Insmed Incorporated (INSM) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the Insmed 12-month results from ongoing open-label extension study of TPIP in PAH patients Conference Call. [Operator Instructions] I'd now like to turn the call over to Bryan Dunn, Head of Investor Relations. You may begin.

Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss the 12-month results from our ongoing open-label extension study of TPIP in patients with PAH. Before we start, please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our SEC filings for more information. I'm joined today by Will Lewis, Chair and Chief Executive Officer; and Gene Sullivan, Chief Product Strategy Officer. The call will begin with some opening remarks from Will before turning it over to Gene to walk us through the study results in detail. After Gene's remarks, we will welcome Dr. Raymond Benza, who is the George M. and Linda H. Kaufman Academic Chair of Cardiology at Cardiology at Sentara Health. Dr. Benza will share some of his thoughts on these data. After Dr. Benza, we'll turn it back over to Will to share some closing remarks. When we open it at the end for the Q&A session, Martina Flammer, Chief Medical Officer; and Sara Bonstein, Chief Financial Officer, will also join us. The slides we will review today were furnished with the 8-K we filed with the SEC this morning and can also be found on the Events and Presentations section of our website. Now let me turn the call over to Will Lewis.

Thank you, Bryan, and welcome, everyone. I am thrilled to announce the exceptional results from the first 12 months of our open-label extension study of TPIP in patients with PAH, which continue to validate our conviction in its transformative potential for patients with PAH. Let me step back and remind everyone why TPIP could represent such a meaningful advancement in the PAH treatment landscape. TPIP is a prodrug of treprostinil that our research team specifically engineered to unlock the full therapeutic potential of prostacyclin therapy. We designed TPIP to address 3 critical treatment challenges: efficacy, safety and convenience. On efficacy, TPIP's inhaled delivery targets the lung tissue directly, which has demonstrated efficacy advantages over other delivery methods. But TPIP is unique even amongst other inhaled options due to its ability to release the active drug slowly once it reaches the lung. This creates higher drug availability exactly where patients need it most with consistent 24-hour coverage, including overnight protection. On safety, we also believe that the slow conversion of TPIP to active drug within the lung may reduce systemic side effects from high peak exposure. In addition, because patients aren't inhaling the active drug itself, TPIP may also improve cough. Our preclinical cough models show that TPIP only induced a cough response when the dose was increased to approximately 7x the dose which induced a cough response with active treprostinil. And on convenience, TPIP requires just once daily dosing versus the typical 4 times per day dosing with other inhaled options. A single breath delivers up to 640 micrograms of TPIP, which contains nearly 60% more active drug than the highest label dose of TYVASO DPI and doses up to 1,280 micrograms would require only 2 breaths once per day. Additionally, this less frequent dosing may have the advantage of improving patient adherence. Before we move into the OLE results, it is important to ground the discussion in the randomized Phase IIb study in PAH that preceded it. Those results showed a highly statistically significant 35% placebo-adjusted reduction in pulmonary vascular resistance, which far exceeds the numerical reductions shown for any other prostacyclin treatment of which we are aware. Treatment effects across other efficacy measures were similarly impressive with a placebo-adjusted 35.5 meter improvement on 6-minute walk distance and a 60% placebo-adjusted reduction in NT-proBNP at week 16. What makes these results even more compelling is that they were measured roughly 24 hours after the most recent administration of TPIP, demonstrating TPIP's sustained therapeutic effect. Safety was equally encouraging with 90% of patients completing the study and no unexpected safety signals observed. Importantly, all incidences of cough in the trial were mild or moderate with more than 85% classified as mild. As you will see, all of these efficacy results for TPIP are numerically superior to the published results for other forms of inhaled treprostinil, both nebulized and dry powder. They are also comparable to the results that have been published for sotatercept. Given the strength of the data produced in the randomized lead-in trial, our desire was to see those efficacy measures sustained over the longer OLE period. I am pleased to report that patients in the continued TPIP group were able to sustain those demonstrated improvements on 6-minute walk distance and NT-proBNP through the first 12 months of the extension study. Additionally, those patients saw further improvement in functional class from the end of the randomized trial and saw clinically meaningful reductions in their risk of morbidity and mortality as assessed by the REVEAL Lite 2.0 score. Patients who were randomized to placebo in the lead-in trial saw a clinically meaningful response once switched to TPIP with overall improvements in 6-minute walk distance, NT-proBNP, functional class, and REVEAL Lite 2.0 risk scores catching up with those in the continued TPIP group by month 12. Equally important, over 90% of patients completed the first 12 months of the OLE with no new safety signals being identified at doses up to 1,280 micrograms or double the highest dose in past trials. This is a remarkable result for patients and one that we believe will drive additional interest from investigators and patients for our Phase III trials. Now I will turn it over to Gene to walk us through the data.

Thank you, Will, and good morning, everyone. I'm very pleased to be with you today to share the 12-month results from our ongoing open-label extension trial of TPIP in patients with pulmonary arterial hypertension. First, I will provide a review of the study's design. The PAH open-label extension study is a 24-month study, allowing patients to continue on treatment with TPIP and to move patients receiving placebo in the lead-in study on to treatment with TPIP. The study was designed to allow up titration to doses as high as 1,280 micrograms, which is double the maximum dose that was allowed in the lead-in Phase II study. Using a blinded double-dummy approach during the first 3 weeks of the trial, patients who had received TPIP in the lead-in study were able to remain on the dose that they had achieved in that study and patients who had received placebo in the lead-in study underwent up titration to their individual maximum tolerated dose of active drug. During the open-label period, investigators were permitted to titrate patients to the level required to optimize clinical benefit up to as high as 1,280 micrograms. This means that patients who were doing well could remain on a stable dose, while patients who may not have achieved optimal clinical status or who showed signs of disease progression could be further up titrated during the course of the study. The ability to increase the dose of TPIP over the long term is one of the more important differentiating features of TPIP. There is wide variability between patients in terms of their sensitivity to prostanoids, meaning that the initial safe and effective dose will differ across patients. We saw this in the lead-in study, where the safety and efficacy of TPIP were demonstrated as the drug was titrated to each patient's individual maximum tolerated dose rather than to a specified dose. But another important aspect of prostanoid dosing is that patients will typically require increasing doses over time as the disease progresses. With parenteral prostanoid treatment, for example, the patient's dose is typically gradually increased over time. However, with the currently available inhaled prostanoids, there is a limit to the ability to titrate the dose up over time. And therefore, patients often have to come off of inhaled therapy in favor of parenteral therapy. As a result of its pharmacokinetic profile, the dose of TPIP can be increased over time in a manner similar to the approach taken with oral or parenteral prostanoid formulations. With this in mind, in this study, physicians were not encouraged to increase the dose, rather they were given the opportunity to do so if they felt that a patient's condition warranted it over time. In that sense, they were able to utilize TPIP in the same manner that they are accustomed to utilizing oral or parenteral prostanoids. The primary endpoint of this study focused on the safety and tolerability of TPIP during long-term use. Secondary efficacy endpoints include change from baseline in 6-minute walk distance NT-proBNP, WHO functional class and the REVEAL Lite 2.0 score, which is a validated measure of the risk of morbidity and mortality in PAH patients. Finally, it is important to remember as we review these data that all efficacy measures in this open-label extension study were taken at trough exposure or roughly 24 hours after the most recent dose of TPIP, consistent with the timing of the efficacy assessments in the randomized trial. On this slide, you can see the baseline characteristics of the patients who participated in this open-label study. It is important to note that all baseline characteristics reflect the measurements taken at the start of the lead-in trials, not at the start of the OLE. We chose that approach so that we could assess the performance of the patients who had initially been randomized to placebo in comparison to those who were randomized to TPIP. The baseline characteristics were comparable between these 2 groups with only minor imbalances, most notably in the number of background medications. Note that these baseline data described the open-label study population of 91 patients, not the entire Phase IIb lead-in study population, which was 102 patients. This open-label extension study was fed by 2 prior Phase II studies: The first was a randomized placebo-controlled trial that enrolled 102 patients randomized 2:1. A total of 95 patients, 62 treated with TPIP and 33 treated with placebo completed that study. And it is that study that was a major source of patients who rolled into this OLE. Some of you may remember the second lead-in study shown here, which was a single-dose 24-hour PVR monitoring study that we initiated around the time of the COVID epidemic. We enrolled only 1 patient in that PVR study and chose to give that patient the opportunity to receive TPIP in the OLE once it was initiated. We were very pleased that 95% of patients who completed those Phase II studies chose to enroll in this open-label extension. Of the 91 patients who entered the OLE, 83 patients or 91% completed at least 12 months of treatment in the OLE. Of the 8 patients who discontinued, 4 were due to death, none of which were considered study drug related, 3 were due to an adverse event, and 1 was lost to follow-up. For reference, a typical mortality rate for patients resembling this population is around 8% versus the 4% incidence of death described here. Only 1 patient or about 1% of the total discontinued TPIP due to cough in the first 12 months. TPIP was generally safe and well tolerated with no new safety signals identified. 89% of patients experienced a treatment-emergent adverse event, the vast majority of which were mild and moderate. 19% of patients had a serious AE, which we believe is in line with what one might expect in patients with serious diseases like PAH over a 12-month period. Only 1 serious AE was considered related to the study drug by the investigator. That one was a case of orthostatic hypotension, which did not lead to discontinuation or dose reduction of TPIP. The patient was hospitalized and subsequently discharged after a precautionary workup was completed. The most common events observed in the OLE were headache, cough, nasopharyngitis and diarrhea. Importantly, all TEAEs of cough were mild or moderate with over 85% being mild. Given that this study is the first to report the clinical experience of patients who received TPIP at doses higher than 640 micrograms, we've included some safety information specifically for those patients. Among patients who titrated up to doses greater than 640 micrograms, there were no deaths or TEAEs leading to discontinuation. Only 10.5% of these patients experienced an SAE compared to 18.7% overall and only 1 patient experienced a TEAE of cough, which was categorized as mild. There were no new safety signals observed among these patients. Before I walk through this slide, I want to remind you again that the placebo-adjusted 6-minute walk distance benefit reported in our Phase IIb trial was 35.5 meters, which is by far the largest improvement we have seen from a prostanoid in a randomized trial. This figure shows that over the following 12 months, patients in the continued TPIP arm maintained and even slightly improved their 6-minute walk distance. PAH is a progressive disease, meaning that you might expect this measure to gradually decline over time, which makes this outcome even more impressive. Patients who had crossed over to TPIP from placebo had a similarly positive outcome on 6-minute walk distance. In fact, these patients essentially caught up with the continued TPIP group by month 12, with both groups showing around a 55-meter improvement in 6-minute walk distance from baseline. This figure illustrates the changes from baseline in NT-proBNP, an important biomarker of cardiac stress. We were very pleased to see that the continued TPIP group maintained its improvement in NT-proBNP during the OLE period after an already impressive result during the randomized trial. Perhaps even more striking, the placebo crossed group had completely caught up to the continued TPIP group's result by month 6 and maintain that benefit through month 12. Both groups showed approximately 60% reductions from baseline at month 6 and month 12. Now let's discuss the impact of TPIP that we saw on WHO functional class. The WHO functional classification system categorizes patients according to the magnitude of the limitation that the disease places on their physical activity. Patients in functional Class III experienced marked limitation in their physical activity. While they are comfortable at rest, even less than ordinary activity triggers symptoms, and this can have a significant impact on a patient's quality of life. At baseline, all patients were in Functional Class II or III. By month 12 in the open-label extension, more than 25% of patients in both groups had achieved Functional Class I status, meaning that they no longer had any limitation on their physical activity and 80% of patients in both groups reached either functional Class I or functional Class II. Also encouraging is that 50% of patients in the continued TPIP group and 42% of those in the placebo crossed group saw at least a one category improvement in functional class by month 12. Now let's move to the topic of risk stratification. REVEAL Lite 2.0 is a validated instrument that has been shown to predict the risk of mortality and morbidity in patients with PAH. This type of risk stratification is commonly used in clinical practice with many large centers requiring an assessment at every visit. The score is often used in treatment decisions with the aim of achieving low-risk status for the patient. The REVEAL Lite 2.0 score incorporates BNP or NT-proBNP, functional class, 6-minute walk distance, systolic blood pressure, resting heart rate and renal insufficiency. High intermediate and low scores are associated with mortality risk of greater than 10%, between 5% and 10% and between 1% and 5%, respectively, at 1 year. A refined low-risk score of less than or equal to 4 points is associated with mortality risk of less than 5% at both 1 year and 3 years. And beyond mortality, low and refined low-risk scores have been shown to predict improved morbidity as compared with higher scores. Based on the excellent work by Dr. Benza, who we will hear from in a moment, we know that a 1-point reduction in REVEAL score corresponds to a 23% reduction in the risk of mortality and a 21% reduction in the risk of clinical worsening. This is important context for the study results on the next slide. On this slide, you'll see the results of REVEAL Lite 2.0 scores. I'd like to note that risk stratification was not one of the prespecified efficacy endpoints in the Phase IIb lead-in study. However, it is a prespecified endpoint in this OLE. And because we collected all of the necessary elements to calculate the score at baseline time point in the lead-in study, we can now show those data here alongside the OLE data. On average, both the continued TPIP and the placebo crossed groups began the randomized trial with intermediate risk scores. While the average score for patients taking placebo remained roughly flat during the 16-week trial, patients on TPIP saw a meaningful drop in score, bringing their average into the low-risk category. Within just 6 months in the OLE, the mean score in both the continued TPIP and the placebo crossed groups had dropped below 4 into the refined low-risk category. As discussed in the previous slide, this means that at the start of the trial, the average mortality risk for these patients was 5% to 10% at 1 year. And by the end of 12 months in the OLE, their average mortality risk declined to less than 5% at 3 years. In fact, patients in the continued TPIP group saw about a 2-point average improvement and patients in the placebo cross group saw a 1.4 point average improvement in their REVEAL scores. This is very encouraging, particularly in light of the data that I mentioned previously, which showed that a 1-point improvement in REVEAL Lite 2.0 score has been shown to result in a 23% reduction in the risk of mortality and a 21% reduction in the risk of clinical worsening. It is also notable that 65% of patients in both groups were able to reach a refined low-risk category by month 12 of the OLE. Looking at the current PAH treatment landscape, we see established inhaled treprostinil like Tyvaso, which have offered meaningful advances but remain constrained by tolerability concerns, dose limitations and 4 times daily dosing. More recently, WINREVAIR has provided another step forward with its potentially complementary mechanism of action, yet clear need remains for improved prostanoid therapies. We believe TPIP could represent the next major advance in the treatment of PAH. While cross-trial comparisons require caution due to differences in patient populations, trial designs and how and when endpoints are measured, among other things, we are excited by what we have seen from TPIP so far and its potential impact. This slide provides some examples of what we mean. Let me just walk through the first 2 of them. TPIP's 35% PVR reduction matches the best result we've shown for WINREVAIR's clinical program. On 6-minute walk distance, TPIP's placebo-adjusted 35.5 meter improvement in the randomized trial and 55-meter improvement in the OLE compares favorably to Tyvaso's 20-meter improvement in the 12-week trial and 25 to 38 meters in the OLE at 12 months. WINREVAIR showed a 41-meter improvement in a randomized trial and 47 meters at the top improvement in its OLE, both of which are relatively comparable to TPIP's results. Similar patterns are shown across other endpoints shown on this slide as well. Once again, I want to emphasize that each of these individual comparisons across trials should be noted with caution. However, it's not the individual data points, but rather the totality of this data that we find so encouraging. Today's results suggest that TPIP has the potential to become the prostanoid of choice and they deliver benefits that could be seen as comparable to those of WINREVAIR. Combined with favorable safety, tolerability and once-daily dosing, we believe that TPIP would be well positioned for an expanded role in the modern PAH treatment, assuming future clinical and regulatory success. With that, I'm now pleased to hand the call over to Dr. Ray Benza to share his thoughts on these data. Dr. Benza?

Thank you so much, Gene, and it's a real pleasure to be here this morning and to speak with all of you about this open-label extension trial and it's fairly impressive results. And I have to remind everyone on this phone call that pulmonary arterial hypertension, the disease that we treat as clinicians is probably one of the most devastating diseases that I've treated in my clinical practice. And the results of this open-label study really give us a genuine reason for optimism. The results, just to put in perspective to the various people on the phone call were probably the most impressive results I have seen not only with an inhaled product, but really across the entire landscape of medicines that we use to treat this devastating disease. The impressive efficacy improvements that we're seeing with an inhaled treatment are really quite remarkable. And going back to what we saw in the Phase IIb study, both the reductions in PVR and the improvement in 6-minute walk test are both well within what we consider the minimally important treatment difference to push our patients in the right direction. And what I mean by that is that patients who have achieved an improvement in walk distance greater than 30 meters not only have improved functionality, but improved quality of life. And this is really the measure that we hold all our drugs against because we want people to function better and feel better at the same time. In addition, that reduction in PVR that you noticed is at the accepted range that we need in order to ensure appropriate right ventricular remodeling. And remember, right ventricular remodeling is really the essence of predictability of patient outcome with this disease and having a reduction that significant ensures that we will have right ventricular remodeling and improved outcome. And this is seen very impressively through the very robust changes in the REVEAL risk score. In fact, a 2-point reduction is probably the largest reduction in REVEAL risk score that I have seen throughout many of the clinical trials that I participated in. And achieving ultra-low risk, which we define as a REVEAL score less than 4, not only ensures that our patients are going to survive more, but they're going to survive better because they're not going to have morbidity events, which is really the major thing that we fight now given the improved overall survival rate with the current landscape of current medications. And it does all this with a really great safety profile. The most important thing being the lack of systemic side effects, particularly a systemic hypotension, which we always want to avoid in patients with high pulmonary vascular resistance. I think one of the other points to really stress is that more than 1/4 of patients by month 12 received functional Class I status. This means that people do not even recognize that they have the disease anymore. That is really impressive. In fact, most of our patients always get stalled in functional Class II, which means they're still symptomatic. But having a large proportion -- they're virtually asymptomatic is a really unique finding to this study. The results to me are impressive enough where it will probably change my clinical practice once this drug becomes approved as I have always considered inhaled products, particularly inhaled prostacyclin as an edge drug. If I needed to push a person a little bit more in a favorable direction, that was the drug I've used. This changes the entire landscape with TPIP, which is now going to be a major contender for additional therapy when we want to move people from intermediate risk to low risk. With, I feel, efficacy signals similar to what we're seeing with remodeling therapy like sotatercept, but without the significant side effects that we see with that injectable drug. So I just can't tell you how enthused I am with the results of this particular study and very much looking forward to see if we can reproduce these results in our upcoming studies. And I'd be happy to answer any questions that the audience might have.

Thank you, Dr. Benza, for joining us today and for sharing your valuable insights with our audience. Today's compelling results strengthen our conviction that TPIP has the potential to become the prostanoid of choice. Let me summarize the key takeaways that reinforce this belief. First, patients who were initially randomized to TPIP in the prior lead-in trial were able to sustain those best-in-class improvements over 12 additional months of treatment and patients who switched from placebo achieved comparable benefits. In addition, patients experienced meaningful reductions from baseline in their average REVEAL Lite 2.0 scores, a validated measure of morbidity and mortality risk. Importantly, TPIP demonstrated a favorable safety and tolerability profile even at higher doses with low rates of cough, which was predominantly mild. Given the strength of the results we have shared, we are incredibly excited for what is to come for TPIP. This slide illustrates our TPIP clinical program that is currently underway in 4 large indications: Our Phase III PH-ILD study initiated in December last year, and it is currently progressing well. Our Phase III PAH study opened its first trial site in April of this year and sites are now screening patients. Our Phase III trial in PPF is on track to initiate later this year, and our Phase III trial in IPF is expected to begin in the first half of next year. Finally, keep in mind that this current OLE study is still ongoing. We expect the 24-month data readout from this trial to be available around this time next year. We are energized by TPIP's potential to transform treatment across all 4 conditions. Our team remains committed to advancing this program with urgency, knowing that each milestone brings us closer to potentially changing lives for patients who need better options. Before we turn to your questions, I want to personally thank the patients and investigators whose continued participation makes this progress possible. We will now be pleased to take your questions. Operator, may we take our first question, please?

[Operator Instructions] Your first question today comes from the line of Joe Schwartz from Leerink Partners.

Congrats on the exciting data. I was wondering if you could talk some more about how TPIP's efficacy compares for the PAH patients who were titrated to higher doses versus those who weren't. And is there as much rationale to believe that higher doses of TPIP could be more beneficial in the other indications you're pursuing?

Gene, do you want to start off on that question?

Yes. I'm glad you brought it up because this is a topic that comes up fairly often. It brings up the whole topic of how prostanoids are dosed in the clinic and how the difference -- how that differs from how most other drugs are dosed. I'm going to -- I tried to address a little bit of this in the introductory comments, and I'll make a few comments here. And then I'm probably going to ask Dr. Benza to give you his perspective. But it's important to remember how prostanoids are dosed, particularly the oral and parenteral prostanoids. As I mentioned in the opening comments, the inhaled prostanoids have a limitation that they can't be continued titrated -- continue to be titrated. But parenteral and oral prostanoids are dosed to the individual sensitivity to prostanoid, meaning trying to achieve the best therapeutic effect while maintaining optimal tolerability. And there's a wide variability between patients in terms of how sensitive they are to prostanoids. So you may get an equal therapeutic benefit at one dose, but you need a higher dose for another patient to achieve the same therapeutic benefit. There's just some intrinsic differences in the sensitivity. So with oral and parenteral prostanoids, doctors tend to titrate the dose up limited by tolerability to try to achieve best efficacy and land wherever they land for that patient. And we saw that in the randomized trial, where we allowed patients to go up to 640, but some patients stopped before getting to 640. They were getting good effect, and we saw the outstanding hemodynamic effects and 6-minute walk distance effects that were shown in that trial. But another point about prostanoids is that over time, patients tend to require more. And so as we talk to the doctors and among them, Ray, the doctors would like the opportunity in an individual patient to be able to keep titrating up the way they titrate up the, say, Remodulin. And so that's why we opened up in the longer-term study, we saw it might be necessary, doctors might want that opportunity. They wouldn't necessarily need it, but they might want that opportunity in an individual patient to -- in order to maximize that benefit. But as you saw, the outcomes of these patients were dramatic. And so if you can achieve a patient in functional Class I or even II in a low REVEAL score at a certain dose, there's no need -- the physician wouldn't necessarily increase the dose. So I just want to emphasize that the increase in the ceiling to 1,280 was just to give doctors the ability to respond to any individual patient. And it really wouldn't make sense to look at the effect of a patient who the doctor decided to go to greater than 640 and compare that to a patient who was doing well and the doctor decided to stop at the dose at 640 or lower. So that's the general background on prostanoid dosing and how to think about dose escalation. Again, one -- in my mind, one -- and Ray, I'll stop in a minute and ask you to comment on this. But in my mind, one of the problems with the existing inhaled prostanoids is that you get to this maximum dose and you can't respond to that need by increasing the dose. With TPIP, you can dose it the way you might increase the dose of Remodulin. If a patient came in on parenteral prostanoid and you thought they could achieve a better efficacy and they were tolerating it fine, you might increase the dose. And so we wanted to be able -- doctors to be able to use TPIP in that same manner. Ray, maybe I'll ask you to comment on that approach to prostanoids in clinical practice. You've been dosing prostanoids for a long time.

Yes. It's almost 40 years. Having a titratable prostacyclin is really the holy grail of prostacyclin therapy, not only for all the reasons that Gene mentioned because some patients do have tachyphylaxis to those and require dose adjustments every now and then. But having the first really titratable inhaled product that improves significantly hemodynamics opens the window for countless additional opportunities to really push right ventricular remodeling and normalize hemodynamics to achieve complete remission. So I am totally excited about the ability to really titrate this drug given the known baseline significant improvements in hemodynamics so that I can challenge patients when they get at low risk and try even to push for remission using a titratable product like this.

Your next question comes from the line of Jessica Fye from JPMorgan.

I wanted to ask about some potential differences between the Phase II and Phase III in PAH for the clinician and just the potential implications for the Phase III results. So the 3 things that I'm thinking about are, I think in Phase III, how to see 6-minute walk is being assessed like 1 to 3 hours after dosing compared to trough that was used in Phase II. I think the primary endpoint is being assessed at 24 weeks instead of, was it 16 in Phase II? And then lastly, I know sotatercept is allowed in Phase III. I was curious what proportion of the patients might be expected to be on sotatercept at the time they initiate prostacyclin therapy with TPIP and what implications that could have?

Thanks, Jess. Well, Gene, do you want to run through the response on that?

Yes, sure, sure. Thanks for the question. And those differences you've identified are right on target. In the Phase II study, I think we held TPIP to the highest standard. We knew that we were introducing a drug that would be dosed once daily and wanted to make sure we had evidence that it was maintaining its activity throughout the dosing interval. If we had measured, for instance, the hemodynamics at what might be peak exposure, I think there would have been questions and legitimate questions in everyone's mind, is there still an effect at the end of the 24-hour dosing interval. So we chose to kind of actually handicap TPIP in the Phase IIb. Some people at the time asked us, why -- you could probably get better numbers if you measured hemodynamics in 6-minute walk at the peak exposure. And we decided that wasn't what we needed. What we needed was real evidence to feel confident going into Phase III that we're doing the right thing for patients and that a once-daily administration was, in fact, ideal. So that's why we did it at the trough during the Phase II study. Now we recognize that there's cross-study comparisons and effect sizes and so forth. And -- we also recognize that FDA has allowed the primary endpoint to be at the peak exposure. And so we've chosen to kind of now put the best face now that we know for sure that this is a once-daily drug, let's explore what the maximum benefit is shortly after dosing. So that's the intention behind that change. In terms of the duration of the study, right, the Phase IIb was 16 weeks. The Phase III will be 24 weeks. I think that we are really impressed by the ability to maintain patients in the study. So for instance, in this 12-month study, 91% of patients stayed in the study for that time. Often, you worry and at least I did in the old days of PAH trials that if you make them super long, you're going to end up with more missing data and missing data is hard to handle statistically. And so maybe we should use a modest treatment duration. We felt some confidence that we would have -- we wouldn't have that degree of missing data. And we also see that patients continue to get better with continued exposure beyond 16 weeks. We've shown some of that data here now where there's continued accrual of benefit in some of these endpoints. And so with the Phase III, we'll give a longer period for patients who have been on drug. And hopefully, that might translate into even more dramatic findings at least for certain endpoints than we had already seen in Phase II. And I think your third question was about sotatercept. Obviously, sotatercept wasn't approved at the time of Phase II study. So we don't have patients that were -- began the trial on sotatercept. But we recognize that that's a new player in the field and physicians are going to want to know how do these interact, does it work on top of sotatercept? What's the -- how should we think about them? Dr. Benza may comment after me, I might bring him in to talk about that. But one of the questions will be, when should you move to a prostanoid versus sotatercept? Or if a patient is on one of these 2, what's the benefit of the other one? And so we think it's important to inform clinical practice to include patients on sotatercept in the Phase III trial, we plan to do so, knowing that we don't really know what the added benefit will be. We just don't have that data yet. And we're making some cautious assumptions about the effect size that we might see in patients who are already on sotatercept to inform the powering of the trial. We're going to limit the number of patients who are on sotatercept who are allowed to be on sotatercept in this background. So we'll get some information, but we don't think we're jeopardizing the end result of showing efficacy because we have plenty of patients who are much like the patients we've seen in the Phase II study. And we hope and expect that there will be added benefit on top of sotatercept, although we're not counting on it. Let's see. So that's it -- and maybe, Ray, you had some comments about -- I mean we spoke about this data about sotatercept and its role and how you might use a drug like TPIP if we continue to show the type of effects that we've seen so far.

Yes. I think it's going to be a really interesting decision tree point. As we use sotatercept more and more, we're continuing to see additional issues with this product that we hadn't seen in the randomized clinical trials, including the increasing number of patients we're seeing with exercise-induced hypoxia due to the development of AV malformations in the lung and intrapulmonary shunting, not to mention the pericardial effusions and other potential side effects that we see with sotatercept. So in my mind, having an inhaled product with a safety background that we have demonstrated to make it a very close competitor with sotatercept in the decision tree when you're on someone with dual upfront combination therapy and you're looking for a third medication to push them to low risk. So I think TPIP, if it continues to show these type of favorable effects will be a competitor to sotatercept in that area.

And Jess, just to clarify on 6-minute walk, we are measuring primarily at the 1 to 3 hour after administration, but we are also taking measurements 24 hours after administration. So we will have that data to compare to what we saw in Phase II. And it's worth noting that the 24 weeks versus the 16 weeks also will permit a longer period of titration -- up titration should the physician conclude that for that individual patient, they want to go to a higher dose to try to achieve some of these in what has been characterized a remarkable reduction to refine low-risk categories in the REVEAL Lite 2.0 score or functional class reductions, which is certainly the goal of therapy.

It also gives us an opportunity to really look for true right ventricular remodeling because you know that doesn't happen overnight. So I actually like the longer observation period to determine if that's something we can actually achieve.

Your next question comes from the line of Ritu Baral from TD Cowen.

I think some of the client focus I've been getting this morning, guys around the higher doses is sort of less Eugene comparison across patients, understanding that they can get to different levels, required levels of treatment and more about how these patients fared sort of intrapatient as they dose escalated? I believe at one point, you had mentioned that 7 patients were able to get up to the 1,280. As you followed these patients, did they have sort of continued improvement in 6-minute walk or proBNP as they dose escalated? And as they tolerated sort of that dose escalation, were there any patients that had to then sort of dose reduce because of the cough that was triggered after a certain dose?

Gene, go ahead.

Yes. Thanks for that. And these become very complicated to try to assess over the course of time, whether the increase in dose that a doctor decides to go to has resulted in a benefit. And we haven't done those kind of analysis. I think that's very fraught. I think that the main point here is that we're giving the doctors the ability if they so choose to maximize the benefit in those individual patients. And the end result is an assessment of what that strategy achieves. And that strategy of allowing patients to go wherever they need to go, achieves the results that we've shown here, the number of patients that achieved functional Class I and the reduction in REVEAL scores and so forth. It's that strategy rather than looking at the individual patients. I think we have in the deck that -- I think there was -- in terms of the safety, as we continue, of course, to me, that's the main question. It's not should you compare the efficacy how they were doing before and after because presumably, the doctor made the decision to increase the dose for a reason. And ultimately, we see the results that we've seen. But we -- so my focus really was on are we going to start to see the emergence of any new safety signals as we got higher. And that really wasn't the case. I think in the slide deck, we show that in those patients who went above because a lot of attention is paid to cough, we feel like cough has not been extremely problematic. We don't have a lot of dropouts due to cough. And if you look at the -- which we did look at the patients who received greater than 640, there was only 1 TEAE of cough didn't lead to discontinuation or anything. So we felt like there was nothing that emerged in terms of safety. It was the typical -- the same pattern that you might see at lower doses in patients who are more sensitive to prostanoids.

Your next question comes from the line of Vamil Divan from Guggenheim Securities.

Congrats on the data. And I do -- again, I have a titration question. A couple of follow-ups, if I could. So one, it sounds like there were 19 patients that got over 640 and then they got to the 1,280. Can you just -- what was the reason or a limiting factor in terms of why patients are not able to get all the way to the 1,280? Maybe you can just share that. And what is the plan in Phase III in terms of how dose titration is being managed? Is there specific criteria? Or is it more left to the investigator's discretion? Any details there would be helpful.

Yes. So just to clarify, in all of our Phase III studies, we are permitting patients to go as high as 1,280 micrograms, which is a remarkable opportunity for physicians to get to those higher doses. And it is important to understand that many of these patients, as demonstrated by the fact that we're able to get 65% of patients in both groups to the refined low-risk category by month 12. So in some of these cases, the physicians made a decision they don't need to go any higher because they're getting the patient to the asymptomatic goal, which is a remarkable accomplishment and outcome. But Gene, do you want to comment on this question?

Yes. I mean I think you put it just right. And so for that reason, there isn't like a CRF in the case report, there isn't an entry of, hey, this patient isn't at 1,280, why aren't they? Because that's not really a clinically relevant question. We're not intending or expecting every patient to get to that dose nor are we wanting to apply to physicians that they should. Physicians dose these medications and in certain circumstances, add another medication in clinical practice in order to achieve what the clinical outcome they desire in that patient, hopefully, to move that patient to as low risk as can be. So if a patient is at a low-risk status, the patient is doing well, there would be no reason to keep dose escalating. And so we wouldn't really query the doctor, hey, why haven't you -- if you have a patient with a REVEAL score of 2 and a functional Class I, there's no reason to ask them why haven't you increased the dose any further. Ray, maybe this is really to be kind of challenging and it reflects the prostanoids themselves, how they're dosed in the clinic and because they're dosed differently than other drugs, and this sort of goal-oriented treatment, which has emerged over the last decades where the goal is to improve patients into a low-risk category and be happy when you're there. But I can see from these questions that it does -- it's a little bit confusing. And so I think it's best maybe to hear from Dr. Benza his perspective on these issues. In other words, why wouldn't you, if you have a patient on parenteral treprostinil, just turn the knob all the way to the right rather than that being guided by their clinical circumstance. So Ray, can you help with this kind of complex topic?

Yes. I mean the decision to titrate parenteral prostacyclins or any prostacyclin really revolves around several central issues, and they're all related to achievement of various goals. Obviously, we want to achieve low risk. And so in most patients, we will continue to titrate parenteral prostacyclins until we achieve low-risk status. So that is probably our primary goal and the primary reason for titrating actively prostacyclins when they're first initiated on patients. The second thing is really to achieve secondary goals. So once we've achieved low risk, we look to determine whether, one, we can achieve hemodynamic remission, meaning normalization of PVR, cardiac output and right atrial pressure. And secondly, we determine whether there is a further need to restore right ventricular function to normal. So those are 2 of the reasons once low-risk status is achieved to continue to titrate prostacyclins in any form. The ability to do that with an inhaled product is now opened with TPIP. We've never been able to do this with our other inhaled prostacyclins and the fact that we can almost double the dose and achieve levels similar to what we see with parenteral prostacyclins is very impressive with a once-day inhaled product. So this really opens the door for not only our standard titration schemes, but also these alternative titration schemes that are ultimately very important. The last thing to note is that, as we've mentioned several times before, many patients who are on stable dose of prostacyclin need a little tweaking now and then, not only because they can tachyphylax to prostacyclin at certain doses, and that doesn't happen with everyone, but in a small minority of patients with tachyphylaxis is a real phenomenon and you have to increase doses to make sure that you continue to keep someone at low risk.

Your next question comes from the line of Olivia Brayer from Cantor Fitzgerald.

Another follow-up from me on higher dose levels. Have you seen anything from the OLE that maybe changes how you're thinking about the potential to see a dose effect in your Phase III programs? And how do you plan to actually look at dose response in the Phase III as you try to measure the different titration schemes? And then if I could ask a question on cough. Maybe just what do you make of that 15% cough rate? It looks like you're maybe just looking at new onset of cough. So is that reported number lower just because it's a bigger denominator of patients? Or is there maybe something else that you're seeing around a better cough profile? Just trying to get a better understanding of where that number comes from and whether patients who previously reported cough were excluded even if they did have a lingering cough.

Sure. And let me just make it very clear. There is nothing in this study that does anything other than encourage us to believe that our Phase III data will be nothing short of impressive. These results, giving patients to a -- many of the patients to an asymptomatic status is, to the best of our knowledge, without precedent in this quantity. And to do so with the mild safety profile that's presented here, I think, is what we find to be most compelling. Now we will apply that to broader groups of patients with different conditions and giving the physician the ability to go all the way up to such a high dose level affords many benefits, one of which is that you can continue to increase the dose to achieve the best possible outcome for the patient. And then as Gene and Dr. Benza mentioned, over time, should the need to increase the dose present itself, that opportunity will remain for the patients that aren't already at 1,280. So this opens the door to a usage of this drug in a way that is without precedent at the moment. So that's one of the things we're very encouraged by. But Gene, do you want to go through perhaps some -- her points directly?

Yes, sure. And again, this gets to how prostanoids are different than other drugs. For other drugs that are being developed, you need to do a dose -- Phase II dose ranging. You randomly assign patients to 2, 3, 4 different doses and you see the dose response. Prostanoids are not dosed that way. If you look at the oral prostanoids, the parenteral prostanoids, there wasn't a selection of a particular dose. It was an accepted dosing strategy, and it's obviously accepted by the FDA and accepted in terms of our Phase III trial design that we're not doing a dose response. We're testing that if you administer prostanoids in this way with an individually maximum tolerated dose approach, what's the safety and what's the efficacy. So there's no comparison of how people that got to one dose compared to people that got to another dose because those aren't randomly assigned. Those are defined by individual patient biology. So I think that's -- it's in keeping with a lot of the discussion today, and I'm really glad we're having these conversations because it is complex. But so we shouldn't look at Phase III nor Phase II. We didn't do a dose response trial because that's not what's done with prostanoid therapy. We're testing the strategy of if you take this drug and you administer it in an individually maximum tolerated dose, what's the ultimate safety and efficacy of that approach. So I think I just want to make that point in terms of dose ranging and such to keep in mind that this is different. We obviously agreed with the agency on this. We came out of Phase II and they said, fine go to Phase III. And the designs of the other parenteral studies -- parenteral and oral studies reflect the same idea that it's an high MTD dosing approach rather than a specified dose. I think your second question was about cough and noting that the incidence of cough overall was 15%. I think it was higher in the Phase II in the active, maybe 40%. I think these AEs are -- AEs that are new after entering the study. So there may be doctors who didn't continue to report cough in patients who came into the study on the cough. Probably the best way to do kind of apples-to-pears is to look at the data in the open label, what's the incidence of cough among patients who crossed over from placebo. And I don't believe that's on the chart, but I can say that, that's about 26%. So if patients came in on placebo and then were obviously not randomized, they began on active drug, cough was about 26%. And so that's roughly -- it's a little bit lower than what we saw in the Phase II trial, but I think within the realm of noise. And importantly, of those 25%, I think it was 8 patients, all of them but one were mild, and I think there was one that was moderate. And none of those costs, I think ultimately, the test is the cough problematic such that you come out of the trial, none of them led to discontinuation. So that may help to put into context why you're seeing on the slide that we showed a percentage that's 15% when in the randomized trial, it was higher in the active group. I think all those factors come into play.

Your next question comes from the line of Leonid Timashev from RBC Capital Markets.

I just want to stay with the safety topic for 1 minute. There were a couple of AEs of anemia and then some of nose bleed. I don't necessarily recall these earlier. So I was wondering if that's a new signal, if that's somehow related to the underlying disease or if that was in any way correlated to the higher dose?

Gene, do you want to take that?

Yes. So I'm pulling up the chart in front of me to see. I think these are kind of background adverse events that one might see in any population and maybe in the PAH population. So we have not looked at this and said, this is any new signal at all. I'm very clear about that, that these kind of background low rates over the course of the year. So there are going to be some differences in terms of the frequency that you might see any random adverse event in a study that's 16 weeks compared to one that's gone over a year, over a year, almost all patients are going to have some AE, and that's what we've shown in the high 80s, almost 90% had any AE. So over time, you're going to start to see things. There's nothing that we're concerned about in terms of -- I think you mentioned anemia. There's no suggestion that prostanoids could cause anemia or that it's a drug-related phenomenon. I think I'll leave it at that.

Your next question comes from the line of Matt Phipps from William Blair.

Good to see durability here with longer follow-up. Just wanted to clarify the -- on the dose again, the 19 patients who achieved greater than 640 microgram dose, was that at month 12 or at any point throughout the OLE? And I guess, were there other patients that got above but then went back down?