Q1 2024 Insmed Inc Earnings Call

Dee: Thank you for standing by. My name is Dee, and I will be your conference operator today. At this time, I would like to welcome everyone to the Insmed First Quarter 2024 Financial Results Call. All lines have been placed on mute to prevent any background noise.

Thank you for standing by my name is D and I will be a conference operator today at this time I would like to welcome everyone did in Smith first quarter 2024 financial results call. All lines have been placed on mute to prevent any background nice after the speakers' remarks, there'll be a question and answer session. If you would like.

Dee: After the speaker's remarks, there will be a question and answer session. If you would 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, press star one again. Thank you. I would now like to turn the call over to Bryan Dunn, Head of Investor Relations. Please go ahead. Thank you, Dee.

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 Press Star. One again. Thank you I would now like to turn the call over to Brian <unk> head of Investor Relations. Please go ahead.

Bryan Dunn: Good morning, everyone, and welcome to today's conference call to discuss Insmed's first quarter 2024 financial results and provide a business update. I am joined today by Will Lewis, Chair and Chief Executive Officer, Gene Sullivan, Chief Product Strategy Officer, and Sara Bonstein, Chief Financial Officer, who will each provide prepared remarks before we open it up for your questions. Before we start, please note that today's call will include forward-looking statements based on our current expectations.

Brian: Thank you D.

Brian: Hey, everyone and welcome to today's conference call to discuss <unk> first quarter 2024 financial results and provide a business update.

Brian: I'm joined today by will Lewis Chair, and Chief Executive Officer Gene Sullivan, Chief product strategy Officer, and Sara Bond Steen, Chief Financial Officer, who will each provide prepared remarks before we open it up for your questions.

Bryan Dunn: 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 filings with the Securities and Exchange Commission for more information concerning the risk factors that could affect the company.

Brian: Before we start please note that today's call will 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.

Brian: Please refer to our filings with the Securities and Exchange Commission for more information concerning the risk factors that could affect the company.

Bryan Dunn: Also note that our call today will include blinded observations from our ongoing phase two study of TPIP and pulmonary arterial hypertension. These observations may not be representative of results once the study is completed and all data is collected and analyzed. As a result, any future interim data readouts and the final data from this study may be materially different from the observations described. Finally, the information on today's call is for the benefit of the investment community. It is not intended for promotional purposes, and it is not sufficient for prescribing. I will now turn the call over to Will Lewis for prepared remarks. Thank you, Bryan.

Brian: Also note that our call today will include a blinded observations from our ongoing phase two study of T. P. IP in pulmonary arterial hypertension.

These observations may not be representative of results. Once the study is completed and all data is collected and analyzed as a result, any future interim data readouts and the final data from this study may be materially different than the observations described today.

Finally, the information on today's call is for the benefit of the investment community. It is not intended for promotional purposes and it is not sufficient for prescribing decisions I will now turn the call over to will Lewis for prepared remarks.

William Lewis: Welcome, everyone. Today, we intend to review the progress of three of the company's main programs, Error Case, TPIP, and Brenso CADET. Let's begin with TPIP. The first of this quarter's two important data readouts came this morning with the announcement of the top line results from our phase two study examining TPIP in patients with pulmonary hypertension associated with interstitial lung disease, as well as an update of blinded data from our ongoing phase two study in pulmonary arterial hypertension.

William Lewis: Thank you, Brian and welcome everyone. Today, we intend to review the progress from three of the company's main programs Erra case T P IP and Brent So get it let's begin with TPI P. The first of this quarter's two important data Readouts came this morning with the announcement of the topline results from our phase II study.

Speaker Change: <unk> <unk> in patients with pulmonary hypertension associated with interstitial lung disease as well as an update of blinded data from our ongoing phase II study in pulmonary arterial hypertension in a moment, Jim Sullivan will review these data in greater detail, but let me just say that we couldnt be more pleased with the progress and the clinical results.

William Lewis: In a moment, Gene Sullivan will review these data in greater detail, but let me just say that we couldn't be more pleased with the progress and the clinical results that continue to come from this exciting program. Turning to Brent Socata, the highly anticipated top-line release of the Phase III Aspen trial remains on track to read out in the second half of this quarter. Let me take one additional moment to touch on the detailed events and timelines relating to Brenso Cadet.

Jim Sullivan: But continue to come from this exciting program.

Jim Sullivan: Turning to Brent So Canada, the highly anticipated top line release of the Phase III Aspen trial remains on track to read out in the second half of this quarter.

Jim Sullivan: Let me take one additional moment to touch on the detailed events and timelines relating to Brent So Canada at the end of March all adult patients in Aspen have completed their 52 week visit which is the point at which the primary and secondary efficacy endpoints are measured in the trial as a result, we remain confident that the readout will come during the 45 days.

William Lewis: At the end of March, all adult patients in Aspen had completed their 52-week visit, which is the point at which the primary and secondary efficacy endpoints are measured in the trial. As a result, we remain confident that the readout will come during the 45-day window from mid-May to the end of June that we have outlined previously. We look forward to sharing the top-line results, which will include the pre-specified primary and secondary endpoints, as well as safety data across treatment arms, once the work to clean, compile, lock, and analyze the data is completed.

Jim Sullivan: Window from mid May to the end of June we have outlined previously.

Jim Sullivan: We look forward to sharing the top line results, which will include the pre specified primary and secondary endpoints as well as safety data across treatment arms once the work to clean compile locked and analyzed the data is completed.

William Lewis: In regard to AERCASE, we were pleased that AERCASE delivered double-digit year-over-year growth across all three of our geographic regions and 16% growth overall compared to the first quarter of 2023. We delivered this result despite minor headwinds that occurred in the marketplace, which Sara will walk you through in her remarks.

Jim Sullivan: In regard to Air case, we were pleased that Eric has delivered double digit year over year growth across all three of our geographic regions and 16% growth overall compared to the first quarter of 2023.

Jim Sullivan: We delivered this result, despite minor headwinds that occurred in the quarter, which Sarah will walk you through in her remarks, notwithstanding those isolated events. Our performance this quarter keeps us on track to deliver on our previously announced revenue guidance for the year.

William Lewis: Notwithstanding those isolated events, our performance this quarter keeps us on track to deliver on our previously announced revenue guidance for the year. Turning now to the potential expansion of ERROR CASE to all MAC-NTM patients, I'm pleased to report that our presentation of the full ARISE results has been selected for a plenary session at the upcoming ATS conference in San Diego later this month, which speaks to the significance of that study and the excitement for it within the medical community.

Jim Sullivan: Turning now to the potential expansion of Erra case to all Mac MTM patients I am pleased to report that our presentation of the full arise results has been selected for a plenary session at the upcoming Ats conference in San Diego later, this month, which speaks to the significance of that study and the excitement for it within the medical community I'm all.

William Lewis: I'm also pleased to report that the Data Monitoring Committee for the ongoing ENCQOR trial held its fourth meeting in April, which resulted in a recommendation to continue the study unchanged. As a reminder, there are no interim efficacy analyses built into the on-course study, so this represents a best-case outcome from that meeting. With regard to securing agreement on the PRO, we are now scheduled to meet with the team of patient-reported outcome experts at the FDA in late June, after which we will settle on the final statistical plan for on-call.

Jim Sullivan: So pleased to report that the data monitoring committee for the ongoing Encore trial held their fourth meeting in April which resulted in a recommendation to continue the study unchanged. As a reminder, there are no interim efficacy analysis built into the Encore study. So this represents a best case outcome from that meeting.

Jim Sullivan: With regard to secure an agreement on the CRO. We are now scheduled to meet with the team of patient reported outcome experts at the FDA in late June after which we will settle on the final statistical plan for Encore, we intend to provide you with additional updates once that work is complete.

William Lewis: Finally, I want to take a moment to note the changing approach within the medical community to the treatment of NTM and bronchiectasis and the clear synergies that are being recognized by patient advocacy groups and physicians as they contemplate how to bring the best possible care to patients with these two diseases. This quarter, we signed on to be the founding sponsor of the COPD Foundation's new Care Center Network for Patients with Bronchiectasis and NTM. Through this initiative, the COPD Foundation aims to create 150 multidisciplinary centers of excellence across the U.S.

Jim Sullivan: Finally, I want to take a moment to note the changing approach within the medical community to the treatment of MTM in bronchiectasis and the clear synergies that are being recognized by patient advocacy groups and physicians as they contemplate how to bring forward the best possible care to patients with these two diseases.

Jim Sullivan: This quarter, we signed on to be the founding sponsor of the COPD Foundation's New care Center network for patients with Bronchiectasis and MTN.

Jim Sullivan: Through this initiative the COPD Foundation aims to create 150 multidisciplinary centers of excellence across the U S.

William Lewis: This will establish consistent standards of care coming from expert-led academic centers and share them with the broader community in an effort to bring more comprehensive care to patients with MTM and bronchiectasis as they strive to meet treatment goals. This effort recognizes the clear synergy that can be achieved by physicians treating NTM and bronchiectasis, and we will be structuring our medical support efforts to augment this new approach to patient care across the United States.

This will establish consistent standards of care coming from expert led academic centers and share them with the broader community in an effort to bring more comprehensive care to patients with MTM in bronchiectasis as they strive to meet treatment goals.

Jim Sullivan: Separate recognizes the clear synergy that can be achieved by physicians treating MTM and bronchiectasis and we will be structuring our medical support efforts to augment this new approach to patient care across the United States. We consider it an honor to be supporting this important work on behalf of patients now.

William Lewis: We consider it an honor to be supporting this important work on behalf of patients. Now, let me turn the call over to Gene to talk about the big news of the day, the results from our TPIP program. Thank you, Will, and good morning, everyone.

Jim Sullivan: Now, let me turn the call over to Jim to talk about the Big news of the day the results from our <unk> program.

Jim Sullivan: Thank you will and good morning, everyone I'm pleased to share with you. The data we have produced to date from each of our two programs that have been running in parallel for TPI P. I.

Gene Sullivan: I'm pleased to share with you the data we have produced to date from each of our two programs that have been running in parallel for TPIP. I will start with the top line results from our recently completed Phase 2 safety study of TPIP in patients with pulmonary hypertension associated with interstitial lung disease, which were posted to our website this morning. I will then walk through the most recent blended blinded data from our ongoing phase two efficacy study of TPIP in patients with pulmonary arterial hypertension. Let's begin with PHILD.

Jim Sullivan: I will start with the topline results from our recently completed phase III safety study of <unk> in patients with pulmonary hypertension associated with interstitial lung disease, which were posted to our website. This morning.

Jim Sullivan: I will then walk through the most recent blended blinded data from our ongoing phase II efficacy study of <unk> in patients with pulmonary arterial hypertension.

Jim Sullivan: Let's begin with ph ILD.

Gene Sullivan: This study originally targeted an enrollment of 32 patients but was over-enrolled with 39 patients. The study utilized a three-to-one randomization. As a result, 29 patients were randomized to receive TPIP and 10 were randomized to receive placebo for the 16-week treatment period. The maximum TPIP dose allowed in the trial was 640 micrograms once daily. As a reminder, a TPIP dose of 640 micrograms contains roughly 60% more triprostanil as compared with the total daily dose of the current market-leading triprostanil dry powder product, which is dosed four times daily.

Jim Sullivan: This study originally targeted an enrollment of 32 patients, but it was over enrolled with 39 patients.

Jim Sullivan: The study utilized to a three to one randomization scheme and as a result, 29 patients were randomized to receive <unk>.

Jim Sullivan: And 10 were randomized to receive placebo for the 16 week treatment period.

Jim Sullivan: The maximum TPI dose allowed in the trial was 640 micrograms once daily.

Jim Sullivan: As a reminder, TPI dose of 640 micrograms contains roughly 60% more tree Prost enel as compared with a total daily dose of the current market, leading coprostanol dry powder product, which is dosed four times daily.

Gene Sullivan: 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 five-week visit. However, patients were not permitted to increase their dose for the remaining 11 weeks of treatment.

Jim Sullivan: 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 five week visit.

Jim Sullivan: Patients were not permitted to increase their dose for the remaining 11 weeks of treatment.

Gene Sullivan: Participant demographics and baseline characteristics were generally well balanced between study arms. However, a higher percentage of female participants were randomized to the TPIP arm at 31% versus the placebo arm at 20%. Also, on average, patients in the TPIP arm of the study required one additional liter per minute of supplemental oxygen at baseline. The study's primary objective was to evaluate the safety and tolerability of TPIP in patients with PHID, including assessments of oxygenation at rest and during exercise. Let's begin with tolerability.

Jim Sullivan: Participant demographics and baseline characteristics were generally well balanced between study arms. However.

Jim Sullivan: Higher percentage of female participants were randomized to TPI PR at 31% versus the placebo arm at 20%.

Jim Sullivan: Also on average patients in the Tpa IP arm of the study required one additional liter per minute of supplemental oxygen at baseline.

Jim Sullivan: The study's primary objective was to evaluate the safety and Tolerability of <unk> in.

Jim Sullivan: In patients with ph D, including assessments of oxygenation at rest enduring exercise.

Gene Sullivan: Among patients in the TPIP arm, 79.3% were successfully able to reach the maximum dose of 640 micrograms by week five, compared with 100% of those taking placebo. Furthermore, if we look at the patients who were able to reach at least 480 micrograms by week five, nearly 90% of TPI patients were able to achieve that threshold. This indicator of the tolerability of TPIP in this patient population is very encouraging given the relatively short titration period included in the trial and considering the severity of the underlying disease process.

Jim Sullivan: Let's begin with Tolerability.

Jim Sullivan: Among patients in the TPI PR 79, 3% were successfully able to reach the maximum dose of 640 micrograms by week, five compared with 100% of those taking placebo.

Jim Sullivan: If we look at the patients who were able to reach at least 480 micrograms by week five nearly 90% of TPI patient patients were able to achieve that threshold.

Jim Sullivan: This indicator of the Tolerability of TPI P. In this patient population is very encouraging given the relatively short titration period included in the trial and considering the severity of the underlying disease process.

Gene Sullivan: Of note, while we adopted a titration period of five weeks for the purposes of this trial, in clinical practice, a more prolonged titration period could be applied, which may allow for even more patients to reach higher doses. Additionally, we saw that patients taking TPIP were less likely to experience a treatment emergent adverse event that would lead them to discontinue the treatment, with 13.8% of patients in the TPIP arm experiencing such an event, compared to 30% in the placebo arm.

Jim Sullivan: Of note, while we adopted a titration period of five weeks for the purposes of this trial and clinical practice are more prolonged titration period could be applied which may allow for even more patients to reach higher doses.

Jim Sullivan: Additionally, we saw that patients taking <unk> were less likely to experience a treatment emergent adverse event that would lead them to discontinue the treatment with 13, 8% of patients in the TPI PR experiencing such an event compared to 30% and the placebo.

Jim Sullivan: Arm.

Gene Sullivan: We consider a higher treatment discontinue rate in the placebo versus treatment to be very noteworthy. In terms of overall safety, 93 percent of patients in the TPIP arm experienced any adverse event, which was similar to 90 percent of patients on placebo. And 20.7% of TPIP-treated patients experienced a serious adverse event compared to 40% of placebo-treated patients. However, zero patients in either arm experienced a serious adverse event that would be judged to be related to study drugs.

Jim Sullivan: We consider a higher treatment discontinue rate in the placebo versus treatment to be very noteworthy.

Jim Sullivan: In terms of overall safety, 93% percent of patients and the TPI PR experienced any adverse event, which was similar to the 90% of patients on placebo.

Jim Sullivan: And 27% of TPI <unk> treated patients experienced a serious adverse event compared to 40% of placebo treated patients.

Jim Sullivan: Zero patients in either arm experienced a serious adverse event that was judged to be related to study trial.

Gene Sullivan: There were four deaths in the trial, including 6.9% of patients randomized to the TPIP arm and 20% of patients randomized to the placebo arm. All deaths in the trial were related to disease progression or comorbid causes, and none were attributed to study drugs.

Jim Sullivan: There were four deaths in the trial, including six 9% of patients randomized to the <unk> arm and 20% of patients randomized to placebo arm.

Jim Sullivan: All deaths in the trial were related to disease progression or comorbid causes and none were attributed to study drug.

Gene Sullivan: One of the key reasons to conduct an initial safety trial in this population was to confirm that inhalation of TPIP would not negatively impact oxygenation. Therefore, we were very pleased that we saw no worsening of oxygen saturation levels at rest and no increase in the use of supplemental oxygen for patients taking TPIP. Additionally, we also measured oxygen saturation continuously during and after the six-minute walk test to capture the lowest blood oxygen levels reached during that entire period of time and found no meaningful differences between the TPIP and placebo arms on that measure, which is what we had hoped to see.

Jim Sullivan: One of the key reasons to conduct an initial safety trial in this population was to confirm the inhalation of <unk> would not negatively impact oxygenation.

Jim Sullivan: Therefore, we were very pleased that we saw no worsening of oxygen saturation levels had breast and no increase in the use of supplemental oxygen for patients taking TP IP.

Jim Sullivan: Additionally, we also measure oxygen saturation continuously during and after the six minute walk test to capture the lowest blood oxygen levels reached during that entire period of time and found no meaningful differences between the <unk>.

Jim Sullivan: And placebo arms on that measure, which is what we had hoped to see.

Gene Sullivan: I do want to note that we did see a slight decrease in oxygen saturation from baseline levels when measured after the six minute walk test, with the TPIP arm showing an absolute decrease of 8% compared to placebo patients who saw an absolute increase at baseline of 1%. However, I would emphasize that there was no standardization in the trial regarding the timing for when that measure was recorded following exercise. So there is likely to be significant variability in that data point.

Jim Sullivan: I do want to note that we did see a slight decrease in oxygen saturation from baseline levels when measured after the six minute walk test with a tpi's arm showing an absolute decrease of 8% compared to placebo patients who saw an absolute increase from baseline of 1%.

Jim Sullivan: However, I would emphasize that there was no standardization in the trial regarding the timing for when that measure was recorded following exercise. So there is likely to be significant variability in that data point.

Gene Sullivan: As a result, we believe that the values reflecting resting and the lowest oxygen saturation are the best indicators of the effect of the drug on oxygenation. Although we were previously not sure whether we would have any results from our exploratory endpoints in this study to share with you at the time of the top-line safety readout, I'm pleased to report that we do have several of those data points available to share today. Let me begin with a six-minute walk.

Jim Sullivan: As a result, we believe that the values, reflecting the resting and the lowest oxygen saturation are the best indicators of the effect of the drug on oxygenation.

Jim Sullivan: Although we were previously not sure whether we would have any results from our exploratory endpoints in this study to share with you at the time of the topline safety readout I am pleased to report that we do have several of those data points available to share today.

Jim Sullivan: Let me begin with a six minute walk distance, we were pleased to see a 30 meter improvement compared to placebo at week 16, and patients taking TPI P. Using the study's prespecified analysis for that comparison.

Gene Sullivan: We were pleased to see a 30-meter improvement compared to placebo at week 16 in patients taking TPIP, using the study's pre-specified analysis for that comparison. However, let me provide a note of caution on over-interpreting that exploratory endpoint in a study this small. As we have said many times in the past, the six minute walk distance often includes a substantial amount of variability, as emphasized by the wide confidence intervals we see in this data set.

Jim Sullivan: However, let me provide a note of caution on over interpreting that exploratory endpoint in our study this small.

Jim Sullivan: As we have said many times in the past six minute walk distance often includes a substantial amount of variability as emphasized by the wide confidence intervals, we see in this dataset.

Gene Sullivan: As expected in a study this small, the improvement in the six-minute walk distance did not approach statistical significance. On NT probium P levels, the TPIP arm showed a slight improvement from baseline, and the placebo group showed a slight worsening. However, the difference between the groups was not meaningful, which is to be expected in this small of a study.

Jim Sullivan: As expected in our study this small improvement in six minute walk distance did not approach statistical significance.

Jim Sullivan: On NT pro BNP levels, the TPI arm showed a slight improvement from baseline and the placebo group showed a slight worsening.

Jim Sullivan: The difference between groups was not meaningful which is to be expected in this small study.

Gene Sullivan: Finally, in this study, we measured events of clinical worst, which was defined as a hospitalization due to a cardiopulmonary indication, a lung transplantation, death from any cause, or a decrease in six minute walk distance of 15 percent or more from baseline. To be clear, we did not expect to see a signal on this exploratory measure, given the study's small size. However, clinical worsening events were shown to be more common in the placebo arm, with 50% of placebo-treated patients experiencing such an event, compared to 10.3% of TPIP-treated patients. This difference produced a nominally significant p-value of 0.0164.

Jim Sullivan: Finally in this study we measured events of clinical worsening, which was defined as a hospitalization due to our cardiopulmonary indication.

Jim Sullivan: Lung transplantation death from any cause or a decrease in six minute walk distance of 15% or more from baseline.

Jim Sullivan: To be clear, we did not expect to see a signal on this exploratory measure given the study small size.

Jim Sullivan: However, clinical worsening events were shown to be more common in the placebo arm with 50% of placebo treated patients experiencing such event.

Impair to 10, 3% of TPI peak treated patients.

Jim Sullivan: This difference produced a nominally significant P value of 0.0164.

Gene Sullivan: We are extremely encouraged and pleased with today's results and look forward to sharing more of the pharmacokinetic and additional safety and exploratory endpoints from the study at an upcoming medical conference later this year. Importantly, based on today's data, we intend to move this program forward to phase three, aiming to initiate a global study in 2025. Now, let me spend a few moments providing you an update on our ongoing phase two trial of TPIP in patients with pulmonary arterial hypertension.

Jim Sullivan: We are extremely encouraged and pleased with today's results and look forward to sharing more of the pharmacokinetic and additional safety and exploratory endpoints from the study at an upcoming medical conference later this year.

Jim Sullivan: Importantly, based on todays data, we intend to move this program forward to phase III aiming to initiate a global study in 2025.

Gene Sullivan: The trial is progressing as expected, now with well more than half of the target enrollment achieved. In March, the second Data Monitoring Committee meeting was held to review the safety data from this trial, and the committee's recommendation was to continue the trial without any changes.

Speaker Change: Now, let me spend a few moments providing you an update on our ongoing phase II trial of <unk> in patients with pulmonary arterial hypertension.

Speaker Change: The trial is progressing as expected now with well more than half of the target enrollment achieved.

Speaker Change: In March the second data monitoring Committee meeting was held to review the safety data from this trial and the committee's recommendation was to continue the trial without any changes.

Gene Sullivan: Regarding dosing, among the first 43 patients in the trial to complete their five-week visit, 79% were able to reach the maximum dose of 640 micrograms or matching placebo, which is consistent with our last update and is very encouraging. We have already received the necessary regulatory approvals in 10 of 17 countries where the study is being conducted to amend the protocol in the open-label extension of this trial to allow for even higher doses up to a maximum of 1,280 micrograms once daily.

Speaker Change: In regard to dosing among the forced 43 patients in the trial to complete their five week visit.

Speaker Change: 79% were able to reach the maximum dose of 640 micrograms or matching placebo, which is consistent with our last update and is very encouraging.

Speaker Change: We have already received the necessary regulatory approvals and 10 of 17 countries, where the study is being conducted to amend the protocol and the open label extension of this trial to allow for even higher dosing up to a maximum of 1280 micrograms once daily.

We are excited about what these higher doses could potentially mean for patient outcomes.

Gene Sullivan: We are excited about what these higher doses could potentially mean for patient outcomes. Today, I would like to share an update on the blinded efficacy data we have seen thus far in this trial. This update includes data from the first 44 patients randomized in the trial. Of those patients, four discontinued the trial prior to completion, leaving 40 patients who completed the full 16 weeks of treatment.

Speaker Change: Today, I would like to share an update on the blinded efficacy data we have seen thus far in this trial.

Speaker Change: This update includes data from the first 44 patients randomized in the trial.

Speaker Change: Those patients for discontinued the trial prior to completion, leaving 40 patients who completed the full 16 weeks of treatment.

Gene Sullivan: As a reminder, this trial is randomized two-to-one, so roughly two-thirds of the patients will be receiving TPIP, and one-third will be on placebo. Starting now with the blinded data on pulmonary vascular resistance, or PVR. Among the 40 patients who completed the study as of the data cutoff, the mean percentage reduction in PVR at week 16 compared to baseline was 19.9%. This observed reduction in PVR is comparable to the best clinical results produced with prostanoid treatments in the past, despite the fact that our result for TPIP is a blend of treated and placebo patients.

Speaker Change: As a reminder, this trial is randomized two to one so roughly two thirds of the patients will be receiving TPI and.

Speaker Change: And one third will be on placebo.

Speaker Change: Starting now with the blinded data on pulmonary vascular resistance or PBR.

Speaker Change: Among the 40 patients who completed the study as of the data cutoff. The mean percentage reduction in PDR at week 16, compared to baseline is 19, 9%.

Speaker Change: This observed reduction in PBR is comparable to the best clinical results produced with process and oil treatments in the past. Despite the fact that our result for TPI P is a blend of treated and placebo patients.

Gene Sullivan: What is equally encouraging is that we continue to see patients in the study who experience dramatic improvements in PVR. We're also excited by what we're seeing in the six minute walk distance, which is another key efficacy measure for these patients. On average, across these 40 patients, including the TPIP and placebo arms of the trial, the improvement in six-minute walk distance from baseline was 43 meters. As I mentioned a few moments ago, this is a highly variable measure and especially difficult to interpret on a blinded basis, but we are nonetheless encouraged by what we have seen so far.

Speaker Change: What is equally encouraging is that we continue to see patients in the study who experienced dramatic improvements in PBR.

Speaker Change: We're also excited by what we're seeing on six minute walk distance, which is another key efficacy measure for these patients.

Speaker Change: On average across these 40 patients, including the <unk> and placebo arms of the trial the improvement in six minute walk distance from baseline was 43 meters.

Speaker Change: As I mentioned, a few moments ago six minute walk distance is a highly variable measure and especially difficult to interpret on a blinded basis, but we are nonetheless encouraged by what we've seen so far.

Gene Sullivan: It is worth pointing out that for both efficacy endpoints that I've described today, PBR and six-minute walk distance, these measures were taken at the end of the dosing interval, or nearly 24 hours after the most recent dose. This was designed intentionally to highlight the potential durability of TPIP's effect. However, this makes these results more difficult to compare to the other key study of inhaled troprostate, which reported hemodynamic measures obtained in the period immediately following the dose at the time of the drug's maximum effect.

Speaker Change: It is worth pointing out that for both efficacy endpoints that Ive described today PBR and six minute walk distance. These measures were taken at the end of the dosing interval or nearly 24 hours. After the most recent dose.

Speaker Change: This was designed intentionally to highlight the potential durability of <unk> effect.

Speaker Change: However, it makes these results more difficult to compare to the other key study of inhaled <unk>, which reported hemodynamic measures obtained in the period immediately following the dose at the time of the drug's maximum effect.

Gene Sullivan: The fact that we are seeing profound effects in some patients in our study, nearly a full day after taking a dose, makes us very excited about the potential of this treatment. As a final reminder, we do not know which of these first 40 patients were taking TPIP and which were taking placebo, and the numbers I have shared today on PVR and six-minute walk distance will continue to change as more patient data is generated.

Speaker Change: The fact that we are seeing profound effects in some patients in our study nearly a full day after taking a dose makes us very excited for the potential of this treatment.

Speaker Change: As a final reminder, we do not know which of these 41st 40 patients were taking TP IP in which we're taking placebo.

Speaker Change: And the numbers I have shared today on DVR and six minute walk distance, we will continue to change as more patient data is generated however.

Gene Sullivan: However, we believe today's data supports our view that TPIP has the potential to be a best-in-class treatment for patients with PAH and PHILD, combining a potentially differentiated clinical profile with the convenience of a once-daily dose. Now, let me turn the call over to Sara to walk through the detailed financial results from the first quarter. Thank you, Gene, and good morning, everyone. I'm happy to be with you to share some of the details of Insmed's financial performance for the first quarter of 2024. We ended the quarter with $596 million in cash and cash equivalents.

Speaker Change: However, we believe today's data supports our view of TPI has the potential to be a best in class treatment for patients with ph and ph ILD.

Speaker Change: And buying a potentially differentiated clinical profile with the convenience of once daily dosing.

Sara M. Bonstein: This represents a cash burn for the quarter of approximately $185 million. As we have stated previously, our cash burn in the first quarter is higher than other quarters in the year due to the timing of our annual employee incentive compensation payout. In addition, this quarter was also impacted by larger payments for contract manufacturing services and inventory bills for clinical and preclinical products than our usual cadence. However, when these items are excluded, the underlying cash burn was approximately $125 million, which is in line with recent quarters.

Speaker Change: Now, let me turn the call over to Sarah to walk through the detailed financial results from the first quarter.

Sarah: Thank you Dean and good morning, everyone.

Sarah: I'm happy to be with you to share some of the details of <unk> financial performance for the first quarter of 2024.

Sarah: We ended the quarter with $596 million in cash and cash equivalents.

This represents a cash burn for the quarter of approximately $185 million.

Sarah: As we have stated previously our cash burn in the first quarter is higher than other quarters in the year due to the timing of our annual employee incentive compensation payout in.

Sarah: In addition, this quarter was also impacted by larger payments for contract manufacturing services and inventory build for clinical and preclinical products than our usual cadence.

Sarah: When these items are excluded the underlying cash burn was approximately $125 million, which is in line with recent quarters.

Sarah: Consistent with our statements on last quarters call, we have not used our aftermarket equity offering since last year and we do not intend to use this program between now and the Aspen data readout.

Sara M. Bonstein: Consistent with our statements on last quarter's call, we have not used our at-the-market equity offering since last year, and we do not intend to use this program between now and the Aspen data readout. Turning to our commercial performance in the first quarter of 2024. Global Net Revenues for the first quarter of 2024 were $75.5 million, representing 16% year-over-year growth compared to the first quarter of 2023; in the U.S., net revenues for the first quarter of 2024 were $56.3 million, up 15% compared to the prior year quarter.

Sarah: Turning to our commercial performance in the first quarter of 2024.

Sarah: Global net revenues for the first quarter of 2024 were $75 $5 million, representing 16% year over year growth compare to the first quarter of 2023.

Sarah: In the U S. Net revenues for first quarter, 2024 was $56 $3 million up 15% compared to the prior year quarter the.

Sara M. Bonstein: The growth this quarter was driven by the highest level of enrollment forms that we have seen in the U.S. since the third quarter of 2019, when Aircase was in its fourth quarter of launch and ramping quickly. The positive impact of this increase in enrollment forms was partially mitigated, however, by temporary disruptions to the distribution of ARICASE due to the changed health care tiber attack, which impacted the dispensing of medicines across the United States, particularly for patients starting a new treatment.

Sarah: The growth this quarter was driven by the highest level of enrollment forms that we have seen in the U S. Since the third quarter of 2019, when Eric case within its fourth quarter of launch and wrapping ramping quickly.

Sarah: The positive impact of this increase in enrollment forms was partially mitigated however by temporary disruptions to the distribution of air case due to the tenet healthcare type of attack, which impacted the dispensing of medicines across the United States, particularly for patients starting a new treatment.

Sara M. Bonstein: That said, we are continuing to work to help patients gain access to Aircase who had difficulty starting treatment due to the cyber attack. In Japan, for the first quarter of 2024, net revenue was $14.9 million, representing 13% growth over the same quarter last year.

Sarah: That said, we are continuing to work to help patients gain access to air Keith who had difficulty starting treatment due to the cyber attack.

Sarah: In Japan first quarter 2024, net revenue was $14 $9 million, representing 13% growth over the same quarter last year.

Sara M. Bonstein: Although foreign exchange did not have a material impact on the overall business, the impact of changes in the foreign exchange rate on our revenue in Japan this quarter was notable. In fact, if average exchange rates this quarter were the same as they were in the first quarter of 2023, the year-over-year growth in Japan would have been approximately 27 percent, or more than double the reported growth rate. I would also point out that the timing of inventory drawdowns led to a sequential decline in sales in Japan compared to the fourth quarter, which saw record-setting strength in error case sales volume.

Sarah: Although foreign exchange did not have a material impact on the overall business.

Sarah: The impact of changes in the foreign exchange rate on our revenue in Japan. This quarter was notable in fact, if average exchange rates. This quarter were the same as they were in the first quarter of 2023, the year over year growth in Japan would have been approximately 27% or more than double the reported growth rate.

Sarah: I would also point out that the timing of inventory draw Downs led to a sequential decline in sales in Japan compared to the fourth quarter, which saw record setting strengthen <unk> sales volumes.

Sara M. Bonstein: Overall, our view on the opportunity in Japan continues to be very positive, and we look forward to the progress from this important region in the coming quarters. In Europe and the rest of the world, net revenue in the first quarter of 2024 came in at $4.3 million, up 42% compared to the same quarter last year and well ahead of our internal expectations, as that region's collective efforts are paying off. While we continue to expect the relative contribution to global sales from Europe to remain modest.

Sarah: Overall, our view on the opportunity in Japan continues to be very positive and we look forward to the progress from this important region in coming quarters.

Sarah: In Europe and rest of World net revenue in the first quarter 2024 came in at $4 $3 million up 42% compared to the same quarter last year and well ahead of our internal expectations.

Sarah: That region's collective efforts are paying off.

Sarah: While we continue to expect the relative contribution to global sales from Europe to remain modest we are pleased to see their efforts gained momentum, especially as we round the corner to the potential launch of <unk>, assuming positive Aspen and regulatory approvals.

Sara M. Bonstein: We are pleased to see their efforts gain momentum, especially as we round the corner to the potential launch of brentsocatib, assuming positive Aspen and regulatory approval. Importantly, today we are reiterating our full year 2024 global revenue guidance of $340 to $360 million. As a reminder, the midpoint of that guidance range represents 15% growth compared to 2023, which is consistent with the 16% year-over-year growth that was delivered in the first quarter. Furthermore, as I mentioned on last quarter's call, the first quarter of each year historically contributes slightly more than a fifth of each year's total sales due to seasonal impacts in both the U.S. and Japan.

Sarah: Importantly, today, we are reiterating our full year 2024, global revenue guidance of $340 million to $360 million.

Sarah: As a reminder, the midpoint of that guidance range represents 15% growth compared to 2023, which is consistent with the 16% year over year growth that was delivered in the first quarter.

Sarah: Furthermore, as I mentioned on last quarter's call. The first quarter of each year historically contributed slightly more than a fifth of each year's total sales due to the seasonal impacts in both the U S and Japan.

Sara M. Bonstein: By that same measure, our first quarter performance puts us squarely on track to achieve our guidance range for the full year. Let me now turn to a few additional financial items. In the first quarter of 2024, our gross SINETs in the U.S. were approximately 21 percent.

Sarah: By that same measure our first quarter performance puts us squarely on track to achieve our guidance range for the full year.

Sarah: Let me now turn to a few additional financial items in.

Sarah: In the first quarter 2024, our gross to nets in the U S where approximately 21% as in prior years, we expect the gross to net in the first quarter of the year to be a bit higher before coming down in the remaining quarters of the year. We continue to expect gross to nets will settle in the mid to high teen range for the full year.

Sara M. Bonstein: As in prior years, we expect the gross SINETs in the first quarter of the year to be a bit higher before coming down in the remaining quarters of the year. We continue to expect gross SINETs to settle in the mid to high teens range for the full year. Cost of product revenues for the first quarter of 2024 was $17.5 million, or 23.1% of revenues, which is consistent with our historical performance.

Sarah: Cost of product revenues for the first quarter of 2024 was $17 $5 million or 23, 1% of revenues, which is consistent with our historical performance.

Sara M. Bonstein: Turning to our GAAP operating expenses, in the first quarter of 2024, research and development expenses were $121.1 million, and SG&A expenses were $93.1 million, reflecting continued investment in both our early and mid-to-late stage pipelines, as well as launch readiness activities for Brenso Catholic. In closing, Insmed's solid financial performance in the first quarter keeps us on track to deliver on our full-year guidance. But more importantly, we remain well-positioned financially as we see double-digit growth from our global commercial efforts, positive top-line results from the investment in clinical work in TPIP, continued progress across all of our clinical programs, and the imminent Aspen data readout, with nearly $600 million of cash giving us substantial optionality on the other Now, we would like to open the call to your questions. Operator, can we take the first question, please?

Sarah: Turning to our GAAP operating expenses.

Sarah: In the first quarter 2020 for research and development expenses were $121 $1 million and SG&A expenses were $93 $1 million, reflecting continued investment in both our early and mid to late stage pipelines as well as launch readiness activities for <unk>.

Sarah: In closing <unk> solid financial performance in the first quarter keeps us on track to deliver on our full year guidance.

Sarah: More importantly, we remain well positioned financially as we see double digit growth from our global commercial efforts positive topline results from the investment in clinical work in CPI P continued progress across all of our clinical programs and the imminent Aspen data readout with nearly $600 million of cash.

Sarah: Cash, giving us substantial optionality on the other side of that event.

Speaker Change: Now we would like to open the call to your questions. Operator can we take the first question. Please.

Operator: Thank you. We will now begin the question and answer session. If you have dialed in and 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. If you are called upon to ask your question while listening via the loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking questions.

Speaker Change: Thank you we will now begin the question and answer session. If you have dialed in I would like to ask a question. Please press star one on your telephone keypad duration hand in giant Q, if you will.

Speaker Change: To withdraw your question simply press Star one again, if you are called upon to ask your question or listening via loud speaker on your device. Please pick up a handset any sure that your phone is snap on mute when asking a question will you do a quest for today's session that you. Please limit to two questions for person and if you wish to ask further you can please rejoin the queue.

Operator: We do request for today's session that you please limit your questions to two per person, and if you wish to ask further, you can please rejoin the queue. Again, press star one to join the queue, and your first question comes from the line of Andrea Tan from Goldman Sachs. Please go ahead. Good morning. Thanks for taking our question. Sara, maybe I could start with you.

Speaker Change: Again press star one to join the queue and our first question comes from the line of Andrea <unk> from Goldman Sachs. Please go ahead.

Andrea Tan: I'm just wondering if you could provide some additional color on what you're seeing that drove such a high rate of enrollment forms this quarter. And when you think about your estimated 1 billion peak sales per error case, what assumptions underpin that with respect to how the drug would be used in the refractory versus the frontline setting? Sure. I'm happy to address that, Andrea, and thanks for the question. You know, I continue to be so impressed with our commercial team and their performance.

Andrea: Good morning, Thanks for taking our question, Sir maybe I could start with you just wondering if you could provide some additional color on what you're seeing and.

Andrea: That drove such a high rate of enrollment forms this quarter.

Andrea: And when you think about your estimated 1 billion peak sales for aerospace what assumptions underpin not with respect to how the drug would be used in the refractory versus the frontline setting.

Speaker Change: Sure happy to address that Andrea and thanks for the question I continue to be so impressed with our commercial team and their performance at.

Sara M. Bonstein: At the beginning of the year, we set out to have double-digit growth, and that's exactly what we showed in Q1, and we saw that across all three of our territories. So, it really gives us great confidence in reiterating the guidance of 340 to 360. The commercial team continues to execute, and as you point out, Andrea, the medical team continues to execute as we are laser-focused now on the potential label expansion. We feel, if you look at the underlying patients, there is a three- to five-fold increase in the patients we think we will be able to attract with a potential label expansion, giving us a clear line of sight to a billion-dollar opportunity pending regulatory approval for ARICASE

Speaker Change: At the beginning of the year, we set out to have double digit growth and that's exactly what we showed in Q1 and we saw that across all three of our territory. So really gives.

Speaker Change: It gives us great confidence in reiterating the guidance of $3 40 to $3 60, the commercial team continues to execute and as you point out Andrea the medical team continues to execute as we are laser focused now on the potential label expansion.

Speaker Change: We feel if you look at the underlying patients. It's a three to five fold increase in the patients. We think we will be able to.

Speaker Change: Attracts with a potential label expansion, giving us a clear line of sight to $1 billion.

Speaker Change: Opportunity pending regulatory approval for aerospace, we believe that the price that we charge today for.

Sara M. Bonstein: We believe that the price that we charge today for refractory will be able to carry forward into the label expansion, and as we've mentioned previously, we are planning on hosting a commercial day on the other side of Aspen to do a deep dive across all of our pillars, including ARICASE, to continue to educate on the broader label expansion opportunity.

Speaker Change: Refractory will be able to carry forward into the label expansion and as we've mentioned previously we are planning on hosting our commercial day on the other side of Aspen to do a deep dive across all of our pillars, including Erra case to continue to educate on the broader label expansion opportunity.

Gene Sullivan: Okay, and then, Jean, maybe I could just ask you quickly about the blinded-blended PAH data, just wondering if you're able to share what proportion of patients did see an improvement in PVR, and of those, what their average rate of improvement was. Just curious if it's still, I guess maybe curious if the magnitudes are still similar to the first cut of the data where the average PVR reduction in those patients was 47%, and there had been some commentary around some patients seeing an excess of 65%. Thanks so much.

Speaker Change: Okay, and then Jim maybe I could just ask you quickly on the blinded blended on ph data just wondering if youre able to share what proportion of patients did see an improvement in PV, Dr and of those what their average rate of improvement just curious if it's still.

Jim Sullivan: I guess, maybe just curious if the magnitude is still similar to the first cut of the data where the average PV or reduction in those patients is 47%.

Speaker Change: And there had been some commentary around some patients seen in excess of 65%. Thanks. So much.

Gene Sullivan: Yeah, sure. Thank you for the question. And as you said last time, we noticed that we could divide them very clearly into those that improved and those that didn't improve, and the ratio that was roughly mirrored our 2 to 1 randomization. And so we presented some data on if you looked at just those who improved. Now, with an increasing number of patients, if we use the definition of any improvement of PBR at all, we would capture some patients who had really negligible improvements, like very, very small, 2%, 3% reduction in their PBR. And so we didn't really feel like that was really representative.

Jim Sullivan: Yes sure. Thank you for the question.

As you said last time, we noticed that we could divide it very clearly into those that improved and didn't improve and.

Speaker Change: Ratio that was roughly mirrored our two to one randomization and so we presented some data on if you looked at just those will improve now with increasing number of patients. If we use that definition of any improvement of PBR at all we would capture some patients who had really negligible negligible improvement.

Speaker Change: Very very small you know.

2%, 3% reduction in their PBR and so we didn't really feel like that was really representative to answer. Your question directly. If you have if you take that exact definition of any improvement of PBR no matter, how small it was more like 75% of the patients had that but again.

Gene Sullivan: To answer your question directly, if you take that exact definition of any improvement in PBR, no matter how small, it was more like 75% of the patients had that. But again, we wouldn't really want to call someone who decreased their PBR by 5% a real responder. And so we didn't do that analysis of responders versus non-responders.

Speaker Change: We wouldn't really want to call someone who decreased their PBR by 5% as a real responder and so we didn't do that analysis of like responders versus non responders. We did talk internally like what it makes sense to then divided into three groups, which is sometimes done like groups that responds.

Gene Sullivan: We did talk internally, like, would it make sense to then divide it into 3 groups, which is sometimes done, like groups that responded, groups that got worse, and a group that sort of stayed about the same. But we didn't want to sort of change the metric that we were reporting from the last time. So we just didn't do that analysis.

Speaker Change: Age groups.

Speaker Change: Got worse in a group that sort of stay about the same and then but we didn't want to sort of change the metric that we were reporting from the last time. So we just didn't do that analysis, we do consider continue to see patients who have.

Speaker Change: The remarkable decreases like remarkable in the sense that this shouldn't happen without the addition of <unk>.

Speaker Change: New therapeutic.

Daniel: We do continue to see patients who have remarkable decreases, like remarkable in the sense that this shouldn't happen without the addition of a new therapeutic. And our investigators are very impressed when you see a 50% reduction in PBR, like, that just doesn't happen. What you would expect, if anything, would be a decline in patients who have not had a change in their therapy regimen because it's a progressive disease. Our next question comes from the line of Vamil Divan from Guggenheim. Please go ahead. Hi, this is Daniel.

Speaker Change: Our investigators are very impressed when you see a 50% reduction in PV.

Speaker Change: It just doesn't happen.

Speaker Change: Like what you would expect if anything would be a decline.

Speaker Change: And patients who have not had a change in there.

Speaker Change: Therapeutic regimen, because it's a progressive disease.

Speaker Change: Okay. Thanks, so much.

Speaker Change: Our next question comes from the line of John <unk> from Guggenheim. Please go ahead.

Daniel: Thanks for taking the questions. I have a couple of questions on TPIP, if I can. So the first one for PHLD, you see that there are about 38% of patients that show a drug-related cough. It seems fairly mild, but are there any things that can be done?

Speaker Change: Hi, This is Daniel on for <unk>. Thanks for taking my questions I have a couple of questions on <unk> if I can.

Daniel: So the first one.

Speaker Change: <unk>.

Daniel: Yes, it's about like 38% of patients that show that drug related costs fairly mild, but I guess are there any things that can be done.

Daniel: to maybe lower this cost for patients. And I guess I was kind of curious if that might be extra important to those patients that might be moving up to an even higher dose in the open label attention in PAH. So that's my first question.

Speaker Change: Maybe lower.

Speaker Change: This cost for patients.

Speaker Change: And I guess I was kind of curious if that is.

Speaker Change: It might be extra important to those patients that might be moving up to an even higher dose in the open label extension and ph.

Speaker Change: That's my first question and then the second question is maybe more on the broader TP IP opportunity. It was previously.

Daniel: And then the second question is maybe more on the broader TPIP opportunity. It was previously said that it's a $2 billion plus opportunity. I was wondering if you could maybe break down this opportunity between the different indications and then maybe between geographies of the U.S. and the ex-U.S. markets.

Speaker Change: $2 billion plus opportunity I was wondering if you can maybe break down the pipe.

Speaker Change: Sandy between the different indications and then may be between geographies of U S and the ex U S markets now I'm just curious if the data.

William Lewis: Now, I'm just curious about the data. I don't know if it has any recent impact on your views on this. Thank you. Daniel, I'll just jump in, and then I'll ask Gene to take the specific question on COFF. I think with regard to the opportunity. Stay tuned. We're going to do a much deeper dive on the commercial day that Sara made reference to in the aftermath of the Aspen data production into what the TPIP opportunity is.

Speaker Change: So it hasn't had any impact.

Speaker Change: Impact on your views on this.

Speaker Change: Thanks.

Speaker Change: Daniel I'll just jump in and then I'll ask Jim to take the specific question on cost I think with regard to the opportunity stay tuned we're going to go in a much deeper dive on the commercial day that Cerro made reference to in the aftermath of the asthma data production.

William Lewis: I will tell you this, our target product profile is completely supported, if not surpassed, by the data that we've seen today. And if that continues, I think we will continue to feel very comfortable with the sort of peak sales at $2 billion plus.

Speaker Change: What the TPI.

Speaker Change: <unk> opportunity is I will tell you. This our target product profile is completely supported if not surpassed by the data that we've seen today and if that continues I think we feel.

Speaker Change: Continue to feel very comfortable with the sort of peak sales at $2 billion plus in and certainly based on what's been happening in ph ILD.

William Lewis: And certainly, based on what's been happening in PHILD and PAH generally, that is a comfortable target for us. These data today, I think, are striking. They're early.

Speaker Change: NPH generally that is a comfortable target for us. These data today I think we're striking there early we want to emphasize the ph ILD study is small.

William Lewis: We want to emphasize the PHILD study is small, but the efficacy measures, while they're exploratory, are encouraging, I would say. And should they end up being the exact target product profile, the commercial profile we've suggested, we feel very comfortable with it. And we'll have more to say about that, Daniel, on commercial day.

Speaker Change: But the efficacy measures.

Speaker Change: While they are exploratory are encouraging I would say and should they end up being the exact target product profile. The commercial profile. We've suggested we feel very comfortable with and we'll have more to say about that Daniel on the commercial day gene do you want to take the question about cost.

Gene Sullivan: Gene, do you want to take the question about COFF? Sure, yeah. You know, the first point to make is that the PHILD population is different than the PAH population. In PAH, the lung parenchyma is essentially normal. The histologic abnormality is in the vasculature, and cough really isn't a significant symptom of the disease, whereas in interstitial lung disease, cough is a significant symptom of the disease.

Daniel: Sure Yeah.

Daniel: The first point to make is that the ph ILD.

Daniel: Population is different than the ph population and PIH to lung parenchyma is essentially normal the histological abnormalities in the vasculature and cough really isn't a significant <unk>.

Daniel: Symptom of the disease, where in interstitial lung disease cough is a significant symptom of diseases, president and most patients to some degree or another so that was sort of part of the reason to go in and do an initial safety study.

Gene Sullivan: It's present in most patients to some degree or another. So that was sort of, you know, part of the reason to go in and do an initial safety study in PHILD, just to see how this drug would be tolerated in patients who have this underlying parenchymal disease. And so you point out that we did see an imbalance in terms of study drug-related adverse events, and that was particularly driven by drug-related cough.

Daniel: In ph ILD just to see how this drug would be tolerated in patients who have this underlying <unk> disease.

Daniel: And so you pointed out that we did see an imbalance in terms of study drug related adverse events and that was particularly driven by drug related costs.

Gene Sullivan: What that means is there was something about the cough in patients on active treatment that made the investigator believe it was related to the drug, and what that was was the temporal association with dosing. So it tended to be, you know, in discussions with the investigators, it tended to be a very mild cough-cough right after taking the drug and really wasn't problematic, was rated as mild, did not, you know, result in anyone discontinuing treatment, and so forth.

Daniel: What what that means is there was something about the cough in patients on active that made the investigator believes it was related to the to the drug and what that was was the temporal association with dosing. So it tended to be in discussions with the investigators are tend to be a very mild cough cough right after taking the drug.

Daniel: It really wasn't problematic.

Daniel: Was graded as mild did not.

Daniel: And to anyone discontinuing treatment and so forth and kind of the proof is in the putting that despite that.

Gene Sullivan: And, you know, kind of the proof is in the pudding that they, despite that imbalance in cough, were able to titrate up to the highest dose, 640. So, you know, we feel pretty good about it. What we wanted to exclude was that in patients with underlying parenchymal lung disease, would this drug somehow, you know, more exacerbate their underlying cough to a degree that was problematic clinically, and really, you know, I think the data suggests that's not the case. And so we're really pretty pleased with that.

Daniel: That imbalance in cost they were able to titrate up to six <unk>.

Daniel: For the highest dose of 640.

Speaker Change: So we feel pretty good about it.

Speaker Change: What we wanted to exclude was that in patients with underlying Franklin <unk> lung disease with this drug would be somehow more.

Speaker Change: Exacerbate their underlying cost to a degree that was problematic clinically and really I think the data suggests that's not the case and so we're really pretty pleased with that.

Speaker Change: I think you raised the question of what happens when we go higher and we will see as we said before.

Gene Sullivan: I think you raised the question of what happens when we go higher, and we'll see, as we said before, the data on more is better, if you will, with prostanoids is very clear. With pulmonary arterial hypertension, you know, with all of the routes of administration of troprostanoids, it's very clear that the higher you can go, the more efficacy you can get. And so we definitely, as I mentioned, amending the protocol to the Open Label Extension to allow for these higher doses to just kind of see where we can go in PAH.

Speaker Change: The data on more is better if you will with <unk> is very clear with pulmonary arterial hypertension, no with all of the routes and administration of Coprostanol, It's very clear that the higher you can go in more efficacy you can get and so we definitely we.

Speaker Change: Our as I mentioned.

Speaker Change: Amending the protocol to the open label extension to allow for these higher doses to just kind of see where we can go and PVH. We chose not to do that in the open label extension for ph ILD.

Gene Sullivan: We chose not to do that in the Open Label Extension for PHILD primarily because the data that more is better is not entirely clear in PHILD, you know; there just is less clinical experience in that regard. So we weren't sure that it was necessary.

Speaker Change: In.

Speaker Change: Primarily the data that more is better it's not entirely clear.

Speaker Change: And.

Speaker Change: Ph ILD they are just as less clinical experience in that regard.

Speaker Change: We werent sure that it was necessary.

Gene Sullivan: And also, we'd like to get some clinical information on PAH patients, how they start to tolerate higher doses. So hopefully, that answers your question. I'll just add one final point on that, Daniel, which is a reminder that treatment emergent adverse events leading to discontinuation were actually higher in the placebo arm than they were in the TPIP arm, with 30% in the placebo arm and 13.8% in TPIP. So, in terms of what it means for patients, as Gene said, continuing to be able to take the drug, it didn't seem to be an impediment. Okay, great. Thank you very much for answering my question. Our next question comes from the line of Jessica Falk from J.P. Morgan. Please go ahead. Great. Good morning.

Speaker Change: And also we'd like to get some clinical information on ph patients how they start to tolerate higher doses. So hopefully that answers your question.

Speaker Change: I'll just add one final punctuation on that Daniel which as a reminder, that treatment emergent adverse events, leading to discontinuation were actually higher in the placebo arm than they were in the TPP TPI P arm with 30% in the placebo arm and 13, 8% in <unk>.

Speaker Change: So in terms of what it means for patients as Jim said continuing to be able to take the drug it didn't seem to be an impediment.

Speaker Change: Okay, great. Thank you very much for answering my questions.

Speaker Change: Our next question comes from the line of Jessica Fye from Jpmorgan. Please go ahead.

Jessica Falk: Thanks for taking my question. It's sort of a two-part question on brentsacadab. Thinking back to the Willow data, can you remind us why or what the hypothesis is behind not really seeing meaningful changes in quality of life, St. George's, LCQ, and those kinds of measures? So, basically, what would explain benefits that are measurable on exacerbations but not those domains? And the second part kind of related to that is I think you've talked in the past about doctors in the Aspen trial kind of suggesting they can tell if patients are on drugs or not, similar to Willow. And I'm curious what they cite. Curious what they would say if, um...

Jessica Fye: Great. Good morning, Thanks for taking my question.

Jessica Fye: Sort of a two part question on <unk>.

Jessica Fye: Thinking back to the Willow data can.

Jessica Fye: Can you remind us why or what the hypothesis is behind not really seeing meaningful changes on quality of life, St. Georges <unk> and those kind of measures.

Jessica Fye: So basically what what would explain benefits that are measurable on exacerbations, but not those domains and the second part kind of related to that is I think you've talked in the past about doctors in the Aspen trial.

Jessica Fye: Suggesting they can tell if patients are on drug are not similar to willow and I'm curious what they cite.

Jessica Fye: Curious what they say is fine.

Jessica Falk: If it may not be, you know, quality of life measures given that exacerbations are fairly infrequent, and I'm not sure that would be kind of the tip off. Hope that made sense. Yeah, so I'll take a shot of that, Jessica, and then I'll invite Gene to comment on anything further he'd like to. I think, with regard to Willow and quality of life, and remind everyone that that was a six-month study, and it takes about a month for the drug to get to full pharmacodynamic effect. So really, it's not a lot of time for patients to be able to capture and express an impact on quality of life. So we didn't really expect to see one there.

Jessica Fye: It may not be.

Jessica Fye: Quality of life measures given the exacerbations are fairly infrequent and I'm not sure that would be kind of the the tip off.

Jessica Fye: Hope that makes sense.

Speaker Change: Yes, so I'll take a shot of that just given then I'll invite.

Speaker Change: Jean to comment anything further you'd like to I think with regard to willow and quality of life.

Jean: To remind everyone that that was a six month study and it takes about a month for drug to get the full pharmacodynamic effect. So really it's not a lot of time for patients to be able to capture in express and impact on quality of life. So we didn't really expect to see one there. We're hopeful we may be able to see one in the.

William Lewis: We're hopeful we may be able to see one in the 12-month study that we're conducting, which is the Aspen study. But once again, I would turn attention to the key focus of the study, which is exacerbations. That is the thing we're really trying to impact.

Jessica Fye: The 12 month study that we're conducting which is the Aspen study, but once again I would turn attention to the key.

Jessica Fye: Focus of the study, which is the exacerbations that is the thing we're really trying to impact.

William Lewis: And if we accomplish that, which is the primary endpoint of the study, then absolutely, we are confident the drug will be adopted and utilized by patients and physicians alike with a lot of enthusiasm. I think when patients talk about their experience with the drug and convey this to physicians. It's a combination of different things that each patient feels. And, of course, one always has to take with a huge grain of salt any qualitative characterization from a physician. But we did hear this in Willow, and we are hearing it again in Aspen.

Jessica Fye: If we accomplish that which is the primary endpoint of the study then absolutely. We are confident the drug will be adopted and utilized by patients and physicians alike with a lot of enthusiasm I think.

Jessica Fye: When when patients talk about.

Jessica Fye: Their experience on the drug.

Jessica Fye: And convey this to physicians, it's a combination of different things that each patient feels and of course, one always has to take with a huge grain of salt any qualitative characterization from a physician, but we did hear this in Willow and we are hearing it again in Aspen and Thats why we mentioned it I think typically this is related to the patient's experience with exacerbations.

William Lewis: And that's why we mentioned it. I think, typically, this is related to the patient's experience with exacerbations. And if they're feeling that those are not occurring, or that they are feeling a greater degree of energy, or perhaps the characterization of the sputum, all of these things are different experiences that patients have that collectively make them feel like they're experiencing a benefit. And so we're hopeful the QOL will capture that, but it's not certain. And, of course, our primary focus is on the exacerbation impact. If we achieve that, then we will certainly have accomplished victory.

Jessica Fye: And if they are feeling that those are.

Jessica Fye: Not occurring or that they are feeling a greater degree of energy or perhaps the.

Jessica Fye: The characterization of the sputum all of these things are different experiences that patients had that collectively make them feel like they are experiencing a benefit and so we're hopeful the qol, we'll capture that but it's not certain and of course, our primary focus is on the exacerbation impact if we achieve that then.

William Lewis: I don't know, Gene, if you want to add anything further. No, I think that was very well said. I really don't have anything to add to that. Can I just add a quickie on TPIP and the PHILD data on oxygen saturation? I don't know if I just missed it somewhere, but can you give us the baseline oxygen saturation for each arm? Gene, I don't know if we have that. Do you want to address that now if it's handy? If not, we can circle back.

Jessica Fye: We will certainly have accomplished victory I don't know, Jim if you want to add anything further.

Jim Sullivan: No I think that was very well said I really don't have anything to add to that.

Speaker Change: Can I just had a quickie on TP IP in ph ILD data on oxygen saturation.

Speaker Change: I don't know if its I just missed it somewhere but can you give us the baseline oxygen saturation for each arm.

Speaker Change: Gene I don't know if we have that you want to address that if it's handy if not we can circle back.

Jessica Falk: Yeah, I don't know that we've included that in the results. Is there something that you're getting at with that question? I mean, Yeah, oh, we didn't conclude that in the baseline demographics information, did we? There was some indication that the TPIP group was a little sicker. Their use of the supplement option was a little bit higher. Their FEC was a little bit lower.

Gene Sullivan: Yes, I don't know that we've included that in the results is there something that youre getting out with that question I mean.

Speaker Change: I was just wondering if there was a allen.

Gene Sullivan: Yes, we didn't conclude that in the.

Gene Sullivan: And the baseline demographics Commission did we.

Gene Sullivan: There was some indication.

Gene Sullivan: <unk>.

Jim Sullivan: <unk> group.

Jim Sullivan: It'll sicker their use of supplement option was a little bit higher RPC was a little bit lower and frankly during the <unk>.

Gene Sullivan: And frankly, during the six-minute walk test, they tended to desaturate at baseline a little bit more, so there was some evidence that they were a little bit sicker. So that's why we presented change from baseline for each of the measures. Great, thank you.

Jim Sullivan: Six minute walk test they tended to desaturate at baseline a little bit more so there were some there was some evidence that that they were a little bit sicker. So that's why we presented.

Jim Sullivan: <unk> from baseline for each of the measures.

Speaker Change: Great. Thank you.

Leiyang Wang: Our next question comes from the line of Leiyang Wang from Barclays. Please go ahead. Hey, thanks for taking my question. Congratulations on the data. So, a couple of questions on TPIP.

Speaker Change: Our next question comes from the line of Leon Wang from Barclays. Please go ahead.

Leiyang Wang: One, on slide seven, the six minute walk distance was not available for the placebo arm. Can you just remind us whether this was because of an inability to collect data or just a lack of data? And also any color on the time to response in PHILD, specifically looking to see if you can characterize the exploratory efficacy measures and how that changed from week 12 to week 16. Thank you. Gene, do you want to take those? Sure, yeah. In slide seven, the N.A.

Leiyang Wang: Hi, Thanks for taking my question and congrats on the data.

Leiyang Wang: So a couple on <unk>.

Jim Sullivan: One.

Leiyang Wang: On slide seven the six minute walk distance was not available for the placebo arm can you just remind us on <unk>.

Leiyang Wang: The inability to collect data or it's just a lack of data.

Leiyang Wang: And also any color on the time to response in ph ILD, specifically looking to.

Jim Sullivan: See if you can characterize the exploratory efficacy measures and how that changed from <unk>.

Jim Sullivan: Week 12, two week 16, thank you.

Jim Sullivan: Gene you want to take those.

Gene Sullivan: refers to the fact that what we're presenting here is the placebo-corrected change from baseline. So, the 30 that appears under week 16 is the placebo-corrected effect size. So, there's no comparable data point to put under the placebo arm. So, it's N.A., meaning not applicable more than not available, if that makes sense.

Gene Sullivan: Sure, Yes, and that slide seven refers.

Gene Sullivan: <unk> refers to the fact that what we're what we're presenting here is the placebo corrected change from baseline. So the 30 that appears.

Gene Sullivan: Under <unk> 16 is the placebo corrected.

Gene Sullivan: Effect size. So there is no comparable.

Gene Sullivan: Data point to put under the placebo arm. So it's it's a meeting not applicable more than not available.

Gene Sullivan: If that makes sense and so what we've included in that box is to emphasize that the point estimate is 30 with a point estimate and that is remarkably similar to the point estimate of the effect size on six minute walk that was seen in the pivotal trial for Thai VSO for ph ILD the so-called increase.

Gene Sullivan: And so, what we've included in that box is to emphasize that the point estimate is 30. The point estimate, and that's remarkably similar to the point estimate of the effect size on the six-minute walk that was seen in the pivotal trial for Tybazo for PHILD, the so-called increased trial, was comparable. However, we want to be very, very clear, and we put two indicators of variability. The confidence intervals are extremely wide in that square, and then the p-value is, you know, not even close to statistical significance. So, that is, I think that hopefully that responds to your question about what that N.A. means.

Gene Sullivan: Trial was it was comparable however, we want to be very very clear and we put two indicators of variability.

Gene Sullivan: The confidence intervals are extremely wide and that in that square and then the P value is.

Gene Sullivan: It doesn't even close to statistical significance so that is.

Speaker Change: I think that hopefully that responds to your question about what that means.

Gene Sullivan: And the other thing you asked about is sort of the cadence of... of the improvement. And we have not released that yet. We haven't analyzed that closely to see, you know, how quickly we start to see a difference. I think that that's data that will emerge as more fulsome presentations of the data. But since, you know, the pivotal trial endpoints would be change from baseline to the end, that's what we decided to focus the top line results on. Thank you. Our next question comes from the line of Joseph Schwartz from Lyrinc Partners. Please go ahead.

Speaker Change: Other you asked about sort of the cadence of.

Speaker Change: Of the improvement and we have not released that yet we haven't analyzed that closely to see how quickly.

Gene Sullivan: We start to see a difference.

Gene Sullivan: I think that Thats.

Gene Sullivan: It is data that will emerge as a more fulsome presentations of the data but since.

Gene Sullivan: Pivotal trial endpoints would be from change from baseline to the end, that's what we decided to focus the topline results on.

Speaker Change: Thank you.

Speaker Change: Our next question comes from the line of Joseph Schwartz from Leerink Partners. Please go ahead.

Joseph Patrick Schwartz: Hi, congrats on the very strong TPIP data. I was wondering how many of the patients in the Phase 2 study of TPIP and PAH have been enrolled in the 10 countries which are allowing you to titrate up to 1280 micrograms? And then I have a follow-up on Brenzo. Yeah, so we are talking to other countries. I can answer that part of it. I don't know, Gene, if you want to take the other one, if we know that. Yeah, I don't have the specific figures because the reason is that we don't think the door isn't closed in other countries.

Joseph Patrick Schwartz: Hi, Congrats on the very strong CPI peed data I was wondering.

Joseph Patrick Schwartz: How many of the patients in the phase II study of <unk>.

Joseph Patrick Schwartz: E&P have been enrolled in the 10 countries, which are allowing you to titrate up to 12 80 micrograms and are you still talking to other countries health authorities about doing this or will it just be.

Joseph Patrick Schwartz: <unk> patients when we see that data and then I have a follow up on Brexit.

Gene Sullivan: It's just that the back and forth is ongoing, you know, either with the regulatory authority, then you have to go through the ethics committee or IRB, so those conversations are ongoing. So we haven't, it doesn't come to mind how many patients are currently covered because I think we expect more of those countries to eventually allow expanded dosing. That's helpful. Thank you. No, please, Will. Sorry about that.

Joseph Patrick Schwartz: Yes.

Speaker Change: We are talking to other countries I can answer that part of it I don't know gene if you want to take the other one if we if we know that.

Gene Sullivan: Yes, I don't have the specific figures because.

Speaker Change: For the reason is that we don't think it's the Doris and closed in the other countries. It's just that the back and forth is ongoing.

Gene Sullivan: Either with.

Gene Sullivan: First you have to go through the regulatory authority that you have to go through the ethics committee or IRB. So those conversations are ongoing so we haven't it.

Gene Sullivan: It doesn't come to mind, how many patients are currently covered because I think we expect more of those countries to eventually allow.

Gene Sullivan: The extended dosing.

Speaker Change: That's helpful. Thank you.

Speaker Change: Sorry go ahead.

Speaker Change: No.

Speaker Change: Please.

Speaker Change: Sorry about that I was just going to say, we haven't given out any specific data about patients that have progressed in the open label extension and just to note that only will be taking place in the ph study not the TPI Pea study.

William Lewis: I was just going to say we haven't given out any specific data about patients that have progressed into the open label extension. And just to note, that only will be taking place in the PAH study, not the TPIP study. Right. Okay. Thank you.

William Lewis: That's helpful. And then on Brenzo, to what extent do you think the market opportunity could be influenced by the magnitude of effect size that we see in Aspen? And what's the right way to contextualize the clinical benefit of something like a 15, 25 or 35% reduction in exacerbation? How have your discussions with physicians and payers gone?

Speaker Change: Right. Okay. Thank you that's helpful and then on <unk>, so to what extent do you think the market opportunity could be influenced by the magnitude of effect size that we see in ASP and then what's the right way to contextualize, the clinical benefit of something like a <unk> 25 or 35%.

Speaker Change: <unk> and exacerbations.

Speaker Change: How have your discussions.

Speaker Change: Physicians and payers gone at that time.

William Lewis: Yeah, I think what we've been trying to be very clear about is that, You know, the clinically meaningful threshold, I think, that everybody sort of agrees as a floor is about 15%. People would like to see 20%, and I think we certainly have tried to design the trial to capture that treatment effect. We have sort of oriented our entire thinking about this by saying that if we can get below 0.01 and a treatment effect of around 20%, that we would, for either dose, consider that a home run.

Speaker Change: Yes, I think what we've been trying to be very clear about is that.

Speaker Change: The clinical meaningful threshold I think that everybody is sort of agrees. There is a floor is about 15% people would like to see 20%.

Speaker Change: And I think we certainly have tried to design the trial to capture that treatment effect, we have sort of oriented our entire thinking about this by saying that if we can get below <unk>, one and the treatment effect of around 20%.

Speaker Change: That we would do for either dose we would consider that a homerun then we've got a drug.

William Lewis: Then we've got a drug, and that we think will be a very successful outcome. Of course, we saw higher rates than that in Willow, and we certainly hope that is replicated in Aspen. We have no reason to believe that it wouldn't be.

Speaker Change: And that we think will be a very successful outcome.

Speaker Change: Of course, we saw higher than that and Willow and we certainly hope that is replicated in Aspen. We have no reason to believe that wouldn't be the baseline characteristics. The execution of the trial all the design elements.

William Lewis: The baseline characteristics, the execution of the trial, and all the design elements are in parallel to what was seen in Willow, so we're very hopeful. But that's sort of how we think about the threshold. As it goes up, it certainly would speak to the demand and the degree of enthusiasm, I think, that people will have in the physician community for calling their patients in, which is a fact we've already heard. If this were to find its way to clinically meaningful thresholds of, call it 20% or more, I think patients will be called in to receive the treatment by physicians with enthusiasm.

Speaker Change: In parallel to what we're seeing in Willow. So we're very hopeful, but that's sort of how we think about the threshold as it goes up it certainly would speak to the demand.

Speaker Change: And the degree of enthusiasm I think that people will have in the physician community for calling their patients in which is the fact that we've already heard but if this were to be.

Speaker Change: Find its way to clinically meaningful thresholds of call it 20% or more I think patients will be called in to receive treatment by physicians with enthusiasm.

William Lewis: If that number goes up even more, it will probably affect enthusiasm. I don't know that it's going to dramatically affect the way we think about the addressable market, but we're certainly going to reflect on the target product profile in its totality, which includes both efficacy and safety and some other considerations. But all of the education about this has already been underway with our medical group and, indeed, in our market access efforts as well.

Speaker Change: That number goes up even more.

Speaker Change: We affect the enthusiasm I don't know that its going to dramatically affect the way, we think about the addressable market, but we're certainly going to reflect on the target product profile in its totality, which includes both efficacy and safety.

Speaker Change: And some other reflections, but all of the education about this has already been underway with our medical group and indeed in our market access.

William Lewis: So we feel like we've got a pretty good understanding of how people are going to react to this, and that's why we emphasize getting below 0.01 with one dose and a treatment effect of 20% or more. Thank you. Our next question comes from the line of Nicole Germino from Truvis Securities. Please go ahead.

Speaker Change: Front as well so we feel like we've got a pretty good understanding of how people are going to react to this and that's why we emphasize getting below point to one with one dose and the treatment effect of 20% or more.

Speaker Change: Thank you.

Speaker Change: Our next question comes from the line Nicole <unk> from <unk> Securities. Please go ahead.

Speaker Change: Okay.

Nicole Germino: Hi, thank you for your question. Regarding our TIC and CHRI updates, um, I've been in the office for almost three years, and this isn't part of the file. I'm sorry.

Nicole: Alright, thank you.

Nicole: Next question.

Nicole: Yes.

Nicole: Okay.

Nicole: Thank you.

Nicole: Okay.

Nicole: Okay.

Nicole: Sorry.

Operator: I'm having a hard time understanding the question. It sounds like your line is a little broken up. Could I just ask you to repeat that, please? Going back to TKIP and PHIL-E, how does the BROB and oxygen model compare to titanium, and does it target that? Gene, did you hear that question? That sounded like, "How does it compare to Taipezo?" How does, which aspect of TPIP on the PHILD side? Is that right, Nicole?

Nicole: I'm, sorry, I'm, having a hard time understanding the question. It sounds like Youre line is a little broken up could I just ask you to repeat it. Please.

Nicole: Sure.

Nicole: Ed.

Nicole: Just going back to the key.

Ed: How does the drop in okay.

Ed: And then contract.

Ed: Jean did you hear that question it sounded like how does it compare to type days, though.

Jean: How does.

Ed: Which aspect TPI.

Jean: Ph ILD side.

Jean: Alright.

Jean: Is that right did I get that right.

Operator: Did I get that right? Yeah, that's right. How does a drop in oxygen levels compare to the typing period? And if it's a non-targeted factor? Well, I'm really having a hard time hearing her.

Speaker Change: Yes, that's right.

Jean: How does it drop off again.

Jean: Eric.

Jean: And.

Jean: Targeted.

Jean: Okay.

Gene Sullivan: I think it was the oxygenation levels in the PHLD. How does it compare to the typhus? She's asking if the oxygen, the drop in oxygen levels, how do they compare to Tyvazzo.

Eric: Well Im really having a hard time hearing I think it was the oxygenation levels in the ph ILD, how does it compare to <unk> she is asking.

Jean: Oxygen the drop in oxygen levels, how do they compare.

Gene Sullivan: You know, we didn't do a direct comparison because, again, this is a small study and we're not trying to make claims against Tyvazzo. I think what we were looking for here was just to see that it didn't harm patients. So, I think the one point I want to make is that patients with interstitial lung disease desaturate when they walk. That is a function of the disease, and we wanted to make sure that, one, there was no negative impact of the drug on their oxygenation at rest or any negative impact on their desaturation during the course of exercise. And we think that's what we saw.

Jean: Two two <unk>.

Speaker Change: We didn't do a direct comparison because again this is a small study and we're not trying to make claims against <unk> I think what we were looking for here was just to see that it didn't harm patients. So I think the port.

Jean: One point I want to make is that patients with interstitial lung disease desaturate when they walk that that is a function of their disease and we wanted to make sure that one there was no negative impact of the drug on their oxygenation at rest or.

Jean: No negative impact on their desaturation during the course of.

Gene Sullivan: The reason we were even looking for that, the reason we were even, you know, considering that as a safety finding of interest is that when you deliver a vasodilator to the lung where there is underlying lung disease, there is a potential danger of dilating the vasculature in an area that's not ventilated. And you get what's called a shunt, blood going past the lung, which is not getting oxygenated because the area of the lung that it's delivered blood to is not getting ventilated.

Jean: And we think Thats, what we saw the reason we were even looking for that the reason we are even considering that as a as a safety finding of interest.

Jean: Is that when you deliver a vasodilator to the lung where there is underlying lung disease.

Jean: There is a potential danger of dilating the vasculature in an area, that's not ventilated and you'll get what's called shunt blood going pass the lung, which is not creating oxygenated because the area of long that it's delivered a blood too is not getting ventilated and there have been.

Gene Sullivan: And there have been problems when systemically administered vasodilators have been used to treat PHILD and, in fact, have led to Contraindications on the product labels for Rio Ciguad and for Ambrosantan, and the general understanding is that it's not a good idea to deliver a vasodilator systemically, orally, or IV in these patients. But as the increased trial showed, the increased trial is the trial, for everyone's benefit, of Tyvazo in this population, was that it wasn't a problem.

Jean: Problems when systemically administered vasodilator as have been used to treat ph ILD.

Jean: And in fact have led to.

Jean: Sure.

Jean: Contraindications and the product labels for a real Sigma and Forever Santana. The general understanding is that it's not a good idea to deliver a vasodilator systemically orally or IV in these patients, but as the increased trial show. The increased trial is the trial for everyone's benefit.

Jean: <unk> in this population was that that wasn't a problem and the theory behind that is that we're delivering.

Gene Sullivan: And the theory behind that is that we're delivering the vasodilator primarily just to the regions that are actually being ventilated because they're delivering it by inhalation. So, we just wanted to, you know, they apparently did not see it in, with PIVASO, and we just wanted to monitor that in our trial as well, and again, we were, we were pleased to see that at baseline pretest, there was no change; in fact, patients on placebo required a little bit more oxygen; the patients on active drug had no change in their oxygen supplementation, and then with exertion, there was really no significant decline Our next question comes from the line of Graig Suvannavejh from Missouri Securities. Please go ahead. Hi, this is Jerry on behalf of Graig.

Jean: As a dilator primarily.

Jean: Two of the regions that are actually being ventilated because you're delivering it.

Jean: The inflation.

Jean: So we just wanted to they apparently did not see it in.

Jean: With <unk> and we just wanted to monitor that in our trial as well and again, we were we're pleased to see that.

Jean: At baseline pre test stores, no change attack patients on placebo required a little bit more oxygen that patients on <unk>.

Jean: Active drug had no change in their oxygen supplementation, and then with exertion.

Jean: Really no significant decline compared to placebo.

Jean: Yeah.

Jean: Our next question comes from the line of Greg <unk> from Mizuho Securities. Please go ahead.

Jerry: Thanks for taking our questions. I'm going to grab some of the TPIP data. I guess, first, you know, on TPIP, based on what you know now, what would a phase three study in PHILD look like? And then I do have a follow-up on BRNZO as well. Yeah, I'll take that quickly.

Speaker Change: Hi, This is Jerry on for Greg Thanks for taking my questions and congrats on the <unk> data.

William Lewis: We haven't really put any thoughts in the public domain about what that phase three study will look like. We obviously want to have some interaction with the FDA and other regulatory authorities to ensure that what we produce from that trial will be adequate for full approval. I think today's data certainly suggests that there's going to be a clear path to being able to create such a trial. We'll rely very likely on what has worked in the past, but it's difficult to commit to anything further than that in the design sense because we're just, obviously, the data is fresh, and we're digesting it.

William Lewis: And then we're going to want to have dialogue with regulatory authorities, but as soon as that is accomplished, we'll get that design out to everyone so that they can understand what it's going to look like. Sorry, I can't be more specific. That's fine.

William Lewis: That's helpful. And then for, I guess, the upcoming Aspen readout, since, you know, you mentioned the comment that all patients in Aspen have reached that 52 weeks for all the adults, that time period. I'm wondering if that gives you any more granular timing on the timing of that data release. Boy, I tell you, that is the question of the day.

Jerry: I mean, it has been read out since you know you sometimes you come to the old patient asked and have reached that to be two weeks of all the adults died that time period I'm wondering that gives you a more granular timing on the time you know the date of release.

Jerry: Boy I tell you that is the question of the day [laughter] I wish I could be more specific we tried to narrow it down to the mid made end of June timeframe, which is you know 45 days. That's that's that's pretty specific for a biotech company. Let me just perhaps give a little bit more color on what is the sequence of events when you when you.

William Lewis: I wish I could be more specific. We tried to narrow it down to the mid-May to end of June time frame, which is 45 days. That's pretty specific for a biotech company. Let me just perhaps give a little bit more color on what the sequence of events is when you get to this point in a large trial. It's not simply the production of the top-line results, as is often the case for something like a phase 2 study. In this case, we not only need to produce the top-line results, but we need, by the time we lock the database, every detail and quality issue to be resolved, because this is a submission database.

Jerry: Get to this point and a large trial, it's not simply the production of the top on results as is often the case for something like a phase two study in this case, we not only need to produce the topline results, but we need by the time, we lock the database for every detail and quality issue to be resolved because this is a submission database and what I mean.

William Lewis: And what I mean by that is, this is the database that's going to the FDA and to other regulatory authorities around the world. So, if you will, there's an additional level of quality control and scrutiny to ensure that the database is submission quality. We would hate to snatch defeat from the jaws of victory by having good top-line results and then a database that gets rejected for some quality issue.

Jerry: By that is this is the database, it's going to the F D. A and the other regulatory authorities around the world. So if you will there's an additional level of quality control and scrutiny to ensure that the database is submission quality, we would hate to snatch defeat from the jaws of victory by having good topline results and then a database that got rejected for some.

Jerry: You know quality issue. So we're taking the necessary time to ensure that both goals or accomplish that we can produce the data in the database is in is in good shape and I'm happy to report every aspect of that effort at the company has gone incredibly well and an incredibly proud of our technical team for what they have been able to accomplish in that regard.

William Lewis: So, we're taking the necessary time to ensure that both goals are accomplished, that we can produce the data, and that the database is in good shape. And I'm happy to report that every aspect of that effort at the company has gone incredibly well, and I'm incredibly proud of our clinical team for what they've been able to accomplish in that regard. But it will be within that 45-day window. We're confident of that.

Jerry: But it will be within that 45 day window, we're confident of that and that's that's as specific as we can get but those are the reasons that are sort of pacing when when that database will be ready for for review.

William Lewis: And that's as specific as we can get. But those are the reasons that are sort of pacing when that database will be ready for review. Gaja, thanks for the call there, and congrats again.

Speaker Change: Got it thanks for the caller and congrats again.

Jason Eron Zemansky: Our next question comes from the line of Jason Zemansky from Bank of America. Please go ahead. Good morning.

Speaker Change: Alright next question comes from the line of <unk>.

Jason Eron Zemansky: Congratulations on the data and thanks for taking our questions. I was hoping you could provide some color on the discontinuation rates for TPIP. Appreciating these are small numbers, but about 14%, it's twice what was observed for the Tyvaso BREE study. That said, the rate of treatment-emergent AEs looks to be in line, and it doesn't look like cough was the source of this. Was there something about the four patients who discontinued, whether it was, I don't know, underlying disease severity or dose received?

Speaker Change: Good morning, Congrats on the data and thanks for taking our questions I was hoping you could provide some color on the discontinuation rates for T. P. I P.

Speaker Change: Appreciating these are small numbers, but about at 14%. It's twice what was observed for the Taipei. So brief study.

Speaker Change: That said the rate of treatment emerging as looks to be in line and it doesn't look like cough was the source of this was there something about the four patients who discontinued whether it was I dunno underlying disease severity or dose received or I don't know was it early in the study, especially as you noted.

Jason Eron Zemansky: Or, I don't know, was it early in the study, especially as you noted, the titration schedule was a little more aggressive? And then a follow-up, if I may. Gene, do you want to take this? Yeah, sure.

Speaker Change: Titration schedule was a little more aggressive and then a follow up if I may.

Speaker Change: G and you wanted to take that.

Gene Sullivan: Um, I think, you know, when we sort of use Tyvazo as the benchmark, we don't so much look at the BREE study as we do the INCREASE study. And I think that the discontinuation of treatment in our study actually compares favorably to the graph that you'll see in the publication that shows the discontinuations of treatment in the active arm with Tyvazo. So I guess I'd try to point you to the INCREASE study as a better comparator than the BREE study.

G: Yeah sure Yeah, I I think when we.

G: Sort of use the <unk> is the benchmark we don't so much look at the brief study as we do the increase steady and I think the discontinuation of treatment and our study actually compares favorably to the the breath that you'll see in the in the publication that shows the discontinuation of treatment.

G: The active arm with with <unk>. So so I guess I try to point you to the increase study is that better comparator then the breeze.

G: Study.

G:

Gene Sullivan: And then the second question was, the second part of it was, Well, was there something specific about these four patients? And like you'd said, the titration schedule is a little bit more aggressive than what you normally see with type A. So is that why they dropped out?

G: And then the second question was a second part of it was.

G: Well.

G: Was there something specific about these four patient, saying like you said the titration schedule is a little bit more aggressive than what you normally see what tie V. So is is that when they dropped out or I again was there something about the dose that they receive it just curious if there was something consistent amongst the patients.

Gene Sullivan: Or again, was there something about the dose that they received? I'm just curious if there was something consistent amongst the patients. Oh, the actual dropouts from the study were not drug related, and there was no signal of an inability to titrate the drug or anything like that in the PHL-B study. Got it.

Speaker Change: Oh, the actual dropouts from this study, we're not drug related and nothing you know.

Speaker Change: Nothing no no signal of.

Speaker Change: And the ability to titrate, the drug or anything like that and a ph all the study.

Speaker Change: Study.

William Lewis: Okay. And then just kind of thinking more broadly, when thinking about TPIP's potential under your guidance, how important is it that patients get to the 640 milligram or microgram dose or higher? You know, is it the assumption that the drug will provide more benefit given the higher dose, or, you know, is its value really in, you know, moving from four times daily to once daily administration? Yeah, so I'll just jump in on that one and then ask Gene to comment.

Speaker Change: Got it Okay, and then just kind of thinking more broadly when thinking about T. P. I P as potential and your guidance how important is it that patients get to the 640 milligram or microgram dose or higher.

Speaker Change: The assumption that the drug will provide more benefit given the higher dose or you know is is its value really and you know moving from four times daily to once daily administration.

Speaker Change: Yeah. So I'll just jump in on that one and then asked Jean to come in I think what you hear from treating physicians is the higher they can go the better from their point of view Indeed, when we first develop the drug and we're working on the target product profile, we spend a lotta time with Kols and ask them would they prefer a drug that had lower side effects.

William Lewis: I think what you hear from treating physicians is the higher they can go, the better from their point of view. Indeed, when we first developed the drug and were working on the target product profile, we spent a lot of time with key opinion leaders (KOLs) and asked them, would they prefer a drug that had lower side effects at a dose consistent with what's already being used, or a drug that had perhaps some side effects but could go up in quantity of the drug administered?

Jean: At at a dose consistent with what's already being used or a drug that had perhaps some side effects, but could go up in quantity of drug administered and the Universal response quite enthusiastic was go as high as you can because that's what we do with patients we push them to Max tolerated dose in practice. So we.

William Lewis: And the universal response, quite enthusiastic, was go as high as you can because that's what we do with patients. We push them to the max-tolerated dose in practice. So we picked 640 micrograms for this study, which is 60% greater than what is the equivalent of troprosinol that's already been administered four times already. So it's quite a substantial step up. Physicians are very encouraged by that.

Speaker Change: <unk> 640 micrograms for this study, which is 60% greater than what <unk> is the equivalent for possible. It's administered over four times already so it's quite a substantial step up the physicians are very encouraged by that they've now <unk> encouraged us in the P H setting.

William Lewis: They've now encouraged us in the PAH setting to double that yet again based on the safety profile that they've seen. And we consider that to be a ringing endorsement not only of what we've been able to accomplish so far but what the future may hold given some of the improvements we've seen in PBR just getting patients to 640. So I think there's a lot of promise here for the clinical results that we expect to see from PAH as patients move from 640 to even higher levels.

Speaker Change: <unk> to double that yet again based on the safety profile that they've seen and we consider that to be ringing.

Speaker Change: A ringing endorsement not only of what we've been able to accomplish so far but but the what the future may hold given some of the improvements we've seen in P. B R. Just getting patients to 640. So I think there's a lot of promise here for the clinical result that we expect to see from P. A H as patients moved from <unk>.

Speaker Change: <unk> 40 to even higher levels and that is a wonderful clinical objected that we have set for ourselves and it's a very high bar, but you know being able to get the higher doses should produce that result to be able to do it with a once a day administration is is the benefit of convenience as well as the clinical side I just.

William Lewis: And that is a wonderful clinical objective that we have set for ourselves, and it's a very high bar. But being able to get to higher doses should produce that result. And to be able to do it once-a-day is a benefit of convenience as well as the clinical side I just mentioned.

William Lewis: And the once-a-day piece was enough to rouse enthusiasm from treating physicians in and of itself, even if the clinical profile is the same. The fact that we're able to suggest we may be able to get even better clinical outcomes and have the once-a-day is really sort of the holy grail we're after and why we think this will be, as some have said, the potential go-to prosanoid of choice for the treatment of these patients. I don't know, Gene, if you have any other reflections.

Speaker Change: Mentioned in the once a day piece was enough to get enthusiasm from treating physicians in and of its own right. Even if the clinical profile with the same. The fact that we're able to suggest we may be able to get even better clinical outcomes and have the once a day is really sort of the Holy Grail, where after why we think this will be some absurd.

Speaker Change: The potential go to approximate of choice for the treatment of these patients I Dunno gene if you have other reflections.

Gene Sullivan: Yeah, I mean, the only thing to add to that is, first of all, the basic assumption with prostanoids in PAH is that the more you can get in, the better. And generally, patients and doctors tolerate a little bit of prostanoid-related side effects to kind of match the efficacy. I will say that there tends to be a spectrum of tolerability, like some patients tend to get just, you know, become more sensitive to the prostanoid-related side effects than others.

Gene Sullivan: Yeah, I mean, I, just the only thing to add to that.

Gene Sullivan: First of all the basic assumption with Prost noise.

Gene Sullivan: N P. A H is that the more you can get into veteran generally patients and doctors tolerate a little bit of press noted related side effects to kind of match the efficacy I will say that there tends to be a spectrum of tolerability like some patients tend to get just you know get are more sensitive to the the <unk> related side effects than other so yeah. If you.

Gene Sullivan: So, if you look at a population of patients on remodulin, for instance, there will be patients at lower or higher doses depending on their individual sensitivity to the prostanoid-related side effects. So, I don't necessarily think we need to get everyone up to the top dose. It's more a matter of the ability to keep going up if the patient is tolerating it, the ability to keep increasing the dose. And you have that ability with remodulin to just keep increasing the dose. With Tyvazo, because of the peak systemic exposure immediately after dosing, you kind of don't. You get up to, you know, you titrate up to the target dose, and then you stay there.

Gene Sullivan: Look at a population of patients on <unk> for instance, you know there'll be patient at lower or higher doses, depending on their individual sensitivity to the approximate related side effects. So I don't necessarily think we need to get everyone up to the top dose it's more a matter of that there's the ability to keep going up if the patient is tolerating it the ability.

Gene Sullivan: Keep increasing the dose and and you have that ability with <unk>, but just to keep increasing the dose with <unk>. So because of the you know the the peak systemic exposure immediately after dosing you kind of don't you'll get up to you know the the trade up to the the target dose and then use.

Gene Sullivan: Stay there and you and the label does not include continuing to Dos escalate I think that's probably related to the you know the the pharmacokinetic pattern, so because of our lung kinetics.

Gene Sullivan: And the label does not include continuing to dose escalate. I think that's probably related to the, you know, the pharmacokinetic pattern. So, because of our lung kinetics, we hope to be able to dose TPIP in a manner more similar to the way ivitroprostenil is dosed.

Gene Sullivan: We hope to be able to dose.

Gene Sullivan: T P I P and a man are more similar to the way <unk> is toast in other words, you can continue to increase the dose. According to the patient's Tolerability and we think that you know in addition to the once daily versus four times a day, that's a great distinction, but this is another distinction you'll get the benefit of delivering along the drug directly to them.

Gene Sullivan: In other words, you can continue to increase the dose according to the patient's tolerability. And we think that, you know, in addition to once daily versus four times a day, that's a great distinction. But this is another distinction. You get the benefit of delivering the drug directly to the lung, but also the ability to titrate it in a manner that they do with the parenteral product. Interesting. Thanks for the color.

Gene Sullivan: <unk>, but also the ability to tie trade it in a manner that they do with a <unk> a product.

Speaker Change: Interesting thanks for the color.

Ritu Subhalaksmi Baral: Our next question comes from the line of Ritu Baral from TD Cohen. Please go ahead. Hi, guys. Thanks for squeezing in, and I apologize in advance.

Speaker Change: Alright next question comes from the line <unk>. Please go ahead.

William Lewis: I still swear I hate biostatistics more than any of you. But when we did the analysis on Willow and Aspen for Brenzo, our statistical consultant basically said that it was the distribution of the data that mattered far more, almost than the event rate. And then, looking back at the distribution constants between the arms and historical studies, we noted that Willow obviously had a very low variance, 0.04 to 0.1, and historicals were in the 0.4 to 0.5 range.

Speaker Change: Hi, guys. Thanks for thanks for squeezing in I apologize in advance I still swear I hate by statistics more than any of you but.

Speaker Change: Did the analysis on yellow and <unk> are statistical consultant basically got that eight y E.

Speaker Change: <unk> what date are that mattered far more almost sandy about right and then.

Speaker Change: Back to the distribution Constance between the arms or historical studies, we noted that Willow, obviously, <unk>, Sir 0.04, 0.1 historical summer.

Speaker Change: <unk> for them to 0.5 range.

William Lewis: Have you been able to look at all the Aspen data and what distribution of data that has been seen either over time or at the very end? Because it does seem to make an important difference in power, and we've got a quick follow-up. Yeah, I hate to disappoint Ritu, because I know the work that you've put into this, and I appreciate the focus on this particular aspect of the data set.

Speaker Change: Been able to look at all I'll be asking data on what distribution of data that.

Speaker Change: Has been seen either of time or at the very end because it does seem to make an important difference in power.

Speaker Change: Quick follow up.

Speaker Change: Yeah, I I hate to disappoint redo because I know the work that you've put into this and appreciate the the focus on this particular aspect of the dataset, but that's not something we we've talked about publicly other than to say that generally looking at everything in the study we continue to feel very positive about what <unk>.

William Lewis: But that's not something we've talked about publicly, other than to say that, generally, looking at everything in the study, we continue to feel very positive about what we're seeing. And, you know, no one variable controls for, but, you know, there really is nothing in this study that has given us pause or alarm with regard to what the expected results will be. We'll know it shortly enough, but I think we've seen remarkable consistency with Willow across many parameters. And that's about as far as, unfortunately, I can go.

Speaker Change: <unk> and you know no one variable controls, but you know there really is nothing in this study that has given us pause or alarm with regards to what the expected results will be will know it shortly enough, but I think we've seen remarkable consistency with willow across any parameters.

Speaker Change: That's about as far as unfortunately I can go.

William Lewis: Fair enough. Just on discontinuation rates in Aspen, have you tallied the final discontinuation rate, and whether it stayed within expected parameters per the last update? Yeah, what we can say is that while we haven't given any update on the final data, with the vast majority of data already in, we've been indicating that the safety is as good, potentially even a little better than Willow. We'll obviously see once we unblind it by various arms, etc., but the blended blinded data continues to look very favorable with regard to safety. And just get to know each other.

Speaker Change: Fair enough.

Speaker Change: <unk> discontinuation make an aspirin can have you Kelly that final discontinuation rate, whether uhm. It stayed with an expectant parameters for the last decade.

Speaker Change: Yeah, what we can say is that while we we haven't given any update with the the final data.

Speaker Change: <unk> with the vast majority of data already and we've been indicating that the safety is as good a potentially even a little better than willow well, obviously see once we unblind by by various arms et cetera, but the blended blinded data continues to look very favorable with regard to safety.

Speaker Change: <unk> and <unk>.

William Lewis: Got it. Got it. And I'm going to squeeze one last in.

Gene Sullivan: On the TPIP-ILD study, Eugene, I think you mentioned that cough was the main reason to stop the titration upward. Were there any other unusual symptoms that could be unique to TPIP that emerged either to impact titration or discontinuation? Thanks. Gene, do you want to take that?

Speaker Change: Got it and with one last thing on the T. P. I T. T. <unk> study you can I think you mentioned that cop was the main reason to stop the titration upwards were there any other unusual symptoms that could be unique pet that emerged either to impact titration.

Speaker Change: Or discontinuation thanks.

Gene Sullivan: Yeah, and just to be clear, I think what I was commenting on before was patients would study drug-related adverse events and that, in fact, when there was a cough, doctors tended to identify it as study drug related. You know, it's up to the investigator to decide, do I think this is study drug related or not? And they tended to attribute cough to the drug more frequently in TPIP and did not attribute it to the placebo. And again, that's probably related to the temporal nature.

Speaker Change: Jean she wanted to <unk>.

Jean: Yeah, and and just to be clear I think what I was commenting on before with the patients with study drug related adverse events and that and that in fact, when they're worse cough.

Jean: Doctors tended to identify this study drug related you know that it's a tough to the investigator to decide do I think this study drug related or not and they tended to attribute cough to the drug more frequently N N T P I P and did not.

Jean: Uhm I attribute it to the placebo and again, that's probably related to the temporal nature of <unk>. There's a lot of these patients have an underlying cough that would be just representative of the disease Uhm. So just to just to clarify what I meant that <unk> brought brought her question we are not seeing any particular.

William Lewis: A lot of these patients have an underlying cough that would be just representative of the disease. So just to clarify what I meant by that. But to your broader question, we are not seeing any particular safety finding that would be unique to TPIP, anything unexpected at all, and certainly nothing that's impinging upon dose escalation because we're getting so many people up to really the maximum dose or, you know, we also released the number of patients who got to the second to the top dose, and that was pretty high, too.

Jean: Safety, finding that's that would be unique to T. P. I P something unexpected at all and and certainly nothing that's impinging upon a dose escalation because we're getting so many people up to really the maximum or we also released.

Jean: The number of patients who got to the second second to the top dose and and that was pretty high too that if you. If you go to that it's 90 per cent of patients. So we're not seeing problematic eight he set limit a dose escalation.

William Lewis: If you go to that, it's 90% of patients. So we're not seeing problematic AEs that limit dose escalation, and we're not seeing any novel, you know, safety events that would give us concern. That's something unique to TPIP.

Jean: And we're not seeing any novel you know.

Jean: Uhm safety events that would give us concerned that's something you need to take P. I P.

Gene Sullivan: And I would only add that the time frame we have for that titration, Ritu, is five weeks. In the real world, physicians could continue to try to dose escalate over perhaps a longer period of time and might find greater success. But the backbone here is 80 percent of patients are getting the maximum tolerated dose of 640 in this study, in the ILD study, and 90 percent of them are getting to the penultimate level, which is just a remarkable outcome from our point of view. [inaudible] Our next question comes from Jeff Hung from Morgan Stanley. Please ask your question. Thanks for taking my questions.

Speaker Change: And I would only add the time frame, we have for that for that titration route to as five weeks. So in the real world physicians could continue to try to dose escalate over perhaps a longer period of time and might find greater success, but backbone here is 80 per cent of patients are getting the maximum tolerated dose of 640 in this study and the ILD stuff.

Jean: 90% of them are getting into the penultimate level, which is just a remarkable outcome from our point of view.

Jean: Thanks.

Speaker Change: Our next question comes her line chat from Margate for me. Please answer my question.

Margate: Thanks for taking my questions Uhm for T. P. I P. Based on the data can you just comment if you see any evidence of disease modification and then I have a follow up.

Jeff Hung: For TPIP, based on the data, can you just comment if you see any evidence of disease modification and then have a follow-up? Gene, do you want to address that? Yeah, and by disease modification, I presume you're referring to the underlying pulmonary fibrosis, which I know that was an observation made in the increased trial that there may be some evidence of effect on pulmonary fibrosis, and United Therapeutics is currently conducting a large trial to try to detect that.

Speaker Change: G and you wanted to address that.

Speaker Change: Yeah, and by disease modification, I presume, you're referring to the underlying pulmonary fibrosis, which I know that that was a.

Speaker Change: And it was the observation made in the increased trial that there may be some evidence of of effect on a pulmonary fibrosis and and the United Therapeutics is currently conducting a large trial to try to detect that where we might see any effects on the underlying disease process would be the lung function and we we have not analyze that data yet.

Gene Sullivan: Where we might see any effects on the underlying disease process would be in lung function, and we have not analyzed that data yet. However, it's extremely unlikely that we would see any evidence of that with such a small study and such a small placebo group. It's only, you know, 10 patients. We really intended the three-to-one randomization because what we really wanted to do was just get some safety information, give this drug to patients with PHILD and make sure nothing untoward happened, and that's what we saw. So, we don't expect to see any information that could inform whether or not troprostanil impacts pulmonary fibrosis. Okay, great. And then you started education efforts for Brenzocat fairly early.

Speaker Change: However, it's extremely unlikely that we would see any evidence of that with such a small study and in such a small.

Speaker Change: Small placebo group, it's only 10 10 patients we really the three to one randomization was intended because what we really wanted to do is just get some safety information till it give this drug to patients with P. H I L D and make sure nothing untoward happened and that's what we saw so we don't expect <unk>.

Speaker Change: See any information that could inform whether or not uhm <unk> impacts the the pulmonary fibrosis.

Speaker Change: Okay, Great and then you started education efforts for Brent Academy fairly early but can you just talk about how far that's come in and how much more education, you think it's still needed for physicians for potential lunch. Thanks.

William Lewis: Can you just talk about how far that's come and how much more education you think is still needed for physicians for a potential launch? Thanks. Well, I'm happy to report that we have the similar experience of being a first-in-disease drug and the first-ever approved drug for air case use in refractory MAC patients. So that experience informs our approach, once again, to the larger opportunity that would be represented by bronchiectasis using brensocatib.

Speaker Change: Well I'm happy to report that we have the the similar experience of being a first and disease drugs and the first ever approved drug for the your case <unk> used in refractory Mac patients so that experience in forums. Our approach once again to the larger opportunity that would be represented by bronchiectasis excuse me <unk>.

William Lewis: And so, medical education got underway with the American Thoracic Society really last year at this time and has been ongoing. And that will continue right up through our expected launch in the U.S., which would be the middle of 2025.

Speaker Change: And so that the medical education got under way with the American Thoracic Society really last year at this time and has been ongoing and that will continue right up through our expected launch in the U S, which would be the middle of 2025 in parallel to that we are also Ah right now.

William Lewis: In parallel to that, we are also, right now, starting at the end of last year, working on the market access front to make sure that education on the disease state is handled appropriately and that everybody is informed. Our experience is that by doing these things, people are in a much better place to understand if there is a drug that is approved and it has an effect. People know how to place that into context and what that would really represent for patient care. And that's the purpose behind all of it.

Speaker Change: It started at the end of last year working on the market access front to make sure that that education on the disease. State is is is handled appropriately and that everybody has informed our experiences that by doing these things people are in a much better place to understand if there is a drug that is approved and it has an effect people.

Speaker Change: No how to place that into context, and what that would really represent for patient care and and that's the purpose behind all of it but certainly starting early when you're first in disease is crucial and we've been doing that and that's a critical investment we've been making I'll also report that on the commercial from the <unk> the progress with regard to.

William Lewis: But certainly, starting early when you're first in the disease is crucial, and we've been doing that. And that's a critical investment we're making. I'll also report that on the commercial front, progress with regard to bringing additional resources in, first in the U.S. and then in Japan and Europe, is also underway at the area director and regional director levels. Those critical promotions and hires have taken place. I will say I am shocked at the degree of interest that is coming from the outside world for these positions. When we indicate that there might be a position available, we get scores of candidates signing up to try to gain access to the opportunity.

Speaker Change: Bringing additional resources in first in the U S and then in Japan and Europe is also under way at the area director and regional director level those critical of promotions and hires have taken place I will say I am shocked at the degree of interest that is.

Speaker Change: Coming from the outside World for these positions when we indicate that there.

Speaker Change: There might be a physician available we are getting scores of of candidates signing up to to try to gain access to the opportunity. So I think everybody feels what is coming is incredibly exciting and want to be a part of that appropriate disease education and ultimately the the commercial launch at the drugs should have.

William Lewis: So I think everybody feels what is coming is incredibly exciting and wants to be a part of that appropriate disease education. And ultimately, the commercial launch of the drug should everything go as expected by the middle of 2025. Hopefully, that's helpful. Great, thank you. Our next question comes from the line of Liisa Bayko from Evercore ISI. Please go ahead.

Speaker Change: I think it was expected about the middle of 25, hopefully that's helpful.

Speaker Change: Great. Thank you.

Speaker Change: Alright next question comes from the line at Lisa Baker from Africa car I S. I. Please go ahead.

Liisa Ann Bayko: Hi guys, congrats on the TPIP data. I just have a couple of follow-up questions on Aspen. To kind of play off of what Ritu was saying, but in a more high-level way, I noticed there were a lot of patients in your baseline paper from the Latin America region. It was, I think, more than a quarter of the population, and they seem to have milder disease. Can you talk about your comfort level in making sure that some specific large groups like that are, you know, well-balanced across the arms?

Lisa Baker: Hi, guys will pass on the T. P. I P data just a couple of follow up questions on Aspen.

Lisa Baker: Kind of play off of what particular thing, but in a more high level way I noticed there was a lot of patience and your baseline paper from the Latin America weekend. It was I think more than a quarter of the population, which they seem to have milder disease can you talk about your comfort level and making sure like some specific large groups like that.

Lisa Baker: Are you know well balanced across the arms that that's my first question and my second question relates to Uhm, how they can think of apply appearing around the data are you planning.

William Lewis: That's my first question, and then my second question relates to how we can think of a quiet period around the data. Are you planning, you know, kind of a couple-week quiet period, or a couple of days?

Lisa Baker: You know kind of a couple of the quiet period, a couple of days just wondering if we can if we stop hearing from you guys. If they might think date is kind of an X.

William Lewis: Just wondering if we can, if we stop hearing from you guys, if we might think data's coming. I'll take the second question first and just tell you that when the moment comes, I think that certainly we'll be going quiet, but I think that is more a byproduct of us needing to take a step back and make sure that, as I mentioned earlier, the quality of what we're doing is meeting the standard. The hierarchy here is very clearly and always has been quality first, speed second, budget third, in that order of priority in terms of making sure we produce the best possible outcome here.

Speaker Change: I'll take the second question first [laughter] just tell you that when when the moment comes I think the the certainly will be will be going quiet, but I I think that is more a byproduct of us didn't take a step back and make sure that as I mentioned earlier the quality of of what we're we're doing is meat.

Lisa Baker: The standard the hierarchy here is very clearly it always has been quality first speed second budget third and that order of priority in terms of making sure. We produce the the best possible outcome here. So I don't know to be transparent how long it will take from the moment that we decided we're ready to lock the database at the moment that we're analyzing the data.

William Lewis: So, I don't know, to be transparent, how long it will take from the moment that we decide we're ready to lock the database to the moment that we're analyzing the data and interpreting the results. Obviously, some of that will depend on the results themselves, but so it's hard to give guidance, Liisa, as to how long we will be quiet. It's just, it could be any length of time, and, most importantly, I would not interpret a longer period of silence as meaning that there is, in any way, something wrong.

Lisa Baker: In interpreting the results obviously some of that will depend on the results themselves, but so it's hard to give guidance Lisa as to how long we would be quiet.

Lisa Baker: It's just it could be any length of time, and most importantly, I would not interpret a longer period of silence as meaning that there isn't any way something wrong. Indeed, we are very focused as I said before on the quality and that may be something that we just want to refine so so that would be my answer to that we.

William Lewis: Indeed, we are very focused, as I said before, on quality, and that may be something that we just want to refine, so that would be my answer to that. With regard to the concentration of patients in different parts of the world, we remain very comfortable with the profile of what we have recruited into the study. There is remarkable, I would say, consistency in our experience with this trial so far based on our careful monitoring of regions on a weekly basis down to the country level to ensure that there weren't significant deviations or aberrations from other areas of the world. And so, that's been an ongoing process that we have had. I think what we saw in terms of concentration from Latin America is not in any way problematic or concerning.

Lisa Baker: Regard to the concentration of patients in different parts of the world. We remain very comfortable with the profile of what we have recruited into the study there's remarkable I would say consistency in our experience with this trial so far based on our Ah careful monitoring of regions on a weekly basis.

Lisa Baker: Down to the country level to ensure that there weren't significant deviations are aberrations from other areas of the world and so that's been an ongoing process that we've had I think what we saw in terms of concentration from Latin America is not in any way problematic or concerning in fact I think.

William Lewis: In fact, I don't know how to respond to the comment about milder disease because that is not something that we would identify as being necessarily the case, but I can tell you we feel very good about the baseline demographics here and the distribution around the world. Hopefully, that answers the question. Did you stratify for Latin America specifically, or did that just go into the rest of the world? We didn't stratify, in that sense, to the best of my knowledge.

Lisa Baker: I don't know how to respond to comment about milder disease, because that that is not something that we would identify as being necessarily the case, but but I can tell you. We feel very good about the based on demographics here and the distribution around the world hopefully that answers the question.

Speaker Change: Okay did you stratify for Latin America, specifically or does that just go into rest of the world's ratification.

Lisa Baker: We didn't stratified in that sense to the best of my knowledge someone else incorrectly if I'm wrong, but we do obviously track out where patients come from and we can certainly cut the data that way it should it become necessary to do so.

William Lewis: Someone else can correct me if I'm wrong, but we do obviously track where patients come from, and we can certainly cut the data that way should it become necessary to do so. Let me step in here for just a second. We actually did stratify based on region, so Latin America is on the list, but other regions as well, Western Europe, Eastern Europe.

Speaker Change: Alright, let me look at it.

Speaker Change: Let me let me step in here for just a second we actually did stratify based on region. Latin America is on the list, but other reasons as well Western Europe, Eastern Europe et cetera.

William Lewis: Okay. Okay, great. Thank you. And your next question comes from the line of Jennifer Kim from Canter Fitzgerald. Please go ahead.

Speaker Change: Alright. Thank you you go.

Speaker Change: [laughter].

Speaker Change: And your next question comes from the line of Jennifer came from Cantor Fitzgerald. Please go ahead.

Jennifer M. Kim: Hey guys, thanks for taking my questions and congrats on the TPIP data. Maybe to start with Brento, I think the answer is yes, but I just want to confirm. Is it fair enough to say that the data isn't coming at ATS just given the timing of deadlines? And then also to follow up on the last question, when you're monitoring on a regional basis, on a blinded blended rate basis, are you saying that the rates are sort of in line with what you would expect on a regional basis? And does that also take into account the differences in, I guess, macro-wide background measurements?

Jennifer: Hey, guys. Thanks for taking my questions and congrats on that <unk> data, maybe they start with <unk> I think the answer is yes, but I just want to confirm is it fair enough to say that the data isn't coming at a T. S. Just given that the timing of deadlines Uhm and then all set to follow up on the last question when you're monitoring on a regional basis Unimplanted blended.

Speaker Change: Right basis are you, saying that the rates are started in line with what you would expect on a regional basis and does that also take into account the differences in I guess macolyte backgrounds regiments looking at Japan I know we found the paper there's a much higher you said that for example, thanks.

William Lewis: Looking at Japan, I know we saw in the paper that there's a much higher use of that, for example. Thanks. So I'm not going to comment on the timing of the data any more than I already have. We've given the window from mid-May to the end of June, and sometime in that time frame, we'll produce it.

Speaker Change: So I'm not going to comment on the timing of the data any more than I already have we've given the window from mid may to the end of June and some time in that timeframe will will produce it regard to the the specific question about what we're monitoring on a on a country basis. I think there are a lot of things we look at I don't Wanna go into the specifics of.

William Lewis: Regarding the specific question about what we're monitoring on a country basis, I think there are a lot of things we look at. I don't go into the specifics of how we, what we've seen or what we conclude or any of that interpretation. I would just encourage everybody to not over-interpret comparisons from the past or other studies. I think the simple answer is we're close enough to the actual data from Aspen to just sort of wait for that data.

Speaker Change: We.

Speaker Change: What we've seen or what we conclude or any of that interpretation I would just encourage everybody to not over interpret comparisons from the past or or other studies I think the simple answer is where proximate enough to the actual data from Aspen to just sort of wait for that data.

William Lewis: I don't think it is possible, and we have much better information than all of you do, to interpret what these results will really be until we are unblind. We feel good about the direction of everything that is contained within this study. We see remarkable consistency with Willow.

Speaker Change: I don't think it is possible and we have much better information than all of you to interpret what these results will really be until we unblind. We feel good about the direction of everything that is contained within the study we see remarkable consistency with Willow those things were encouraging the qualitative commentary from physicians, but the data will ultimately.

William Lewis: Those things are encouraging, the qualitative commentary from physicians, but the data will ultimately control, as we all know and understand. I think, at this point, the simple and most honest answer is we need to just unblind the data and see what we have. I don't know, Bryan, if you want to add anything specifically about the question, just in light of the last one. Nope.

Speaker Change: Limited control as we all know understand and I think at this point is simple and most honest answer is we need to just unblind the data and see what we have I don't know, Brian if you want to add anything specifically about the question just in light of the the last one.

Brian: Nope I'm good.

Bryan Dunn: Okay, thanks. And, maybe for Gene, I wanted to confirm, is phase 3 advancement in PHLD still contingent on getting PAH top-line data, maybe to get a better sense of powering? And I know that the confidence intervals are wide, but can you say what the 6-minute walk change was in placebo in PHLD and what the baselines were for both arms?

Brian: Okay, Thanks, and if I could ask a question keep it maybe for for Jean I wanted to confirm if phase III advancement and pay channel T <unk>.

Speaker Change: Contingent on getting P. A H top line data maybe to get a British sense of <unk> and I know that the confidence intervals are white, but can you say what the six minute walk change was in placebo and ph healthy and what the basslines were for both arms. Thanks.

Gene Sullivan: So, the question is about Phase 3 and moving forward into Phase 3. I think, you know, that will be primarily based on the results of this trial as we analyze these results and the ones that will come in subsequently, and also on the experience of tybazo in this population. I think it's harder to extrapolate data on efficacy and data on a lot of things from a PAH population to PHILD. It's such a different disease process that I don't think we're going to be looking at the PAH data to inform key aspects of the design of a Phase 3 trial for PHILD.

Speaker Change: Sure. So the question is about about phase three and moving forward into phase three I think that'll be primarily based upon the results of this trial as we analyze these results and and the ones that will come in subsequently and also on the experience of <unk> in this.

Speaker Change: Nation, I think it's harder to extrapolate data on efficacy and data on a lot of things from a P. A H population two P. H I L. D. It's such a different disease process that I don't think we're gonna be looking at the P. A H data to inform key aspects of a design of a of a face we try.

Speaker Change: Bill for four P H I L D.

Gene Sullivan: And I think your second question had to do with the six minute walk test. We've given the delta rate of 30 meters, which is placebo controlled. And so were you asking what was the actual change from baseline in the treatment groups? I was asking what the placebo six-minute walk change was. I think you've given the placebo-adjusted change and then also the placebo change and then also what the baselines were for both arms.

Speaker Change: And I think your second question has to do with the six minute walk test, we've given the delta right 30 meters placebo controlled and and so you were you asking what was the actual change from baseline in the <unk> in the treatment groups.

Speaker Change #100: I was asking what the placebo six minute locked changed once I think he you've given the placebo adjusted change and then so the placebo change and then also what the basslines were for both arms.

Gene Sullivan: So I'll just say broadly that, you know, probably the best way to do it is through placebo control. That would be the primary analysis. In general, what we saw in the primary analysis was that there was a decline among placebo patients and a stability among active treatment patients. So that, you know, general pattern was what resulted in the 30-meter delta between the two arms. Okay, thanks for taking my question. Your next question comes from the line of Stephen Wiley from Stifle. Please go ahead. Yeah, good morning. Thanks for squeezing me in. Um, just a quick Aspen question.

Speaker Change: So I'll just say broadly the you know the the.

Speaker Change: Probably the best way to do it is to see if a control that would be the primary analysis in general it had to do it what we saw in the primary analysis was that there was a decline among placebo patients and a stability among active treatment patients so that <unk>.

Speaker Change: General pattern was what resulted in a the 30 meter delta between the two.

Speaker Change: Okay. Thanks for taking my question.

Speaker Change: Yeah next question comes from the line of state from Wildlife Stifle. Please go ahead.

Stephen Douglas Willey: So, um, the manuscript detailing patient baselines suggests that there were about 20% of patients with elevated Sinaphil levels as it pertains to willow, and then just kind of curious as to thoughts around... You know, the impact of Brenso in this elevated eosinophilic population, where maybe... The short answer is I don't know the answer to that question, Stephen. I can ask Gene if you know offhand; otherwise, or Bryan if someone else wants to comment.

Wildlife Stifle: Yeah. Good morning, Thanks for squeezing me and just a quick aspen questions. So.

Wildlife Stifle: The the manuscripts detailing patient baseline suggested that there were about 20 per cent of patients with elevated instead of those curious as to whether or not you said anything about <unk>.

Wildlife Stifle: He is senate fill levels as it pertains to Willow and then it just kind of curious as to your thoughts around.

Wildlife Stifle: The impact the branch so in this elevated you sort of feel like population, where maybe inflammation, maybe not so neutral village in nature.

Speaker Change: Yeah. The short answer is I don't know the answer to the question Steven I can ask Jim if you know off hand, otherwise or Brian if someone else wants to come in otherwise, we'll have to get back to you.

Stephen Douglas Willey: Otherwise, we'll have to get back to you. Yeah, the only comment I'd make is that when, you know, patients have elevated eosinophils in their secretions, either sputum or nasal secretions, it doesn't mean that all of the inflammatory cells are eosinophils; it just means there are a lot of them. And actually, there are a lot of neutrophils; even in patients who have, you know, elevated eosinophils, a lot of the inflammation is still neutrophil-driven.

Speaker Change #106: The only comment I'd make is that when you know patients have elevated eosinophils in their secretions, either speed them or or nasal secretions. It. It doesn't mean that all of this inflammatory cells are eosinophils just means there's a lot of them and actually there are a lot of neutrophils, even in patients who have elevated eosinophils a lot.

Gene Sullivan: So I think there's, you know, still a reason to expect a benefit, even in those patients. That's why we didn't like to exclude eosinophil patients. So that's the only thing I want to clarify, because sometimes people think that when there's elevated eosinophils, it's at the expense of neutrophils.

Speaker Change #106: The inflammation is is still neutrophil driven so I think there's still.

Speaker Change: Still a reason to expect uhm a benefit even in those patients. That's why we didn't like exclude <unk>. So that's the only thing I I'd want to clarify cause sometimes people.

Speaker Change: People think that when it's <unk>, it's at the expense of the neutrophils, but in in that milieu in amber and the inflammatory milieu.

Gao Yi Chen: But in that milieu, in the inflammatory milieu, there are plenty of neutrophils there as well. We can get to the specific numbers if we have them and they're public, with a follow-up. All right. Your next question comes from the line of Andy Chen from Wolfe Research. Please go ahead. Hi, this is Amand speaking for Andy.

Speaker Change: There are plenty of neutrophils, there as well.

Speaker Change: We can get to the specific numbers, if we have them in their public.

Speaker Change: With a follow up.

Speaker Change: Alright.

Speaker Change: Your next question comes from the line of Andy Chin from Wolf Research. Please go ahead.

Speaker Change #102: Hi, This is I'm on for Andy Thanks for taking my question and congrats.

Sara M. Bonstein: Thanks for taking our call. Just a couple quick ones on our end, I guess. How big is the existing Aircase sales force? Target Sales First Size there.

Speaker Change #102:

Speaker Change #108: On our end I guess.

Speaker Change #104: And then S swimming franchise successful what's the target.

Sara M. Bonstein: And then on PAH, regarding the average, how should we interpret this data point? I know during the call it was mentioned it's a highly variable measure, so you should kind of interpret this, but would you say this is a modest... So, Sara, do you want to take the question on Salesforce expansion?

Speaker Change #105: And so that's fine and then M P H regarding that.

Speaker Change: Six minute long distance from me sign up for it.

Speaker Change #101: How should we interpret this data.

Speaker Change #101: During the call is mentioned, it's a highly variable.

Speaker Change #101: To kind of interpret this.

Speaker Change #101: Kind of an internal bar.

Speaker Change #103: So Sir do you want to take the question on Salesforce expansion in G and you can take the one on on the six minute walk on T. P. I P.

Gene Sullivan: And, Gene, you can take the one on the six-minute walk on TPIP, 65, 70 reps existing in the U.S. We will look to expand that. You know, what we've said publicly, 200 to 220 is what we've said publicly. We'll share more on those details on the commercial day that we've alluded to throughout the Q&A session. What I would like to comment on is the immense crossover between Aircase and Brenso Captive and the synergies that we will have. Aircase obviously calls on pulmonologists and ID doctors.

Sir: Sure happy to thanks for the question I existing sales person that you asked me of about you know 65, 70 wraps I'm existing in the U S. We will look to expand that you know what we said publicly 200 to 220th what we said publicly will share more on those details on the commercial day that we've alluded to them throughout the Q&A Sasha and when I.

Speaker Change #101: Would like to comment on is the immense crossover between ARIKAYCE in France, a captive in the synergies that we will have air case, obviously cause I'm pulmonologist, an I D dogs branch out primary call us Pulmonologists, how it's Ah that's cute very synergistic products that you don't necessarily see them. So we're really excited about being able to <unk>.

Sara M. Bonstein: Brenso, you know, his primary call is a pulmonologist. So, it's two very synergistic products that you don't necessarily see. So, we're really excited about being able to leverage the infrastructure. Gene, over to you. Yeah, sure. So, on the six-minute walk distance in the blended blinded of 43 meters, of course, you know, we say this over and over again, it's a very variable measure. And more importantly, we don't know who's on active treatment and who's on placebo. And so, it's very difficult to interpret 43 meters.

Speaker Change #101: <unk> to the infrastructure Jean over to you.

Jean: Yeah sure. So on the six minute walk distance Uhm Interblended blinded of 43 meters Uhm of course, you know we say this over and over again. It is it's a very variable measure and more importantly, we don't know who's on active and who's on placebo and so it's very difficult to interpret 43 meters, but we are happy to see improvements we're seeing patients.

Gene Sullivan: But we are happy to see improvements. We're seeing patients with improvements. And if those, you know, represent patients who are on active drugs, that's great. And the 43 meters would be plenty.

Jean: And improvements and if those you know represent patients who aren't active drug that's great and and a 43 meters would be would be plenty. The other point I want to make though is that even at the end of this trial. It's it's it's a larger trial then the P. H I L. D study, but with 99 patients were not power to <unk>.

Gene Sullivan: The other point I want to make, though, is that even at the end of this trial, it's a larger trial than the PHILD study. But with 99 patients, we're not powered to see a statistically significant effect on six-minute walk distance, even with the final unblinded data. You know, we'll get a point estimate; we'll get a sense. But I just wanted to point out that even with 99 patients or so, we, you know, that's probably not enough.

Jean: C. A statistically significant effect on six minute walk distance, even with the final unblinded data you know, we'll get a point estimate will get a sense, but I just wanted to point out that even with 90.

Speaker Change #101: 99 patients are so we you know that it likely is not enough. If you look at the pivotal trial for Tiger S. O N P. A H that was over 200 down it was 230 or so patients to show a statistically significant benefit so we see the improvement in the blended population who is an act.

Gene Sullivan: If you look at the pivotal trial for Tybazo in PAH, that was over 200 patients, I think it was 230 or so patients to show a statistically significant benefit. So, you know, we see improvement in the blended population. I don't know who's on active and who's not.

Gene Sullivan: But we're pleased with it. It's a good number, and there are patients who are clearly improving. We'll just have to wait to see the unblinded data.

Speaker Change #101: Women, who is not but we're pleased with it is a good number in it and there are patients who are clearly improving and we'll just have to wait to see the the online of data.

Stephen Douglas Willey: Great. I appreciate the, And that concludes our Q&A session for today. I would like to hand back to management for closing remarks. Thanks very much, everyone, for joining us today. This concludes today's conference call. Enjoy the rest of your day. You may now disconnect.

Speaker Change #110: Okay I appreciate the answers.

Speaker Change #112: And that concludes that to you one day session for today I would like to hand back to management for closing remarks.

Speaker Change #109: Thanks, very much everyone for joining us today.

Speaker Change #107: This concludes today's conference call enjoy the rest of your day you may now disconnect.

Speaker Change #107: [music].