Insmed - Cantor FC TPIP (11-16-2023)

The transcription is a conversation between two individuals discussing the topic of TPIP, which stands for troposinopalmitate inhalation powder. TPIP is an asset developed by Innsmed and is a prodrug of the drug troposinil. The goal of TPIP is to address the limitations of troposinil, such as systemic side effects and short lung residence time. The scientists at Innsmed wanted to achieve intermittent delivery directly to the lung with continuous therapeutic exposures. They explored the use of liposomes but ultimately focused on prodrugs as a solution. Hey, guys, we're going to give it another few seconds for people to start trickling in. Okay. Hey, everyone. Welcome to our Fireside Chat with Dr. Gene Sullivan, the Chief Product Strategy Officer of Intimate. Gene, thanks for joining us. Thanks for having me. So, maybe just to set the stage for this call, Intimate talks about its four pillars, the first being error case, the second being forensic active. Consequently, your third pillar, TPIP, tends to fall a bit behind the wayside in terms of investor attention. So, the goal of this Fireside is to really focus on that asset, TPIP, especially on the back of some interesting data we saw during your most recent earnings update. So, that's why I'm excited to have Gene here with us. That might be a good segue. Gene, to start things off, can you give some background about yourself and your role at Intimate? Sure. Yeah. Hi, everyone. I'm Gene Sullivan. I'm Chief Product Strategy Officer. I've been with InsMed for eight or nine years. I joined initially as Chief Medical and Scientific Officer and after several years kind of transitioned to my current role. By background, I'm a physician. I trained in pulmonary and critical care medicine and really have had a longstanding interest in rare pulmonary disease and, as time went on, rare disease in general. After I finished my fellowship training, I joined the staff at the Cleveland Clinic and there, at least at that time, most of the doctors, like myself, saw general pulmonary medicine, but I also had a particular focus in rare lung disease, interstitial lung disease, end-stage lung disease of various kinds. I was on the lung transplant team and I cared for patients with pulmonary hypertension. And as it happened, so this would have been the late 90s, I was a co-investigator on the initial pivotal trial to achieve approval of parental subcutaneous remodulin. So I've been connected to that molecule for some time. I left the Cleveland Clinic and joined the FDA and I spent about seven years at the FDA, all of it in the Center for Drugs, all of it in the Division of Pulmonary and Allergy Products. You know, as you join the FDA, you join as a medical officer. I became a medical team leader and then was the deputy director of that division for probably about three years before I left. You may know that the pulmonary hypertension drugs are reviewed in the Cardiorenal Division, so that was not part of my purview while I was at FDA. We did consult with other divisions on certain things. We consulted with the Endocrine Division on inhaled insulin because it was inhaled, and we consulted with Cardiorenal on the first inhaled prostanoid product, which was called Ventatus, Iloprost. And so I provided some consultation on certain aspects of the inhalation delivery. After I left the FDA, I joined United Therapeutics. I initially joined United Therapeutics as the CMO of a wholly owned subsidiary at that time called LungRx. And LungRx, when I joined, was just starting the pivotal trial for Tyvaso. So during my tenure there, we conducted the trial and results were positive and we submitted the NDA and got the drug approved. So I stayed in that role and chief clinical development officer at LungRx, but also a couple of years into it, became the CMO of the parent company, United Therapeutics. So while I was at UT, I had a couple of different hats. I spent, I think, six years total at UT, and then left to do independent consulting. I did consulting with large and small firms on sort of regulatory and clinical aspects of drug development. And that's how I initially met Innsmed, was in my consulting capacity. I consulted with Innsmed for a year or two and was super impressed with the group and eventually joined, as I said, as chief medical and scientific officer in 2015. Okay. It's great to have you here today. You seem like the perfect guy for the topic today. So let's just start with the basics because we have up to an hour. What is TPIP? How does it work? What is it trying to do? And how did the company come across this asset? There's a lot there. So TPIP is troposinopalmitate inhalation powder. Obviously, the IP inhalation powder refers to a formulation. We did, just for clarity, have an early in development, we had a liquid formulation for a nebulizer, and we called that TPIS, troposinopalmitate inhalation solution. So in some publications and things, you can see that reference to that. We decided pretty early on that a DPI was more attractive to patients and would be probably superior to a nebulizer device. So we switched over to the inhalation powder formulation. So troposinopalmitate is the molecular entity. It's a prodrug of the drug troposinil. And what I mean by that is a prodrug, it's inactive on its own. It has no biological activity as troposinopalmitate. It only becomes active in vivo when the endogenous esterases cleave off the 16-carbon chain that we've appended to the molecule. So it's essentially troposinil with a 16-carbon chain appended to it that makes it a prodrug. So, you know, this was an asset developed entirely within Innsmed. It was the inspiration of the Innsmed scientists now a number of years ago to go after this type of thing. And the inspiration was really sort of based on the recognition that troposinil is a good drug. You know, at that time, it had already been shown to be safe and effective for PAH now. Over the years now, it's also safe and effective for PHILD. And it had helped a lot of patients. So, you know, it's from that starting point, it was an attractive active moiety known to be effective, but it had limitations. And so what the scientists at Innsmed tried to do is figure out what are those limitations and how can we address them and make it better? So, I mean, when I say limitations, prostanoids in general, all prostanoids have a set of what we call prostanoid side effects, systemic side effects. They're associated with the use of prostanoids like headache and jaw pain and flushing and GI, nausea, and diarrhea and stuff. And those generally limit tolerability of prostanoids, whatever administration, whatever prostanoid. The other limitation of troposinil is its short path life. When remodulin was first developed, it was an improvement in terms of half-life. So, when I was practicing medicine, all we had was Flolan. And Flolan had a half-life of minutes. And so remodulin was a big advancement over that. It had a half-life essentially of 45 minutes. So, that was better. Patients were less tenuous, but still, it was brief enough that you had to administer it by continuous infusion for the parenteral product. So, like the subcutaneous and IV needs to be continuously infused because of the short half-life. So, that was somewhat problematic for the use of prostanoids clinically. So, then come to the inhalation product, the inhaled troposinil product, Tyveza, that was meant as an advancement over the parenteral. And as much as the intention was to deliver the drug directly to the lung in hopes of achieving therapeutic concentrations where they need to be in the lung with lower corresponding blood levels. So, the idea was to achieve vocal efficacy with fewer side effects. So, that's all well and good. And it was an advancement. It allowed patients who otherwise weren't ready for a continuous infusion device being tied to, you know, a pump and everything, allowed them to start using troposinil maybe earlier. But inhaled troposinil has a problem, and the problem is sort of analogous to that, you know, short half-life that I mentioned, and that's the lung residence time. So, when you inhale troposinil into the lung, it fairly quickly leaves the lung and goes into the systemic circulation. And that you can see if you look at the decay curves of Tyveza, you'll see this high peak soon after dosing, that's the drug leaving, you know, as it has left the lung and into the systemic circulation, and then is eliminated just the way remodeling would be troposinil in the circulation. And that turns into somewhat transient pharmacodynamic activity. So, the duration of vasodilatation after inhalation of troposinil is relatively short. Now, just like remodeling was an advancement over Flolan, Tyveza was an advancement over the one that I mentioned, Ventavis, because Ventavis was so short in the lung, so short-acting that it had to be dosed like six or nine times a day, that was in the product label. So, Tyveza was an advancement over that, it could now be dosed four times a day, but given the way it leaves the lung pretty quickly, and given the kinetics, the pharmacodynamics, when you dose Tyveza four times a day, you're probably not getting pharmacologic coverage, pharmacodynamic coverage throughout the course of the day, you know, certainly overnight, and probably even in between dosing, there is a return of the PBR, probably. So, those were the identified issues, like, you know, prostanoids were the cornerstone of treatment, everyone thought they were, you know, very, very important, but they had these limitations. So, the insomniac scientist says, how can we take, you know, this very good drug and make it great? And how can we get the best of both worlds? How can we get intermittent delivery directly to the lung, along with the kind of continuous therapeutic exposures that remodeling gives you? And I guess that boiled down to, how can we keep it in the lung longer? You know, that was really the nut that they tried to crack. And, I mean, you may know that the team at Innsmed, even back then, has a lot of experience with liposomes. So, one of the early ideas was, well, what if we put in a liposome? Would that, could that help? And so, we did some work in that. We got liposome experts. And eventually, though, that was set aside. There were some technical issues related to that, related to the use of liposomes for proprosin for this use. And also, at the same time, we had been doing these experiments looking at prodrugs. And that's, so we abandoned the liposome and said, really, the path forward is this prodrug. And what the team had been able to show is that by adding this carbon side chain that I referred to, you could increase the lung residence time. And interestingly, you could actually really modulate that. The length of the chain, and this stuff is published in Animal Models, and you could find it to show that the length of the chain, as you lengthen the chain, the lung residence time increased. So, a series of experiments in several animal models, you know, sort of landed on this 16-carbon chain as being kind of the sweet spot, the ideal kinetics for what we wanted to achieve. And that's what we went forward with. So, when you think of the molecular mechanism of action of TP, TPIP, it's the same as troprosin. You know, the active moiety is troprosin, same thing. But because it's TPIP, this prodrug stays in the lung longer, and it gradually releases the active moiety locally. So, the way I think about it, it's almost like a continuous infusion of troprosin, like the modulin, but directly in the lung, like typhasia. And that was, you know, kind of what we thought was really intriguing and had a lot of promise. And so, you know, there were a ton of animal models, animal studies done. We've talked about these on previous calls, and much of this is published. But what we're able to show that, yeah, we could achieve prolonged residence of the TP and troprosin in the lung. And that, in fact, prolonged the duration of the pharmacodynamic activity. So, you could give a single dose and have vasodilatation for 24 hours. And it resulted in a systemic PK when you, you know, when you think about the tolerability side of the equation, the systemic PK looked a lot more like oral, not quite like parenteral, which is pretty flat, but like oral, where there was a much smaller peak and a much longer curve, the curve went out for much longer. So, that was, you know, really intriguing. And that's sort of when I came on. I think we had about that time, you know, a lot of these, this determination of 16-carbon chain, a lot of this animal model work had been done. And so, then we moved into phase one. We did phase one with the prior liquid formulation that I mentioned. That's been published. It was presented at the European Respiratory Society a number of years ago. And then, obviously, more recently, we did phase one work with the dry powder. And, you know, so far, I've been really pleased with that. So, we saw good tolerability, healthy volunteers, single dose. In the second study, we had multiple dose for seven days, but very good tolerability. We had the systemic, what I really like to see is, I really wanted to see, okay, we've seen rats and dogs and pigs and all these animals that the curves looked about the same, but, you know, it was reassuring to me to see the PK profile in humans and healthy volunteers looked really much like what we saw in animals. So, we were accomplishing the same thing in humans as we demonstrated in animals. So, you know, we're very hopeful in general. We know troprosinol is an active void and we know its safety when delivered by all kinds of routes of administration now. So, oral, in-mail, you know, it's got a real track record. And now we know that we are achieving sustained troprosinol exposure in the lung, which is what we're after, which is the kind of the problem we're trying to solve. So, that's sort of the story of TP from the idea of how can we make this good drug better to where we stand now, which is having done the phase one work and in the process of studying it in actual patients. Okay. I mean, that was a great overview. And that takes us to more recently, you have the phase two trials going on in PAH and PHILV. You disclosed some blinded blended data from those trials in your latest earnings call. First, could you go over the rationale for choosing to disclose this type of data, the blinded blended data set? Right. It's not always done. And we have to be careful because we always are emphasizing, remember that this is blinded data. So, you can learn certain things from it, but you have to, you know, take it with a grain of salt. I mean, you know, I mentioned that we'd done the volunteer work in, you know, single dose and brief multiple dose. This is our first foray into patients and, you know, we're pretty excited about it. We see the data as it's coming in, in a blinded fashion, obviously. And, you know, we show it to the investigators who are involved in the trials and taking care of these patients. And they've been very impressed by both the tolerability, the ability to titrate up and the hemodynamic changes, that the docs who are actually taking care of those patients are going, wow. And then we tell the other doctors who may not have enrolled the patient yet, and everyone's pretty excited. You know, in terms of the tolerability, you know, we chose a certain dose escalation strategy for this trial. And with that strategy, we're seeing that the majority of patients are able to dose escalate to what we thought were fairly high doses over a fairly brief titration period. And so we're, you know, that makes us super excited, the ability to titrate that well in this setting means, you know, encourages us that over longer periods of time, we can even go higher. And the reason why that's important is it's long been known about prostanoids from flow land to the initial study that I mentioned, the initial remodeling study, that basically, the higher the dose you can get into the patient and they can tolerate, the better the benefit. The problem has been getting a high enough dose into the patient. And so we think that the smooth PK curve that we're seeing with inhaled administration with TP is going to allow us to titrate. We've shown it allows to titrate up already to the 640 level. And probably we can go even higher. And we've talked about that. And then the, obviously the hemodynamics, and we can get into the hemodynamics, but, you know, you don't expect a, otherwise, a stable patient or even an unstable patient. Because when you're unstable in PH, you're usually getting worse. You don't really expect patients with PH to have that kind of a dramatic improvement in TBR. And so, you know, we just thought this was really important. I mean, the tagline of today's event refers to TPIP being, you know, underappreciated. And I think that's true. We've got all other promising assets in our case in Brunswick Catholic. So sometimes TPIP must, you know, gets a little overshadowed by those. And so it was really a matter of, you know, this enthusiasm that we're seeing from the investigators, and our enthusiasm. And we thought, you know, let's share it more broadly. Let's be careful. Let's be diligent about presenting it. And you'll probably, each time I talk about it, you'll hear me say, well, you know, remember, it's blinded. So we don't know. But given the things that I mentioned, that you don't usually see improvements in TBR without a new therapy being added, we think it's still interesting. Yeah, let's go through some of those data points. So dose titration, you already talked about. And you also, the company also talked about going to that higher dose in the open label extension in PH. First, you know, why not higher doses in PHLD? Yeah, well, let me talk about titration in general first, because I think that's actually another major point of differentiation between Tyvazo and TPIP. Eventually, we're planning to dose TPIP in a manner that's more analogous to the way the parenteral, the IV and subcube, and the oral are dosed. And with those products, you know, you start a patient low, and you just keep increasing the dose over time as they tolerate it. So it's sort of an individual patient maximum tolerated dose. Tyvazo, on the other hand, is dosed differently. There's an initial titration period. And this is the way we conducted the study, where you get the patient to a target dose, and then you sit there. And in part, that posology is, you know, dictated by that's the way we studied it. We, that was the design of the trial. We got them up to nine breaths, and then kept them there. And also, because, you know, I think there are, because of that ducate profile, because of some local irritation and so forth, it's hard to dose patients with Tyvazo higher than the label dose. So the point I want to make is that we're, this is more analogous to the oral and parenteral products. So we went into this, the PAH trial, and we had to decide how we're going to do this, how we're going to handle it. But first of all, how are we going to craft this titration? And we, you know, we kind of had to make it up, because we don't have a lot of patient data. We knew when pharmacokinetically, you'd reach a steady state. So, okay, we should wait that long. How quickly can you dose them up? And then another question we had is, look, at the end of the day, we're going to be dosing it in this individual maximum tolerated dose pattern. So for longer term studies, we plan to let the dose continue to rise. Should we do that in this trial? Should we, eventually we decided, okay, let's get them up to a dose over a period of about five weeks, three to five, depending on how they're tolerating. And then sit them at that, so we can see the PBR change at that dose. That was the decision, but it was a hard decision. Alternatively, we could have just kept dose escalating. So we picked a dose, the 640, which we thought was a pretty substantial dose. And thought, okay, we'll target this substantial dose. We'll see who gets there. We'll have everyone stop at week five. And then we'll do the PBR at week 16. And that's the way we did it for the purposes of this trial. But I just want to emphasize that in the future, we can titrate even further as tolerated. And so doing that in the open label extension will give us some experience that we can draw upon as we design the dose escalation strategy and stuff in future trials. And also, when we showed the data to our steering committee on look, 80% of people have gotten up to the top dose. You know, all these docs, they are of the same mind, where if you can get more prostate noise into the patient, you should. And so they encouraged us to raise the dose. So we're going through the process to do that. The other thing that, in my mind, and I'm sticking to PAH for the moment. And I'll get back to your question about PHILV in a second. Because a lot of the, much more of the experience about dosing prostate noise, obviously, is from PAH rather than PHILV. There's a more limited data set in PHILV. But the other thought that went through my mind in terms of, you know, I was really encouraging the team also to advance, to increase this maximum dose, maximum allowable dose. Now, we don't know. Patients may get to 640 and we try to go a little higher. They may, some may fall off, some may, we don't know how high they'll go, you know, or how long it will take them. But since it's an open label, it's a longer period of time with which you can let patients get accustomed to the dose and then move it up. And in my mind, you know, I keep in mind that PAH is a bad disease. It's a progressive disease. And so, these patients, you know, are expected to progress over time. And that's what happens in the clinic. And what happens in the clinic is when your patient is getting worse, if they're tolerating the prostanoid dose, you increase the prostanoid dose. And I was worried that if that wasn't an opportunity, that doctors in the trial didn't have the ability to turn up the dose in response to their patient's, you know, condition, that they'd pull them out of the trial and say, okay, I'm going to put them now on parental because they're getting sick. So, I'd like having, giving them the flexibility that, listen, if you need to pull your patient out of the trial, to put them on parental, do it, you know. But if you're comfortable and you like the way it's worked, you know, maybe you can keep your patient in longer by having that ability to increase. So, that's the way we handle the PHLD. The, like I said, with, I mean, the PAH. With PHLD, as I said, there's a little less, there's a lot less data. And we can't necessarily assume that more, that victim of like more is better applies also to PHLD. I mean, it is a different disease. There was technology that's different. We just don't really know. And when I look at the increased study results, it does seem like the patients who were able to get to higher number of breaths in that study had a better effect on their six-minute walk, even though the text of the label doesn't say that. So, there is some evidence of it. But we've, you know, this PHLD study is really primarily a safety study. When we talked about going into PHLD, we had obviously seen that the results with Tybazo were, you know, duly impressed by those. And some thought was, well, why don't we just go straight to that? But, you know, we want to respect the fact that these are sick patients. And besides having pulmonary hypertension, they have this fibrotic progressive interstitial disease, which is probably going to take their life, probably going to be the reason to take their life, and also is contributing to their exercise intolerance. So, in this, we really wanted to just, let's get some experience dosing it in these patients. Let's make sure it's safe. Let's make sure there isn't desaturation, like, you know, is the concern with systemically administered vasodilators. So, there didn't really seem to be a real need to do that in the current setting. I don't think we've made a definitive decision about how we would dose a future study in PHLD. But that's sort of why, you know, and it could well be that we change our mind and doctors are asking us, hey, my patient's doing great, why can't I increase? And we might respond to that. But for the time being, we're focusing that dose escalation, the higher target to the PH population. Okay, that's fair enough. You also, you talked about the PBR reduction data. First of all, like very, very kindergarten. Let's start, what is the role of PBR in the pathogenesis of PH? And why is it important to reduce PBR? Well, I like that idea of teaching about PBR in kindergarten. Different kindergarten. So, I mean, in PAH, it's really the pulmonary vascular resistance, PBR is pulmonary vascular resistance. That's the primary problem. That's where the histopathology lies. When I was in medical school, in fact, we referred to PAH, not as PAH, but as PPH, primary pulmonary hypertension. And what that conveyed is that the primary pathology is in the lung vasculature. As many people know, there's other reasons for getting pulmonary hypertension. You can have a problem in the left heart, where the primary problem is in the left heart. Either the pump isn't working or the mitral valve is stenotic and the pressure backs up. But the primary problem there is in the heart. Here, the primary, in PAH, the primary problems in the pulmonary arterioles. So, the histopathology results in a reduction in blood flow, impairment of the ability for blood to go through the pulmonary vasculature. And, you know, that has a number of effects, including putting strain on the right heart. So, the right heart is what's pumping blood through the heart, through the lungs. And when you start increasing the resistance of those vessels, it has to pump through. Now it has to get stronger. It has to raise the pressure in order to keep the blood, you know, flowing through. So, that's why when you think about sort of the, what you're trying to accomplish when you treat patients with PAH is a reduction in the pulmonary vascular resistance. That's sort of the primary thing you're aiming to do. And that's why, you know, doctors really key in on that value in making the diagnosis and often in following their patients is understanding what their PVR is. And that, you know, obviously then has impacts on what the cardiac output is and so forth. But because the histopathology is there, and that's why we look at it, particularly in early stage studies. And I say that because I think, again, the audience all knows that for the FDA to grant approval, we ultimately will need to show some clinical benefit, that reduction in the pulmonary vascular resistance and improved cardiac function, you know, turns into something clinically meaningful. But PVR is really, you know, where the action is in pulmonary hypertension. Yeah. So, some of the data you showed, again, blinded, blended, but, and I think Will has also talked about some comparisons, like supatocephalus north of 30% PVR reduction. I think you guys, you could argue that you could see like north of 40%. And you've said that you've seen a few patients north of 60%. So, all that has been laid out. One might argue that different trials had either different patient populations or different background therapies. And also that inhaled delivery might be more potent than systemic delivery. So, how does someone account for that when you're trying to benchmark? And do we know how much PVR reduction Tybaso can achieve in a similar patient population? Yeah, I mean, I think you're absolutely right. As an ex-FDA person, I'll be the first to say that cross-study comparisons of any therapeutic in any disease state have to be, you know, looked at carefully and, you know, with a grain of salt. The nature of the patients that get enrolled into trials can differ over time, can differ even at contemporary trials can enroll different patients because of different inclusion criteria. With PAH, one of the big ones is, you know, the background medicines that they're on. So, the earlier trials that were done in PAH, some of the earliest, there was no available treatment. So, there was no background medicine. So, whatever you were administering was on naive patients. And then as time has gone by, obviously, there have been more and more treatments available. So, the background medications is something that you can really, it's one of the objectives things that you can look at. We always worry that there's some other you know, unnameable differences between patient groups and populations. So, absolutely, you should, you know, we have to be cautious in cross-study comparison. We don't really have a lot of information in a comparable patient population. And by that, I mean that so our patients were on one or two and oftentimes two background therapies. Obviously, they couldn't be on three, they couldn't be on a carcinoid, but our patients are on the early Tyvazo work where, you know, you're asking about, you know, what's the TDR response for Tyvazo? There is some data on that. But keep in mind that it's usually in either naive patients or in patients on only one background therapy. So, I would point you to articles that look at the hemodynamic effect of inhaled troposinol. A very early work done out of Wiesen, Germany, was published by a guy by the name of Robert Boeswinkel in the early 2000s. And that gives you, you know, they use different doses of troposinol. They compared it to the existing inhale, the Ilopros. They administered over different periods of time and so forth. But they have single dose pharmacodynamics. And then probably the one that is more similar to what we have is a publication by Dr. Richard Chanock, where they looked at 10 or 11 TAH patients dosed with Tyvazo for 12 weeks. And those patients were on only Bosuntan as a background at that time. So, this is back in the early 2000s. At that time, that was the only thing available. And they saw about a 26% reduction in the PVR. And, you know, kind of relevant to what I was saying earlier, you can see the time course of it. So, they reached that maximum effect of pulmonary vascular resistance at about 45 minutes. But by about an hour and a half, they're back to baseline. So, that's a place to look for what inhaled troposinol can do to the PVR in prior studies. There is, you know, the label for remodulin has some data on pulmonary vascular resistance. So, that's another source. And I want to say that's 20% or less. And then I recently was reminded of the, there's data on the oral remodulin, the, I shouldn't call it oral, it's erenitram, oral troposinol, the product name is erenitram. From that, one of their studies, the FREEDOM-EV study, they did a sub-study where some patients underwent right heart cath, and they saw about a 20% decline. So, you know, take it, it's prosthetic comparison. On the other hand, one could argue that, you know, earlier studies in patients on fewer background therapies may have had an opportunity to have an even more robust response than if you have someone already on an ERA, endothelial receptor antagonist, or, and a PD5 inhibitor, that, you know, that might sort of handicap your ability to show PVR. So, we're excited about what we have. It's absolutely, it's blinded. But in that sense, you know, the number I gave you above with Rich Chanock's paper of 26%, those were all, it was open label. It was all placebo. So, because it's blinded, obviously the numbers that we're giving are all comers. So, about a third of those patients will be on placebo. It's two to one randomization. So, it's, you know, it's about a third will be on. And you alluded to the numbers. I'll just say them again that, you know, overall, you know, we can look at that number. But if you look at, it turns out, you know, we don't know what to make of this. Two-thirds of the patients are randomized to active, and two-thirds of the patients had a reduction in their PVR. One-third didn't. So, I don't know if they're the same, but, so we're making sort of the best case assumption. If you said, you know, lo and behold, two-thirds are on drug and two-thirds have a reduction. And if you look only at the magnitude of reduction among those who did have a reduction, it was 47%. And that's the, you know, like, wow. And that's what our, you know, investigators are, you know, really intrigued by. But I also want to pick up on, you made a comment about the relative potency of inhaled versus parenteral IV. And I think that, to me, that's a really exciting and interesting phenomenon that we've started calling the local effect of inhaled Triprostano. And it's something that was shown by investigators associated with UT back in the early 2000s. A lot of these are old studies. But they did a study in sheep that suggested that if you give the same amount of Triprostano by inhalation, you get more, a better effect than if you've given it by IV. And then we, and we've published this and we've discussed these data in the past as well. We showed in a couple of different models that if you, looking at that comparison, if you give Triprostano by inhalation or by parenteral, and you look at the vasodilatory action at any particular blood level, at the same blood level, you get a much bigger vasodilatory effect if the drug has been administered by inhalation than you do if the drug had been administered by parenteral. So there's something there. There's this local effect. And this is why, this is really why I think, I mean, it's one of the many reasons, but it's really why I think the idea of continuous release of Triprostano locally is really ideal. Because inhaled Triprostano, Tyvaso, can take advantage of that. Obviously, it's given by inhalation. You can get it more bang for your buck. But it's so, it's transient. And so with TPIP, the idea is we can make, take, you know, better advantage, more full advantage of this local phenomenon. So that's something I, you know, I've showed this to a lot of our investigators. It's a pretty neat thing. When you look at the exposure response curves in dogs and rats by inhalation versus sub-Q or IV, and you see the separation of those exposure response curves, it's pretty interesting. Does that go back to some of the accompanying comments about potential, like, disease modification? Is that the hope? Well, that is the hope. And, you know, it's the hope. And let me be 100% clear, and I'm a, you know, I'm a pessimistic FDA guy. So I, you know, want to see it real. But we, you know, when you look at, like, the putative mechanisms and benefit of prostanoids in PAH, there's, you know, the number one that we always think about is visibilitation. It also has some anti-platelet effect, and to the extent that in situ thromboses may be contributing, it helps that. But it also has an anti-proliferative effect. So if you look at pulmonary artery smooth muscle cell proliferation, it impacts proliferation of pulmonary artery muscle cells. And when you look at the histopathology of PAH, there's a lot of cellularity, a lot of proliferation. So that the thought is that, you know, maybe, though, with the current means of administering troprostanoid, IV, there's a limitation, you can't get too much because they start getting headache and so forth. Inhale, you can get it high for a very short amount of time. It may be that we haven't been able to fully take advantage of that anti-proliferative effect of prostanoids until TPIP. And, you know, that's just totally hypothetical. But we did do the sugin hypoxia model studies, and sugin hypoxia is sort of the best we have of an animal model of pulmonary hypertension. It does result in a histopathology that kind of looks like pulmonary hypertension. And when we did the sugin model, we convinced ourselves, and I think hopefully others, that by giving TPIP, we're able to finally affect the readouts from that model that relate to vascular proliferation. So the thickness of the vessels and so forth, we were able to show a benefit on. So that's absolutely the theory that, you know, by getting sustained local concentrations associated, you know, and better tolerated, we may be able to have that kind of a remodeling effect. Okay. Looking forward, you talked about this, eventually you have to show like a functional benefit. Can you comment on the six-minute, like early again blended-blinded, but the six-minute data you talked about, and then some comments that you made about potentially like improvements on cardiac index. I don't think we got much detail on that, but, you know, any color you can give around those? Yeah. So, I mean, first, the six-minute walk, you have to take that. It's such a small sample size. Six-minute walk is such kind of a messy endpoint. It's been very successful for getting drugs and pH approved. You are able to show a benefit on their exercise capacity as it's expressed in six-minute walk. But it's very much effort-dependent, motivation-dependent on the part of the patient. The patient who, you know, otherwise is clinically, you know, quite stable could perform differently from day to day. And so that's why usually the pivotal trials that are intended to show an effect on six-minute walk have to be pretty large, because there's a lot of variability. So the fact that this is blinded, the fact that it's such a small, and I think you really have to take six-minute walk with a grain of salt. That said, you know, as we were releasing it, we're like, well, you know, we're measuring it. We should probably say something about it. Let's just give the actual data as it is. And so we have seen, we have seen in the pools analysis a 31-meter improvement. And, you know, but I personally take that with a grain of salt. That said, there's no reason that, I mean, we think the whole reason, the whole mechanism by which these drugs confer benefit, confer benefit on exercise capacity and so forth has to do with their effect on the pulmonary vasculature. So I don't doubt that there will be one. I just don't know that in 30 patients, you can really say much. It was really my, myself, put a lot of weight on it. The cardiac output, cardiac index thing, it was really, I mean, that's what you would expect in sort of normal kindergarten physiology, as you described. You lower the pulmonary vascular resistance, you should be, you should have an increased cardiac output. There's less resistance to flow. That right heart has less to pump against. And, you know, I'm under the impression that improved cardiac output, it contributes to improved exercise capacity, improved clinical sense of health because you're, you know, you're delivering more oxygen. You know, we really only commented on it because we're aware that some more recent programs have not seen it. And that finding of a reduction of the PBR with no corresponding increased cardiac output isn't, like, intuitively obvious what that, why that is. And that sort of merits discussion and, you know, elaboration and explanation. And we just said, listen, let's just tell them. We're not, we don't, we're not giving a lot of details in the cardiac output, but sort of don't you worry, you know, our cardiac output is going up too, just as you otherwise would have expected had it not been for some more recent data that there's been a disconnect. Okay. So, let's go a couple of questions past that blinded, blended data. Actually, so the other day, I think Will said that enrollment has, I think the word has skyrocketed after a slight adjustment was made to the protocol of the PHILD trial. Can you say anything about what that adjustment was? Yeah, not to give specifics, but in general, there were a few aspects of the inclusion criteria that our investigators were saying, hey, I've got a great candidate that doesn't meet this inclusion criteria. And that often happens in clinical trials. And you look at that inclusion criteria and you say, do we really need that? Is it really, you know, is that an important aspect of the population we want to study? And, you know, particularly given that this is primarily a safety study, we felt that there was, you know, every reason to be able to spend that, you know, the kind of thing that would be is like, you know, we require the demonstration of pulmonary hypertension by a right heart cath. And first of all, not every patient with ILD, sick patient with ILD who has maybe echocardiographic evidence of pulmonary hypertension, not all of those will the doctor want to go ahead and get a right heart cath. So, it's not a, you know, very frequent procedure. And so, you know, we had in order to be enrolled, you might have to have a right heart cath in a certain period of time, whether it's a month or something before you have them. And we said, no, it really doesn't matter. If they had a right heart cath several months prior, we know they have pulmonary hypertension associated with ILD. So, we can relax that. And so, there were a few things like that, that just allowed enrollment of patients who we think are still entirely appropriate for the study, but were otherwise being excluded by the investigators, you know, because of our inclusion criteria. Okay. And I think that the PHILD data, that's still guided to come before the BRENSO data. First of all, are there any plans in terms of future data disclosures from either the trials ahead of that data? And then what can we expect in that first like top line readout? What can we expect to be included? Yeah. So, I don't know if we're going to give any further interim, you know, data from the ongoing PH study. I don't think we've made a firm decision, yes or no. But I think, you know, the message here is what we've heard, that it's pretty exciting and there may be no other reason to do anything more. So, probably the next thing you'll hear about the TTIP would be the PHILD data. And, you know, I want to remind everyone that the PHILD study is primarily safety. We really just wanted to make sure these patients with fibrotic interstitial lung disease are going to tolerate the drug, they're not going to cough a lot, they're not going to desaturate. We just wanted to get some... So, you know, we have some of the typical measures, six-minute walk and so forth, that will relate. We don't have pre- and post-radar CAF that we would be able to enroll patients, that's really not what doctors want to see. And also, that study, because we just wanted to get a lot of clinical experience, it's a three-to-one randomization. So, most of the patients, excuse me, are on drug. So, we will get, you know, I expect, I don't know how it will be programmed exactly in terms of what comes out as initial top line versus, you know, subsequent data. But, you know, as I think about it, the important aspects are, you know, tolerability, patients titrating ups and safety, and then some of the secondary type of things like that. Okay. And now I have a market question, because one of the pushbacks that we've heard from investors is sometimes it's hard to predict how the PH market, at least, will change in a world where Merck's Supatercept is approved and available. So, can you just talk about where you see this drug potentially fitting in? Is it to take share away from PIPBase? So, are there other opportunities? And how do you see that changing over time? I know it's sort of a crystal ball question. Yeah, but an understandable crystal ball question. Whenever there's a new player, you know, you wonder how it's going to change the dynamic of the existing, you know, treatment paradigms and so forth. And, of course, that Supatercept data was certainly very strong. You know, and I have every reason to believe that it's going to be approved. And once it's approved, you know, the uptake will be brisk. And although the uptake, I would think, at least initially, would be guided by the label and the clinical trial results. And, of course, in the clinical trial, it was added to background care if the patients were on either two or three drugs, including a prostanoid. And so, I would think that the initial uptake will be in that setting. And that, you know, further studies may be needed to really define where it stands, kind of in the way we initially were adding an ERA to a PE5 or a PE5 to an ERA. And it took a study to say, no, if you start them with both, it's better than starting with one. So, there should be additional studies to really work out where it fits in the paradigm. But, you know, the hallmark of the treatment of PAH over the years, as these new drugs with new novel mechanisms in action have been added to the environment, it's been combination therapy. And I think that's still the way it will go, combining drugs with different mechanisms of action. You know, it may vary on which comes first, depending on the data. But either way, as the disease progresses, people add drugs. And, you know, prostanoids, you know, are still, and I think for good reason, sort of the cornerstone and sort of the gold standard of the treatment of PAHs. I think they still will be. But one of the problems with prostanoids historically is that oftentimes patients are never started on it because of these challenges. You know, there was papers saying, look how many people are dying never having been put on a prostanoid. And that's a crying shame, you know. But it's because they didn't want the pump or they didn't stand the side effects and so forth. So, we're hopeful that TPIP, you know, if we've addressed some of these limitations that I described, that you can get more drug to the lung, better tolerate it, that more patients will be put on a prostanoid, TPIP. Maybe they'll be put on earlier. You know, you'll get the sort of parenteral-like kinetics earlier in the course of disease. A lot of times people wait until patients are pretty sick to go on parenteral. And so, maybe we can start earlier. And then also, maybe you can stay on them longer. So, you know, if somebody starts to fail Tybazo now, I think that a natural thing would be to put them on another route of administration or parenteral or oral. And maybe, you know, patients can stay on. So, I mean, in a sense, we think that wherever Tybazo is safe and effective, we should be as well if it all plays out. We have to do the studies. We have to, you know, really understand the safety and the benefits. But the way we're thinking is it should be, you know, it should work everywhere Tybazo does and more. You know, in theory, it could allow a better therapeutic response than Tybazo. So, that's sort of how I'm thinking about it. It'll be part of combination therapy. Okay. And then stepping back from market opportunity, one other question has been, again, you know, related to Cytatricept, but more on uncertainty and potential snags. Are there an enrolling for this or future trials or how Cytatricept might add risk to that? How are you thinking about this and how are you preparing for that? Yeah, I mean, that's, we're certainly well aware. PH has been a crowded investigational space for a long time. You know, as a former doctor taking care of these patients, it's a wonderful problem for that community to have that there's just so many drugs being studied in this rare disease. So, you know, I think that's net plus, but we do know that going into, you know, conducting clinical trials is complicated because of the fact that there's competitive trials out there and doctors will have to decide, you know, which studies to participate in, which studies to enroll, to offer enrollment to their patients, you know, based on their understanding of the promise and so forth. And, you know, so I think we're coming from a good place in that regard, because I think there's such a respect for prostanoids in the treating community and such an understanding of treat prostano and a respect for all it has done for patients. And we're hoping that, you know, both the theoretical advantages that TPIP could confer, and then hopefully data like our phase two, if it really looks that promising, may also encourage, you know, doctors, investigators enthusiastic about enrolling their patients in our trial. So that's, you know, addressing this sort of competition in the clinical trial space in general. Whenever you have a new drug added to the mix, then you'll have, that might be part of the background therapy, depending on when doctors want to add some kind of stuff. And so will we be able to enroll? We'll have to see. I mean, when we were doing the TIDASO pivotal trial triumph, when the trial was originally begun, the only treatment available was Bosuncan. So that was the way it was written. It was going to be on Bosuncan. And then the PD5s came aboard and we had to amend the protocol and say, okay, now you can be on either one. And so, you know, we're going to have to probably allow that. And we'll see, you know, Sotatercept showed benefit on top of triples and we haven't yet seen data to see, you know, what the other therapies will do on top of Sotatercept. So the fact that they have complimentary mechanisms of action, I think, does help at least, you know, the hope that they would be complimentary in the clinic. Fair enough. Actually, we have a question from the audience about clinical trials. Do you mind if we go through that? Sure, sure. So this person's asking, what is the pivotal design approach? Do you run non-inferiority or even superiority to type A? So given the therapy is entrenched, so sham may not be very compelling? Yeah, well, first of all, we have not decided on or disclosed the phase three program. You know, there are sort of a well-trod path of designs that have been conducted in the past, starting with the six-minute walk type of studies, the time to clinical worsening studies. You know, I think we'd have to think there's complexities to having an active control, not the least of which is you have to have access to placebo versions of the active control. And then patients have to have a double dummy type of design. They're taking different inhalers, three times, you know, four times a day for Tyvezo and once a day for us. And, you know, you're probably, we think it's going to be more effective. It's obviously easier to show a benefit of a drug against a placebo control than against an active control. And there aren't really that many pivotal clinical trials for approval that rely on superiority. Sometimes you might do that if you have a safety liability, like, look, we're going to need to show what's better because we've got a safety problem that's worse. But in our case, we think the safety, the tolerability may be better. We've done, like, for instance, these studies and cough models of getting big cough models and now we have clinical data to say it's pretty well-tolerated. So, you know, the short answer is we, I don't know what we'll do. And we'll talk about all these things. We continue to talk about them. We just have got to the point where we have to nail it down. That's kind of how we're thinking about it. That's fair. So, what is the company's latest thinking in terms of prioritization or potential monetization of CPIP compared to, you know, Brento and Eric Case? You know, we've gotten that question. I think Will got that recently. You know, and I'll answer in part, like, from my perspective, I'm, you know, less a spokesperson for the entire company, but I'll say that we see CPIP as a really important asset in our portfolio. And we and I look forward to continuing to develop and commercialize it. You know, any time you have an asset like this with a lot of potential, you're going to get strategic interest and TPIP is no exception. And this is kind of an, well, I'm not an expert in this area, but I think a somewhat unusual or a disjointed situation where there does seem to be a disconnect between the value, the perceived value of CPIP from the investment community versus from people with a strategic interest. So, the people with a strategic interest are see its values are really excited about it. And when you have that disconnect, you have to figure out what to do with that. Now, you know, I think I'm not going to speak for the entire company, but you always have to do what's best for shareholders. That said, I really would like to continue to develop this thing. I think it offers a lot and I'd love to be able to be part of the whole, you know, the evolution of the product and see it through to actually, you know, should we be able to demonstrate efficacy and safety and merit approval? I'd love to see it get more younger patients. I really loved that with Eric's, you know, the idea of running that trial and then saying, okay, we have done this and now there are patients benefiting from it. So, that's sort of more of a personal take, but just to acknowledge this, you know, the reality that it's attractive and it's going to be attractive to people who want, who are in this space. Yeah, fair. I'm going to actually ask you to speak on behalf of the company one more time. Don't worry. It's just, last question. What else do you think investors should take away from this webinar or pay attention to looking ahead? Oh, that was easy. And, you know, okay. Well, first of all, hopefully you have like a better understanding of the nature of TPIP, you know, what it is and how it's differentiated, how it's potentially an advancement from the existing means of getting a prostanoid to the target tissue. I mean, the idea, and I'm, you know, super proud to be associated with the scientists at InsMed who came up with this. These are the same folks who came up with Ericase. It's not common that you have, you know, a drug come from conception to market within the company and we have it. The idea that you can engineer a molecule, you know, to address what we think is standing in the way of fully realizing the effect, you know, the benefit of prostanoids in the treatment of pulmonary hypertension, you know, to make the, to make those changes to the molecule, to in effect, deliver a steady dose of triprostanoid locally right to the pulmonary vasculature. You know, that's, hopefully that I've made that case. I've explained that to you well enough. And, you know, we'll look through the, you know, the animal model data that says we seem to have accomplished what we wanted. TK data from healthy volunteers that says we seem to have accomplished what we wanted. And you'll see the emerging data. This is the first look. We're going to keep, you know, working hard, advancing these trials and we'll share with you the results, you know, when they're available. Great. Gene, thank you so much for taking the hour today to run us through, you know, maybe INSTEDD's most underappreciated asset. For everyone in the audience, thanks for joining us. If you have any questions, reach out to me. In the meantime, enjoy the rest of your day. Thanks. Thanks.