Thank you for standing by and welcome to the Insmed Phase II-B PAH Topline Results Conference Call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you'd like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, again, press star one. Thank you. I'd now like to turn the call over to Brian Dunn, Head of Investor Relations. You may begin.
Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss the top-line results of the phase II-B study of TPIP in patients with pulmonary arterial hypertension. 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 Jean Sullivan, Chief Product Strategy Officer. The call will begin with some opening remarks from Will before turning it over to Jean to walk us through the study results in detail.
After Jean's remarks, we will turn it back over to Will to close out the presentation and start the Q&A session, where we will be joined by Martina Flammer, Chief Medical Officer, and Sarah Bonstein, Chief Financial Officer. The slides we will review today were furnished with the 8-K we filed with the Securities and Exchange Commission this morning and can be found on the Events and Presentations section of our website. Now, let me turn the call over to Will Lewis.
Thank you, Brian, and welcome, everyone. I am enormously pleased to announce that the phase II-B TPIP study in PAH is a clear and unequivocal success. More than that, it is historic. Today's results exceeded even our highest expectations, with the primary and both secondary efficacy endpoints achieving clinically meaningful improvements, with associated p-values well below 0.05, even in cases where the trial was not powered to demonstrate statistical significance. We also saw consistently positive results for all exploratory endpoints, which have been evaluated to date. Let's take these each in turn. Patients on TPIP experienced a highly statistically significant and clinically meaningful placebo-adjusted PVR reduction of 35%. To put this result into context, it represents the largest placebo-adjusted PVR reduction ever demonstrated in a well-controlled clinical trial of patients with PAH of which we are aware, including all other prostaglandins and all other medicines in every other class.
In addition, although this trial was not designed or powered to show a statistical outcome on a six-minute walk distance, TPIP demonstrated a placebo-adjusted improvement in a six-minute walk of 35.5 m with a p-value of 0.003. This result easily surpasses the 15 m-20 m directional improvement we were hoping to see and establishes a solid foundation upon which we'll design our phase III program with a six-minute walk distance as the likely primary endpoint. We also saw improvements in NT-proBNP, a biomarker of cardiac stress, and other exploratory endpoints. It is a remarkably consistent picture, with every measure of efficacy we tracked in this study indicating a positive improvement for patients on TPIP. It is important to keep in mind that we gave ourselves no built-in advantages that might assist these results.
For example, all efficacy measures in this study were evaluated at trough or roughly 24 hours after the latest dose. We also did not attempt to limit the number of patients for whom it is generally considered more difficult to show a treatment effect, including functional class two patients and those who are already on multiple background PAH therapies. We intentionally designed our trial this way because if it proved to be successful, as it now has, it would be a clear and unequivocal win, establishing that once-daily dosing with TPIP has the potential to improve outcomes for patients across severities and background treatment regimens. Our goal was to develop the best-in-class prostaglandin therapy, and we believe these results clearly demonstrate that potential for TPIP.
In addition to the impressive efficacy results, we were also very pleased by the safety and tolerability profile that emerged for TPIP, which builds on the positive data we reported last year in our phase II-A trial in patients with PAH ILD. In the PAH study, we saw a low rate of treatment discontinuation and a very high rate of enrollment in the open-label extension study. In summary, TPIP delivered historic and potentially physician practice-changing results that exceeded the best-case scenario that we articulated ahead of this top-line readout. Today's results validate our broader strategy to bring forward medicines with the potential to be first-in-disease, first-in-class, or best-in-class treatment options for patients facing serious diseases. Our first product, Arikayce, transformed the way physicians thought about treating patients with refractory MAC lung disease and became the first-ever approved product for that disease.
brensocatib has the potential to do the same for patients with bronchiectasis if it is approved. We believe today's data put TPIP on a similar path toward redefining the treatment of patients with pulmonary hypertension. As a company, we are now three for three, with each of our late-stage programs exceeding challenging targets for safety and efficacy in their respective disease areas. We are delighted by these results and what they could mean for patients. I will now turn the call over to Jean, who will walk us through the results in more detail.
Thank you, Will, and good morning, everyone. I'm very pleased to be with you today to share the top-line results from our TPIP trial in patients with pulmonary arterial hypertension. Before we review the data in greater detail, I'd like to first remind everyone why we developed TPIP and how it works. Prostaglandins have long been considered a cornerstone in the treatment of PAH. That said, certain characteristics of treprostinil and other prostaglandins have presented challenges in achieving consistent high local exposures in the lung. These characteristics include rapid systemic metabolism, systemic and local adverse effects, and brief lung residence time when administered by inhalation. The development of a prodrug using an appended 16-carbon chain was intended to address these challenges, allowing for the achievement of high and consistent lung concentrations of treprostinil and improved tolerability. When initially inhaled, TPIP is inert.
It is activated once the 16-carbon chain is cleaved from the prodrug. In addition to potentially mitigating acute upper airway-related adverse events, this approach increases the compound's lung residence time. Because enzymes in the lung gradually cleave the 16-carbon chain, the active moiety can be released slowly over time. In this way, treprostinil palmitil acts as a locally administered depot of treprostinil, analogous to a slow infusion of treprostinil at the local site of action. We believe that the ability to achieve high and consistent treprostinil lung exposure will enable TPIP to unlock the full potential of prostaglandin therapy. Like all our programs at Insmed, we design TPIP with the patient in mind. We chose the specific length of the carbon chain, 16, to facilitate once-daily dosing. We believe that once-daily dosing will be preferred by patients and may promote improved adherence.
We also paid close attention to the needs of patients when designing TPIP's formulation. We initially developed an inhalation suspension formulation of treprostinil palmitil, which required administration using a nebulizer. We realized that a dry powder formulation would greatly simplify administration and would be preferred by patients. In fact, we've further taken the time necessary to simplify the DPI formulation so that a patient will be able to administer their dose using a single capsule. We believe today's results underscore our thoughtful approach. It has taken us a long time to get here, and these data are the result of excellent work conducted by Insmed's brilliant scientists. I want to take this moment to acknowledge a special colleague, Dick Chapman, who played an integral role in the development of TPIP and unfortunately passed away before being able to celebrate today's impressive data.
He is truly missed, but his legacy of scientific excellence and rigor can be clearly seen in this successful result. Now, let me turn to a brief review of the trial design. This phase II-B trial of TPIP enrolled 102 PAH patients who were randomized two-to-one to receive TPIP or placebo. As a result, 69 patients received TPIP and 33 received placebo for the 16-week treatment period. The maximum TPIP dose allowed in the trial was 640 mcg, delivered once daily. As a reminder, a TPIP dose of 640 mcg contains roughly 60% more treprostinil compared with the total daily dose of the current market-leading treprostinil dry powder product, which is dosed four times per day. Patients were titrated up to their maximum tolerated dose over the course of the first three weeks of treatment, with a final dose increase allowed at the week five visit.
While this is an abbreviated time for up-titrating versus real-world experience, it was done to ensure patients would remain on a consistent dose of TPIP for at least 11 weeks so we could evaluate the effects of those dose levels in this time frame. The primary, secondary, and exploratory efficacy endpoints were measured at the end of the 16-week treatment period, with all efficacy measures taken approximately 24 hours after the most recent dose was administered. Today, we will discuss the endpoints listed on the right side of slide 8, which represents all the endpoints we have analyzed up to this point. Additional PK and exploratory endpoints were also studied in this trial but were not analyzed as part of this initial top-line data package. These data will be presented at future medical meetings. Slide 9 summarizes the key baseline characteristics for the trial by study arm.
Patients were stratified by poor functional class and baseline number of medications, which resulted in reasonably well-balanced arms. Notably, 66% of patients in our study were classified as functional class two, and 80% were on two background PAH medications. Although the study's design allowed for patients to be on zero background medications, all participants in the study were on at least one stable background therapy at baseline. This illustrates that the study's overall population was both more heavily pretreated and less symptomatic than many earlier PAH trials. Slide 10 details TPIP's titration and tolerability over the treatment period. An important component of these results is how many patients were able to titrate up to or near the highest allowed dose in the study by the week five visit.
We were pleased that 75% of patients taking TPIP were able to reach the maximum dose of 640 mcg by week five, with 84% titrating to at least 480 mcg. Outside of the clinical trial environment, we would expect even more patients could reach maximum dose levels given the ability to titrate over a longer period. In addition to titration, it was gratifying to see that TPIP was well tolerated, with 90% of patients receiving TPIP completing the study. Overall, 95% of all patients who completed the study chose to enroll in the open-label extension study, where they are permitted to continue to titrate to a maximum dose of 1,280 mcg. Now, let's turn to the primary endpoint. Increased pulmonary vascular resistance, or PVR, is the hallmark of PAH, representing the primary pathology of the disease.
Elevated pulmonary vascular resistance contributes to exercise intolerance and results in strain on the right heart, leading to right heart failure and eventually death. As such, decreasing pulmonary vascular resistance is the primary physiologic goal when treating patients with PAH. In this study, treatment with TPIP demonstrated a placebo-adjusted reduction of PVR of 35%, yielding a highly statistically significant P-value of less than 0.001. This result is remarkable in multiple ways. First, this represents the highest placebo-adjusted PVR reduction ever recorded in a controlled clinical trial of patients with PAH of which we are aware. As Will mentioned, all PVR measurements in this study were taken approximately 24 hours after the most recent dose of TPIP, and they were measured in patients who were less symptomatic and more heavily pretreated.
Therefore, this result was achieved in a patient population that was primed to be more challenging to show a treatment benefit, making it even more impressive. Additionally, this result was driven entirely by the performance of the TPIP. It did not benefit from an overall deterioration in the placebo group, highlighting that patients in our trial were well controlled on stable background medications. In fact, PVR for patients in the placebo arm remained relatively unchanged during the 16-week treatment. Overall, the efficacy achieved with once-daily TPIP makes us extremely excited. We believe TPIP could change the treatment paradigm for PAH if it is similarly successful in phase III. Treatment with TPIP also showed clear benefits on our secondary efficacy measures, the first of which is six-minute walk distance.
As a reminder, this trial was not powered to show a statistically significant benefit on exercise capacity, so we were thrilled to see that patients in the TPIP arm experienced a placebo-adjusted 35.5 m improvement in their six-minute walk distance at week 16, with an associated P-value of 0.003. On slide 14, you can see the impact of TPIP treatment on NT-proBNP levels at week 16. NT-proBNP is a biomarker that reflects cardiac stress. Treatment with TPIP reduced NT-proBNP levels by 60% compared to placebo, representing a placebo-adjusted reduction that is among the largest ever observed in patients with PAH. The associated P-value was less than 0.001. Several exploratory endpoints were also investigated in this study, including the number of patients who had an improvement from baseline in their functional class designation at the end of the 16-week treatment period.
In the TPIP arm, 21 patients, or 30% of the 69 total randomized patients, showed an improvement in functional class, including 11 patients who went from class three to class two, nine who went from class two to class one, and remarkably, one patient who experienced a two-step improvement in functional class going from class three to class one in just 16 weeks. As a reminder, functional class one is defined as a patient being symptom-free both at rest and with ordinary physical activity, which underscores how significant this level of improvement could be for patients' quality of life. In the placebo arm, five patients, or 15% of the total 33 randomized patients, showed an improvement in functional class. Three patients improved from class three to class two, and two patients improved from class two to class one. On this measure, the P-value was 0.098.
We also looked at changes in cardiac index as an indicator of TPIP's impact on cardiac function. The reduction in PVR that we captured in the primary endpoint means that the right side of the heart is now pumping against a lower resistance. This allows for increased forward blood flow, which is measured by the cardiac index. We were very pleased to see TPIP patients achieved a placebo-adjusted improvement in cardiac index of 15% at week 16, with a P-value of 0.006. In any clinical trial, it's comforting when all efficacy measures tend to trend in a similar direction because it adds confidence to the study's overall conclusions regarding the drug's clinical benefit. One of the greatest strengths of today's data is the consistency of the results across all measures: primary, secondary, and exploratory.
In addition to the levels of improvement themselves, the fact that every measure we examined went in favor of patients receiving TPIP is extremely encouraging for the potential of this drug over the long term, and we are excited to explore this further in future studies. Turning now to safety. Treatment-emergent adverse events were experienced by 88% of patients in the TPIP arm and 76% of patients taking placebo. The most common adverse events that occurred at higher rates in the TPIP arm were cough, headache, fatigue, chest discomfort, and flushing, all of which is consistent with the known tolerability profile of inhaled treprostinil. Serious adverse events occurred in 7% of patients on TPIP and 3% of patients in the placebo arm. There were no deaths in the study.
Encouragingly, only four patients in the TPIP arm experienced an adverse event which led to treatment discontinuation, and two of those were for adverse events that were deemed to be mild. Only one of the adverse events leading to treatment discontinuation was determined by the investigator to be potentially drug-related. For added context, that patient experienced elevated liver enzymes and was hospitalized for treatment and monitoring. In addition to TPIP, this patient was taking Bosentan, which has a known risk for this adverse event, including a black box warning in its label. Treprostinil has not historically been associated with those risks. Notably, when TPIP was discontinued, the patient's liver enzymes remained elevated and only resolved after treatment with Bosentan was discontinued. Given that cough is often cited as a concern for patients taking inhaled treprostinil, we highlighted some additional cough details on the bottom of slide 16.
As you can see, all cases of cough in the TPIP arm were mild or moderate, with greater than 85% of instances being mild. Importantly, only one patient discontinued treatment due to cough. As a physician who previously treated patients with PAH and PH-ILD, I view today's TPIP data as overwhelmingly positive and further confirmation of the promising profile that emerged in the positive phase II-B PH-ILD study last year. In the efficacy and safety profile that we have seen so far, if the efficacy and safety profile that we have seen so far continues to be confirmed in future studies, we believe TPIP would become the prostanoid of choice for patients living with PAH or PH-ILD and the physicians who treat them. Let me now turn the call back over to Will for some closing remarks.
Thanks for walking us through those results, Gene.
Many years ago, when we first began developing TPIP in our research labs, our ambition was simple: to find a way to unlock the full potential of treprostinil therapy. While treprostinil is an effective drug, all available formulations are limited in some crucial way. Parenteral presentations offer continuous dosing, but the drug must pass through the body to get to the lung, often leading to systemic side effects and inconvenience for patients. Inhaled treprostinil offers direct dosing to the lung, but it passes through the tissue so quickly that relief is transient, requiring multiple doses each day and leaving patients untreated overnight. Our goal was to use innovative chemistry to combine the continuous dosing of parenteral treprostinil with the local delivery of inhaled treprostinil in a once-daily dry powder capsule that can be administered in a single inhalation.
Today's results underscore that we are closer than ever to making this ambition a reality. While these results are meaningful, we hope they are just the beginning of what TPIP can offer to patients. We intend to initiate a phase III program for PH-ILD before the end of this year and start the phase III program for PAH in early 2026. In each of these phase III programs, we intend to lengthen the titration window and increase the maximum dose of TPIP up to 1,280 mcg. Given what we know from past studies of treprostinil, which have shown that higher dosing is closely correlated with improved efficacy, we are extremely excited to see what higher doses of TPIP could mean for patients living with PAH and PH-ILD.
Before we turn to Q&A, I want to first take a moment to thank all of the patients and investigators who participated in making this study a success. Our sincerest gratitude goes to each of you for your courage and strength, without which we could not have achieved today's remarkable results. I'd now like to open the call for questions. Operator, may we take the first question, please?
Thank you. We will now begin the question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one again. We ask that you please limit yourself to one question and one follow-up. Your first question comes from the line of Andrea Newkirk from Goldman Sachs. Your line is open.
Good morning.
Thanks for taking the question, and congratulations on the data this morning. Will or Gene, just a question for you here. Just based off of the results that you've seen, super impressive here on PVR as well as six-minute walk and the other exploratory endpoints, but how did the data change your view in any way on where TPIP could fit into the PAH treatment paradigm, particularly as it does look to be nearing the efficacy levels of sotatercept? And then relatedly, how would that then impact your peak sales potential that you see for TPIP in both PAH and PH-ILD? Thanks so much.
Sure. Thanks for the question. I'll start and then turn to Gene for any perspective he has. I would just tell you that I think this unlocks the full ambition that we had for this drug.
We see this as becoming the cornerstone of therapy for PAH and PH-ILD, regardless of background therapies and regardless of patient profile. I think that's what these results really convey. Moreover, I think as we think about the landscape of other medicines that are available, the arrival of TPIP does open the door to consider repositioning some of those that have been successful. Take, for example, sotatercept. There has been some discussion of the bleeding risk associated with that. Now, we think very highly of that medicine, and we think it has an important role to play, and it is clearly being used extensively.
Perhaps there could be a scenario where TPIP, should it continue to prove successful and be approved, could be chosen as a first go-to medicine, and then you might even titrate down to limit the risk of bleeding associated with sotatercept if, for example, that was something that we could demonstrate was possible to be accomplished. I think the short answer is there's lots of opportunity here for this drug, and yes, we will be revisiting our forward forecast on revenue. Gene, I do not know if you have any other thoughts.
Yeah, sure. Thanks. We always thought that it would make sense that a once-daily product, an inhalation product, would be superior to a four times a day inhaled treprostinil. In that sense, thought that depending on the outcome of the data, it would sort of supplant inhaled treprostinil.
We had hoped, based upon a lot of our preclinical data, including animal models of pulmonary hypertension and so forth, that actually we could do more than just be a once-daily version of inhaled treprostinil. I think these data sort of support what we had hoped, based upon the preclinical data, that we're seeing substantial benefit beyond even what would be expected with inhaled treprostinil. I think that depending on the outcome of future studies, this could be not just the preferred inhaled prostaglandin, but rather the preferred prostaglandin end of statement. I'm not sure what an IV treprostinil would add to an efficacy profile like this. I think it definitely expands, in our mind, the idea of where this product could be used in the armamentarium.
If you now have a very effective, relatively safe, easy-to-administer prostaglandin, it could move up the use of prostaglandins earlier in the course of treatment of a patient.
Okay. Thank you. Congratulations again.
Your next question comes from a line of Jason Zemansky from Bank of America. Your line is open.
Great. Good morning. Congrats on the data, and thanks so much for taking our question. I appreciate you may not necessarily have some of the PKPD data, but I guess for Gene, given the strength of the 640 mcg dose, where do you think you could get with the 1,280 in terms of PVR and six-minute walk, considering the largest PVR reduction of placebo-reduced PVR improvement? How much could you push that bar?
Yeah, that's a good question. The data we have is for 640, and it looks very, very impressive.
The basic understanding of prostaglandins over the years has been that if you can deliver more, you can get even better efficacy. We will be exploring higher doses in the open-label extension. We will not be doing another right heart cath, but we'll be following these patients with the other measures, six-minute walk, NT-proBNP, and symptoms and so forth. We'll kind of see how that plays out. I think the ability for doctors to find a dose that works for that patient, that's tolerable, and to be able to slowly increase that over time as necessary is really important. It's sort of the way doctors use parenteral prostaglandin now, where over the course of time, they're able to continue to increase the dose as needed. I think that's we only know what we know.
We only know what the effect is when the maximum tolerated dose up to 640 is, and it's quite dramatic.
Got it. I guess secondarily for Will, I have to ask, does the top line here change your thinking about the potential regarding an accelerated path forward?
I think the next step for us is to take these data and bring them to FDA and have an open discussion about how we think about this. For now, it is certainly the appropriate thing to continue to plan for phase III work, as we have already expressed. To pick up on the theme of the last question as well, that phase III study will now set at the upper limit, 1,280 mcg, and will open the window a little bit wider in terms of time for patients to be able to titrate up to a higher level.
The answer to your first question may be contained in whatever phase III work we will be doing in both PAH and PH-ILD as we explore those upper-level doses consistent with the physician's judgment for the patient, what's best for the patient. The regulatory path forward here certainly begins with an immediate conversation with FDA .
Great. Thanks for the comment.
Your next question comes from a line of Joseph Schwartz from Leerink Partners. Your line is open.
Thank you. Congratulations on the terrific results here. I was wondering, sort of following on to the last question, if you could discuss your plan for phase III design and the timeline in PAH and PH-ILD a bit in terms of any potential differences we might see versus phase II, such as their size, geography, how many patients might be on Winrevair, and what is the window for dose titration?
Thank you. Yeah. I think our next step is really to talk to FDA and get alignment on the meaning of these data and what the implications are for an appropriate design phase III program, both for PAH and PH-ILD. Our original intention was to start ILD before the end of this year, and we are still on track to do that. We had already stated that we thought we would start PAH at the beginning of next year, and that is still our intention. Whatever we learn from FDA will obviously influence that potentially, but our perspective is that these are very compelling data, and the sooner we can start phase III, the better.
I'd also just observe that I think, as we saw with the blended blinded data, these now top-line results data are very likely, we think, to improve the ability to recruit for the trial as we get ready for whatever that next clinical study work is going to be required. This is as good as it could have been, and I think because we can titrate potentially higher, it may yet get better.
Agreed. Thank you.
Your next question comes from a line of Vamil Divan from Guggenheim Securities. Your line is open.
Great. Thanks so much for taking my question. Congrats also on the data here. Maybe two questions I could. One, just on the safety side, if you have a little more information on the serious and the severe treatment emergency that we're seeing in the trial, that'd be helpful.
In terms of the manufacturing side, I think you talked about working towards a single capsule for the phase III program. Maybe you can just kind of fill us in on where things stand there and what steps are left before you can start the program. Besides finalizing the design of the trials, is it true in the manufacturing? What steps do we need before we can start the trial? Thanks.
Yeah. I'll take the manufacturing question and then flip the safety one to Gene. Manufacturing remains on track. We just are trying to make sure that for convenience of the patients, every single dose that we have as a potential treatment is administered successfully by one capsule. That just requires some additional tech ops work to accomplish. We're well on the way to bringing that about.
I do not see risk there, but we do think it is important to be pivoting toward a single capsule. In fact, as we go up to 1,280, that is also an ambition we keep in the back of our mind. For now, we are willing to accept as many as two capsules to achieve a 1,280 dose, but in the future, we may even pursue getting that down to one if we can. For now, the tech ops work is right on track. I do not know, Gene, if you want to talk about safety and serious and severe.
Yeah, sure. Thanks. In regard to the serious and severe adverse events, there was one serious AE in the placebo group, and that was a right ventricular failure case. The serious AEs in the TPIP group were kind of mixed.
There was no single organ system or type of adverse event among them. The one I mentioned in my opening comments was this transaminase elevation. Both we and also our DSMB, after looking at the time course of it and the fact that the patient was on Bosentan and when the transaminases resolved, are pretty comfortable that this is likely related to the Bosentan in the background because that's a known side effect. There were just a smattering of other types. There was a tachyarrhythmia in one patient who had a known history of arrhythmia. The patient was admitted and treated with amiodarone, and that resolved. There was a patient with rhabdomyolysis, which is when there's a—that's a condition that occurs when there's skeletal muscle breakdown. One of the causes of rhabdomyolysis can be strenuous physical activity.
In discussing with the investigator, we found out that the patient actually felt so good that he went back to the gym and started exercising in the gym and after that developed the rhabdomyolysis. There was no other case of that. There was one TIA in a person who came in and was found to have carotid disease, underwent a thromboendarterectomy, discharged two days later, and remained on study drug, went into the open label. We think that was probably related to the underlying carotid disease. There was one case of chronic bronchitis. The patient was hospitalized, discharged two days later, remained in the study. The experience from the serious TAEs did not suggest to us any particular problem related to TPIP.
Thank you so much.
Your next question comes from a line of Jessica Fye from JP Morgan. Your line is open.
Hey, guys. Good morning.
Congrats on the strong results. How do you think about phase III enrollment timelines? I know you guys look at analogs. What enrollment curves in the space might be more analogous to what you'd expect here? How do you think the enrollment timeline might differ in PH-ILD relative to PAH? Thank you.
Yeah. It's hard to say, Jess. I mean, to be honest, we haven't finalized our design. Without knowledge of the numbers, it's hard to then project against a backdrop of precedent. I do think we all know that PAH and PH-ILD studies tend to take a long time to enroll. I think what we're excited about is the strength of these data and the likely prioritization that this drug candidate may receive for clinical trial use across patients just because of the mixed profile that we have in the background here.
We've got patients that you would expect would be hard to treat, and we had a very impressive result. All those things point to accelerating our phase III timelines. We certainly will be bringing all efforts to bear to accomplish that. The team did a remarkable job on the Aspen trial timeline, getting that done in under two years. That was during COVID. I think I have ambition that this will be an accelerated timeframe. We won't really know until we've decided final numbers. I can tell you that our intention behind phase III will once again be to fully power to ensure that we achieve the clinically meaningful result needed for approval and not so much trying to replicate exactly what we have right here. It's all about ensuring that the drug clears the regulatory hurdle and the market access hurdle.
Certainly, today's results suggest that we're going to be able to do that very comfortably.
Your next question comes from a line of Ritu Baral from TD Cowen. Your line is open.
Good morning, guys, and congratulations on this. Actually, the question I was going to ask piggybacks on your last answer to Jessica's question, this idea of the phase III design and market access. You've got such a rich data set here of differentiated data points across the board, six-minute walk, safety. How are you thinking about these in terms of your phase III design and any potential innovative design that will help with market access? I mean, we all know that you serve the 12,000-pound gorilla in this space. How can you design the phase III to give you an edge into that market? And then follow-up.
Yeah.
I think, once again, it's going to be difficult to give too much more detail about the phase III design until we've had the conversation with the FDA. What we can presume is that the FDA will see these data, as we do, as a very clear demonstration of the efficacy and safety of this drug in a mixed population, which is heavily pretreated. Given that, I think the most tried-and-true way to get approval is six-minute walk. We clearly have shown that benefit not just in this study, but in the PH-ILD study last year. We feel that that is the tried-and-true path, but we'll be open in our discussions with the FDA to considering alternatives. I don't think we need to get more creative than that.
Once we secure approval, we're quite confident that the target product profile presented here today is going to be extremely attractive to the treating physician community because they are the ones that guided us that these sorts of results would be game-changing in the way they think about the use of the drug.
Do you have any other plans for data release from the OLE, specifically from those 1,280 patients? I mean, today you gave the rollover rate, but anything updated on what percentage of those patients were able to successfully titrate to 1,280 and when we might see their data? Remind us if you're capturing any efficacy in the OLE as well.
Yeah. In the OLE, we are looking at six-minute walk and NT-proBNP.
One of the nice things about today's data is that you see remarkable consistency across all the measures so that if we were to see six-minute walk benefit and/or NT-proBNP benefit in that open label extension study, one would assume that that would correlate to the other measures that we've captured here. That gives us a lot of comfort. The exact timing for when we're going to put out that data, we haven't been specific about. What we can say is that this is a two-year open label extension study, and so this data will be collected for a long time. We're not going to wait two years to put it all out, but we certainly want to make sure that there are enough patients in and on medicine for a longer period of time that it will be meaningful.
You can expect updates to come, and certainly the best place for that is a peer-reviewed setting. There is no immediate timeline for that. I can tell you we do have some patients that have made it to 1,280, and that is exciting to us because of what we see here at 640 and even 480. Time for exact provision of that data is not yet clear.
Joe had asked about the 1,280 titration schedule. Could you just round back to that?
In terms of the titration schedule, I am not sure what you mean by that. Do you mean how long they get to go up to 1,280?
Yeah. Exactly.
Gene or Martina, do you want to take that question?
Yeah. I mean, we create—oh, sorry. Go ahead, Martina.
Okay. No worries. Yeah.
What we do in the open label is the patients for the first three weeks will be titrated. Those patients who were on placebo will be titrated to TPIP. For patients who were on TPIP, we'll have a double-dummy titration and stay on their last dose that they had achieved in the study. After the first three weeks of titration, throughout over the next two years, patients can then be titrated up an increment of 160 mcg throughout the study. We will have those measures that were mentioned at the end of the study and take them also in between to get a good understanding how the exposure will relate to this endpoint.
Probably one of the most exciting things about today's data release, in my opinion, Ritu, is the fact that what we're seeing here today is incredibly exciting, but it really speaks to the patients that got to 480 mcg or 640 mcg. We have this whole other leg of the journey that is to be explored as to whether or not they continue to see even more benefit as we continue to titrate up. This is just the beginning.
Thanks, Will.
Your next question comes from a line of Leonid Timashev from RBC Capital Markets. Your line is open.
Hey, guys. Congrats on the data, and thanks for taking my question. I guess given the impressive results across a number of primary and secondary endpoints, can you speak to what you think is going to resonate most with patients and physicians in the commercial market?
I mean, is it more about feel and function and patient-reported outcomes and WHO class, or is it the NT-proBNP and cardiac changes? I guess can you just contextualize what actually is going to drive adoption and differentiation? Thanks.
Yeah. The one thing I'll say is we've heard repeatedly, and those of you who have been along this journey for this drug have been a part of this conversation, that the once-a-day was really the big selling point to physicians. They said, "If you can do what's already been done with a once-a-day formulation, that's going to be a big advance. It's going to help patients with compliance and all the other challenges that face a four-times-a-day administration." We said our bar lower. We said we would also like to show better clinical results. And today we've obviously done that.
As far as which among those or the once-a-day is the most important gene used to treat these patients, what's your perspective?
Yeah. I agree. I mean, once-a-day is obviously preferable and would lead to quite a significant adoption. It is kind of an interesting scenario here because, as we all know, for approval, the FDA requires some clear demonstration of how a patient feels, functions, or survives. Typically, six-minute walk has been the indicator of exercise capacity and function. Of course, patients, they come in complaining of exercise intolerance and so forth and would like to see that improved. In that way, things like six-minute walk, things like a functional class, I think will be important to patients.
The flip side to that is that the physicians who take care of the patients and therefore who counsel the patients on what drug to use and so forth, they really are aware that the primary pathophysiology is the pulmonary vascular resistance and that the health of the right side of the heart is super important. Interestingly, I think that physicians will look at the PVR data that we have here today, and I think they'll be quite impressed. It's that kind of data. We have an echo sub-study that was a part of this study. We haven't analyzed, so we'll have some look at the echocardiographic effects on the right heart. We have already released the cardiac index, which shows improvement in heart function.
I think for physicians caring for the patients, they really are going to look at that data as really sort of really important to the more feels, functions data. I think that'll go into their discussions with patients.
Our next question comes from a line of Kelly Shi from Jefferies. Your line is open.
Congrats on the impressive result. The phase II-B trial involved a more functional group of two patients compared to some other PH trials. Wonder if you have a granularity on the treatment effect across different groups and how broad of patient base would you expect the TPIP to access when approved? Thank you.
Yeah. We have not done those analyses specifically looking at the effect size in patients who are on two versus one.
As you point out, the percentage of patients on one was smaller than two, so the N will be larger there. Those are the type of analyses and PKP analyses that we'll do in the weeks and months to come and probably present those in various scenarios. Was there a second part to your question about the population?
How broad of a patient base do you expect the TPIP to access?
Yeah. I think that what we accessed here is patients who are stable on their current treatment, whether it's zero, one, or two. It turns out there were none that were zero, and that's pretty understandable. I think the data that we have today are directly applicable to those. I think this is a very broad population.
As you may know, oftentimes the initial treatment of patients diagnosed with PH for the first time might be two drugs upfront. We now have data to show that even in patients who appear clinically stable, you can get additional benefit if you add TPIP to the drug regimen. We will see as we continue to generate data and as the academic community digests the data that we generate, we will have to see what the guidelines end up recommending and so forth. We hope to generate the data that will help them make those decisions.
Thanks.
Your next question comes from a line of Graig Suvannavejh from Mizuho. Your line is open.
Okay. Thanks. Good morning and congratulations on the data.
My question is on the efficacy that you have shown and, again, very impressive across the board.
I was curious, I think on the PVR reduction data, maybe there are seven patients that were excluded from the analysis that led you to 35% placebo-adjusted reduction there. And I think there were eight patients that were discontinued from your analysis on the six-minute walk test. So I'm just wondering if you had a sense of what that data might have looked like if you had included those patients.
Gene, do you want to take that and maybe also talk about what we do with missing data as well?
Yeah, sure. I mean, in any trial, you want to avoid as much missing data as you can because there's no perfect way to handle missing data. But also in any trial, there will be patients who discontinue, and you may not have the final value.
I think the two principles that most people would follow are, one, do everything you can to minimize missing data, and two, pre-specify how you're going to handle it. I think we did that. I think we're pretty pleased with seven or eight patients' missing values for the six-minute walk and the PVR. We're pretty happy with that magnitude of missing data as being not an amount that is usually considered problematic. We did create an SAP. We got input from the FDA on statistics to be applied in the trial, and we drafted an SAP. In that SAP, we specified how we would handle missing data.
In both instances, we used a multiple imputation strategy, which is essentially using the existing data from all the other patients and the characteristics of those patients to model what the data would have been in those few missing patients. Of course, without the data, you do not know what it would have been. That is what I meant by there is no perfect way to handle it. This is a very typical way of handling missing data. As you know, if you read FDA reviews and so forth, typically what they will do and what any good firm should do is to first look at what the data show with the pre-specified imputation strategies and then subject the data to further interrogation where you use alternative imputation strategies. I am sure ultimately this data will be subjected to those kinds of things. What if you used more egregious imputation strategies?
I think that with the P-value as low as it is, we have not done those. This is the top-line pre-specified approach. I cannot say what those sensitivity analyses would show. With a P-value as low as it is, it would be very unlikely that it would change the conclusion of the trial.
Your next question comes from a line of Jennifer Kim from Cantor Fitzgerald . Your line is open.
Hi. Thanks for taking my questions and congrats on the data. I appreciate all the details you have included here. Maybe related to the last question, was the imputation strategy similar across the different endpoints? I was also wondering how many patients in each arm discontinued treatment but not the study, and were those patients handled in a similar way?
Gene, do you want to take that?
Sure.
Any patient for which there is data at 16 weeks in this case would be included in the analysis. The approach to missing data that I just mentioned applied to the PVR and the six-minute walk distance. For endpoints like NT-proBNP, there isn't a necessity. What we did there is use the MMRM, that mixed models for repeated measures. That uses all the data from a particular patient and all the other data to model what the 16-week value would be. The only requirement there is that only patients who have both a baseline value and at least one post-baseline value. Once they have those, we can use the MMRM to impute the final result. The way I mentioned is really for the PVR and the six-minute walk distance.
Let me just emphasize that everything we're doing is above board with regard to FDA and precedent.
Everything we're describing here is the details of what is a common practice.
Okay. Awesome. Maybe one more question. This may fall into the future analyses bucket. Have you looked at and did you see a relationship between, I guess, patients who achieved a higher titrated dose and the treatment benefits they accrued?
No, we haven't done that type of analysis yet. That wasn't included in our top-line programming.
Fair enough. Thanks, guys.
Your next question comes from a line of Maxwell Skor from Morgan Stanley. Your line is open. Great.
Thank you for taking my question, and congratulations on the update.
I was wondering how potentially titrating higher could impact the safety profile if you can maybe comment on any historical data or these data in the phase II and elaborate a bit on how clinically meaningful the proBNP and cardiac index results are regarding impact on long-term cardiac function. Thank you.
Go ahead, Gene.
Yeah. The second part of the question was the clinical significance of NT-proBNP and cardiac output. We believe they are significantly—they're very important from—they're not a direct measure of clinical benefit, but they're really important measures of the stress on the right heart. As we know, patients with PAH ultimately succumb to heart failure. That's usually the cause of death. If we can improve cardiac—reduce cardiac stress, improve cardiac output by means of improving the pulmonary vascular resistance, I think that's really important.
We think that the magnitude of changes that have been shown are definitely clinically significant in addition to being nominally statistically significant. The first part of your question was about titrating up and what it might do to the safety profile. I think that, of course, we won't know until we do it. Anytime you use an IMTD approach, you're sort of asking patients to get to the point where they start to feel some side effects. Then between the patient and the doctor to decide whether that degree is acceptable and let's just continue at the current dose. If that degree of adverse event is not acceptable, maybe let's creep back. It's sort of the story with prostanoids that can be revisited between the patient and the doctor over time.
They might get to a certain level and say, I'm getting flushing. I hate it. It's really bothersome. Okay, let's drop back for now. Later, let's take another run at it. Often that's successful. I think that we already, by using the IMTD approach, sort of knew we were bumping up against the prostanoid side effects. That was intentional. That was at the direction really of the experts that we spoke with. I'll tell you that when we first developed this compound and were doing the animal models, Walter Perkins, the head of our research group, said, "We could probably pick a dose that the patient would hardly notice, and it would still be therapeutic based upon the animal data." We sort of took that to the experts, and they said, "No, no, no, no, no. We want to maximize the efficacy.
That's what we do with prostanoids. We're comfortable with the prostanoid side effects. We've been using them for years. Pursue this IMTD approach." That is what we've done. I think one never knows when you get to higher doses. Will something show up? We'll find out. That is why we're doing this. In general, I think that we'll probably just, again, be bumping up against the prostanoid side effects as we already have.
It's also worth mentioning that it was that same group of advisors that initially recommended that we double the 640 dose to 1,280 and to go down this next part of the journey. I consider that to be further confirmation of what Gianna just said. In light of today's data, it's a particularly exciting possibility to think about what it may produce.
Great. Thank you very much.
Your next question comes from a line of Liisa Bayko from Evercore ISI. Your line is open.
Hi. Perfect. Perfect timing for the question. I just wanted to follow up on—and by the way, congratulations. This is a great way to start off a Tuesday. As a follow-up to the prior question, as you think about the kind of next higher dose, can you talk about any sort of dose response you've seen? I know you had some patients that titrated up to the second highest dose in this study and then to the higher dose and the highest dose in this particular study. When might we get the full 1280 mcg dose data? As you think about whatever—I know it's small numbers, but any trends you're seeing would be helpful.
As you think about where the 1280 could get you, maybe you could just give us your blue sky thinking on what that might deliver. Thanks.
We are as excited as you are to do that work. We have not yet done so. We only have the top-line results today. We will start to look at response based on dose, etc. That will certainly be something we provide probably in a future academic meeting. We have not set a timeline for that because we have not conducted the work yet. There is this other leg of that analysis, which will include the two-year open-label extension study. We will be looking at that periodically to see how patients are doing. When there is enough data that has a story to tell, we will certainly share it. I do not know, Gene, if you want to add anything.
Yeah.
The only thing I'd add is that it's typical of prostanoids that between patients, they seem to have a different sensitivity, certainly to the side effect. One patient may tolerate an initial dose of X, but another patient may not and may need to have a lower dose. There is this sort of intrinsic variability to individual patients' tolerability. It's quite possible that we haven't done those analyses to look at exposure response in terms of efficacy. It's quite possible that the patient who has significant enough prostanoid-related side effects that they stay at 480, they may be getting sort of the maximum effect that they would get and not need to go to 640. I think the way I look at the open label is not sort of a, "Gosh, we really hope that everyone gets to 1280," by any means.
I think our physicians just wanted the ability to go up if the patient could tolerate it and they wanted to do it. I think it'll be neat to see what % of patients get to the 1280. If patients get somewhere between 640 and 1280 and are doing well, I think that's fine. I guess that's just the one caveat about future data that I'd like to plan, which is that this is not like we really hope or have to get patients to 1280. We certainly saw this wonderful effect with a maximum dose of 640. We'd like to give doctors the ability to go higher if it's appropriate for the individual patient.
Okay. That's helpful. One follow-up. How do you think about the dose titration schedule that you might utilize in phase III?
We're still finalizing that.
We want to do that in consultation with FDA. The window here was five weeks, really three weeks to titrate up, and then one final opportunity at week five, which is a very abbreviated timeframe. We wanted the patients to be on a stable dose for 11 weeks so we could evaluate the impact. I think as we think about the real world, there's obviously no time limit on when you want to titrate the patient. My expectation would be that you'd be able to go even higher with time and patience. The patient themselves and how they respond to the medicine is going to dictate whether or not the physician feels it's appropriate to keep going higher. I mean, as Jean just pointed out, I think rightly so, the goal here is not to get to the highest dose.
The goal here is to get to an effective treatment position for the patient. That is going to be done happily, we think, with this medicine starting out as the cornerstone element in that calculus.
All right. Thanks a lot.
Your next question comes from a line of Nicole Germino from Truist Securities. Your line is open.
Hi. Good morning. Thank you for taking my question. Congrats again on the impressive and game-changing data. With Tyvaso going generic soon, how do you see the treatment paradigm changing, assuming TPIP data holds in phase III? Do you think that you could get TPIP in front of Tyvaso, or would you be comfortable doing a head-to-head study to achieve that?
I do not think a head-to-head study is necessary.
I think what we have here is a very effective drug that is very importantly for people to understand is very different than the other medicines that are available in the characteristics and profile that Gene was describing in the opening remarks. The idea that it's once a day, that it's dry powder, easily administered, and that it has this safety and efficacy profile is really very compelling in its own right. I think our ambition has always been that this would be the drug of choice that physicians would turn to as they evaluate patients and bring them onto a prostanoid. I think we've accomplished that with today's data. If we are able to replicate that and still provide an opportunity to titrate even further, that's pretty much the killer combination. I don't know, Gene, if you want to add anything to that.
No, I think you said it well. Yeah. Yeah. I mean, because this really is almost more analogous to Remodulin than it is to Tyvaso, just in the steady-state levels, the effect of the drug throughout the dosing interval. I don't look at it as really a—I don't think we should look at it—think of it as, "Should we go with Tyvaso first?" I think this is really the prostanoid choice.
Do you think payers would agree? Sorry to squeeze in a quick question on that. Do you think payers would agree with that?
Yeah.
We know from the very preliminary work we've done in exploring the target product profile we presented, which we shared with you all, which is that there would be a directional benefit in six-minute walk that we could then use to secure a phase III successful trial coupled with PVR reductions in the 20-25% range, that that was a compelling profile. More importantly than just the market access world is the physician world. To a person, when we were presenting these data in blended-blinded format, the physicians who were skeptical about yet another treatment for PAH or PH-ILD became quite enthusiastic. That's how we were able to accelerate the enrollment of the trial last year and present the results today, which you may recall were originally intended for the second half of the year.
All of that accelerated as a byproduct of physicians seeing the blended-blinded data and believing in the potential. Now that it's been clearly demonstrated, I think that enthusiasm is going to build, and that will carry through to market access. I am not worried about market access or physician adoption given the strength of the data we see today.
Great. Thank you so much.
Your next question comes from a line of Trung Huynh from UBS. Your line is open.
Hi, guys. Congrats on the data. I have one follow-up and one question. Just on the follow-up, can you qualitatively talk about your efficacy measures in functional class two versus functional class three patients? Was that similar, or was it easier to drive an impact on PVR six-minute walk in those with worse functional class? Now you've got this data in hand, which is compelling.
Have your thoughts changed on TPIP in IPF? Do you have any increasing interest in pursuing IPF? Thanks.
I'll just hit the second one quickly and then hand it over to Gene. We are tracking the IPF study carefully. If that is successful, you can expect to see us initiate a trial to pursue that as well very rapidly. That's a very difficult-to-treat condition. We want to be cautious and see the results first. If Teton works, then you can expect us to be there rapidly.
Yeah. To follow on that, I think that by having continuous exposure of treprostinil to the lung as opposed to the kinetics of treprostinil when it's given in the form of inhaled treprostinil, if treprostinil is having an antifibrotic effect, we believe that TPIP would only accentuate that, would have a greater effect.
We've done some work on the effect of treprostinil on fibroblasts and collagen production in fibroblasts. We know it does impact collagen production. As Will said, we'll be looking at that data. Frankly, if the data is even close, we might think about it that we could take it over the line with our kinetics. The first part of your question was looking at whether these endpoints, PVR and six-minute walk, the effect size differed in patients who came in in functional class two versus functional class three. We haven't done that analysis. That's the kind of thing we'll be doing in the coming weeks and months.
Your next question comes from a line of Andy Chen from Wolfe Research. Your line is open.
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