tyvaso product in these studies. The figure on the left shows the PK curve for inhaled doses of 30 mcg, 60 mcg, 90 mcg, and 120 mcg of treprostinil. Consistent with the PK findings from our TPIS phase I study, you can see that there was a rapid Cmax, followed by a fairly rapid elimination, such that by two hours, the systemic exposure was minimal. The figure on the right illustrates the pharmacodynamic time course of the drug expressed as the pulmonary vascular resistance. While inhaled treprostinil resulted in a significant reduction from baseline in pulmonary vascular resistance, that effect was relatively short-lived. This is the clinical data on inhaled treprostinil that I mentioned earlier when I showed you our corresponding data in the rat, where I believe the pattern is quite similar. In animal studies, we've shown that treprostinil palmitil has been retained in the lung, where it exerted extended pharmacodynamic activity. In the clinic, we've shown, first with TPIS, and now with TPIP, that inhaled treprostinil palmitil resulted in a similar pharmacokinetic pattern, characterized by a low Cmax and a prolonged exposure in healthy volunteers. As we now move into clinical studies in patients with PAH, we hope to extend these observations and to determine whether TPIP may be able to achieve extended pharmacodynamic activity in the lung, and eventually, significant clinical benefit. With that, I'll turn the call over to Martina, who will discuss the path forward for TPIP. Thank you, Gene, and good morning, everyone. We are very excited about this encouraging result from our phase I study in healthy volunteers. Let me now take a few minutes to discuss our clinical development plan for TPIP, followed by a current treatment landscape of approved therapies and the market opportunity. Beginning on slide 20. With the phase I top-line results now in hand, we intend to advance as quickly as possible to the next stage of clinical development. This will follow two paths in parallel. First, we will gather information on the impact of TPIP on pulmonary vascular resistance, or PVR, over a 24-hour period in patients with PAH in an open-label study. Data from this proof of mechanism study will be informative and complementary, but not necessary to inform our next trial design. As planned, we anticipate sharing top-line patient data from this study in a handful of patients in the second half of this year. The second path will investigate the effect of TPIP on PVR and six-minute walk distance over a 16-week treatment period. We plan to initiate this trial in PAH patients in the fourth quarter. In addition, we plan to initiate a separate study for Group 3 PH-ILD patients. Both studies would use an uptitration dosing schedule to the maximum individual tolerated dose exceeding 600 mcg once daily. I'd like to take a moment to discuss TPIP in the landscape of currently approved prostacyclin therapies for the treatment of PAH. If we are able to continue to demonstrate in humans what we have shown in animal models, we think TPIP could become the cornerstone of therapy for PAH. Let's now turn to slide 22, which lays out the addressable PAH patient population and market potential for TPIP. The key point here is the significant opportunity for growth beyond the immediate patient population with pulmonary arterial hypertension. We hope to reach these patients as we continue to explore potential development pathways for TPIP in PH-ILD and IPF. In summary, we remain excited about the many ongoing activities within our TPIP program and look forward to providing an update on each of these studies later this year. With that, I would like to turn the call back to Will. Will? Thank you, Martina. I would like to close out our prepared remarks by reiterating the excitement conveyed by our team today. We are encouraged by the positive results observed to date, which we believe validate several critical aspects of TPIP's profile at a fairly early stage in its development program. Stay tuned for more updates in the second half of this year. I would like to thank the Insmed team for their diligent efforts in advancing this important candidate from the lab to the clinic. I would also like to thank the volunteers and patients who participate in our studies, as well as their physicians, who provide purpose to our efforts as we try to improve treatment outcomes. With that, let's now open the call to questions. Operator, can we take the first question, please? Certainly. Our first question is from Matthew Harrison with Morgan Stanley. Your line is open. Hi, all. This is Connor on for Matthew. Thanks for taking the question. Just a couple from us. Do you expect the PK parameters to be significantly different between upcoming patients versus the healthy volunteers? I guess, what is driving the need for two proof-of-concept studies? Martina, it sounds like you referred to maybe one of them not necessarily being 100% necessary to proceed. I guess we are just wondering why not move more aggressively given the mechanism appears to be well-described so far. Thank you. Appreciate the questions, and I'll take the second one first. The phase II-A is a study that we envisioned prior to seeing the phase I results. I think you raise a good point. The strength of these phase I data probably make it so that the phase II-A study is less necessary than it might've been before in terms of validating what we're developing here. Nonetheless, we think it could be interesting to see that pulmonary vascular resistance profile over a 24-hour period if we can find a handful of patients willing to undergo that kind of procedure who have PAH. Indeed, we have several clinical sponsors who are willing to do that. That information, as Martina described, is interesting, but not rate limiting in terms of our ability to move forward. We are proceeding with all due speed to develop this drug in a safe but expeditious way. I don't know, Gene, do you want to comment on the PK question and the variability and what our expectations are there? Then Martina, I'll invite you to add any comments. Yeah, sure. Hi. I don't think we're expecting any substantial differences. Of course, we always like to check PK in patients as well as healthy volunteers. Unlike diseases like asthma or COPD or IPF, where there are substantial abnormalities in the airways and in the parenchyma, the airways in patients with PAH are essentially normal. We don't expect there to be notable differences in systemic PK. Martina, any comments about the phase II-A and the other programs we're pursuing? No, I think you've talked about the phase II-A. It's not absolutely necessary. It gives us additional understanding. I think as with the next study where we talk about showing PVR reduction and six-minute walk test, the key goal for us is to understand the range of doses that we can bring patients to and we know that a progressive dose escalation and titration to the highest tolerated doses eventually leads to an improved outcome. That is the goal. Got it. Thank you. Your next question is from Marty Auster with Credit Suisse. Your line is open. Hey, guys. Thanks for taking the question. Thanks for the update this morning. I had a couple of quick ones. I wanted to check in, is the molar equivalency of TPIP to Tyvaso, is that similar to what you've disclosed for TPIS? I think it was 85 mcg was thought to be kind of molar equivalent to 54. The second question, I guess, is on the development path. I was wondering, I expect you'll be engaging the FDA to kind of figure out ways that the phase II proof of concept can kind of rapidly port into a registration study once you identify a dose titration, kind of a max dose. What are the kind of key steps you need to get out of that phase II to kind of progress towards registration? Does that trial need to be fully completed before those activities can begin? Thanks for the questions, Marty, and I'll turn to Gene to answer the molar equivalent question and Martina to answer the development path. I think now that we have the data, we can begin that dialogue with FDA, which we obviously weren't able to do before. Gene, you want to take the molar equivalent question? Yeah, sure. Yes, Marty, it's the same because it reflects the molecular weight of the drug substance. treprostinil palmitil is the same drug substance in both the inhalation suspension and inhalation powder formulation. It's a matter of the 16 carbon chain being a little bit heavier, so each molecule of TP is a little bit heavier than each molecule of treprostinil, but it's the same ratio. Yeah, Marty. Martina, do you want to take the development path question? Yes. We're now, of course, discussing with the FDA what is the fastest path forward. What's really important for us is to show in our development path the full potential for TPIP. Because we believe based on these results, that this is a true paradigm changer. We'll discuss the results that we've seen in the PK phase I study with the FDA, and then how quickly can we progress to the approval pathway and whether we have to complete the phase II study, or what the FDA wants to show, we will see in our discussions with the agency. Okay. Thank you. Your next question is from Joseph Schwartz with Leerink Partners. Your line is open. Thanks very much. Congrats on all the progress. It seems like you have the potential for much less spillover hypotension. I was wondering if you could talk a little bit more about the magnitude of systemic blood pressure effects in the patients given TPIP, and how much blood pressure information have you collected from these patients, and will you be presenting more of it in more detail so that we can appreciate the differentiation from Tyvaso in terms of this relationship between pulmonary and systemic blood pressures? Gene, you want to take that one? Yeah, sure. Absolutely, we'll be putting out all the results from the trial, and as it might be typical, we have blood pressure. One thing I wanted to point out is that particularly the high dose, it's a super high dose that the lung vasculature is seeing. To some extent, it may be hard to tease out how much of the if there is a drop in blood pressure, as we did see in a couple of patients at the very highest dose when we started with that high dose. Whether that's in fact systemic effect, which is an implication of your question, or a preload effect in these healthy volunteers. If you suddenly vasodilate the pulmonary vasculature extensively in a healthy volunteer, their left ventricle is getting less preload, that could have an effect on the blood pressure. We'll try to tease that out. As I try to point out that scenario of hitting a patient with 675 mcg upfront, single dose, and in this case, a healthy volunteer who doesn't even have pulmonary hypertension to start with, that's not something that's clinically relevant for our future development because we wouldn't anticipate doing that. Yes, of course, as we publish the more complete results of the phase I trial, we'll have that information. Great. Thanks. Could you talk a little bit more about your dose selection and the metrics you're considering to ensure that you're not stretching the administration schedule too much by giving it once per day? My understanding is that patients on other inhaled prostanoids tend to get pretty low right before their next dose. Gene, you want to take that? What we know from Tyvaso is, I think I showed you the PK curves, and the PD curves of what's happening at least in those studies in the pulmonary vasculature. We know that Tyvaso achieves what you've seen, these sort of intermittent drops in the PVR, and in between dosing and likely overnight, the pulmonary pressure's probably back up to the baseline. We know that translates into clinical benefit, as has been demonstrated in the clinical trials to support approval. We think that, at least what we know at the moment and looking at these kinetics, putting together what we saw in the animal data and so forth, that once daily should certainly be a therapeutic dosing interval. That makes sense. Thanks for taking my questions. Again, if you'd like to ask a question, please press star followed by the number one on your telephone keypad. Your next question is from Ritu Baral with TD Cowen. Your line is open. Hi, guys. It's Lila on for Ritu. Thank you for taking the question, and thanks for the update. Maybe just really quickly on the systemic exposure of treprostinil. Do you guys have the data for the area under the curve? Maybe how do you think the 24-hour area under the curve compares to Tyvaso versus the doses that you tested for TPIP? Just trying to understand how that might fit versus patients that get multiple doses of Tyvaso during a day. Thank you. Gene, you want to take that? Sure. Yeah. That's a very good question. Of course, in the publication, we didn't give all the detailed numbers in just these top-line results, but we'll have those, and you can make those comparisons. One thing I'd like to point out or have you think about is that you can compare the total AUC, but we think it's a matter of how that AUC is utilized. For the AUC of Tyvaso, what it represents is intermittent very high peaks and then rapid metabolism. Is it better, at least in theory, to use that same AUC but extend it over the dosing interval so you avoid the very high and you have a longer period of substantial exposure. The short answer is yes. When we release the rest of the results, you'll see the numbers and so forth. You can do those calculations as to where we stand. I think you'll see that even when you multiply the Tyvaso AUC by four as we get up to 225 and higher, we'll be clearly a greater AUC even calculated over a 24-hour period, but maybe even more importantly, a more kind of efficient use of that AUC. Less time spent super high, more time spent at a therapeutic range, so that you cover a longer period of time. Got it. Thank you. You said you would expect it to be higher over 24 hours? Just want to make sure I heard you correctly. Yeah. We got up to, for instance, 675 mcg. The total dose, even with the molar equivalents that Marty was talking about, making that transition, we've administered much more than 54 mcg four times a day. Characterize the findings too much, but you can imagine as we increase the dose, we're administering much more treprostinil. Got it. Thank you. That's very helpful. Your next question is from Stephen Willey with Stifel. Your line is open. Stephen Willey, your line is open. Sorry about that. Good morning. Thanks for taking the questions. I guess when I just look at the single ascending dose cohort and the multiple ascending dose cohort adverse event data, I guess specifically at the 225 dose, right? There's some suggestion here that some of the AEs that you're seeing are not necessarily, I guess, first exposure or Cmax-driven adverse events, and maybe this is more of an accumulation issue. Can you maybe just speak to what the kinetics on some of these adverse events are? I guess I'm just trying to figure out if in the uptitration cohort, the fact that you're only on 225 for three days, is that just something that you expect to see with greater or longer exposure, or do we think that the uptitration regimen is really kind of changing the narrative here? Gene, you want to take that? Sure. I think it's the latter. I think that our clear conclusion is that when we did that uptitration, it was much better tolerated and that in general, it's not depicted here because, as you say, this is a collection of all the adverse events that occur over the period of dosing. The observation we made is that the majority of the adverse events did occur early in dosing, even in the 225 cohort, that you tended to see them early, and in some cases, they went away with continued dosing. That's not evident when you just sum them up the way we did here. I really don't think because the patients in the uptitration cohort got the drug at 225 for three days, and it looked really, as you can see, very well tolerated. We're really pleased with this and think that this is the way to go. Okay, maybe just as you think about the phase II-A, and I guess the eligible patient population you're looking to enroll there, should we expect that you're going to be focusing just on the Class III patients like Tyvaso was labeled for, or do you maybe try to expand that phase II-A opportunity out a little bit in terms of eligibility? Thanks. The plan right now is to go after, I believe it's actually type 1 patients that Tyvaso is approved for. The PH-ILD patients will be the subject, the so-called type 3's, or at least a subset of the type 3's, will be the subject of clinical study alongside the type 1's for the more advanced clinical trials that Martina was referring to. The phase II-A study will focus on PAH patients, so-called type 1's. Type 1. Okay. Thanks for taking the questions. Your next question is from Liisa Bayko with Evercore. Your line is open. Hi. Thanks for taking the question. I was having some problems with what was happening there, but thank you for accommodating. Can you maybe just talk about how we should think about what we've seen so far, this is healthy volunteers, obviously, from safety and MTD perspective. How should we think about the kind of application of that to your next studies, which will be in patients? That's my first question. Gene, you want to address that? Yeah, sure, I think implicit in your question, Liisa, is this idea that these are healthy volunteers, so first of all, they don't have pulmonary hypertension, so they may react differently to the drug physiologically. The other is, as I mentioned in the presentation, it's a really artificial, an SAD, particularly for prostanoids, is a really artificial setting. We gave a healthy volunteer 675 mcg right off the bat, which you would never do in a clinic. Translating the tolerability, say, of 225 or 450 when given as a single inhalation to a healthy volunteer is challenging. We were very pleased that despite that, we just see mild events. We think that as we learned, we did a little bit of learning. We only had seven days of the MAD to do a dose escalation, and as I mentioned, like the Tyvaso label, you start at 18 and then over every one to two weeks, you increase by three breaths to get up at two to four weeks, you're up to the maintenance dose. We felt like this titration that we used in the second cohort of the MAD was rapid in comparison to what Tyvaso does, and yet we saw really good tolerability. I think that it's hard to port over the sort of artificial information you get from a phase I study in healthy volunteers. It was very promising, and we think that this likely means that in patients, if we, for instance, and we're not set on this, started at 112, we could titrate up, and we think we'll be able to get even much higher. Interesting. Okay, great. In terms of PVR and six-minute walk, can you maybe set some benchmarks? What kind of level of activity on those parameters are you eyeing? Are there any other compounds out there, sort of benchmarks, maybe you can give us some insights there? I don't know whether Gene or Martina, maybe first Gene and then Martina, if you want to add. Sorry. Well, I'll start, and Martina can add too. I think, if you look in the literature, the effect size that has been seen for treprostinil on six-minute walk ranges around 20 m to 30 m or so, depending on the route of administration, and that's after three months. There was less information on the hemodynamics with the approved formulation. That group, that paper that I cited was from the Giessen group in Germany, who did a lot of it, what was essentially the phase II work for Tyvaso. Because it was early and done by them, although the device was manufactured by the same manufacturer, it was administered in a slightly different way. In the first experiments, they just kept the same concentration, and they altered the duration of inhalation for patients, and sometimes they changed the concentration, and ultimately they got to a device that delivered it in breath. It's not direct evidence of the PVR data from Tyvaso, but it's a good approximation of what you see. Again, the active moiety in our compound is treprostinil. We think it should have the biological activity of treprostinil. What's different is how it's delivered to the lung, how it remains in the lung, how it affects sort of a more prolonged effect in the lung. Gene, is there any way to speculate what we would consider to be meaningful in a phase, more advanced study, in terms of effect on six-minute walk or pulmonary vascular resistance changes? Or is it best to just sort of refer to the paper? Yeah, I think you can refer to that paper. You can refer to other products that were developed for pulmonary hypertension, the PDE5 inhibitors. In some of those development programs, they had early hemodynamic data, and then, as you know, the FDA doesn't approve on hemodynamic data, so they have subsequent clinical data, and you can kind of see the extent of, say, the early PDE5s, what they did to PVR. It's a little bit different because that was a different world. Oftentimes those were studies done in patients who are on no background or one background therapy. The PVR effect in patients who are on two background therapies may be different. Ultimately, the six-minute walk, you can also look at what the effect size is that have been demonstrated for the various drugs. I mentioned specifically treprostinil, but you know, of course, a lot of the other drugs have conducted studies using six-minute walks. You can look at that range, which was like 20 to maybe the earliest when they were on patients with no background, I think they were up to maybe 40 or even in the 40 m. That sort of calculated effect on six-minute walk has turned into what most people believe are really important therapies that have clinical benefit. Martina, anything you want to add? Not that much really to add. I think Gene said it all on what we're looking for. I think one thing to sort of to keep in mind is with the profile of TPIP and where we wouldn't go into this up and downs on the Cmax and on the AUC and have a longer duration, so there wouldn't be as many swings. One of the things you'd be looking for is how do patients actually do when they don't experience the swings, and how do they benefit in hemodynamics that eventually translates into the clinic incomes and that then shows you six-minute walk test results. Okay. Just to clarify, what doses are you going to be now focusing on as you move forward? Martina, do you want to address that? Yes. We'll start with the same dose ranging as we go into the larger study. We will start with dose ranging similar and then titrate them up as much as the maximum tolerated dose for patients. I think this is where we get the best effect for the patient and show also over a period of time, because it does take some time until a patient actually has achieved that maintenance dose, where they now can experience that clinical benefit of that. We'll start with the same dose ranging than we did in this study. Okay, just off topic, when are we going to get an update on COVID? That's my last question. Oh. If there's any additional information on the COVID trial that is using brensocatib, which is an investigator-initiated study out of the U.K. by the principal investigator of our WILLOW study, James Chalmers. When that information is available from his study, we will share it. We previously said that we would expect that that data would be out sometime by sort of the end of March, beginning of April kind of timeframe. It's hard to know. Again, we're distant from that study. I just want to reiterate that our expectation for that study is to find directional information that may be complementary to the strong data that came from WILLOW. We look forward to sharing that when he's gathered it and it becomes available. All right. Thanks a lot. Your next question is from Graig Suvannavejh with Goldman Sachs. Your line is open. Hi, everyone. This is actually Jack on for Graig. First of all, congrats on the data. I was wondering if you could delve in a little more. You obviously talked about what you're seeing in terms of systemic serum concentration of treprostinil, but in terms of kind of local concentration of active treprostinil, the cleaved form, do you have any sense of what that could look like relative to Tyvaso, or is that kind of hard to get a read on? Gene, you want to take it? Yeah. That's a good question. Of course, it's something we can't discover in humans. Of course, when straight treprostinil is administered, all that's in the lung is straight treprostinil. When we administer TP, it comes in as TP and then is slowly converted. I think the animal data suggests to us that it's converted, it sort of stays as a depot, and that's what is really the whole charm of the molecule. It stays as a depot there, and it's slowly converted, and the rate of conversion seems to be appropriate and achieve a pharmacologic effect. That's why I really wanted to emphasize the importance of checking to see that, yes, we know it stays in the lung, and it slowly leaves the lung and goes into the blood. It was important to see in animals, which we did, I showed one species, and we've done it in others, and I showed some of that at Research Day, is that it stays in the lung, it's slowly converted, and it's converted at a rate such that you're achieving continuous pharmacodynamic activity, vasodilation. While we can't measure it in humans, take out their lungs and homogenize them and so forth. There are some challenges with just assaying it, because even during the assay, you don't know whether something's being converted. That's why I thought that animal data was so key, because it shows what you're getting at, which is how do we know that just because it's staying in the lung, it's staying in the lung in an active, and achieving its pharmacologic effect. That we're quite confident based on all these animal models that that's what's occurring, and of course, we'll see in humans. That makes a lot of sense. Maybe as a quick follow-up, do you think that that conversion rate from inactive to active would stay relatively constant regardless of dose level, or is there any chance that you'd kind of hit this point of diminishing returns, where even if you dose higher, the conversion rate doesn't increase such that you're getting more local exposure? That's a good question. Our understanding is that these esterases are ubiquitous and voluminous, so we won't hit a maximum. I think the PK data suggests that in the range that we studied, we have not, because we saw dose proportionality. What we're showing here is the systemic treprostinil concentrations, and there isn't TP. We couldn't detect TP in the system. To me, that means that as we increased and we saw dose proportional systemic treprostinil concentrations, that means that those enzymes, that conversion, the question you're asking is happening in the same manner irrespective of the dose. At least up to 675, my interpretation of the PK results is that that's not problematic, that there are plenty of esterases there to handle it. Okay. That's hugely helpful. Thank you. Our final question is from Anita Dushyanth with Berenberg Capital Markets. Hi, good morning, and thanks for the detailed update today. Just a couple of questions from me here. I know the study's being designed as a once a day as compared to the standard of care, which is four times a day. Just wanted to know about the dosing itself. I know you said that for the studies forward, that you will be looking into having it as a single dose and then maybe up titrate it. Just to get an understanding of how are a lot of patients or more patients probably require this uptitration, or would there be more that would benefit from just a single dose? Another question is related to the COVID adjustments. Have you had the studies decentralized and in terms of the phase II trials, would there be an increase in the number of sites to offset the impact of COVID? I'll just maybe to address the first question. You see titration used widely as the practice in the clinical practice, and that is also what was anticipated as expressed by the Tyvaso label. They start low, and then over a period of time, you titrate up. That allows the patient to get to a higher level of treprostinil administration, which is considered clinically beneficial. I think what's compelling about this phase I data is it suggests that we will be following the same approach, able to accomplish significantly higher doses of treprostinil and also, if phase I and the animal data continues to prove out in subsequent studies, able to do so with a very acceptable tolerability profile. All of the objectives we set out to accomplish with this study, we feel we have accomplished. That's why we're so excited about the data. Let me just stop there and see if Gene or Martina want to make any additional comments. No, I just think. Yeah. I'll start. I'll start. Go ahead. Oh, go ahead, Martina. Sorry. No, go ahead. Well, okay. I'll just start. One of the. This is the problem with being remote. The experts that we speak to, the experience with prostanoids in general is that the more is the better, they would like to get as much as they can in that bio phase where it's active. The problem has been that in order to do that, you have such high systemic levels, there's tolerability issues. So far, the input that we've gotten from the doctors is that while you may achieve some benefit at a lower dose, we'd rather keep pushing the dose because we think more is better. That's behind what Martina was saying, this individually maximum tolerated dose approach, which is generally the way prostanoids are dosed. Tyvaso, the way it was studied was this slow titration up to a target dose, then it sits there. That's different from, say, the IV and the subcu and the oral, where individual patients continue to titrate up. That's what we're looking at. Sorry, Martina. Go ahead. No, I think this is exactly the way we would plan it also in the studies. Remember, always, if we give a single dose, the patient hasn't really had a chance to adapt to the benefit of the titration. When a patient gets up to a certain level of dosing, they adapt and have now the opportunity to go to a higher dosing. They reach a maintenance dose for themselves, which then we'll say at this dose level, the best opportunity to translate now into a clinical benefit. That is individually different. Some patients may have that at a level of 450, some others may have that in excess of 600, and others at a lower level. We have to look at this and what's the best maintenance dose for the patient. Just in response to your second question, I would say, much like with our other clinical trials, we absolutely are taking into account COVID. This next phase of trial work will be initiated as quickly as possible. We would anticipate certainly by the end of the year. There's some regulatory discussions to have, clearly, and some initiation work to be done. Hopefully by the time we're really kicking the main portion of the study off in terms of recruitment, COVID will be largely a thing of the past. In regards to the phase II-A study, that clearly has an impact because ICU beds right now are clearly focused on treating COVID patients. We think this too is a temporal component, we continue to feel confident that we can produce, as we said, a handful of patient data from the II-A study, which I think is complementary but not necessary still by the second half of this year. I hope that answers your questions. Yes, thank you. That's all from me. There are no further questions at this time. I turn the call back to Will Lewis for closing remarks. Just want to thank everyone for joining us today. We're obviously very excited about these data, and we look forward to keeping you updated throughout the year. Have a good day. This concludes today's conference call. You may now disconnect.