Insmed Incorporated (INSM) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Insmed TPIP's Phase I Data Call. [Operator Instructions] I would now like to hand the conference over to your speaker today, Eleanor Barisser. Thank you. Please go ahead.

Thank you, Megan. Good morning, and welcome to today's conference call to discuss our Phase I top line results for Treprostinil Palmitil Inhalation Powder. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Such statements represent our judgment as of today and may involve risks and uncertainties that may cause actual results to differ materially from the results discussed in the forward-looking statements. Please refer to our filings with the Securities and Exchange Commission, which are available through the SEC's website at www.sec.gov or from our website for information concerning the risk factors that could affect the company. Joining me on today's call are members of the Insmed executive management team, including Will Lewis, Chair and Chief Executive Officer; Dr. Eugene Sullivan, Chief Product Strategy Officer; and Dr. Martina Flammer, Chief Medical Officer. Let me now turn the call over to Will Lewis to begin the prepared remarks. Upon completion of those remarks, we will open up the call for your questions.

Thank you, Eleanor. Good morning, everyone, and thank you for joining us to discuss top line results from our Phase I study of Treprostinil Palmitil Inhalation Powder, or TPIP. We are very pleased with these top line results and appreciate the opportunity to provide some additional color around the data. At Insmed, we are fully committed to transforming the lives of people with serious rare diseases. I'm proud of what the team has accomplished across our pipeline, and the progress we've made with TPIP builds upon our prior successes with both brensocatib and our commercial ARIKAYCE franchise in the U.S. and Europe. We believe TPIP is a product candidate that sits directly within the mission of Insmed because it has the potential to transform the lives of patients suffering from the serious rare disease, pulmonary hypertension. The Phase I study results exceeded our expectations. While all drugs are subject to the outcome of future studies in patients, these results demonstrate the potential for TPIP as a once-daily administered drug, potentially at a dose levels exceeding 600 micrograms. This is a dose level considerably greater than what can be achieved with Tyvaso, one of the most widely used inhalation therapies for the treatment of PAH, placing us one step closer to unlocking the full potential of the prostanoid pathway. Further, TPIP may also have utility in the treatment of Group 3 PH-ILD and IPF patients, and we look forward to advancing this program. Let me now turn the call over to Gene, who will walk through these Phase I results in greater detail, followed by a clinical development update from Martina. Gene?

Thank you, Will, and good morning, everyone. I'd like to begin on Slide 4. Previously, Treprostinil Palmitil has demonstrated promise in nonclinical models as a potentially paradigm changing advance in the prostanoid class for the treatment of pulmonary arterial hypertension, or PAH. Today, we report the top line results of a Phase I single ascending dose and multiple ascending dose study of TPIP in healthy volunteers. The highest dose tested as a single dose was 675 micrograms and the highest dose tested in 7-day repeated dosing was 225 micrograms once daily. To put these doses into context, the product label for Tyvaso states that dosing should begin at 18 micrograms 4 times a day, with the dose being escalated as tolerated over a period of 2 to 4 weeks to reach the target maintenance dose of 54 micrograms 4 times a day. The data from our trial demonstrates that TPIP was generally well tolerated. Adverse events were generally mild and were consistent in nature with those that might be expected with an inhaled prostanoid drug despite nominal doses that were well in excess of the recommended maintenance dose of Tyvaso. And also consistent with the experience with other prostanoid drugs, tolerability was improved by utilizing an up-titration approach. The pharmacokinetics that we observed were consistent with our expectations based upon preclinical experience as well as the prior single dose healthy volunteer study that we conducted using a nebulized inhalation solution formulation. This prior Phase I study of Treprostinil Palmitil Inhalation Solution, or TPIS, included a Tyvaso comparator arm. These results suggest that TPIP may be safely dosed at doses far in excess of Tyvaso and support moving forward with once-daily dosing. Turning to Slide 5. Prostanoids have long been considered to be the cornerstone or gold standard therapy for PAH. However, this class of drugs has also been plagued by challenges related to rapid metabolism and dose-limiting tolerability issues. These factors may have hindered the ability to harness the full therapeutic potential of prostanoid drugs. We believe that TPIP has the potential to address the shortcomings of the existing prostanoid therapies by providing prolonged local exposure and pharmacodynamic activity with fewer systemic prostanoid-related side effects. In addition, animal model data suggests that the prolonged local exposure in the lung may allow for potential disease-modifying effects. Let's now turn to Slide 6. First, a few words about the product candidate, TPIP, which is a dry powder formulation of treprostinil palmitil. Treprostinil palmitil is a prodrug, consisting of treprostinil linked by an ester bond to a 16-carbon chain. The prodrug is itself inactive. In vivo, endogenous lung esterases gradually cleave off the 16-carbon chain, resulting in the active moiety, treprostinil. The dry powder is formulated for use in a simple palm-sized capsule based inhalation device manufactured by Plastiape. Before proceeding to the next slide, I'd like to refer you to the extensive materials that we discussed at our R&D Day last September. That presentation is available on our website. The team at Insmed has done extensive preclinical work to develop and evaluate treprostinil palmitil. For those who may be interested in even more detailed information on that work, I suggest searching the literature for papers by Dr. Richard Chapman. Dr. Chapman has been one of the key researchers driving the work on this compound here at Insmed. So if you search his name, you will find rich information on treprostinil palmitil. In fact, Dr. Chapman is the lead author on a comprehensive review article on treprostinil palmitil, which has just become available online in the journal Pulmonary Pharmacology and Therapeutics. Let's turn now to Slide 8 to review some data from preclinical experience comparing treprostinil palmitil to treprostinil when administered to rats by nebulization. The figure on the left shows that while straight treprostinil rapidly leaves the lung, treprostinil palmitil had a very prolonged lung residence time. These kinetics impart 2 important characteristics shown on the right, prolonged lung residence time translates into a prolonged duration of pulmonary vasodilatory activity, as shown in the figure on the top right. Also, as might be expected, the prolonged lung residence time impacts the systemic exposure. As shown in the figure on the bottom right, inhalation of treprostinil resulted in an immediate high systemic treprostinil plasma concentration, whereas inhalation of treprostinil palmitil does not. We believe that this difference in the pharmacokinetics may have important clinical implications regarding systemic adverse reactions. Turning to Slide 9. This slide summarizes experiments conducted in 2 species, the rat and the dog, and shows that the exposure response curve of inhaled treprostinil palmitil was shifted to the left of the exposure response curve of IV treprostinil. This implies that at any given plasma treprostinil level, the vasodilatory effect is greater if the drug was administered by inhalation and if it was administered intravenously. These data provide evidence that in these animal models, treprostinil is at least in part a locally acting drug when administered by inhalation. This is potentially very important because it implies that a portion of the pharmacologic activity of treprostinil can be achieved locally before the drug reaches the circulation, where it contributes to systemic adverse effects. This phenomenon makes the prolonged lung residence time that we've seen animals potentially even more important. Moving to Slide 10. This slide illustrates data from a widely accepted animal model of PAH rat sugen-hypoxia model. In this study, in addition to TPIP, we included inhaled, oral and intravenous prostanoids as comparators. The spider graph visually depicts the various readouts from the sugen-hypoxia model, including indices of hemodynamics, right ventricular hypertrophy and vascular remodeling. In the graph, the individual parameters are represented on separate axes, radiating out from the center of the figure. Each parameter is normalized between the normal healthy state, a score of 0 at the center of the figure, and the vehicle control sugen-hypoxia injury, a score of 1 at the periphery of the figure. The findings for each compound are depicted in various colors. In this type of a figure, the closer that the lines are to the center, the more efficacy they demonstrate. Here, you can see that the high dose TPIP in dark green demonstrated a superior overall profile. With that background, let's move to the top line results from our Phase I study with TPIP. As shown on Slide 12, this Phase I study was intended to assess the safety, tolerability and pharmacokinetics of TPIP in healthy volunteer subjects. The intent was to verify the systemic pharmacokinetic properties of our new inhalation powder formulation and to characterize the safety in the setting of single dose and 7-day multiple dose administration in healthy volunteers. The intention was to explore the upper end of the dose range in order to understand where adverse events would begin to occur. In this study, serial cohorts of subjects were enrolled. In the first cohort, subjects were randomized to receive single doses of 112.5, 225 or 450 micrograms of TPIP in a blinded fashion. In the next cohort, subjects were randomized to receive single doses of 675 micrograms of TPIP or placebo. The next cohort was the first multiple dose panel in which subjects were randomized to receive 225 micrograms once a day for 7 days or matching placebo. The final cohort incorporated a placebo-controlled up-titration approach, in which subjects began at 112.5 micrograms once a day for 4 days, then advanced to 225 micrograms once a day for 3 days. Let's now turn to Slide 13. This table shows the adverse events that were seen in the single ascending dose cohorts of the study. Included here are all adverse events that occurred in more than 2 subjects, as well as others that were considered to be of interest because we believe they might be related to the prostanoid pathway or the inhalation route of administration. Most of the adverse events were mild in severity. The few moderate events are noted in purple text. There were no severe or serious adverse events. As expected, we approach -- as we approach the highest single doses, we began to see more adverse events. In terms of the potentially prostanoid related AEs, it's important to remember that patients generally tolerate a particular prostanoid dose better if it is achieved through an up-titration approach and a therapy is initiated at that dose. Thus, in the clinical setting, prostanoids are generally administered in an up-titrating fashion. So while we explored a wide range of doses in the single ascending dose, or SAD study, in future studies, we would not anticipate initiating dosing at doses as high as 450 or 675. Turning to Slide 14. This table provides the subject disposition and shows the adverse events that were seen in the 2 multiple ascending dose cohorts of the study. And consistent with the previous slide, this also includes adverse events that may be related to the prostanoid pathway and/or the inhalation route of administration. One subject in the 225-microgram once-a-day for 7 days cohort chose to discontinue treatment after dosing on day 2 due to chest discomfort. As was seen in the SAD cohorts, most of the adverse events were mild. One patient in the 225-microgram once-a-day for 7 days cohort experienced syncope that was temporarily related to a blood draw 8 hours after dosing. This subject continued in the study with no further episodes of syncope. The key takeaway from this multiple dose experience is that tolerability was notably improved in the up-titration cohort. The patients who began at 112.5 micrograms and progressed to 225 showed better tolerability than those who started at 225 micrograms. This learning will be incorporated into future development and we believe this up-titration approach may allow us to reach much higher doses. Let's turn to Slide 15. This slide shows the pharmacokinetic profiles of the SAD portion on the left and the MAD portion on the right. First, in regard to the single-dose PK. The Cmax and AUCs were dose proportional across the range of doses, and treprostinil was detected in the plasma at 24 hours at all doses. In regard to the multiple dose kinetics, the green line represents the subjects who received 225 micrograms once daily for the entire period, whereas the pink line represents the subjects who received 112.5 micrograms once daily for 4 doses followed by 225 micrograms once daily. Turning to Slide 16. Here, the PK curves for the SAD cohorts in the current study are reproduced. For comparison, I will now overlay the PK curve that we previously saw in the Tyvaso cohort in the Phase I single ascending dose study that we conducted with TPIS, our first clinical formulation of TP. Keep in mind that the Tyvaso dose depicted here is the label target maintenance dose of 54 micrograms, which is to be achieved after gradual dose escalation over 2 to 4 weeks according to the product label. The differences in the PK profile are notable. First, the Cmax for Tyvaso is higher than the Cmax demonstrated by TPIP, even at a dose of 675 micrograms. Second, the plasma half-life of treprostinil with TPIP administration was considerably longer than that of Tyvaso. The plasma concentrations of treprostinil fell below the lower limit of quantitation after the 4-hour time point with Tyvaso, whereas treprostinil was present in the plasma out to 24 hours at the lowest dose and throughout the 48-hour sampling period for the 2 highest doses. Moving on to Slide 18. We are very pleased with these top line results from our Phase I study, and a few of our takeaways are listed here. First, the safety data showed adverse events consistent with an inhaled prostanoid, and the events were primarily mild despite the fact that there was no up-titration phase in the single dose cohorts. Along those lines, and consistent with prior clinical experience with prostanoids, the tolerability of TPIP was improved with an up-titration approach. We plan to incorporate such an approach in our further clinical development. We believe that the findings from this study suggests that TPIP may be safely administered at doses far in excess of Tyvaso. And TPIP showed substantially lower Cmax longer and half-life when compared to Tyvaso. Finally, we believe that the PK supports the continued development of TPIP with once-daily dosing. Let me close on Slide 19. As we move to the next phase of clinical development of TPIP, it may be worthwhile to consider these data on the pharmacokinetics and pharmacodynamics of inhaled treprostinil, which were published in the journal of the American College of Cardiology in 2006. In a series of clinical trials, these investigators characterized the PK and PD of various doses of inhaled treprostinil in patients with moderate-to-severe PAH. It should be noted that these academic investigators did not utilize the currently marketed Tyvaso product in these studies. The figure on the left shows the PK curve for inhaled doses of 30, 60, 90 and 120 micrograms of treprostinil. Consistent with the PK findings from our TPIS Phase I study, you can see that there was a rapid Cmax, followed by a fairly rapid elimination, such that by 2 hours, the systemic exposure was minimal. The figure on the right illustrates the pharmacodynamic time course of the drug expressed as the pulmonary vascular resistance. While inhaled treprostinil resulted in a significant reduction from baseline in pulmonary vascular resistance, that effect was relatively short-lived. This is the clinical data on inhaled treprostinil that I mentioned earlier when I showed you our corresponding data in the rat, where I believe the pattern is quite similar. So in animal studies, we've shown that treprostinil palmitil has been retained in the lung, where it exerted extended pharmacodynamic activity. And in the clinic, we've shown, first with TPIS and now with TPIP, that inhaled treprostinil palmitil resulted in a similar pharmacokinetic pattern, characterized by a low Cmax and a prolonged exposure in healthy volunteers. As we now move into clinical studies in patients with PAH, we hope to extend these observations and to determine whether TPIP may be able to achieve extended pharmacodynamic activity in the lung and eventually significant clinical benefit. With that, I'll turn the call over to Martina, who will discuss the path forward for TPIP.

Thank you, Gene, and good morning, everyone. We are very excited about these encouraging results from our Phase I study in healthy volunteers. Let me now take a few minutes to discuss our clinical development plans for TPIP, followed by a current treatment landscape of approved therapies and the market opportunity. Beginning on Slide 20. With the Phase I top line results now in hand, we intend to advance as quickly as possible to the next stage of clinical development. This will follow 2 paths in parallel. First, we will gather information on the impact of TPIP on pulmonary vascular resistance, or PVR, over a 24-hour period in patients with PAH in an open-label study. Data from this proof of mechanism study will be informative and complementary but not necessary to inform our next trial design. And as planned, we anticipate sharing top line patient data from this study in a handful of patients in the second half of this year. The second path, we'll investigate the effect of TPIP on PVR and 6-minute walk distance over a 16-week treatment period. We plan to initiate this trial in PAH patients in the fourth quarter. In addition, we plan to initiate a separate study for Group 3 PH-ILD patients. Both studies would use an up-titration dosing schedule to the maximum individual tolerated dose exceeding 600 micrograms once daily. I'd like to take a moment to discuss TPIP in the landscape of currently approved prostacyclin therapies for the treatment of PAH. If we are able to continue to demonstrate in human what we have shown in animal models, we think TPIP could become the cornerstone of therapy for PAH. Let's now turn to Slide 22, which lays out the addressable PAH patient population and market potential for TPIP. The key point here is the significant opportunity for growth beyond the immediate patient population with pulmonary arterial hypertension. We hope to reach these patients as we continue to explore potential development pathways for TPIP in PH-ILD and IPF. In summary, we remain excited about the many ongoing activities within our TPIP program and look forward to providing an update on each of these studies later this year. With that, I would like to turn the call back to Will. Will?

Thank you, Martina. I would like to close out our prepared remarks by reiterating the excitement conveyed by our team today. We are encouraged by the positive results observed to date, which we believe validates several critical aspects of TPIP's profile at a fairly early stage in its development program. Stay tuned for more updates in the second half of this year. I would like to thank the Insmed team for their diligent efforts in advancing this important candidate from the lab to the clinic. I would also like to thank the volunteers and patients who participate in our studies as well as their physicians who provide purpose to our efforts as we try to improve treatment outcomes. With that, let's now open the call to questions. Operator, can we take the first question, please.

Our first question is from Matthew Harrison with Morgan Stanley.

This is Connor on for Matthew. So just a couple from us. Do you expect the PK parameters to be significantly different between patients -- upcoming patients versus the healthy volunteers? And then, I guess, what is driving the need for 2 proof-of-concept studies? Martina, it sounds like you referred to maybe one of them not necessarily being 100% necessary to proceed, but I guess we are just wondering why not move more aggressively given the mechanism appears to be well described so far.

So appreciate the questions, and I'll take the first one -- the second one first. The IIa is a study that we envisioned prior to seeing the Phase I results. I think you raised a good point. The strength of these Phase I data probably make it so that the Phase IIa study is less necessary than it might have been before in terms of validating what we're developing here. Nonetheless, we think it could be interesting to see that pulmonary vascular resistance profile over a 24-hour period, if we can find a handful of patients willing to undergo that kind of procedure who have PAH. And indeed, we have several clinical sponsors who are willing to do that. So that information, as Martina described, is interesting, but not a rate limiting in terms of our ability to move forward. We are proceeding with all due speed to develop this drug in a safe but expeditious way. I don't know, Gene, do you want to comment on the PK question and the variability and what our expectations are there? And then Martina, I'll invite you to add any comments.

Yes. Sure. I don't think we're expecting any substantial differences. Of course, we always like to check PK in patients as well as healthy volunteers. But unlike diseases like asthma or COPD or IPF, where there is substantial abnormalities in the airways and in the parenchyma, the airways in patients with PAH are essentially normal. So we don't expect there to be notable differences in systemic PK.

Martina, any comments about the IIa and the other programs we're pursuing?

No, I think you've talked about the IIa. It's not absolutely necessary. It gives us additional understanding. I think as we -- with the next study where we talk about showing PVR reduction in 6-minute walk test, the key goal for us is to understand the range of doses that we can bring patients to and we know that a progressive dose escalation and titration to the highest tolerated dose eventually leads to an improved outcome, and that is the goal.

Our next question is from Marty Auster with Credit Suisse.

I had a couple of quick ones. I wanted to check-in is the molar equivalency of TPIP to Tyvaso, is that similar to what you disclosed for TPIS? I think it was -- 85 micrograms was thought to be kind of more equivalent to 54. And the second question, I guess, was on the development path. I was wondering -- I expect you'll be engaging with FDA to kind of figure out ways that the Phase II proof-of-concept can kind of rapidly port into a registration study once you identified dose titration in kind of a max dose, but what are the kind of key steps you need to get out of that Phase II to kind of progress towards registration? Does that trial need to be fully completed before those activities can begin?

Thanks for the questions, Marty. And I'll turn to Gene to answer the molar equivalent question and Martina to answer the development path. I think now that we have the data we can begin that dialogue with FDA, which we obviously weren't able to do before. But Gene, you want to take the molar equivalent question?

Yes, sure. And yes, Marty, it's the same because it reflects the molecular weight of the drug substance. Treprostinil palmitil is the same drug substance in both the inhalation solution and inhalation powder formulation. So it's a matter of the 16 carbon chain being a little bit heavier. So each molecule of TP is a little bit heavier than each molecule of treprostinil, but it's the same ratio.

Yes, Marty...

Martina, do you want to take the development path question?

Yes. So we -- yes, we're now, of course, discussing with the FDA what is the fastest path forward. What's really important for us is to show our -- in our development path the full potential for TPIP because we believe, based on this result, that this is a true paradigm changer. We'll discuss the results that we see in the PK Phase I study with the FDA, and then how quickly can we progress to the approval pathway. And whether we have complete the Phase II study or what the FDA wants to show, we will see in our discussions with the agency.

Your next question is from Joseph Schwartz with SVB Leerink.

Congrats on all the progress. It seems like you have the potential for much less spillover hypotension. I was wondering if you could talk a little bit more about magnitude of systemic blood pressure effects in the patients given TPIP? And how much blood pressure information have you collected from these patients? And will you be presenting more of it in more detail so that we can appreciate the differentiation from Tyvaso in terms of its relationship between pulmonary and systemic blood pressures.

Gene, you want to take that one?

Yes, sure. And absolutely, we'll be putting out all the results from the trial. And as is might be typical, we have blood pressure. One thing I wanted to point out is particularly at the high dose, it's a super high dose that the lung vasculature is seeing. And to some extent, it may be hard to tease out how much of the -- if there is a drop in blood pressure, as we did see in a couple of patients at the very highest dose when we started with that high dose, whether that's in fact systemic effect, which is an implication of your question or a preload effect in these healthy volunteers. So if you suddenly vasodilate the pulmonary vasculature extensively in a healthy volunteer and so their left ventricle is getting less preload, that could have an effect on the blood pressure. So we'll try to tease that out. But as I try to point out that, that scenario of hitting a patient with 675 micrograms upfront, single dose, and in this case, a healthy volunteer who doesn't even have pulmonary hypertension to start with, that's not something that's like clinically relevant for our future development because we don't -- wouldn't anticipate doing that. But yes, of course, in the -- as we publish the more complete results of the Phase I trial, we'll have that information.

Great. And then could you talk a little bit more about your dose selection and the metrics you're considering to ensure that you're not stretching the administration schedule too much by giving it once per day? My understanding is that patients on other inhaled prostanoids tend to get pretty low right before their next dose.

Gene, you want to take that?

Yes. So I mean, what we know from Tyvaso is we -- I think I showed you the PK curves and the PD curves of what's happening in the -- at least in those studies in the pulmonary vasculature. So we know that Tyvaso achieves what you've seen, these sort of intermittent drops in the PVR. And in between dosing, and likely overnight, the pulmonary pressure is probably back up to where -- back up to the baseline. And yes, we know that, that translates into clinical benefit, as has been demonstrated in the clinical trials to support approval. And so we think that, at least what we know at the moment and looking at these kinetics, putting together what we saw in the animal data and so forth that once daily should certainly be a therapeutic dosing interval.

[Operator Instructions] Your next question is from Ritu Baral with Cowen.

It's Lyla on for Ritu. Maybe just really quickly on the systemic exposure of treprostinil. Do you guys have the data for like the area under the curve? And maybe how do you think the 24-hour area under the curve compares to Tyvaso versus the doses that you tested for TPIP? Just trying to understand how that might fit versus patients that get multiple doses of Tyvaso during a day.

Gene, do you want to take that?

Sure. Yes. Yes, that's a very good question. And we -- and of course, in the publication, we didn't give all the detailed numbers in just these top line results, but we'll have those and you can make those comparisons. But one thing I'd like to point out or have you think about is that you can compare the total AUC, but we think it's a matter of how that AUC is utilized. Like for the AUC of Tyvaso, what it represents is intermittent very high peaks and then rapid metabolism. So is it better, at least in theory, to use that same AUC but extend it over the dosing interval. So you avoid the very high and you have a longer period of substantial exposure. So the short answer is yes. When we release the rest of the results, you'll see the numbers and so forth. You can do those calculations as to where we stand. And I think you'll see that even when you multiply the Tyvaso AUC by 4, as we get up to 225 and higher, will be clearly a greater AUC even calculated over 24-hour period, but maybe even more importantly a more kind of efficient use of that AUC. Less time spent super high, more time spent at a therapeutic range so that you cover a longer period of time.

Got it. And you said you would expect it to be higher over 24 hours? Just want to make sure I read you correctly.

Yes. As we -- so we got up to, for instance, 675 micrograms. So the total dose even with the molar equivalent that Marty was talking about, making that transition, we've administered much more than 54 micrograms 4 times a day. And so I won't characterize the findings too much, but you can imagine, we've -- as we increase the dose, we're administering much more treprostinil.

Your next question is from Stephen Willey with Stifel.

So I guess when I just look at the single ascending dose cohort and the multiple ascending dose cohort adverse event data, I guess, specifically at the 225 dose, right? I mean there's some suggestion here that some of the AEs that you're seeing are not necessarily, I guess, first exposure or Cmax-driven adverse events, and maybe this is kind of more of an accumulation issue. So can you maybe just speak to what the kinetics on some of these adverse events are? And I guess, I'm just trying to figure out if in the up-titration cohort, the fact that you're only on 225 for 3 days, is that just something that you expect to see with greater or longer exposure? Or do we think that the up-titration regimen is really kind of changing the narrative here?

Gene, you want to take that?

Yes, sure. I think it's the latter. I think that our clear conclusion is that the -- when we did that up-titration, it was much better tolerated. And that in general, it's not depicted here because, as you say, this is a collection of all the adverse events that occur over the period of dosing. But the observation we made is that a large amount of -- the majority of the adverse events did occur early in dosing even in the 225 cohort that you tended to see them early. And in some cases, they went away with continued dosing. And that's not evident when you just sum them up the way we did here. But I really don't think because the patients in the up-titration cohort got the drug for 3 -- got it at 225 for 3 days, and it looked really, as you can see, very well tolerated. So we're really, really pleased with this and think that this is the way to go.

Okay. And then maybe just as you think about the IIa and I guess the eligible patient population you're looking to enroll there. Should we expect that you're going to be focusing just on the Class III patients like Tyvaso was labeled for or do you maybe try to expand that IIa opportunity out a little bit in terms of eligibility?

The plan right now is to go after -- I believe it's actually type 1 patients that Tyvaso is approved for. The PH-ILD patients will be the subject -- the so-called type 3s or at least a subset of the type 3s will be the subject of clinical study alongside the type 1s for the more advanced clinical trials that Martina was referring to. The Phase IIa study will focus on PAH patients, so-called type 1.