Insmed Incorporated (INSM) Earnings Call Transcript & Summary

Welcome to our fireside chat with Dr. Gene Sullivan, the Chief Product Strategy Officer of Insmed. Gene, thanks for joining us.

Thanks for having me.

So maybe just to set the stage for this call, Insmed talks about its four pillars, the first being ARIKAYCE, the second being Brensocatib, 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 Insmed?

Sure. Hi, everyone. I'm Gene Sullivan, I'm Chief Product Strategy Officer. I've been with Insmed for 8 or 9-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 long-standing 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 care for patients with pulmonary hypertension. And as it happens, so this would have been the late '90s. I was a co-investigator on the initial pivotal trial to achieve approval of parenteral, subcutaneous Remodulin, so have been connected to that molecule for some time. I left the Cleveland Clinic and joined the FDA, and I spent about 7-years at the FDA, all of it in the [indiscernible] drugs, all of it in the division of pulmonary and allergy products. 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 3-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 [indiscernible] while I was at FDA. We did consult with other divisions on certain things, we consulted on with the endocrine division on inhale insulin because it was inhaled, and we consulted with cardiorenal on the first inhaled prostanoid product, which was called Ventavis 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 Lung Rx, and Lung Rx when I joined was just starting the pivotal trial for Tyvaso. So during my tenure there, we conducted a trial and results were positive, and we submitted the NDA and got that approved. So I stayed in that role and Chief Clinical Development Officer at Lung Rx 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 paths I spent, I think, 6 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 -- Insmed was in my consulting capacity and I consulted with Insmed for a year or 2, and it was super impressed with the group and eventually joined, as I said, as Chief Medical and Scientific Officer in 2015.

It's great to have you here today. It seems 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 Treprostinil Palmitil Inhalation Powder. Obviously, the IP Inhalation power refers to the formulation. We did, just for clarity, have an early in development, we had a liquid formulation for a nebulizer. And we call that TPIS Treprostinil Palmitil Inhalation Solution. So in some publications and things, you may see reference to that. We decided pretty early on that a [indiscernible] was more attractive to patients and would be probably superior to nebulizer device. So we switched over to the inhalation powder formulation. So Treprostinil Palmitil is the molecular entity. It's a prodrug of the drug Treprostinil. And what I mean by that is a prodrug, it's inactive on its own. It has no biological activity as Treprostinil Palmitil. It only becomes active in vivo when the endogenous esterases cleave off the 16-carbon chain that we were appended to the molecule. So essentially Treprostinil with a 16-carbon chain at the -- appended to it that makes it a prodrug. This was an asset developed entirely within Insmed. It was the inspiration of the Insmed scientist 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 Treprostinil is a good drug. 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 PH-ILD and it has helped a lot of patients. So 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 Insmed 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 -- prostanoid side effects, systemic side effects that are associated with the use of prostanoids like headache and Jaw pain and flushing and GI, nausea, diarrhoea and stuff. And those generally limit tolerability of Prostanoids whatever route of administration, whatever Prostanoid. The other limitation of Treprostinil is its short half-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 about 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 products. So that 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 Treprostinil product Tyvaso. That was meant as an advancement over the parenteral in 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 local 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 and being tied to a pump and everything, allowed them to start using Treprostinil maybe earlier. But Inhaled Treprostinil has a problem, and the problem is sort of analogous to that short half-life that I mentioned, and that's the lung residence time. So when you inhale treprostinil 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 PK curves of Tyvaso, you'll see this peak soon after dosing, that's the drug leaving, as it has left the lung and into the systemic circulation. And that's eliminated just the way Remodulin would be -- treprostinil circulation. And that turns into somewhat transient pharmacodynamic activity. So the duration of vasodilatation after inhalation of treprostinil is relatively short. Now just like Remodulin was an advancement over Flolan. Tyvaso was an advancement over the one that I mentioned, Ventavis, Ventavis was so short of the lung, so short acting that it had to be dosed like 6 or 9 times a day. That was in the product label. So Tyvaso was an advancement over that. It could now be dosed 4 times a day. But given the way it leaves along pretty quickly and given the kinetics of the pharmacodynamics, when you dose Tyvaso 4 times a day, you're probably not getting pharmacologic coverage -- pharmacodynamic coverage throughout the course of the day, certainly overnight and probably even in between dosing there is a return of the PVR probably. So, those were the identified issues like prostanoids were the cornerstone of treatment, everyone thought they were very, very important, but they have these limitations. So the Insmed scientists said, how can we take 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 Remodulin gives you. And I guess that boil down to how can we keep it in the lung longer. That was really the nut that they tried to crack. And I mean, you may know that the team at Insmed even back then has a lot of experience with liposomes. So one of the early ideas was we [ work with ] a liposome, could that help? And so we did some work on that. We've 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 treprostinil for this use. And also at the same time, we had been doing these experiments looking at prodrugs. And that's -- so we had been in the liposomes and said really the path forward is this prodrug. And what the team has been able to show is that by adding of 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 change -- as you lengthen the chain, the lung residence time increased. So a series of experience in several animal models sort of landed on the 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 treprostinil. The active moiety is treprostinil, 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 treprostinil like Remodulin, but directly in the lung like Tyvaso. And that was kind of what we thought was really intriguing and add a lot of promise. And so 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, yes, we could achieve prolonged residence of the TP and treprostinil 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 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 -- the curve went out for much longer. So that was really intriguing and that's sort of when I came on. I think we had -- about that time, a lot of these is the determination of 16-carbon chain, a lot of this animal model work had been done. And so then we moved into the Phase I. We did Phase I with the prior liquid formulation that I mentioned. There's -- 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 I work with the dry powder. And -- and so far, we've been really pleased with that. So we saw good tolerability, healthy volunteers, single dose. In the second study, we had multiple dose for 7 days, but very good tolerability. We had the systemic -- what I really like to see because I really wanted to see, okay, we've seen rats and dogs and pigs and all these animals that curves looked about the same. But it was reassuring to me to see the PK profile in humans, in healthy volunteers looked really much like what we saw in animals. So we're accomplishing the same thing in humans as we demonstrated in animals. So we're very helpful in general. We know treprostinil is an active moiety, we know it's safety when delivered by all kinds of routes of administration now. Something like oral. Inhale. It's got a real track record. And now we know that we are achieving sustained treprostinil exposure in the lung, which is what we are after, which is kind of the problem that 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 I work and in the process of studying it in actual patients.

I mean, that was a great overview. And that takes us to more recently, you have the Phase II trials going on in PAH and PH-ILD. 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 to the 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 take it with a grain of salt. I mean I mentioned that we've done the volunteer work and single dose and brief multiple dose. This is our first foray into patients, and we're pretty excited about it. We see the data as it's coming in, in a blinded fashion, obviously, and 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 well. And then we tell the other doctors who may not have enrolled the patient yet, and everyone's pretty excited in terms of the tolerability, 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 -- that makes us super excited, the ability to titrate that well in this setting means -- 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 Flolan to the initial, the study that I mentioned, the initial Remodulin study that basically the higher the dose you can get into the patient and they can tolerate, the better the benefit. And the problem has been getting a high dose into the patients. And so we think that the smooth PK curve that we're seeing with inhaled administration with TP is going to allow us to -- we've shown it allow us to titrate up already to the 640 level and probably we can go even higher, and we talked about that. And then the -- obviously, the [ hemodynamics ] and we can get into the hemodynamics. But you don't expect an otherwise a stable patient or even an unstable patient because when you're unstable, and PAH usually getting worst, you don't really expect patients with PAH to have that kind of a dramatic improvement in PVR. And so we just thought this is really important. I mean the tagline of today's event refers to TPIP being underappreciated. And I think that's true. We've got other promising assets in ARIKAYCE and Brensocatib. So, sometimes TPIP might gets -- it's a little overshadowed by those. And so it's really a matter of this enthusiasm that we're seeing from the investigators and our enthusiasm, and we thought, 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, remember, it's blinded. So we don't know. But given the things that I mentioned that you don't usually see improvements in PVR without immunotherapy being added, we think it's still interesting if taking a...

Yes, 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 PAH. First, why not higher doses in PH-ILD?

Yes. Well, let me talk about titration in general first. Because I think that's actually another major point of differentiation between Tyvaso and TPIP. Eventually, we're planning to dose TPIP in a manner that's more analogous to the way the parenteral, the IV and subcu and the oral are dosed. And with those products, 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. Tyvaso, 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 dictated by that's the way we studied it. We -- that was the design of the trial, but the up to 9 breaths and then kept them there. And also because I think there are -- because of that PK profile, because of some local irritation and so forth, it's hard to dose patients with Tyvaso higher than a labeled 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 decided how we're going to do it, how we're going to handle it. But first of all, how are we going to craft this titration and we kind of had to make it up because we don't have a lot of patient data. We knew when pharmacokinetically reach a steady state. So okay, we should wait that long. How quickly can you dose them up? And then another question you 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 5 weeks, 3 to 5, depending on how they're tolerating and then sit them at that so we can see the PVR 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 the dose to 640, which we thought was a pretty substantial dose and, okay, we'll target the substantial dose. We'll see who gets there. We'll have everyone stop at week 5, and then we'll do the PVR 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, all these docs, they are of the same mind where if you can get more prostanoid 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 PH-ILD in a second. Because a lot of the -- much more of the experience about dosing prostanoids obviously is from PAH. Rather than PH-ILD, there's a more limited dataset in PH-ILD. But the other thought that went through my mind in terms of -- 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 get a little higher than they -- some may fall off and they -- we don't know how high they'll go 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, I keep in mind that PAH is a bad disease. It's a progressive disease. And so these patients 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 prostanoids dose. And I was worried that if that wasn't an opportunity, if doctors in the trial didn't have the ability to turn up the dose in response to their patient's condition, that they pull them out of the trial and say, okay, I'm going to put them now on parenteral, because they're getting sick. So I'd like having -- giving them the flexibility that, listen, you need to pull your patient out of the trial to come on parenteral, do it. But if you're comfortable, and you like the way it's worked, maybe even keep your patient in longer by having that ability to increase. So that's the way we handle the PH-ILD. The -- like I said, with -- I mean, the PAH. With PH-ILD, as I said, there's a little less -- there's a lot less data, and we can't necessarily assume that more -- that dictum of like more is better applies also to PH-ILD. I mean it is a different disease. The histopathology looks different. We just don't really know. When I look at the increase study results, it does seem like the patients who are able to get to higher number of breaths in that study had a better effect on their 6-minute walk, even though the text of the label doesn't say that. So there is some evidence of it, but we -- this PH-ILD study is really primarily a safety study. When we talked about going into PH-ILD, we had obviously seen the results with Tyvaso were duly impressed by those and some thought was, well, why don't we just go straight to that. But we want to respect the fact that these are sick patients. And besides having pulmonary attenuation, 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 a saturation like -- is the concern with systemically administered vasodilators. So they 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 PH-ILD. But that's sort of why -- and it could well be that we change our mind and doctors are asking us, hey, my patient is doing great. Why can't I increase and we might respond to that. But for the time being, we're focusing that dose escalation to higher target to the PAH population.

Okay. That's fair enough. You also -- you talked about the PVR reduction data. First of all, a very, very kindergarten. Let's start, what is the role of PVR in the pathogenesis of PAH? And why is it important to reduce PVR?

Well, I like that idea of teaching about PVR in kindergarten.

Different kindergarten.

So I mean in PAH, it's really the pulmonary vascular resistance, PVR, pulmonary vascular resistance. That's -- that's the primary problem. That's where the histopathology lies. When I was in medical school, in fact, we referred to PAH, not like as PAH but as PPH, primary pulmonary hypertension. And what that conveyed is that the primary pathology is in the lung vasculature. As you -- 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, 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 pumps in the pulmonary arterials. So the histopathology results in reduction in blood flow. Impairment of the ability for blood to go through the pulmonary vasculature, and 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 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 doctors really key in on the value and in making the diagnosis and often then following their patients is understanding what their PVR is. And that obviously then has impacts on what your 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 turns into something clinically meaningful. But PVR is really where the action is in pulmonary hypertension.

Yes. So some of the data you showed, again, blinded blended, but -- and I think Will has also talked about some comparisons like sotatercept is 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 Tyvaso can achieve in a similar patient population?

Yes. I mean I think you're absolutely right, now as an ex FDA person, I'll be the first to say that cross-study comparisons of any therapeutic in any disease, that have to be looked at carefully and with a grain of salt. The nature of the patients that get enrolled into trials can differ over time, can differ even a -- contemporary trials can enroll different patients as a different inclusion criteria. With PAH, one of the big ones is 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're 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 unnameable differences between patient groups and population. So absolutely, you should -- 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 the -- so our patients were on one or two and often times two background therapies. Obviously, they can be on three, they can be on a prostanoid that our patients are on. The early Tyvaso work where you're asking about what's the PVR response for Tyvaso. There is some data on that. But keep in mind that it's usually in either naive patients or in patients who are only on one background therapy. So I would point you to two articles that look at the hemodynamic effect of inhaled treprostinil. But the very early work done out of these in Germany was published by a guy by the name of Robert Voswinckel in the early 2000s. And that gives you -- they use different doses of treprostinil. They compared it to the existing inhaled, the iloprost. They administered over different periods of time and so forth that they have single-dose pharmacodynamics. And then probably the one that is more similar to what we have is a publication by Dr. Richard Channick where they looked at 10 or 11 PAH patients dosed with Tyvaso for 12 weeks. And those patients were on only bosentan as a background at that time, so this is back in early 2000s. At that time, that was the only thing available. And they saw about a 26% reduction in the PVR. And 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 1.5 hours, they're back to baseline. So that's a place to look for what inhaled treprostinil can do to the PVR in prior studies, there is -- the label for Remodulin has some data on pulmonary vascular resistance, so that -- that's another resource. And I want to say that's 20% or less. And then I recently was reminded of that there is data on the oral Remodulin. They -- I shouldn't recall that as Orenitram, oral treprostinil product, maybe it was orenitram. 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 take it -- it's cross-study comparison. On the other hand, one could argue that earlier studies in patients on fewer background therapies may have had an opportunity to have an even more robust response and if you have someone already on an ERA, Endothelin receptor antagonist, and a PD-5 inhibitor that might sort of handicap the ability to show up PVR. So we're excited about what we have. It's absolutely -- it's blinded. But in that sense, the number I gave you above with Richard Channick's paper of 26%, those were all -- it was open label. It was all no placebo. So because it's blinded, obviously, the numbers that we're giving are all comers. So about 1/3 of those patients will be on placebo. It's 2:1 randomization. So it's about 1/3 will be on. And you alluded to the numbers, I'll just say them again that overall, we can look at that number. But if you look at -- it turns out we don't know what to make of this, 2/3 of the patients are randomized to act and 2/3 of the patients had a reduction in PVR. 1/3 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 low and behold, 2/3 are on drug and 2/3 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 like, wow. And that's what our investigators are 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 treprostinil. And it's something that was shown by investigators associated with UT back in the early 2000s, a lot of these are on studies, but they did a study in sheep that suggested that if you give the same amount of treprostinil 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 treprostinil 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 treprostinil locally is really ideal because inhaled treprostinil, Tyvaso can take advantage of that. Obviously, it's given by inhalation. You can get a more bang for your buck, but it's transient. And so with TPIP, the idea is we can make -- take better advantage, more full advantage of this local phenomenon. So that's something -- 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 subcu or IV and you see the separation of those disclosure response curves, it's pretty interesting.

Does it go back to some of the company comments about potential like disease modification? Is that the hope?

Well, that is a hope. It's the hope and let me be a 100% clear and I'm a pessimistic FDA guy, so I want to see it real. But when you look at like a putative mechanisms and benefit of prostanoids in PAH, there's -- the number one that we always think about is vasodilitation, also has some antiplatelet effect and to the extent that in C2 thrombosis may be contributing -- it helps that. But it also has an antiproliferative effect. So if you look at pulmonary artery smooth muscle cell proliferation, it impacts proliferation of pulmonary artery muscle cell. And when you look at the histopathology of PAH, there's a lot of cellularity, a lot of proliferation. So the thought is that maybe though, with the current means of administering treprostinil. IV, there's a limitation you can't get too much because they start getting headache and so forth. Inhaled, 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 antiproliferative effect of prostanoids until TPIP. And that's just totally hypothetical. But we did do the sugen hypoxia model studies and sugen hypoxia is sort of the best we have about 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 sugen 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 -- so that's absolutely the theory that by getting sustained local concentrations, associate and better tolerated, we may be able to have that kind of a remodeling effect.

Right. Looking forward, you talked about this, eventually, you have to show like a functional benefit. Can you comment on the 6-minute -- very like early again blended blinded, but the 6-minute data you talked about and then some comments that you made about potentially seeing like improvements in cardiac index, I don't think we got much detail on that, but any color you can give around those?

Yes. So I mean, first, the 6-minute walk, you have to take that. It's such a small sample size, 6-minute walk is such kind of a messy endpoint. It's been very successful for getting drugs in PAH approved. You are able to show a benefit on their exercise capacity as it's expressed in 6-minute walk. But it's very much effort-dependent, motivation dependent on the part of the patient. The patient who otherwise, is clinically 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 6-minute walk have to be pretty large because of 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 6-minute walk as the grain of salt. That said, as we were releasing and we're like, well, 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 in the pooled analysis of 31-meter improvement. And -- but I personally take that with a grain of salt. That said, there's no reason -- I mean, we think the whole reason -- the whole mechanism by which these drugs confer benefit -- confer benefit on actually has 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 really might put a lot of weight on it. The cardiac index thing 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 have an increased cardiac output. There's less resistance to flow, at right heart has less to pump against. And I'm under the impression that, that improved cardiac output, it contributes to improved exercise capacity, improved clinical sense of health because you're delivering more oxygen. 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 PVR with no corresponding increased cardiac output, isn't like intuitively obvious what that -- why that is and that sort of merits discussion and elaboration and explanation, and we just said, listen, let's just tell them. We don't want to give you a lot of details on a cardiac output but sort of don't you worry, 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 was skyrocketed, after a slight adjustment was made to the protocol of the PH-ILD trial. Can you say anything about what that adjustment was?

Yes. 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. But 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 -- is that an important aspect of the population we want to study and particularly given that this is primarily a safety study, we felt that there was every reason to be able to expand that. The kind of thing that would be is like we require the demonstration of pulmonary hypertension by a right-heart cath. And first of all, not every patient with ILD -- sick patients with ILD who has maybe [ equitable ] cardio-graphic evidence of pulmonary hypertension. Not all of those will the doctor want to go ahead and get a right-heard cath. So it's not a very frequent procedure. And so we had -- in order to be enrolled, you have to have had to right-heart cath in a certain period of time, whether it's a month or something before you had 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 investors because of our inclusion criteria.

Okay. And I think the PH-ILD data, that's still guided to come 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 topline readout, what can we expect to be included?

Yes. So I don't know if we're going to give any further interim data from the ongoing PH study. I don't think we've made a firm decision, yes or no, but I think 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 TPIP would be the PH-ILD data. And I want to remind everyone that the PH-ILD 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 -- desaturate. We just wanted to get some -- so we have some of the typical measures -- 6-minute walk and so forth. That will -- we don't have a pre and post right-heart cath -- that we'll be able to enroll patients going out there, what doctors want to see, and also with that study because we just wanted to get a lot of clinical experience, it's a 3:1 randomization. So most of the patients are on drug. So we will get -- we'll -- I expect -- I don't know how it will be programmed exactly in terms of what comes out as initial topline versus subsequent data. But as I think about the important aspects are tolerability, patients titrating up and safety and then when some of the secondary type of things that have done...

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 PAH market at least will change in a world where Merck's sotatercept 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 Tyvaso, are there other opportunities? And how do you see that changing over time? I know it's sort of a crystal ball question.

Yes, but an understandable crystal ball question, whenever there's a new player, you wonder how it's going to change the dynamic of the existing treatment paradigms and so forth. And of course, that sotatercept data was certainly very strong. And I have every reason to believe that it's going to be approved. And once it's approved, the uptake will be brisk. And although the uptake, I would think, at least initially would be guided by the label under clinical trial results and of course, in the clinical trial, it was added to background therapy patients were on either two or three drugs including the prostanoid. And so I would think that the initial uptake will be in that setting. And that further studies may be needed to really define where it stands kind of in the way we initially were adding ERA to a PD5 or a PD5 to an ERA and it took a study to say, no, if you are starting 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 the hallmark of the treatment of PAH over the years as these new drugs with new novel mechanisms and 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. It may vary which comes first depending on the data. But either way, as the disease progresses, people add drugs and prostanoids are still, and I think for good reason, sort of a cornerstone and sort of the gold standard of the treatment of PH. I think the they still will be. But one of the problems with prostanoids historically is that often times patients are never started on it because of these challenges -- there was paper saying, look, how many people are dying never having been put on a prostanoid, [indiscernible] but it's because they didn't want the pump or they didn't put the standard side effects and so forth. So we're hopeful that TPIP, if we've addressed some of these limitations that I described, that you can get more drug to the lung, better tolerated, that more patients will be put on a prostanoid, TPIP. Maybe that we put on earlier, you'll get the sort of parenteral like kinetics earlier in the course of the disease, a lot of times people wait till patients are pretty sick to go on parenteral and so maybe we can start earlier. And then also maybe even stay on them longer. So if somebody starts to fail Tyvaso now, I think a natural thing would be to put them on another route of administration or a parenteral, oral and maybe patients can stay on. So I mean, in a sense, we think that wherever Tyvaso is safe and effective, we should be as well if it all plays out, we have to do the studies. We have to really understand the safety and the benefits. But the way we're thinking is it should be it should work everywhere, Tyvaso does and more. In theory, it could allow a better therapeutic response on than Tyvaso. So that's sort of how I'm thinking about it. It will be part of a combination therapy.

Okay. And then stepping back from market opportunity. One other question has been -- again, related to sotatercept but more on uncertainty and potential snags, either in enrolling for this or future trials or how sotatercept might add risk to that? How are you thinking about this? And how are you preparing for that?

Yes. I mean that's -- we're certainly well aware, PAH has been a crowded investigation space for a long time as a -- when the 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 I think that's net-net the plus. But we do know that going into conducting clinical trials is complicated because of the fact that there's competitive trials out there and doctors will have to decide which studies to participate and which studies to enroll -- to offer enrollment to their patients based on their understanding of the promise and so forth. 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 treprostinil and a respect for all it has done for patients. And we're hoping that both the theoretical advantages that Tyvaso -- that TPIP could confer. And then hopefully, data like our Phase II, if it really looks that promising, they also encourage doctors, investigators, enthusiastic about enrolling their patients in our trial. So that's addressing the 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 sotatercept. And so will we be able to enroll in -- we'll have to see. I mean, when we were doing the Tyvaso pivotal trial TRIUMPH, when the trial was originally begun, the only treatment available was bosentan. So that was the way we [indiscernible], it could be on bosentan. And then the PD-5s came aboard, and we had to amend the protocol and say, okay, now you can be on either one. And so we're going to have to probably allow that. And we'll see, sotatercept showed benefit on top of triples, and we haven't yet seen data to see what the other therapies will do on top of sotatercept. So the fact that they have complementary mechanisms of action, I think does help at least the hope that they would be complementary in the product.

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 is asking what is the pivotal design approach? do you run noninferiority or even superiority to Tyvaso given the therapy is entrenched. So sham may not be very compelling?

Yes. Well, first of all, we have not decided on nor disclosed the Phase III program. There are sort of a well-trod path of designs that have been conducted in the past, starting the 6-minute walk type of studies, the Time to Clinical worsening studies. 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 or taking different inhalers 3 times -- 4 times a day for Tyvaso and once a day for us. And 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 controlled 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 it's better because you'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 -- Guinea pig cough models, and now we have clinical data to say it's pretty well tolerated. So 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 haven't got to a 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 TPIP compared to Brenso and ARIKAYCE.

We've gotten that question. I think Will got that recently. And I'll answer in part like from my perspective, I'm less a say spokesperson for the entire company, but I'll say that we see TPIP as a really important asset in our portfolio. And we and I look forward to continuing to develop and commercialize it. 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 a -- 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 TPIP from the investment community versus from people with a strategic interest. So the people with a strategic interest see its values, are really excited about it. And when you have that disconnect, you have to figure out what to do with that. And 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 and I think it offers a lot, and I'd love to be able to be part of the whole -- the evolution of the product and see it through to actually -- should we be able to demonstrate efficacy and safety and merit approval, I'd love to see it get millions of patients. I really love that with [indiscernible] the idea about running that trial and then saying, okay, we Insmed 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 the reality that it's attractive and it's going to be attractive to people who we want, who are in this space.

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.

That one's easy. Okay. Well, first of all, hopefully, you have like a better understanding of the nature of TPIP, 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 super proud to be associated with the scientists at Insmed, who came up with this. These are the same folks who came up with ARIKAYCE. It's not common that you have a drug come from conception to market within the company and we have it. The idea that you can engineer a molecule to address what we think is standing in the way of fully realizing the effect, the benefit of prostanoids in the treatment of pulmonary hypertension, to make those changes to the molecule in effect, deliver a steady dose of treprostinil locally right to the pulmonary vasculature. That's -- hopefully, that I've made that pace. I've explained that to you well enough. And we'll look through the animal model data that says we seem to have accomplished what we wanted. PK data from healthy volunteers that we seem to accomplish what we wanted. And -- and you'll see the emerging data. This is the first look. We're going to keep working hard advancing these trials, and we'll share with you the results when they're available.

Great. Gene, thank you so much for taking the hour today to run us through, maybe Insmed'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.