Please note, today's event is being recorded. I now would like to turn the conference over to your host today, Faheem Hasnain. Please go ahead.
Hello, everyone, and thank you for joining us this morning. We're here today to discuss a critical milestone in Gossamer and Seralutinib's history, the positive top-line results of the phase 2 TORREY study in patients with PAH, pulmonary arterial hypertension. Most of you have no doubt seen the press release we issued this morning announcing our top-line results, and we're looking forward to diving into the data a bit further with you on the call today. We'll be making forward looking statements on this call, and I encourage you to read through the details on the slide. Now, with us from the Gossamer team, we have Dr. Richard Aranda, our Chief Medical Officer, Dr. Rob Rizzino, the Clinical Lead of the Seralutinib program, Dr. Larry Zisman, the inventor of Seralutinib and a critical Gossamer team member, Dr.
Ed Parsley, a pulmonologist who acted as our medical monitor for the TORREY study, Matt Cravets, our Head of Biometrics, Dr. Laura Carter, our Chief Scientific Officer, Caryn Peterson, who heads our regulatory group, and Bryan Giraudo, our Chief Operating Officer and Chief Financial Officer. We are also very grateful to have two leading clinical thought leaders in the field of pulmonary arterial hypertension with us today to help contextualize the TORREY's top-line results and to answer your questions. Dr. Ardeschir Ghofrani joins us from the University Hospital Giessen in Germany, where he heads the Pulmonary Hypertension Division and has been at the forefront of the development of PDGFR inhibitors for the treatment of PAH. Dr. Ray Benza joins us from Ohio State University, where he's a Professor of Medicine in the cardiovascular division.
He's also a former Pulmonary Hypertension Association Physician of the Year and developed the REVEAL 2.0 risk score tool that we used in the TORREY study, and we'll be talking about that more later. Both Dr. Gafrani and Dr. Benza have played prominent roles in the development of every approved drug for the treatment of PAH since the introduction of Tracleer in 2001. We're happy to have both of them on our steering committee for the Seralutinib program and here this morning to review our top-line results with you. Let's get into the results. Well, we are very pleased to announce that the phase 2 TORREY study met its primary endpoint and achieved statistical significance in change in pulmonary vascular resistance as compared to placebo. This positive result occurred despite enrolling a less severe PAH patient population as compared to recent studies.
Not only did we meet our primary endpoint of improvement in PVR, but we also had multiple indications that we were improving right heart function. We saw a statistically significant reduction in NT-proBNP, which is a key biomarker measure of right heart stress. The result is congruent with significant and clinically meaningful changes we observed in right heart parameters as measured by right heart catheterization and echocardiography. Remember, though PAH is a disease that initially manifests in the pulmonary vasculature, patients ultimately die of right heart failure. All of these endpoints, both individually and collectively, indicate that Seralutinib is having a clinically meaningful and positive effect on the right heart function. That speaks to the real strength of our data, the striking consistency across all measures in this heavily treated patient population, with meaningful concordance pointing to the benefits of treatment with Seralutinib.
While we did not design this study to see a statistically significant improvement in exercise capacity, we did have a six-minute walk result that favored Seralutinib in our overall population. This result was more robust in patients with elevated risk score at baseline and reached statistical significance in functional Class three patients. We saw positive results in our overall study population, despite a notable imbalance of functional Class two and three patients in the Seralutinib arm as compared to the placebo arm. Class two patients outnumbered the more severe Class three patients by more than two-to-one ratio in the Seralutinib arm compared to a one-to-one ratio in the placebo arm, thus an imbalance in the patient population. Just as importantly, we were able to generate these meaningful improvements in patients without seeing the side effect profile that was observed in the Imatinib development program in PAH.
Seralutinib, with its molecular and PK characteristics alongside its inhaled route of delivery, was specifically designed to avoid these side effects, and we're very happy with the safety experience for the patients in TORREY. Seralutinib was well-tolerated, with a mild cough being the most highly reported adverse event. We didn't see the types of GI and fluid retention side effects that caused a high rate of early dropouts in the IMPRES study. We also saw zero subdural hematomas. Now, before we dive in further, I wanted to quickly mention one thing. We are really excited about these data and we believe that the more transparent we are with you about our results, the more excited you will be about the potential of Seralutinib.
Today, in that spirit, we're going to provide a robust level of detail on the primary, secondary, and exploratory endpoints, as well as safety from the Phase two TORREY study. We'll take the first step into the details of the study as we turn to the next slide. In our overall patient population, we saw a statistically significant 14% reduction in PVR and a 6.5 meter improvement in six-minute walk distance that favored the Seralutinib arm. Now, let me tell you why I'm excited about the data we generated in TORREY. First is the consistency and the concordance observed throughout our entire data set, and what that tells us about Seralutinib's positive clinical effect. Consistent benefits of Seralutinib treatment were seen across all of our pre-specified subgroups and all of the key hemodynamic and right heart endpoints we evaluated in this study.
It's unusual to see improvements in right heart function in a 24-week phase two study. The fact that we observed statistically significant improvements in these measures, some of which have never been reported in a phase two trial, speak to the clinical meaningfulness of the impact that Seralutinib is having on our overall patient population. Second, we observed enhanced effects on hemodynamics and exercise capacity in patients with more severe disease at baseline, similar to prior development programs in PAH. In functional Class three patients, we saw a statistically significant improvement in PVR of 21% and a statistically significant improvement in six-minute walk of 37 meters, which was similar to the walk improvement seen in functional Class three patients in the PULSAR study.
In patients with elevated risk scores at baseline, we saw a significant 23% improvement in PVR and a clinically meaningful 22 meter improvement in six-minute walk distance. The patients who needed the help the most, those who were maxed out on available therapies and who were at higher risk of mortality at baseline, saw a consistent positive effect from Seralutinib treatment. These two factors, the concordance of our data and the enhanced effects we observed in sicker patient groups, give us confidence as we move forward into phase 3 and in the potential impact that Seralutinib can offer as a new mechanism of action for patients with PAH. Before we go deeper, I do wanna set the stage a bit. PAH. PAH is a rare progressive disease that is characterized by vascular remodeling and it has no known cure.
Many treatments have emerged over the past couple of decades, far too many patients continue to suffer with progressive disease and ultimately succumb from right heart failure and other PH, PAH disease complications. All current therapies target three vasodilatory pathways, there's a high unmet need for therapies that address the underlying pathological mechanisms of disease. Seralutinib's anti-proliferative, anti-inflammatory, and anti-fibrotic mechanism of action has the potential to do just that. By directly addressing the biological pathways driving PAH as a potential reverse remodeling agent. Patients with PAH are classified by their physician into functional classes based on how their disease affects their physical activity. Now, we know from registry data that functional class correlates strongly with risk status and predicts survival, which you can see in the bar graphs in the lower right-hand section of this page.
In TORREY, we enrolled patients with either functional Class two or Class three disease. As you can see, patients with functional Class three only have a 57% 5-year survival rate despite currently available treatments. Beyond functional class, other parameters are being incorporated to better categorize risk for morbidity and mortality events. A number of composite risk measures have been developed. The goal of PAH treatment has evolved to helping patients achieve low-risk status, which has been correlated with reduced mortality risk. As mentioned earlier, we use the REVEAL 2.0 risk score that was developed by Dr. Benza in our study. We're especially glad to have him on the call today to help interpret our results. What treatments are currently available to help patients achieve those low-risk scores? As I previously mentioned, there are four classes of therapies that target three vasodilatory pathways.
What's needed are therapies that address the underlying proliferative, inflammatory, and fibrotic causes of the disease. I think we, like the rest of the PAH community, are excited for the first of these therapies, sotatercept, to potentially reach the market. We believe sotatercept is a promising drug that's poised to have a positive impact on the disease course for many PAH patients. I wanna relay to you one of the key messages that came from our steering committee as we reviewed this data with them. PAH is a progressive and heterogeneous disease, and unfortunately, there are no cures. The majority of patients are not currently meeting their treatment goals, and even with the introduction of sotatercept, we expect that will continue to be the case in the future.
The results we generated in the TORREY suggest that Seralutinib, with its novel and complementary mechanism of action, could potentially be an important part of the future treatment algorithm. With that backdrop, let's go into the TORREY results. Now, as you recall, the TORREY was designed to enroll 80 patients, 40 per arm between Seralutinib and placebo. Patients were required to have a PVR of greater than 400 dynes and a 6-minute walk distance of between 150 and 550 meters, among other entry criteria to enroll into the study. Subjects started on a 60 mg dose twice daily, and after two weeks, escalated to 90 mg twice daily. The vast majority of patients on both the placebo and Seralutinib arms were able to reach and stay on the 90 mg BID dose throughout the study.
Randomization was stratified by our primary endpoint of PVR at a cut point of 800 dynes. We assessed our primary endpoint of PVR during screening and week 24. Echo assessments were performed at baseline, week 12, and week 24. Both PVR and echo assessments were evaluated in the study by a blinded central reader. We assessed six-minute walk during screening at baseline, week 12, and week 24. We collected NT-proBNP during most of the in-clinic visits designated by the green triangles on this slide at baseline at weeks 4, 8, 12, and 24. After week 24, patients had the option to roll into an open label extension study. We ended up enrolling 86 patients, 42 in the placebo arm and 44 into the saralutinib arm. We had 1 patient discontinue treatment in the placebo arm and 7 in the saraluntinib arm.
We'll go into further detail for the reasons for discontinuation during a safety discussion. There were no patterns in the adverse events that led to treatment discontinuation. We think the imbalance we saw here was more likely a consequence of enrolling a small study. The patients that discontinued treatment on placebo stayed on study and completed all required assessments, so we ended up with 100% of patients that completed the study in the placebo arm, which is pretty remarkable for any six-month clinical study. We were very pleased with the patients' adherence to their treatment regimen in the study, and the survey results collected suggested that patients were pleased with the convenience and the overall presentation of our dosage delivery via the dry powder inhaler. Approximately 90% of patients entered into the open label extension after finishing the 24-week study.
Getting into the baseline demographics of the enrolled patients, we didn't have any surprises here. We enrolled a mainly female study. Just under 70% of patients came from sites in the U.S., all demographic factors were relatively well-balanced between the treatment arms. We were also very well-balanced in terms of background therapy between the two arms. Approximately 57% of patients in the study were on background triple therapy in both arms, which mirrors the background treatment split from the PULSAR study. 29 subjects on each arm were on prostacyclin or prostacyclin receptor agonist, which broke down evenly to 19 on parenteral prostacyclin and 10 on orals in each arm. That means that roughly 44% of our study population was on background parenteral prostacyclin, a high percentage which speaks to how heavily treated our patients were at baseline.
Turning to the next slide, you'll see that TORREY enrolled a very prevalent patient population, roughly 8.5 years since diagnosis. This was, as I mentioned earlier, a relatively less severe population based on baseline means as compared to other recent studies. If you just direct your eyes to the lower right portion of the table, you'll see that our overall baseline PVR for the study was 669 dynes, or about 110 dynes lower than the population enrolled in the PULSAR study. The mean six-minute walk distance was 408 meters, or about 10 meters higher than the PULSAR study. To our knowledge, these metrics make TORREY an unprecedented study. The PAH clinical trial with the lowest baseline PVR and highest baseline walk distance to achieve a statistically significant result on its primary endpoint.
The two arms were fairly well-balanced in terms of PAH disease classification. The only substantial imbalance between the two arms is in the functional class section of the slide in the black box. Placebo arm was split nearly 50/50 between Class two and Class three patients. While the ratio was greater than two to one in favor of less severe Class two in the Seralutinib arm. We'll go into a bit further detail on how this imbalance may have impacted overall results. This slide is a breakdown of baseline demographics by WHO functional class, with the Class two patients summarized to the left and the Class three patients on the right. What you'll see is that, unsurprisingly, across multiple metrics, the functional Class three patients had more severe disease at baseline.
If you direct your eyes to the highlighted values, you'll see that roughly 60% of the Class 3 patients had elevated risk, compared with 30% of the Class two patients. Moving to other metrics, there's a 70-meter delta between the mean baseline six-minute walks and a roughly 250 nanogram per liter gap for NT-proBNP levels between the two classes. As we've seen in prior development programs, these differences are important. Patients with more severe disease typically have more room to improve than patients who are healthier and are approaching ceiling or floor effects on measures of disease. As happens sometimes in small studies, we had fewer of those sicker, easier-to-improve patients on the Seralutinib arm. Thankfully, as you already know, this imbalance wasn't enough to prevent us from achieving a positive study.
I'm now gonna turn the call over to Doctors Rizzini, Aranda, Gefrani, and Benza, who will walk you through the top-line results and their interpretations of those results in further detail. Rob?
Thanks, Faheem. This first slide shows the results for the primary endpoint of the TORREY study, which was changed from baseline in pulmonary vascular resistance at week 24. We observed a mean 21 dyne increase in the placebo arm and a 75 dyne decrease in the Seralutinib arm, resulting in a least squares mean difference between the two arms of just under 100 dynes or an adjusted reduction of about 14%. Importantly, these results reached a statistically significant P value of 0.031. Recall where these patients started. The mean baseline PVR for the study was about 670 dynes. Accordingly, patients on the study had less room to improve than in prior studies such as the Imatinib studies, where patients came in with a mean baseline PVR exceeding 1,100 dynes.
As Faheem mentioned, one of the strengths of our data is its consistency. This is a forest plot that shows the point estimate for change in PVR for all of our pre-specified subgroups. If the diamond is to the left of the 0 line, the estimate favors Seralutinib, and if it's to the right, it favors placebo. As you can see, every point estimate favors Seralutinib, which is really exciting to us, indicating that Seralutinib is having a positive impact across all of these pre-specified patient groups. There are several that reach a statistically significant result for Seralutinib, but I want to point out two towards the bottom of the slide related to baseline disease severity. Third from the bottom is functional class. In functional class three patients, we saw a 137 dyne difference favoring Seralutinib with a P value of 0.04.
The bottom row shows patients with an elevated REVEAL 2.0 risk score of greater than or equal to six at baseline. This subgroup includes both functional Class two and three patients. This was our best-performing subgroup with a 168 dyne difference favoring Seralutinib with a P value of 0.0134. This next slide provides more detail on those two pre-specified subgroups. On the left is change in PVR by WHO functional class, and on the right is PVR change by REVEAL 2.0 risk score. You will notice that Seralutinib has a positive effect in all these pre-specified subgroups, decreasing PVR in functional Class two or three, low or elevated risk patients. In Class 3 in elevated risk patients, Seralutinib has an enhanced effect. As you can see, the placebo arm PVR increases in both of these subgroups.
This is what you might expect, as higher functional class and elevated risk score both correlate with disease progression and mortality risk. Seralutinib treatment not only prevents that progression, it also drives improvements in PVR in both of these patient subgroups. Ultimately, this leads to more pronounced statistically significant treatment effects. What we see when we look into the components of PVR is that much of the benefit observed in TORREY was driven by a significant reduction in pulmonary artery pressure, which is shown here on the left. We observed a highly significant reduction in mean pulmonary artery pressure, generating a p-value of 0.0094. We do also see a directionally positive improvement in cardiac output on the right, though it doesn't reach statistical significance with a p-value of 0.326.
Contributions from both drivers of PVR confirm that we are achieving a meaningful change in resistance as represented by the overall change in PVR. I think this is a good time to ask Dr. Ghofrani to provide his thoughts on the significance of our hemodynamic data. Marty?
Yeah. Thanks, Rob. I hope you can hear me well. Well, I think the first and most important finding is that the study met its primary endpoint. We all realize how important this primary endpoint for the patient is by means of reduction in the pulmonary vascular resistance, which is actually one of the main drivers of disease progression. It's a desirable and achievable goal to reduce pulmonary vascular resistance with this novel therapy. The response that we've seen is on top of an optimized background standard therapy. Having said that, it is a therapy that has maxed out for a substantial proportion of these patients because it includes triple combination therapy with parenteral prostacyclin.
This is very reflective of the prevalent nature of the disease in the currently studied patient population and also shows that, they have been treated with the best standard of care that is currently available, and nevertheless, had a disease which is still chronic and has the potential to progress. What we also appreciate was that in the higher-risk patients, it is very important to achieve improvements, because they need these improvements in pulmonary hemodynamics and other indicators of disease severity more acutely. Therefore it's a, it's a very encouraging finding to see that the magnitude of response in the more severely affected patients is bigger. Not meaning that those with less advanced disease had no effect, but the margins and the magnitude of response was clearly higher in the more severe patients.
In the field of pulmonary hypertension is known for a very long time that there's a concordance of the PVR with right heart function. The results that we saw here are to be discussed as very important findings. We've seen, unlike with sotatercept in the previously mentioned PULSAR study, in the TORREY trial, directional improvement of the cardiac output. However, it is good to say, or it's fair to say that the cardiac output in the actively treated group was more or less preserved while it deteriorated, even in as short as 6 months in the placebo group. It's a desirable directional change of the cardiac output with Seralutinib.
Regarding the historical perspective, the safety profile that was demonstrated with seralutinib shows that it is safe, effective, and it will be a novel mechanism of action by means of tackling the disease with an inhaled tyrosine kinase inhibitor. Introducing these novel complementary pathways into the treatment armamentarium of pulmonary hypertension is very exciting.
Thank you, Dr. Ghofrani. Now let's turn to our secondary endpoint of change in six-minute walk distance. As you recall, the TORREY study was designed as a hemodynamic study first and foremost, and was not designed as an exercise capacity improvement study. We were not powered to see statistical significance, but we wanted to see trends that would help us design our phase three program. We had a high entry criteria cutoff for the study at 550 meters. We went that high because of the COVID-19 pandemic and patient recruitment competition driven by the sotatercept phase 3 STELLAR study. Despite the challenges that conducting a six-minute walk test during the pandemic presented, we did see some interesting results, particularly in patients with more severe baseline disease consistent with prior studies in PAH.
On the next slide, you'll see our results in the overall study population. As is often seen in clinical studies, we saw a placebo effect represented by the gray line early at week 12, which wanes by week 24. The Seralutinib group, shown in green, has an early improvement that remains relatively constant at about the 15-meter mark, resulting in a difference that favors the Seralutinib arm by 6.5 meters at week 24. With the overlapping error bars at week 24, this isn't a statistically significant result. Again, we weren't powered on this endpoint for statistical significance. Overall, patients entered the study at a very high mean baseline walk distance of 408 meters. On the next slide, we've isolated 6-minute walk data for the functional Class 3 patients.
You'll recall these patients came in with a 6-minute baseline walk distance of about 370 meters, and in general, are much more similar to the overall patient populations that used to be enrolled in PAH clinical studies. What you see is a result that is very similar to what we used to see in successful vasodilator studies on 6-minute walk distance. A placebo arm that holds steady and eventually declines at week 24, and an active arm that improves over time, approaching a 25 meter improvement at week 24, resulting in a clinically meaningful and statistically significant 37 meter difference from the placebo arm. As Fahim mentioned earlier, this effect is dampened in the overall population by the imbalance in Class 3 subjects in the treatment groups, which you can see in the ends at the bottom of the graph.
As with PVR, we broke out the differences in six-minute walk at week 24 for both functional class and risk score. Starting with the leftmost group on the slide, the functional class two patients, you'll see that Seralutinib patients do have an average increase in walk of 14 meters at week 24. What is more notable is what we see in the placebo group. This group of patients began the study with a mean walk distance of 455 meters. An increase of 30 meters means that they ended the study at over 485 meters, which is a very high mean result for a relatively large PAH subgroup in a clinical trial. This played a role in muting our six-minute walk distance treatment effect size in the overall patient population.
The next set of bars to the right depicts results for the functional Class three patients we covered in further detail on the prior slide. To summarize those results, we saw a 37 meter statistically significant difference in this subgroup. Looking at the right side of the page, we do also see a nice improvement in elevated REVEAL risk patients on Seralutinib with an end of study improvement of 27 meters. This results in a non-statistically significant but clinically meaningful placebo-adjusted improvement of about 22 meters. We are confident with these results in hand, we can properly power a phase three study on the 6-minute walk endpoint. We're going to turn to some very encouraging and exciting data Faheem mentioned earlier.
These data confirm to us that not only was Seralutinib having an impact on the disease course for patients in TORREY, but that it was a clinically meaningful impact. This first slide shows mean changes in NT-proBNP over weeks four, eight, 12, and 24. As a reminder, NT-proBNP is a peptide that is released by cardiomyocytes when they are subjected to stress, and it is an important biomarker of right heart failure. What you can see is that there is an early separation of the curves at week 4, which becomes significant by week 12 and is highly significant at week 24. It's fantastic to see such a sustained decrease in NT-proBNP levels throughout the blinded study period, even as the placebo arm increases over time.
We've been calling this our hemodynamic and echo scorecard, and I think it gives you a clear picture of the concordance of the results we've been referencing. Across all of these hemodynamic and right heart functional and structural echocardiographic endpoints, we see either statistically significant changes or results that are directionally favoring Seralutinib. For many of these endpoints, we saw improvements by week 12, which aligns with our early improvement in NT-proBNP. I will first focus your attention on right atrium area. This measurement is in the current European Society of Cardiology, European Respiratory Society guidelines and is a known prognostic indicator of disease worsening and right heart failure, which again, is the leading cause of disease-related mortality for PAH patients.
As a patient's disease worsens, the right atrium enlarges, seeing a statistically significant decrease in right atrium area relative to placebo is a critical finding, indicating a positive change in disease course for patients on the Seralutinib arm. Right ventricle free wall strain is another metric that has been associated with mortality in PAH. Strain is a measure of right ventricle deformation, when we see a significant decrease in strain relative to placebo at week 24, it means we're seeing an important improvement in right ventricular function. We also saw a significant improvement in pulmonary artery compliance, which gives us information about the coupling of the right ventricle to the pulmonary vasculature. Improved pulmonary artery compliance indicates a more normal physiological interaction between the right ventricle and pulmonary circuit, indicating a potential remodeling effect.
We've heard from many of you what you believe are relevant data in a PAH population, including hemodynamics, six-minute walk distance, and NT-proBNP. Looking at this slide, we have an analysis looking at change in REVEAL 2.0 risk score among patients on Seralutinib and placebo. On the left-hand side, you'll see a bar chart. The two columns on the left of this chart represent the proportion of patients that improved by at least 1 point on the REVEAL risk score. The two bars in the center of the chart represent the proportion of patients whose risk score did not change during the study. The paired bars on the right-hand side of the bar chart represent patients that worsened by 1 point or more. Risk score changes are critical in their impact to lives of PAH patients. REVEAL is a broadly used tool that predicts survival.
A single point improvement on the REVEAL 2.0 risk score confers a substantial mortality benefit to a PAH patient. As you can understand, ultimately, what patients and clinicians are the most focused on above all else is long-term outcomes, including survival. I want to point your attention to the left-hand side of the bar chart. As you can see, the majority of patients on the Seralutinib arm experienced an improvement of at least 1 point in risk score over the course of the study. This result narrowly met statistical significance as compared to placebo with a p-value of 0.059.
You can also see that a much smaller portion of patients on Seralutinib demonstrated worsening of risk score on the right-hand portion of the bar chart, as compared to the 40% of placebo patients who saw at least a 1-point increase in risk score. These data further corroborate the changes we're seeing in the right heart. As you can see in our heavily treated study population, Seralutinib made a difference on both disease improvement and disease worsening. Seralutinib patients have almost 2.5 times the odds of achieving a risk score improvement compared to placebo patients. When you look at the totality of the efficacy data we presented today, these are the most clinically impactful data. Our team is thrilled to be sharing it with you. I'm now going to invite Dr.
Benza, as a leading cardiologist in the pulmonary hypertension field, to provide his perspective on the meaningfulness of the data we've presented thus far on right heart parameters and the REVEAL risk score reduction. Ray?
Thanks very much, Rob. I appreciate the opportunity, to express my opinions about what I feel is very exciting results from this new class of agent, that could be used in our patients who have remained ill despite maximally treated therapy.
For most of you who do not know how the REVEAL score work, it is a multiparameter score that comprises not only demographic and demographic features about the patients, but also really gives a great description of the totality of the risk by including things as vital signs, comorbidities, walk and BNP, as well as functional class, and in addition to hemodynamic parameters like the PVR, right atrial pressure, echocardiographic features of high risk, and pulmonary function features of high risk, including low DLCO, so that these scores really give you a composite of how these patients will fare that is statistically much more relevant than looking at individual parameters like six-minute walk test or BNP or functional class.
This is the way the community is now segregating our patients and allowing us to drive patients to what we feel is the ultimate goal of achieving low risk, which is defined by a REVEAL risk score of less than 6 or less than 5% mortality at one year. The fact that we can show this type of reduction in score in a heavily treated patient and a less ill patient is quite remarkable and attests to the, I think the strength of this new class of drug on top of the armamentarium that we're already treating these patients with. I think when you look at the differences in 6-minute walk tests, it's important to note that the less ill patients primarily have a more prominent placebo effect than more ill patients.
That's distinctly seen when you carve out the Class three patients who really have a remarkable change and a meaningful change in six-minute walk tests. As many of you remember, a change of anywhere between 25-35 meters in six-minute walk test correlates with improved quality of life and also improvement in long-term survival. That's a very important finding. The fact that we can see improvements in right ventricular remodeling as measured by a very sensitive test, which is the right ventricular strain rate, is also very important. Again, we were treating a majority of low-risk patients in this trial, and to see a reduction and improvement in right ventricular strain means we're seeing very early signs of right ventricular remodeling in the positive direction.
By coupling, we mean that the right ventricle and the pulmonary vascular system are in sync with one another. That the right ventricle has enough power to eject blood into a high resistance circuit is a very important finding. Showing improvement in compliance, again, with a heavily treated population is quite significant. I think these results are all very consistent and objective and suggest that in the properly used patient, which is, you know, those at higher risk, that this is gonna be a very important part of our armamentarium. I think it's important to point out that the majority of the patients that we see in clinic are people who have elevated risk.
the bulk of our patients are the intermediate risk zone, which is a REVEAL score of seven-eight. The fact that we included patients with REVEAL score six in this patient showed an improvement in them, suggests that even these people at low risk for mortality, that we're gonna have a low risk for morbid events in these patients, which is reflected by achieving a risk score less than six. Again, very excited about the results of this trial and encouraged in these early results.
Thank you, Dr. Benza. I'm now going to turn things over to our Chief Medical Officer, Richard Aranda, to take you through the safety and tolerability profile that was observed in the study. Richard?
Thank you, Rob. Moving into our discussion of safety, it's helpful to remember that seralutinib's design and route of administration was meant to avoid the systemic adverse events that were observed in the IMPRES study of imatinib that was conducted over 12 years ago. The high rate of gastrointestinal and fluid retention events in that study led to a high dropout rate. They also observed a high frequency of severe adverse events, such as subdural hematomas in their study. We are pleased to see that in the TORREY study, seralutinib had an improved safety profile, including no subdural hematomas. On this slide, we present the events observed at a significantly higher frequency in the imatinib arms of IMPRES, provide the event rates from the IMPRES study in the center, and then to the right, report the number of these events observed in the TORREY study.
As you can see, there were far fewer events in TORREY. The events that did occur were much more well-balanced between the seralutinib and placebo arms than in IMPRES. We believe seralutinib's distinct safety profile can be attributed to its kinase inhibition profile, low oral bioavailability, route of inhalation, limited systemic PK, and fast systemic clearance, providing significant differentiation from the imatinib tolerability profile. What events did we see? On this page are all events reported in 5% or more of patients on seralutinib. The top event reported is cough, which is at about 40%, and is consistent with the results seen with dry powder inhaled drugs in other therapeutic areas. Of note, the vast majority of these cases were reported as mild. In the treatment arm, 17 of the 19 cases were mild, with two cases being reported as moderate.
Beyond cough, most of the other AEs on this table are typical events and events rates that one would see in any randomized clinical trial or are events related to the patient's underlying pulmonary arterial hypertension. Of note, all of the events on this slide were reported as mild to moderate in severity. Let me add that 8 severe adverse events were reported during the study, mainly related to the underlying pulmonary arterial hypertension, and only one was also reported as a serious adverse event. That was reported as possibly or probably related to study drug by the investigator. This was a case of hemoptysis in a patient in the seralutinib arm. This patient had underlying interstitial lung disease and lupus and presented to their doctor after finding a small, very small amount of blood in their sputum after coughing.
The patient was briefly hospitalized for observation, had no further events, and discharged the next day. Hemoptysis is known to occur at low background rates in PAH. Here is a list of the adverse events leading to discontinuation that Faheem mentioned earlier. As you can see, there's no pattern in these events. The first patient with lower abdominal pain had issues with their prostacyclin pump and ultimately decided to come off the study. Two patients who discontinued in the seralutinib arm did so more for personal reasons. One patient had dry mouth due to underlying Sjögren's, and this was exacerbated during the study. The other patient had a history of lupus and experienced cough. We had two patients discontinue treatment due to liver enzyme elevations in the seralutinib arm and one in the placebo arm.
In general, with regards to our safety and tolerability profile, I don't think we could ask for much more. We knew that cough would be frequent with the dry powder inhaler, but the overwhelming majority of cases were reported as mild and did not lead to discontinuation except for the case mentioned previously. Further, we avoided high rates of gastrointestinal and fluid retention adverse events, which we believe will be a differentiating factor for seralutinib as we move into phase three. With that, I will turn things back over to Fahim to summarize the results and provide next steps. Fahim?
Thanks, Richard. Look, I know we've thrown a lot of data at you this morning. We felt it was important to share more than our peers have in the past because PAH is a multifactorial disease where there are many components that can lead to both improvement for patients and conversely, deterioration. When we reviewed these data with our key opinion leader steering committee, I was struck by the concept a number of KOLs emphasized. They don't think of the benefits of PAH treatments in terms of relative reductions, but rather by where those treatments can get their patients to with respect to their overall disease state and their risk of progression.
In that vein, I'm excited that Seralutinib was able to get patients on drug to a disease state that's comparable to the end of the study disease state that sotatercept achieved in the blinded portion of the PULSAR study in terms of PVR and other measures of the disease. What does this all mean for Seralutinib going forward? In TORREY, we had a positive phase two study with striking, concordant, statistically significant improvements across multiple hemodynamic biomarker and right heart structural and functional endpoints. We saw all of these effects in the absence of the safety and tolerability issues seen with systemic Imatinib, which we believe will be a differentiating factor going forward. We saw improvements in six-minute walk distance, especially in sicker patient groups, which we believe provides a clear path forward for a phase three program in PAH.
Lastly, this is something we'll spend more time on educating the market in the coming year, we believe our results in TORREY and the mechanistic rationale open up a great opportunity for us in Group 3 pulmonary hypertension. Group three patients have tremendous unmet medical need with inhaled Tyvaso as the only approved drug. Before briefly going over next steps to the program, I just wanna stop and thank every patient and their families and all of the TORREY study investigators that participated in the TORREY study. We're so pleased to have a positive study, and we quite literally could not have gotten there without you. We also want to thank Dr. Ghofrani and Dr. Benza for joining us today and providing their invaluable perspective on the data we've generated in TORREY.
I also want to thank everyone at Gossamer who worked on the TORREY study and in any way touched the Seralutinib program over the years. I personally continue to be inspired by your dedication and your commitment to patients, and know this will carry us forward as we advance Seralutinib into phase three development. Briefly on next steps, our team is working diligently to get in front of global health authorities in the H1 of next year. After we conclude those meetings, we'll go into further detail on our plans for PAH phase three, which we expect to begin in the H2 of next year. Lastly, as I alluded to earlier, we plan on beginning parallel development of Seralutinib in group three PAH later next year and into 2024. We'll have further details for you on what those studies would look like next year.
With that, we're looking forward to answering your questions, and I'll turn the calls over to the operator to begin the Q&A session.
Yes, thank you. At this time, we will begin the question-and-answer session. To ask a question, you may press star then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble the roster. The first question comes from Eliana Merle with UBS.
Hey, guys. Thanks for taking the question. Maybe just first for the physicians on the call, if you could just elaborate a little bit on your thoughts on the results of where you might use Seralutinib relative to Sotatercept from this data. Thanks.
Yeah. Let's, let's start with Dr. Ghofrani. Arnie, maybe you could take that first one.
Yeah. I think that we are all excited that there are novel therapeutics entering this space, most importantly because they are coming from a complementary signaling pathway background to those treatments that we currently have available. Amongst such, Seralutinib obviously is the most welcome addition to our therapeutic armamentarium, it will be used as soon as it is approved according to the label, obviously. It will be used in patients with PAH. We've seen from the study data that there are patients who react very well and have a very significant clinical response to the treatment and tolerate the therapy on longer term. There are also patients who have not such kind of impressive results as we've seen in the clinical studies in the average responses.
There will also be patients most likely who may develop tolerability issues or safety issues over time. Of course, you know, these patients will qualify for treatment with Seralutinib. One other thing that I'm very excited about is that both the signaling pathways for Seralutinib and sotatercept are complementary to each other, which gives space to even combining both treatments provided they both enter the market soon. There is good preclinical evidence that a combination of this kind of tyrosine kinase inhibitor with an activin signaling inhibitor such as sotatercept, may even cause some synergistic effects on the pulmonary vasculature and the right ventricular performance. There is long story short, there is room for both therapies in the field of pulmonary arterial hypertension therapies.
Dr. Benza, anything further to add to that?
I agree with Dr. Ghofrani. I think there's plenty of room for both of these medicines, particularly with the proposed synergistic effect of both of them. I think we'll be using these in the majority of our patients who are, you know, above the very low risk patients, which are really the minority of the patients we see in the clinical environment. I think it's gonna fit in well with our other armamentarium and be complementary to some of the newer therapeutics that are coming out.
Thank you.
Great. Thanks. Just a quick follow-up question. I know you mentioned that next year we'll learn more about potential phase three designs, but just in light of this data, can you elaborate a little bit maybe on how a phase three design could look, maybe relative to the design of the phase three that we saw from Sotatercept? I guess any specific inclusion criteria or anything that, like, you think high level might differ relative to the Sotatercept phase three. In particular, you mentioned, you know, excitement around potential to look at a broader population, even sort of like class three, maybe like, you know, your thoughts there and how you would approach potential studies in the class three patients or say, like, interstitial lung disease. Thanks.
First off, as it relates to phase three for PAH, I think, the results suggests kind of some obvious the design elements. Six-minute walk will clearly be the primary endpoint. We'll be looking to increase the baseline criteria for patients coming in on both six-minute walk and PVR. I think the results certainly suggest that. I would say that the overall trial design probably would look reasonably similar to sotatercept. Richard, our Chief Medical Officer, do you wanna add anything else to that?
Yeah, Fahim. I think the results from the Phase two clearly have provided us some good insights and directionality on how we should approach our inclusion criteria for our next study. Everything that Fahim has outlined. In terms of ILD, you know, we also think the results, particularly our NT-proBNP results, are indicative that we could have an effect in Group three. In addition, we know the underlying mechanism of Seralutinib may be applicable in the lung part of ILD or the fibrotic part, as well as treating the pulmonary arterial hypertension. More to come on what we're exactly thinking about our ILD design.
Great. Thanks.
Thank you. The next question comes from Andreas Argyrides from Wedbush Securities.
Good morning. Thanks for taking our questions. lots of data to dig through here. Could you just start with giving us a little bit more color on how many patients made it to the 90 mg BID dose? What was the distribution of doses? Did any of the patients have to down titrate to 45 mgs, and if so, why?
Yeah. All but a handful made it to the 90 mg BID dose. I believe about five or six stayed at 60 and I don't think we had anyone down titrate to 45 and stay there.
Okay, great. Then for Dr. Ardi Ghofrani and Ray Benza, which other KOLs have we spoken to, an 18% reduction in PVR is typically considered clinically meaningful.
How are you thinking about the reduction in PVR here and, yeah, we'll start there? I don't want to follow up.
Yeah. Maybe I can-
For any of you who want to try.
I can start. Yeah, sure. I think that the magnitude of response that we saw here is something that needs to take into the consideration the baseline PVR at which the patient started off. The baseline PVR was rather moderately elevated as compared to other clinical trials. It's clearly pathological. It's 6 times above normal, but compared to other trial populations, it's a rather moderate elevated PVR. The room for improvement obviously is less, but as Ray Benza pointed out, it's the absolute value that is reached with the novel therapy that is encouraging. Getting into the proximity of the 500 dimes with treatment already, you know, reduces or is one of the key components of a reduced risk score for these patients.
You know, given the magnitude of response in the overall patient population, we should still also acknowledge that the percentage-wise reduction of PVR in the more sicker patient population, in the class 3s and those with higher risk scores, was even more pronounced and was approximating 25% reduction, which then is also getting into proximity of results we've seen with other PH-specific therapies and with seralutinib with sotatercept in particular. For me, it's an encouraging result. Piece of my comment is I was impressed by the subgroups that were shown in the forest plot, and every pre-specified subgroup fulfilled the criteria of changing towards the right direction.
In a study sized like this and looking at forest plots, I'm not so much intrigued by the P values rather than by the direction of the change, and it was all in the right direction. I'm quite pleased with the results here.
Dr. Benza.
Yeah. I think this is similar to what Ardi mentioned. I think thinking about the reductions in PVR relative to the patient population is extremely important in this trial. In a relatively low-risk patient, we really have a significant and impressive drop in PVR. Remember, when you drop the PVR below, 400 dines or 5 Wood units, you have a prognostically important improvement in survival. That's really important not to forget. The fact that we've dropped the PVR by 25% in the more ill patients, that is getting to the point where we see a correlation between PVR and right ventricular remodeling. I think that's a really important point to remember, that when we get a drop of around 25%, we're starting to see that correlation improvement in right heart function.
I think that's what we're going to see in the correct population, which is, you know, the more intermediate and the high-risk patients there that we're seeing more in our clinical environments.
Thank you.
Okay, great. Thanks. I'll jump back in the queue. Yeah, thanks.
Thank you. The next question comes from Joseph Schwartz with SVB Securities.
Hi. Thanks very much. Congrats on the progress. I was wondering if you could help us understand why PVR was not imbalanced at baseline, but six-minute walk, functional class, REVEAL and NT-proBNP were imbalanced. What explains this apparent disconnect, and what kinds of things did you stratify for in TORREY, and will you be doing it any differently in phase three?
The TORREY study was stratified by PVR. That really accounts for the difference. It was not stratified for the other factors you spoke about, functional class or six-minute walk distance.
Yeah. I'm sorry. Would it make sense to do additional stratifications in phase three, given that the primary endpoint is expected to be six-minute walk?
Yeah, absolutely. You know, phase three will be a larger trial. There'll be room to test, you know, up to three or even four potential stratification variables, as opposed to, you know, in smaller studies, it's, you know, out of two cells if you have too many strata.
Right. Okay. That's helpful. Then, some investors have noticed that six patients were missing from the seralutinib arm in the pulmonary arterial pressure, which is used in the PVR calculation. I was wondering if you could explain the imputations you're making for PVR on slide 19, and which imputation was pre-specified and used, and is that similar to the convention for other PH trials? Did you do any sensitivity analyses to evaluate other methods?
Yeah. For the primary endpoint, we had pre-specified a multiple imputation method. There were 50 imputations performed, and then there's a roll-up procedure to get to our estimates. For those 6, we multiply imputed in our primary endpoint. This is a very common procedure done across many different therapeutic areas, including PH. Multiple sensitivity analyses were performed. I can think of off the top of my head at least 12 that I did.
Every single one of them gave me the same answer, with a significant P value and an estimate between a difference of 95 to 102 or 103 dimes, including observed cases, analyses with different covariates in the model, and things like that. What at the end of the day, the message here is that the missing data, the six missing values for PVR did not affect our results in any way. What you saw on the MPAP and the COs were we didn't impute, you know, for all those components. We're showing you the actual values. Especially since the missing data didn't affect our primary endpoint, it's reasonable to show just the data we collected after that point.
It's very helpful. Thanks for the color.
Thank you.
Thank you. The next question comes from Timur Vanikov from Private Investor.
Yeah. Hi, this is Timur. Just in terms of your Phase three study, since the trial is not expected until the H2 of next year, which is getting pretty close to potential sotatercept approval, are you concerned the FDA may ask you to include sotatercept in this study? Also, how do you think, you know, sotatercept's potential adoption may impact your Phase three enrollment?
As it relates to the phase three study, we would expect to see sotatercept on the market in the U.S. by end of 2023, beginning of 2024. Clearly, we will be and are actively working now on getting ourselves prepared to be enrolling not only in the U.S., but also quite extensively in Europe, where sotatercept won't be available for some period of time. In the context of patient enrollment, we feel pretty comfortable given the results that we have here, that we'll be able to enroll that phase 3 study in a similar timeframe, at a similar clip to what you saw with sotatercept.
As it relates to, what the regulatory authorities will be saying about enrolling sotatercept patients, obviously, we gotta wait till our end of phase two meeting to kind of get the full understanding there. I won't jump ahead of kind of what their expectations are. Having said that, it's reasonable to assume that some portion of our phase three will include sotatercept patients. You know, that as Dr. Ghofrani and Dr. Benza has said, we think these mechanisms are quite complementary. You know, and this is a disease that is treated through combination approaches. That could be quite exciting in terms of, potentially, having, that type of combination break through what I call kind of the glass ceiling of effect that we see in these studies.
You know, it's really interesting to see where we ended up on PVR across the entire patient population and our subgroups, and where we ended up on six-minute walk ended up being in the same neighborhood, the same zip code as where the sotatercept patients ended up being. Unfortunately, we keep hitting this in this disease, we keep hitting this ceiling as it relates to six-minute walk and floor as it relates to PVR. Hopefully, through rational combinations, we can actually produce better results.
Okay. Thank you. Just one more question. In terms of the background therapy in TORREY, just can you just talk about to what extent patients were able to vary the background therapy? I think one of the doctors mentioned, you know, the background therapy was already optimal at baseline. I'm just trying to understand you know, did placebo patients increase dosing? If they did, what proportion of them did?
Background PAH specific therapies that you're speaking about were to remain constant throughout the trial, to not add a confounder. If a patient had a clinical worsening event, that is, you know, required hospitalization for worsening PAH or a change in one of those medications, then that event was recorded and was taken into consideration when analyzing for the primary endpoint. There were not changes that occurred in either arm outside of a well-documented clinical worsening event.
Okay. Sorry, yeah, just one final question. It's about the single patient with ALT and AST increase. I mean, what grade of ALT, AST increase was that? What was the bilirubin for that patient? Thank you.
You're talking about in the active arm 'cause we had the single patient in the placebo.
Yeah. There was discontinuation in the active arm.
Yeah. They're above 3x and bilirubin was normal in that particular patient.
Okay. Thank you very much.
Thank you.
Thank you. The next question comes from Paul Choi with Goldman Sachs.
Hi. Thank you. Good morning and thanks for taking our questions. We appreciate all the details, but I was wondering if you could maybe comment on either the numerical or magnitude of changes with what you saw in terms of the WHO functional class assessment at week 24, any numerical trends or commentary you can make on the magnitude of potential changes there? I had a follow-up question.
Just to clarify your question, the magnitude of the changes for functional class three?
Any percentage of patients who were able to change functional classes or any assessment along those lines, potentially.
Yeah. Functional class, obviously, you know, is a very wide and kind of a, you know, there's only 4 levels. It is a challenge to change them, but we did have seven patients drop and improve their functional class in the treatment group, and I believe the same number in the placebo. More importantly, we had 6 patients in the placebos actually have their functional class worsen, including some that moved to functional class 4. We had none of that happen in the treatment group. 14% of placebos got worse, and versus 0% in the treatment group.
Basically, the maintenance or improvement of functional class in the treatment group versus, you know, sort of more variability in the placebo group in terms of improvement, maintenance, or getting worse.
Okay. Thank you. That's helpful clarification. I wanted to maybe ask in terms of the study design and implications for phase three, you did have patients titrate up from the 60 mg dose to 90 mg. Any thoughts, you know, given the safety profile that's been demonstrated here in the phase two with just going with the 90 at the start, which could have a potentially beneficial effect in terms of the treatment effect size? Thank you for taking our questions.
Yeah, sure. just to provide some context, you know, part of the reason we did the titration was for training of patients to use the DPI appropriately. you know, at this time, what we're still thinking about incorporating the rapid titration that we used in our phase two into our phase three program. We're still waiting for our pharmacokinetic data and which will inform us further on around our dosing and what we need to do with respect to further adjustments in that. As we presented, we're really quite pleased with the benefit risk profile of the 90 milligram.
Thank you.
Thank you. The next question comes from Carter Gould with Barclays.
Good morning. Thanks for squeezing me in. I guess first for the doctors on the call, you know, we just came away from the CHEST meeting in which there was a lot of discussion around the challenges in conducting PAH studies going forward. I guess, can you maybe just speak to the practicality of enrolling a potentially, you know, functional Class three population with narrower, six-minute walk distance, criteria going forward? Then maybe for the company, just how you're thinking about managing, expenses here now until you have clarity on that phase redesign, if there's anything you can, do on that front. Thank you.
I'll turn it over to Dr. Gafrani. Before I do, I don't think it would be our intention to just enroll a functional Class three phase three study. We'd be looking at patients certainly in functional Class three, but also functional Class two with higher risk, with a higher risk score and probably higher walk, lower walk baselines, and higher PVR baseline. It would cross both functional Class two and three. Dr. Gafrani, would you like to comment?
Yeah. I think that, you mentioned something very important, Fahim, which is that the risk and disease severity is a multifactorial thing in PAH patients. It's not only defined by functional class or by hemodynamics or by risk score, but it is really a multicomponent assessment. I believe that with adjusting some of the entry criteria, in the phase three program, nevertheless being open to include patients in various functional classes, that the recruitment will not be so much of an issue, particularly as the trial is going to be performed as an international multi-center trial. There are many regions in the world where patients have, you know, are less fortunate to receive many, many background therapies.
There's a high motivation to be included into clinical trials for good reasons, also because the care in clinical trials, even if you should be in a placebo group, is much better than, you know, in the real world out in the field. The patients get the privilege to be treated in expert centers and so forth. There are multiple motivations to be included into a trial. Even more so if you have a phase two study, which is already indicative of a good efficacy complementary to the given drugs available. I don't think it's gonna be a problem for the upcoming phase three studies to recruit.
Thank you.
Carter, on the balance sheet side of the question in expenses, you know, we have, we ended the Q3 with $300 million of cash on the balance sheet. We continue to deploy that capital to get ready for that phase three. As Ardi just said, our ability to go to places, especially, for example, in Europe, where we know the staggered step approval timelines
will be longer, gives us an opportunity to access those patients quickly. Clearly, we're very focused on making sure that we can deploy the capital appropriately, be in a position to get the study up and running. Certainly, as we think about the totality of expenses at Gossamer, we're very focused on continuing to support the Seralutinib program.
Yeah. I also think that, there's clearly the potential for some interesting partnership options as well.
Thank you, guys.
Thank you. The next question comes from Olivia Brayer with Cantor Fitzgerald.
Hey, good morning, guys. Thank you for the question. I wanna ask a follow-up on the dosing strategy for phase three. Could there be an opportunity to actually increase the final dose level or even look at the two dose arms in a registrational program? I know you guys have talked about the 90 mgs, but, you know, given the clean safety and the data to date, just wondering how you guys are thinking about moving forward there.
Well, you know, I just wanna reiterate one thing, I think, first of all, as Faheem mentioned, we need to assemble our data and then speak with the regulators because obviously they'll have an opinion on this, and that's the plan. As I mentioned, we are waiting for our pharmacokinetic data that will inform us on, you know, our population PK, if you will, and what we're seeing. That will guide us, obviously, if we should go beyond the 90-milligram dose that we currently use. I think you're absolutely right. We have a good benefit risk, and once we get that data, we'll be able to more precisely assess that question.
Okay. Got it. Thank you.
Thank you.
Thank you. The next question comes from Yasmin Kiani with Piper Sandler.
Thank you for taking my questions. I have quite a bit for you. Given the encouraging data you see the stock is trading at cash, I think fundamentally it comes down to a few questions. One is what is the probability of a successful phase three within the commentary you made that you will be enrolling Class II, Class III patients, six-minute walk test, modifying, you know, some of the baseline characteristics in favor of a higher PVR and lower six-minute walk test. I would like the doctors to kind of comment the probability of success in translation into a successful phase three. The second question is, you know, how competitive is this product now, I think in terms of its fit in the current marketplace.
Then the third aspect is, can we really drill down a little bit more when we say higher PVR? Like, what would be an ideal PVR inclusion criteria? What would be a good six-minute walk test, lower number that you would wanna stratify patients on? You could provide some commentary around that would be really helpful. Thank you.
Maybe Dr. Benza, you can start off.
Yeah. I think by using risk scores instead of functional class, we get a much more objective baseline characteristic of the patient as opposed just using functional class. So using a REVEAL risk score of six or greater gives us a appropriately risked patient for our phase three, particularly since these patients will more likely have a lower walk and a higher PDHA. Remember, a walk of greater than 440 is associated with a good prognosis. So trying to adjust for that using the risk scores at within the range of 6 or greater usually will give us a population where we would expect to see significant improvement in the walk distance just because they're objectively scored a higher risk.
I think using the scores as one of our enrichment characteristics will allow us to really have the type of patients we want that will manifest the important positive results and magnify the ones that we've seen here in the phase two.
Is there also-
And, and, uh-
Yeah, go ahead, please. Mm-hmm.
I was gonna say maybe Dr. Ghofrani wants to add, and, 'cause I think your other question, Yasmin, was about the profile. How competitive is the profile?
Yeah. I think that Ray mentioned some very important points. In addition, maybe regarding the competitiveness of a clinical trial in the phase three program with sotatercept, I believe that the company is well advised to mainly approach high volume expert centers around the world in which the current priorities are for original trials, for trials that investigate on novel signaling pathways rather than, you know, in times when very few really exciting complementary therapies or classes of drugs were investigated. Many of the sites, particularly in the Western world, were entertained by useless, what I call useless phase four studies of drugs, which were already well characterized, approved, and very well known.
Nowadays, I think the high volume expert sites, they prioritize original, novel, and innovative trials, and amongst such will be the sotatercept study.
I have little doubt that this will fly once the phase three program is initiated. Regarding the segment and pathway, it is complementary to what we have. It is complementary to sotatercept. That's one of the main motivations, knowing that during the Imatinib trial development, the proof of principle for the utility of TKIs has already been delivered on the efficacy side. With this novel TKI, which is now also applied on an inhaled route, I think we have an advanced profile and advanced safety profile as well, which qualifies for further development.
Team, one last question. Is there an opportunity to dose higher in phase three than nationalities?
I say yes, that, we're still evaluating all the PK data. More to come on that. We definitely think there's a maybe a possibility on that front, but I think we've got to understand the totality of the PK data that comes in.
Okay. Thank you.
Thanks, guys.
Thank you. The next question comes from Brian Cheng with JP Morgan.
Hey, guys. Thanks for taking my question. We have a question on your analysis on MPAP and also cardiac output on CY 22. The Seralutinib arm seem to be looking at only 38 patients in the analysis compared to 44 patients in total for the treatment arm. We're wondering if you can provide some color on the reason behind the discrepancy. Secondly, can you talk about the potential contribution of background therapies in your clinical outcomes? We're wondering if the shorter duration of stable background therapies compared to other trials may have contributed to the outcomes that we saw today. 'Cause I think that PULSAR was about three months and TORREY is four weeks for the duration for stable background therapy. Thank you.
Yeah. Well, I'll turn both questions over to Matt. I think you.
I'll take.
You already answered the first question.
I'll take the first question.
Go ahead. Answer it again.
Yeah. We were missing six right heart caths at the end of study, the primary analysis on PVR used an imputation procedure, now it's multiple imputation, to account for that. That's why the N is 44 in the primary analysis. However, as I mentioned earlier, all of our substantive analyses, including an observed cases analysis showed the same results. We did not compute, you know, the components or any other right heart cath variables, which is why when you see the components, there's N of 38.
The background therapy.
Yeah. Can you grab that?
The stable background therapy, you know, the dosing was to remain stable for a shorter period of time, but the agents and then the agents being used were similar. That with what's in PULSAR. Yes, while there could have been a dosing change, this, the regimen itself had to be remained the same. You know, we've looked at this very closely for changes in dosing effect, you know, in that prior period, and really haven't seen that that's what occurred in the study.
Great. Thanks for taking my question.
Yeah. Thank you.
Thank you. The next question comes from David Hong with SMBC.
Hey, thanks for the call. Really informative, and thanks for fitting me in. I just had a couple questions. I think most have already been addressed, but just in terms of some of the phase three criteria you mentioned that may be implemented, do you believe that would flow, any of those would flow over to the label, the drug label itself, and potentially have some limitations there just in terms of labeling language? And then as we think about, you know, the ideal population for a phase three trial, does that change your assumptions at all on the overall market opportunity for Seralutinib?
Well, again, as we mentioned, the expectation on our phase 3 trial will include both functional class 2 and functional class 3 patients, but as Dr. Benza mentioned, would probably be qualified through the REVEAL 2.0 and bringing in patients who have, quite frankly, more room to see improvement. I would expect to see a label that includes both functional class 2, functional class 3. I'll, I'll kind of answer the next part of the question, but I'll also invite Dr. Grafrani or Dr. Benza to comment as well. In context of the profile of a drug like this, where you have such a profound effect on...
A potential profound effect on right heart, and potentially impacting kind of how these patients die, which is right heart failure, there would be an expectation that we would assume that physicians would use this drug earlier in functional class two patients to prevent progression, and certainly use it in functional class 3 patients to prevent mortality. Please, Dr. Ghofrani or Dr. Benza, please comment from your perspective.
Yeah, I can see that the phase three study will be quite comparable to other phase three programs regarding include and exclude criteria. Most likely, the label will not very much differ from, you know, recently approved drugs with the comparable inclusion criteria. Traditionally, and as far as I've noted, you know, raising lower limits for the six-minute walking distance and/or capping the upper limits for it, as well as, you know, having certain inclusion/exclusion margins for the PVR usually doesn't influence the label. It's rather the functional class that has been allowed to enter, and it's the entities of disease subcategories that were included, and the absence or presence of background therapies in general.
It won't be as specific to say, you know, if you have a lower PVR value of 450 dynes, then it will be carried forward into the label. I'm not concerned about that.
Thank you.
Thank you. The next question comes from Gavin Clark-Gartner with Evercore ISI.
Hey, thanks for taking the question. First, did you see a correlation between baseline PVR and PVR reduction or six-minute walk improvement in this trial?
I mean, in typically in PAH trials, the correlation with change in PVR, with change in six-minute walk has been very weak. Across all the studies that we've done, we first reported this with sildenafil, and so that correlation, yes, we've looked at it, but it's no different than what we've seen with other trials.
Got it. Was there a correlation between baseline PVR and PVR reduction here?
Absolutely. Hang on a sec. Which one?
We have Matt, our stats guy, digging into the database on that one.
Okay, great. Thanks.
Yeah. Delta, yeah. Delta PVR compared to PVR. I have it correlated with the components.
We'll have to get back to you on that one.
We'll come back to you, Gavin.
Okay. Sounds good. Thanks. Maybe a second question. Did you see a benefit on time to clinical worsening, hospitalization, deaths, or any of the other outcomes measures?
Yeah, we saw, you know, There weren't a lot of events on time to clinical worsening. There were six for two.
Numerically favor, Seralutinib.
We have. Yeah. There were six events in the placebo group and two in the. I'm sorry, five.
Five.
Got it now. Yeah. It's five to two in the placebo group for a, you know, a hazard ratio reduction of about 60%. It's, you know, very small numbers, so not significant. However, certainly, numerically favored the treatment group in terms of two clinical worsening events on Seralutinib and five on placebo.
Okay. Got it. Maybe a last question then from me. How does the PVR or six-minute walk benefit looks for patients on doublet versus triplet therapy?
I mean, most of our patients are on triple therapy. I don't think we've done the analysis based on number of background therapies. That's a great question.
What's the subgroup that's done the grade, greater than-?
In the greater than or less than three, it's in the forest plot.
They're generally pretty close.
True. Yeah.
Greater than or less than three.
Yeah, very close. The greater than three with a slightly higher byproduct than the less than three. To the forest plot, Gavin.
All right. Great. Thanks for taking the questions, guys.
Thanks.
Thank you. The next question is a follow-up from Andreas Argyrides from Wedbush Securities.
Yeah, thanks for taking the follow-up. I know there are a lot of questions here, but just for clarity's sake here. The baseline PVRs were historically low in this trial, when compared to other PAH trials. What can we expect in PVRs for patients on background therapies just, you know, generally now? Are they much lower? With plans to go into functional Class three, patients in the phase three, what does that look like from a baseline PVR and 6-minute walk distance?
I mean, I think for Phase three on six-minute walk distance, we would kind of shorten, or lower the criteria that was used in TORREY. As we pointed out earlier, the TORREY criteria was a six-minute walk distance up to 550 meters, and we would, you know, kinda go to more traditional six-minute walk distance that's been included in other Phase three trials of the usual, you know, 50-450 meters. To really, you know, to pull down those higher walkers that are approaching the ceiling for a six-minute walk in the Phase three, moving forward.
I'd go one step further. again, recall that we conducted the TORREY study not only with the backdrop of COVID-19, which made things, you know, obviously difficult, but secondarily, against the competition of the sotatercept STELLAR study, where we know that physicians were putting their less sick patients into TORREY. part of the reason why we raised the capital when we did to put the infrastructure in place to be able to get to some of those more normal patients that we see in typical Phase three studies, to be able to do that before sotatercept is broadly approved throughout the globe, we think will allow us to get a more normal patient population for Phase three than what we saw in Phase two.
All right. Great. Thanks for taking my question.
Thank you.
Thank you. And this concludes the question and answer session. I would like to hand the floor to Faheem Hasnain for any closing comments.
All right. Well, thank you very much, thanks to all of you for participating on this call, all the great questions. Special thanks to Dr. Ghofrani and Dr. Benza for your time today. I'll just wrap this up by saying that we're ready to make a difference for PAH patients that where their chances of survival are not great at 5-year context. We've got a drug that not only is active, but demonstrating a meaningful effect across both functional Class two and three patients. We look forward to going into phase III, and we look forward to staying in touch to talk about our progress as we move forward. Thank you, everybody.
Thank you. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect your lines.