Insmed Q1 2024 Earnings Call Transcript

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Provided by Quartr
May 9, 2024

Key Takeaways

  • In the Phase 2 safety study of TPIP in PH-ILD, 79.3% of patients reached the 640 μg dose by week 5 with no worsening of resting or exercise oxygenation, and fewer serious adverse events and discontinuations versus placebo.
  • Blinded interim data from the Phase 2 PAH trial show a mean 19.9% reduction in pulmonary vascular resistance and a 43 m increase in 6-minute walk distance at trough, suggesting durable benefit with once-daily TPIP dosing.
  • The Phase 3 ASPEN trial of brensocatib remains on track for a top-line readout between mid-May and end-June after all adult patients completed their 52-week visits and database lock preparations are underway.
  • ARIKAYCE net revenues of $75.5 M in Q1 grew 16% year-over-year (15% US, 13% Japan, 42% Europe/ROW) despite distribution headwinds, keeping Insmed on target for $340–360 M full-year guidance.
  • Insmed closed Q1 with $596 M in cash and an adjusted burn of ~$125 M, ensuring financial runway for TPIP Phase 3, brensocatib filing and other pipeline milestones.
AI Generated. May Contain Errors.
Earnings Conference Call
Insmed Q1 2024
00:00 / 00:00

There are 18 speakers on the call.

Operator

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. After the speakers' remarks, there will be a question and answer session.

Operator

Thank you. I would now like to turn the call over to Brian Dunn, Head of Investor Relations. Please go ahead.

Speaker 1

Thank you, Dee. Good day, everyone, and welcome to today's conference call to discuss Insmed's Q1 2024 financial results and provide a business update. I am joined today by Will Lewis, Chair and Chief Executive Officer Jean Sullivan, Chief Product Strategy Officer and Sara Bohnstein, 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. 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.

Speaker 1

Please refer to our filings with the Securities and Exchange Commission for more information concerning the risk factors that could affect the company. Also note that our call today will include blinded observations from our ongoing Phase 2 study of TPIP 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.

Speaker 1

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.

Speaker 2

Thank you, Brian. Welcome everyone. Today, we intend to review the progress from 3 of the company's main programs ARIKAYCE, TPIP and brancocatid. Let's begin with TPIP. The first of this quarter's 2 important data readouts came this morning with the announcement of the top line results from our Phase 2 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 2 study in pulmonary arterial hypertension.

Speaker 2

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 brenzocadam, the highly anticipated top line release of the Phase 3 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 brincocadid. 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.

Speaker 2

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. In regard to ARIKAYCE, we were pleased that ARIKAYCE delivered double digit year over year growth across all three of our geographic regions and 16% growth overall compared to the Q1 of 2023. 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.

Speaker 2

Turning now to the potential expansion of ARIKAYCE to all MAC NTM patients, I'm pleased to report that our presentation of the full ARRISE 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 also pleased to report that the data monitoring committee for the ongoing ENCORE trial held their 4th 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 ENCORE 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 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.

Speaker 2

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 forward 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 COP Foundation aims to create 150 Multidisciplinary Centers of Excellence across the U. S. 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 NTM and bronchiectasis as they strive to meet treatment goals.

Speaker 2

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. 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.

Speaker 3

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 2 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 2 efficacy study of TPIP in patients with pulmonary arterial hypertension. Let's begin with PH ILD.

Speaker 3

This study originally targeted an enrollment of 32 patients, but was over enrolled with 39 patients. The study utilized a 3 to 1 randomization scheme. And 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 6 40 micrograms once daily. As a reminder, a TPIP dose of 6 40 micrograms contains roughly 60% more treprostinil as compared with the total daily dose of the current market leading treprostinil dry powder product, which is dosed 4 times daily.

Speaker 3

Patients were titrated up to their maximum tolerated dose over the course of the 1st 3 weeks of treatment, with a final dose increase allowed at the 5 week visit. Patients were not permitted to increase their dose for the remaining 11 weeks of treatment. Participant demographics and baseline characteristics were generally well balanced between study arms. However, a higher percentage of female participants were randomized to TPIP arm at 31% versus the placebo arm at 20%. Also, on average, patients in the TPIP arm of the study required 1 additional liter per minute of supplemental oxygen at baseline.

Speaker 3

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. Among patients in the TPIP arm, 79.3% were successfully able to reach the maximum dose of 640 micrograms by week 5, compared with 100% of those taking placebo. If we look at the patients who were able to reach at least 480 micrograms by week 5, 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.

Speaker 3

Of note, while we adopted a titration period of 5 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. We consider a higher treatment discontinue rate in the placebo versus treatment to be very noteworthy. In terms of overall safety, 93% of patients in the TPIP arm experienced any adverse event, which was similar to the 90% of patients on placebo. And 20.7% of TPIP treated patients experienced a serious adverse event compared to 40% of placebo treated patients.

Speaker 3

0 patients in either arm experienced a serious adverse event that were judged to be related to study drug. There were 4 deaths in the trial, including 6.9% of patients randomized to the TPIP arm and 20% of patients randomized to placebo arm. All deaths in the trial were related to disease progression or comorbid causes and none were attributed to study drug. 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.

Speaker 3

Additionally, we also measured oxygen saturation continuously during and after the 6 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. I do want to note that we did see a slight decrease in oxygen saturation from baseline levels when measured after the 6 minute walk test with the TPIP arm showing an absolute decrease of 8% compared to placebo patients who saw an absolute increase from 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. 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.

Speaker 3

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 6 minute walk distance. 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, 6 minute walk distance often includes a substantial amount of variability, as emphasized by the wide confidence intervals we see in this data set.

Speaker 3

As expected in a study this small, the improvement in 6 minute walk distance did not approach statistical significance. On NT proBNP levels, the TPIP arm showed a slight improvement from baseline and the placebo group showed a slight worsening. However, the difference between groups was not meaningful, which is to be expected in this small of a study. Finally, in this study, we measured events of clinical worsening, which was defined as a hospitalization due to a cardiopulmonary indication, a lung transplantation, death from any cause, or a decrease in 6 minute walk distance of 15% 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.

Speaker 3

However, clinical worsening events were shown to be more common in the placebo arm with 50% of placebo treated patients experiencing such event compared to 10.3% of TPIP treated patients. This difference produced a nominally significant p value of 0.0164. 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 3, aiming to initiate a global study in 2025. Now, let me spend a few moments providing you an update on our ongoing Phase II trial of TPIP in patients with pulmonary arterial hypertension.

Speaker 3

The trial is progressing as expected now with well more than half of the target enrollment achieved. In March, the 2nd data monitoring committee meeting was held to review the safety data from this trial and the committee's recommendation was continue the trial without any changes. In regard to dosing, among the first 43 patients in the trial to complete their 5 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 dosing up to a maximum of 12 80 micrograms once daily. We are excited about what these higher doses could potentially mean for patient outcomes.

Speaker 3

Today, I would like to share an update on the blinded efficacy Of those patients, 4 discontinued Of those patients, 4 discontinued the trial prior to completion, leaving 40 patients who completed the full 16 weeks of treatment. As a reminder, this trial is randomized 2:one, so roughly 2 thirds of the patients will be receiving TPIP and 1 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 is 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 3

What is equally encouraging is that we continue to see patients in the study who experienced dramatic improvements in PVR. We are also excited by what we were seeing on 6 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 6 minute walk distance from baseline was 43 meters. As I mentioned a few moments ago, 6 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 have seen so far. It is worth pointing out that for both efficacy endpoints that I've described today, PVR and 6 minute walk distance, These measures were taken at the end of the dosing interval or nearly 24 hours after the most recent dose.

Speaker 3

This was designed intentionally to highlight the potential durability of TPIP's effect. However, it makes these results more difficult to compare to the other key study of inhaled treprostinil, which reported hemodynamic measures obtained in the period immediately following the dose at the time of the drug's maximum effect. 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. As a final reminder, we do not know which of these first forty patients were taking TPIP and which were taking placebo. And the numbers I have shared today on PVR and 6 minute walk distance will continue to change as more patient data is generated.

Speaker 3

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 once daily dosing. Now, let me turn the call over to Sarah to walk through the detailed financial results from the Q1.

Speaker 4

Thank you, Jean, and good

Speaker 5

morning, everyone. I'm happy to be with you to share some of the details of Insmed's financial performance for the Q1 of 2024. We ended the quarter with $596,000,000 in cash and cash equivalents. This represents a cash burn for the quarter of approximately $185,000,000 As we have stated previously, our cash burn in the Q1 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 build for clinical and preclinical products than our usual cadence.

Speaker 5

When these items are excluded, the underlying cash burn was approximately $125,000,000 which is in line with recent quarters. 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 Q1 of 2024. Global net revenues for the Q1 of 2024 were $75,500,000 representing 16% year over year growth compared to the Q1 of 2023. In the U.

Speaker 5

S, net revenues for Q1 2024 was $56,300,000 up 15% compared to the prior year quarter. The growth this quarter was driven by the highest level of enrollment forms that we have seen in the U. S. Since the Q3 of 2019 when ARIKAYCE was in its Q4 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 ARIKAYCE due to the change healthcare cyber attack, which impacted the dispensing of medicines across the United States, particularly for patients starting a new treatment.

Speaker 5

That said, we are continuing to work to help patients gain access to ARIKAYCE who had difficulty starting treatment due to the cyber attack. In Japan, Q1 2024 net revenue was $14,900,000 representing 13% growth over the same quarter last year. 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% 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 4th quarter, which saw record setting strength in ARIKAYCE sales volumes.

Speaker 5

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. In Europe and Rest of World, net revenue in the Q1 2024 came in at $4,300,000 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, We are pleased to see their efforts gain momentum, especially as we round the corner to the potential launch of brincocatib, assuming positive ASPIN and regulatory approvals. Importantly, today we are reiterating our full year 2024 global revenue guidance of $340,000,000 to $360,000,000 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 Q1. Furthermore, as I mentioned on last quarter's call, the Q1 of each year historically contributes slightly more than a 5th of each year's total sales due to the seasonal impacts in both the U.

Speaker 5

S. And Japan. 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 Q1 2024, our gross to nets in the U.

Speaker 5

S. Were approximately 21%. As in prior years, we expect the gross to nets in the Q1 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 teens range for the full year. Cost of product revenues for the Q1 of 2024 was $17,500,000 or 23.1 percent of revenues, which is consistent with our historical performance.

Speaker 5

Turning to our GAAP operating expenses. In the Q1 2024, research and development expenses were $121,100,000 and SG and A expenses were $93,100,000 reflecting continued investment in both our early and mid to late stage pipelines as well as launch readiness activities for brensocathed. In closing, Insmed's solid financial performance in the Q1 keeps us on track to deliver on our full year guidance. 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 $600,000,000 of cash giving us substantial optionality on the other side of that event. Now, we would like to open the call to your questions.

Speaker 5

Operator, can we take the first question, please?

Operator

Thank you. We will now begin the question and answer please pick up your handset and ensure that your phone is not on mute when asking questions. We do request for today's session that you please limit to 2 questions And your first question comes from the line of Andrea Tan from Goldman Sachs. Please go ahead.

Speaker 6

Good morning. Thanks for taking our question. Sarah, maybe I could start with you. 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 $1,000,000,000 peak sales for ARIKAYCE, what assumptions underpin that with respect to how the drug would be used in the refractory versus the frontline setting?

Speaker 5

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 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 really gives us great confidence in reiterating the guidance of $340,000,000 to $360,000,000 The commercial team continues to execute.

Speaker 5

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, it's a 3 to 5 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 $1,000,000,000 opportunity pending regulatory approval for ARIKAYCE. 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 ARIKAYCE, to continue to educate on the broader label expansion opportunity.

Speaker 6

Okay. And then, Jean, maybe I can just ask you quickly on 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%.

Speaker 6

And there had been some commentary around some patients seeing an excess of 65%. Thanks so much.

Speaker 3

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

Speaker 3

And so we didn't really feel like that was really representative. To answer your question directly, if you take that exact definition of any improvement in PVR, no matter how small, it was more like 75% of the patients have that. But again, we wouldn't really want to call someone who decreased their PVR 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 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 and then but we didn't want to sort of change the metric that we were reporting from the last time.

Speaker 3

So we just didn't do that analysis. 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 PVR, 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 therapeutic regimen because it's a progressive disease.

Speaker 4

Okay. Thanks so much.

Operator

Our next question comes from the line of Vamil Divan from Guggenheim. Please go ahead.

Speaker 7

Hi, this is Daniel on for Vamil. Thanks for taking my questions. I have a couple of questions on TPIP, if I can. So the first one, for PHILOB, you see that there's about like 38% of patients that show a drug related cost. It seems fairly mild, but I guess are there any things that can be done to maybe lower this cost for patients?

Speaker 7

And I guess I was kind of curious if that if this might be extra important for those patients that might be moving up to an even higher dose in the open label extension in PAH? So that's my first question. And then the second question is maybe more on like the broader TPIP opportunity. It was previously, you said, it's $2,000,000,000 plus opportunity. I was wondering if you can maybe break down this opportunity between the different indications and then maybe between geographies of U.

Speaker 7

S. And the ex U. S. Markets. I was just curious if this data has any recent impacts on your views on this?

Speaker 8

Thank you.

Speaker 2

Daniel, I'll just jump in and then I'll ask Gene to take the specific question on cough. I think with regard to the opportunity, stay tuned. We're going to go in a much deeper dive on the commercial day that Sarah made reference to in the aftermath of the Aspen data production into what the TPIP 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 continue to feel very comfortable with the sort of peak sales at $2,000,000,000 plus.

Speaker 2

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. 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.

Speaker 2

And we'll have more to say about that, Daniel, on the commercial day. Gene, do you want to take the question about cough?

Speaker 3

Sure. Yes. The first point to make is that the PAH ILD 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, where in interstitial lung disease, cough is a significant symptom of diseases present in most patients to some degree or another.

Speaker 3

So that was sort of the 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. What that means is there was something about the cough in patients on active 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 in discussions with the investigators, it tend to be a very mild cough, cough right after taking the drug and really wasn't problematic, was rated as mild, did not result into anyone discontinuing treatment and so forth. And kind of the proof is in the pudding that they despite that imbalance in cough, they were able to titrate up to the highest dose, the 640.

Speaker 3

So we feel pretty good about it. What we wanted to exclude was that in patients with underlying parenchymal lung disease, would this drug be somehow more exacerbate their underlying cough 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. I think you raised the question of what happens when we go higher.

Speaker 3

And we'll see, as we said before, the data on more is better, if you will, with prostenoids is very clear with pulmonary arterial hypertension. With all of the routes of administration of treprostinil, it's very clear that the higher you can go, the more efficacy you can get. And so we definitely we are, 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. We chose not to do that in the open label extension for PHILD in primarily the data that more is better is not entirely clear in PHILD. There just is less clinical experience in that regard.

Speaker 3

So we weren't sure that it was necessary. 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.

Speaker 2

I'll just add one final punctuation 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.

Speaker 7

Great. Thank you very much for answering my questions.

Operator

Our next question comes from the line of Jessica Fye from JPMorgan. Please go ahead.

Speaker 9

Great. Good morning. Thanks for taking my question. Sort of a 2 part question on brincicatib. Thinking back to the WILLOW data, can you remind us why or what the hypothesis is behind not really seeing meaningful changes on quality of life, St.

Speaker 9

George's, LCQ and those kind 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 drug or not similar to WILLOW. And I'm curious what they cite. Curious what they cite if it may not be quality of life measures given that exacerbations are fairly infrequent and I'm not sure that would be kind of the tip-off.

Speaker 9

Hope that made sense.

Speaker 2

Yes. So I'll take a shot at that, Jessica, and then I'll invite Gene to comment anything further he'd like to. I think with regard to Willow and quality of life, I'll remind everyone that that was a 6 month study and it takes about a month for 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.

Speaker 2

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 the exacerbations. That is the thing we're really trying to impact. 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 on the drug and convey this to physicians, it's a combination of different things that each patient feels.

Speaker 2

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 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 dispute them, 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.

Speaker 2

And of course, our primary focus is on the exacerbation impact. If we achieve that, then we will certainly have accomplished victory. I don't know, Gene, if you want to add anything further.

Speaker 3

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

Speaker 9

Can I just add a quickie on, TPIP and the PHILD data on oxygen saturation? I don't know if it's I just missed it somewhere, but can you give us the baseline oxygen saturation for each arm?

Speaker 2

Gene, I don't know if we have that. Do you want to address that if it's handy? If not, we can circle back.

Speaker 3

Yes. 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 I just wanted

Speaker 4

to make

Speaker 9

sure it was balanced.

Speaker 3

Yes. We didn't conclude that in the baseline demographics information, did we? There was some indication that the TPIT group were a little sicker. Their use of supplement option was a little bit higher. Their FEC was a little bit lower.

Speaker 3

And frankly, during the 6 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.

Speaker 10

Great. Thank you.

Operator

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

Speaker 2

Hey, thanks for

Speaker 11

taking my question and congrats on the data. So a couple on TPIP. 1, on Slide 7, the 6 minute walk distance was not available for the placebo arm. Can you just remind us on was this because of inability to collect data or it's just 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?

Speaker 11

Thank you.

Speaker 2

Gene, you want to take those?

Speaker 3

Sure. Yes. In that Slide 7, the NA 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.

Speaker 3

So it's NA meaning not applicable more than not available, if that makes sense. And so what we've included in that box is to emphasize that the point estimate is 30. With the point estimate and that's remarkably similar to the point estimate of the effect size on 6 minute walk that was seen in the pivotal trial for Tyvaso PHIL D, the so called INCREASE trial was comparable. However, we want to be very, very clear and we put 2 indicators of variability. The confidence intervals are extremely wide in that square and then the p value is not even close to statistical significance.

Speaker 3

So that is I think that hopefully that responds to your question about what that NA means. And the other you asked about sort of the cadence of the improvement and we have not released that yet. We haven't analyzed that closely to see how quickly we start to see a difference. I think that that's will is data that will emerge as in more fulsome presentations of the data. But since the pivotal trial endpoints would be from change from baseline to the end, that's what we decided to focus the top line results on.

Speaker 2

Thank you.

Operator

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

Speaker 12

Hi, congrats on the very strong TPIP data. I was wondering,

Speaker 3

how many of the patients in

Speaker 12

the Phase 2 study of PIP and PAH have been enrolled in the 10 countries which are allowing you to titrate up to 12 to 80 micrograms? And are you still talking to other countries' health authorities about doing this or will it just be those patients when we see that data? And then I have a follow-up on Brenzo, please.

Speaker 2

Yes. 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.

Speaker 3

Yes, I don't have the specific figures because the reason is that we don't think the door isn't closed in other countries. It's just that the back and forth is ongoing either with first you have to go through 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 currently covered because I think we expect more of those countries to eventually allow the expanded dosing.

Speaker 2

That's helpful. Thank you. Sorry, go ahead.

Speaker 12

No. Please, Will, sorry about that.

Speaker 2

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 PAH study, not the TPIP study.

Speaker 12

Right. Okay. Thank you. 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?

Speaker 12

And what's the right way to contextualize the clinical benefit of something like a 15%, 25% or 35% reduction in exacerbations. How have your discussions with physicians and payers gone in that front?

Speaker 2

Yes. I think what we've been trying to be very clear about is that the clinical meaningful threshold, I think that everybody sort of agrees there's 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, we would consider that a home run.

Speaker 2

Then we've got a drug. And that we think will be a very successful outcome. Of course, we saw higher than that in Willow and we certainly hope that is replicated in Aspen. We have no reason to believe that it wouldn't be. The baseline characteristics, the execution of the trial, all the design elements are in parallel to what was seen in Willow.

Speaker 2

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, that if this were to be 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. If that number goes up even more, it will probably affect the 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 reflections.

Speaker 2

But all of the education about this has already been underway with our medical group and indeed in our market access 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 0.01 with 1 dose and a treatment effect of 20% or more.

Speaker 12

Thank you.

Operator

Our next question comes from the line of Nicole Garmino from Truva Securities. Please go ahead.

Speaker 4

Hi. Thank you for taking my question.

Speaker 2

I'm sorry. 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 it, please?

Speaker 4

Sure. I apologize for any reason. Just going back to the TPIP in patient ILU, how does the drop in to Tyvaso experience and the non target effect?

Speaker 2

Gene, did you hear that question? That sounded like how does it compare to Tyvaso?

Speaker 3

How does which aspect?

Speaker 2

PPIP on the PHILD side. Is that right Nicole? Did I get that right?

Speaker 4

Yes. That's right. How does that drop in oxygen levels compared to the type of period and how target is that?

Speaker 2

Well, I'm really having a hard time hearing, Greta. I think it was the oxygenation levels in the PHILD, how does it compare to TAVAZA?

Speaker 13

She's asking if the oxygen the drop in oxygen levels, how do they compare?

Speaker 3

To Tyvaso, we didn't do a direct comparison because again this is a small study and we're not trying to make claims against Tyvaso. 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 no negative impact on their desaturation during the course of exercise and we think that's what we saw. The reason we were even looking for that, the reason we were even 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.

Speaker 3

And you get what's called shunt, blood going past the lung, which is not getting oxygenated because the area of lung that it's delivered blood to is not getting ventilated. And there have been problems when systemically administered vasodilators have been used to treat PHILV and in fact have led to contraindications in the product labels for riociguat and for embersantan. 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 INCREASE trial showed, the INCREASE trial is the trial for evidence benefit of the Tyvaso in this population was that that wasn't a problem. 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.

Speaker 3

So we just wanted to they apparently did not see it in with Tyvaso and we just wanted to monitor that in our trial as well. And again, 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 compared to placebo.

Operator

Our next question comes from the line of Greg Subbanovia from Mizuho Securities. Please go ahead.

Speaker 13

Hi, this is Jerry on for Greg. Thanks for taking our questions and congrats on the TPIP data. I guess first on TPIP, based on what you know now, what a Phase 3 study in PHILAD look like? And then I do have a follow-up on Brenza as well after.

Speaker 2

Yes, I'll take that quickly. We haven't really put any thoughts in the public domain about what that Phase 3 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 and then we're going to want to have dialogue with regulatory authorities.

Speaker 2

But as soon as that is accomplished, we will 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.

Speaker 13

No, that's fine. That's helpful. And then for, I guess, the upcoming Aspen readout, since you mentioned you commented that all patients that Aspen have reached that to be 2 weeks of all the adults that time period, I'm wondering if I could give you more granular timing on the timing of that data release?

Speaker 2

Well, I tell you, that is the question of the day. I wish I could be more specific. We tried to narrow it down to the mid May end of June timeframe, which is 45 days. 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 get to this point on a large trial.

Speaker 2

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 for every detail and quality issue to be resolved because this is a submission database. And what I mean by that is, this is the database that's going to the FDA and to 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 top line results and then the database that got rejected for some quality issues.

Speaker 2

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 every aspect of that effort at the company has gone incredibly well and 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. And that's as specific as we can get.

Speaker 2

But those are the reasons that are sort of pacing when that database will be ready for review.

Speaker 13

Got you. Thanks for the color and congrats again.

Operator

Our next question comes from the line of Jason Zimansky from Bank of America. Please go ahead.

Speaker 14

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 TPIP. Appreciating these are small numbers, but about at 14%, it's twice what was observed for the Tyvaso BREATHE 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.

Speaker 14

Was there something about the 4 patients who discontinued whether it was, I don't know, underlying disease severity or dose received 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.

Speaker 2

Gene, do you want

Speaker 15

to take that?

Speaker 3

Yes, sure. I think when we sort of use the Tyvaso as the benchmark, we don't so much look at the BREATHE study as we do the INCREASE study. And I think that 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 Tyvaso. So I guess I try to point you to the INCRE study as the better comparator than the BRIS study. And then the second question was the second part of it was?

Speaker 14

Well, was there something specific about these 4 patients? Like you'd said, the titration schedule is a little bit more aggressive than what you normally see with Tyvaso. Is that when they dropped out? Or again, was there something about the dose that they received? I'm just curious if there was something consistent amongst the patients.

Speaker 3

The actual dropouts from the study were not drug related and nothing no signal of inability to titrate the drug or anything like that in the PHILB study.

Speaker 14

Got it. Okay. And then just kind of thinking more broadly, when thinking about TPIP's potential in your guidance, how important is it that patients get to the 640 milligram or microgram dose or higher? Is it the assumption that the drug will provide more benefit given the higher dose or is its value really in moving from 4 times daily to once daily administration? Yes.

Speaker 2

So I'll just jump in on that one and then ask Gene to comment. 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 we're working on the target product profile, we spent a lot of time with 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 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.

Speaker 2

So we picked 640 micrograms for this study, which is 60% greater than what treprostinil is the equivalent of treprostinil administered over 4 times already. So it's quite a substantial step up. The physicians are very encouraged by that. 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.

Speaker 2

So I think there's a lot of promise here for the clinical result that we expect to see from PAH as patients move from 640 to even higher levels. 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. To be able to do it with a once a day administration is the benefit of convenience as well as the clinical side I just mentioned. And the once a day piece was enough to get enthusiasm from treating physicians in and of its own right, 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 a prosenoid of choice for the treatment of these patients.

Speaker 2

I don't know, Gene, if you have other reflections.

Speaker 3

Yes. I mean, I just the only thing to add to that, first of all, the basic assumption with prostenoids in PAH is that the more you can get in the better. And generally patients and doctors tolerate a little bit of prostinoid related side effects to kind of max the efficacy. I will say that there tends to be a spectrum of tolerability like some patients tend to get just get a lot more sensitive to the, carcinoid related side effects than others. So if you look at a population of patients on Remodulin, for instance, there'll be patients at lower or higher doses depending on their individual sensitivity to the prosenoid related side effects.

Speaker 3

So I don't necessarily think we need to get everyone up to the top dose. It's more a matter that there's 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 Tyvaso, because of the peak systemic exposure immediately after dosing, you kind of don't. You get up to the you titrate up to the target dose and then you stay there and that label does not include continuing to dose escalate.

Speaker 3

I think that's probably related to 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 IV treprostinil is dosed. In other words, you can continue to increase the dose according to the patient's tolerability. And we think that in addition to the once daily versus 4 times a day, that's a great distinction. But this is another distinction.

Speaker 3

You get the benefit of delivering the lung, the drug directly to the lung, but also the ability to titrate it in a manner that they do with the parenteral product.

Speaker 14

Interesting. Thanks for the color.

Operator

Our next question comes from the line of Brito Baral from TD Cowen. Please go ahead.

Speaker 4

Hi, guys.

Speaker 16

Thanks for squeezing me in. And I apologize in advance. 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 so looking back to the distribution constants between the arms and historical studies, we noted that Willow obviously had very low variance sort of 0.04 to 0.1 and historicals were in the 0.4 to 0.5 range.

Speaker 16

Have you been able to look at all at 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 just got a quick follow-up.

Speaker 2

Yes. I hate to disappoint Ritu, because I know the work that you've put into this and appreciate the focus on this particular aspect of the data set. 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 no one variable controls, but 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 16

Fair enough. Just on discontinuation rates in Aspen, can have you tallied the final discontinuation rate whether it stayed within expected parameters per the last update?

Speaker 2

Yes. What we can say is that, while we haven't given any update with 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 by various arms, etcetera. But the blended blinded data continues to look very favorable with regard to safety and just get to you.

Speaker 16

Got it. Got it. And let me just squeeze one last in. 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?

Speaker 16

Thanks.

Speaker 2

Gene, do you want to take that?

Speaker 3

Yes. And just to be clear, I think what I was commenting on before was the patients with study drug related adverse events and that in fact when there was cough, doctors tended to identify it as study drug related. It's up 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 in TPIP and did not attribute it to the placebo. And again, that's probably related to temporal nature as a lot of these patients have an underlying cough that would be just representative of the disease.

Speaker 3

So just to clarify what I meant on that. But to your broader question, we are not seeing any particular safety finding that would be unique to TPIP, something unexpected at all. And certainly nothing that's impinging upon dose escalation because we're getting so many people up to really the maximum or we also release the number of patients who got to the second to the top dose and that was pretty high too that if you go to that it's 90% of patients. So we're not seeing problematic AEs that limit a dose escalation, and we're not seeing any novel safety events that would give us concern. That's something unique to TPIP.

Speaker 2

And I would only add that the timeframe we have for that titration, Ritu, is 5 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% of patients are getting the maximum tolerated dose of 640 in this study, in the ILD study and 90% of them are getting to the penultimate level, which is just a remarkable outcome from our point of view.

Speaker 4

Thanks.

Operator

Our next question comes from the line of Jeff Ho from Morgan Stanley. Please ask your question.

Speaker 17

Thanks for taking my question. For TPIC based on the data, can you just comment if you see any evidence of disease modification? And then I have a follow-up.

Speaker 2

Gene, do you want to address that?

Speaker 3

Yes. And by disease modification, I presume you're referring to the underlying pulmonary fibrosis, which I know that that was an observation made in the INCREASE trial that there may be some evidence of effect on the pulmonary fibrosis and 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 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 10 patients.

Speaker 3

We really the 3 to 1 randomization was intended because what we really wanted to do is 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 treprostinil impacts the pulmonary fibrosis.

Speaker 17

Okay, great. And then you started education efforts for Brenzocat fairly early. Can you just talk about how far that's come and how much more education you think is still needed for physicians for potential launch? Thanks.

Speaker 2

Well, I'm happy to report that we have the similar experience of being a 1st in disease drug and the 1st ever approved drug for the ARIKAYCE use in refractory MAC patients. So that experience informs our approach once again to the larger opportunity that would be represented by bronchiectasis using brancicatid. And so that medical education got underway with the American Thoracic Society really last year at this time and has been ongoing. And that will continue to ramp through our expected launch in the U. S, which would be the middle of 2025.

Speaker 2

In parallel to that, we are also right now started at the end of last year working on the market access front to make sure that 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. 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 front, the progress with regard to bringing additional resources in, first in the U.

Speaker 2

S. And then in Japan and Europe, is also underway at the Area Director and Regional Director level. 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 are getting scores of candidates signing up to try to gain access to the opportunity.

Speaker 2

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 commercial launch of the drug should everything go as expected by the middle of 2025. Hopefully that's helpful.

Speaker 17

Great. Thank you.

Operator

Our next question comes from the line of Lisa Bayko from Evercore ISI. Please go ahead.

Speaker 10

Hi, guys. Congrats on the TPIP data. Just 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 was a lot of patients in your baseline paper from the Latin America region. It was, I think, more than a quarter of the population, which they seem to have milder disease.

Speaker 10

Can you talk about your comfort level making sure like some specific large groups like that are well balanced across the arms? That's my first question. Then my second question relates to how we can think of a quiet period around the data. Are you planning kind of a couple of week quiet period, a couple of days? Just wondering if we can if we stop hearing from you guys, if we might think data is coming?

Speaker 10

Thanks.

Speaker 2

I'll take the second question first. Just tell you that when the moment comes, I think the 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. 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.

Speaker 2

But so it's hard to give guidance, Lisa, as to how long we would 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. Indeed, we are very focused, as I said before, on the quality and that may be something that we just want to refine. So that would be my answer to that.

Speaker 2

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's 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'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 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.

Speaker 2

I can tell you, we feel very good about the baseline demographics here and the distribution around the world. Hopefully, that answers the question.

Speaker 10

Did you stratify for Latin America specifically or did that just go into rest of world stratification?

Speaker 2

We didn't stratify in that sense the best of my knowledge. Someone else can correct me if I'm wrong. But we do obviously track out where patients come from and we can certainly cut the data that way should it become necessary to do so.

Speaker 15

All right. Great. Thank you.

Speaker 1

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, etcetera.

Speaker 10

Okay. Okay, great. Thank you.

Speaker 2

There you go.

Speaker 8

And your next question comes from the line of Jennifer Kim from Cantor Fitzgerald. Please go ahead.

Speaker 15

Hey, guys. Thanks for taking my questions and congrats on the TPIP data. Maybe to start with Renzo. 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?

Speaker 15

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, macrolide background regimens? I'm looking at Japan, I know we saw in the paper there's a much higher use of that for example. Thanks.

Speaker 2

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 timeframe we'll produce it. With regard to 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 want to 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.

Speaker 2

I think the simple answer is we're proximate enough to the actual data from Aspen to just sort of wait for that data. 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 are encouraging, the qualitative commentary from physicians.

Speaker 2

But the data will ultimately control as we all know and add anything specifically about the question just in light of the last one.

Speaker 1

No, all good.

Speaker 15

Okay, thanks. And if I could ask a question on Tepid, maybe for Gene. I wanted to confirm, is Phase 3 advancement in PHILD 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 and PHLD and what the baselines were for both arms? Thanks.

Speaker 3

Sure. So the question is about Phase 3 and moving forward into Phase 3. I think that will be primarily based upon the results of this trial as we analyze these results and the ones that will come in subsequently And also on the experience of Tyvaso 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 a design of a Phase 3 trial for PHILD. And I think your second question had to do with the 6 minute walk test.

Speaker 3

We've given the delta, right, 30 meters placebo controlled. And so were you asking what was the actual change from baseline in the treatment groups?

Speaker 15

I was asking what the placebo 6 minute walk change was. I think you've given the placebo adjusted change and then so the placebo change and then also what the baselines were for both arms?

Speaker 3

So I'll just say broadly that the probably the best way to do it is placebo controlled. That would be the primary analysis. In general, it had to do 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 general pattern was what resulted in the 30 meter delta between the 2.

Speaker 15

Okay. Thanks for taking my question.

Speaker 8

Your next question comes from the line of Stephen Willey from Stifel. Please go ahead.

Speaker 2

Yes, good morning. Thanks for squeezing me in. Just a quick Aspen question. So I know the manuscript detailing patient baselines suggest that there were about 20% of patients with elevated eosinophils. Curious as to whether or not you said anything about eosinophil levels as it pertains to Willow?

Speaker 2

And then just kind of curious as to your thoughts around the impact of Bremso in this elevated eosinophilic population where maybe inflammation may be not so neutrophilic in nature? Thanks. Yes. The short answer is that I don't know the answer to that question, Steven. I can ask Gene if you know offhand, otherwise or Brian if someone else wants to comment.

Speaker 2

Otherwise, we'll have to get back to you.

Speaker 3

Yes. The only comment I'd make is that patients have elevated eosinophils in their secretions either sputum or nasal secretions, it doesn't mean that all of the 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 of the inflammation is still neutrophil driven. So I think there's still a reason to expect a benefit even in those patients. That's why we didn't exclude eosinophil patients.

Speaker 3

So that's the only thing I want to clarify because sometimes people think that when it's elevated EOs, it's at the expense of the neutrophils. But in that milieu and the inflammatory milieu, there are plenty of neutrophils there as well.

Speaker 2

We can get to the specific numbers if we have them and they're public with a follow-up. All right. Thanks.

Speaker 8

Your next question comes from the line of Andy Chen from Wolfe Research. Please go ahead.

Speaker 6

Hi. This is Aman for Andy. Thanks for taking our question and congrats on the data. Just a couple of quick ones on our end. I guess, how big is the existing ARIKAYCE sales force?

Speaker 6

And then assuming Brenzo is successful, what's the target sales force size there? And that's one. And then on PAH regarding the average improvement in 6 minute walk distance from baseline of 43 meters, How should we interpret this data point? I know during the call, as mentioned, it's a highly variable measure, so it's difficult to kind of interpret this. But would you say this is a modest or big success?

Speaker 6

Was there kind of an internal bar? Thank you.

Speaker 2

So Sarah, do you want to take the question on sales force expansion? And Jean, you can take the one on the 6 minute walk on TPIP.

Speaker 5

Sure. Happy to. Thanks for the question. Existing sales force in the U. S, we have about 65, 70 reps existing in the U.

Speaker 5

S. We will look to expand that. What we've said publicly, 200 to 220 what we've said publicly. We'll share more on those details on the commercial day that we've alluded to throughout the Q and A session. What I would like to comment on is the immense crossover between ARIKAYCE and BRENSO CAPTIVE and the synergies that we will have.

Speaker 5

ARIKAYCE obviously calls on pulmonologists and ID docs. Brento primary call is pulmonologists. So it's 2 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.

Speaker 3

Yes, sure. So on the 6 minute walk distance in the blended blinded of 43 meters, of course, we say this over and over again, 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.

Speaker 3

We're seeing patients with improvements. And if those represent patients who are on active drug, that's great. And the 43 meters would be plenty. 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 6 minute walk distance even with the final unblinded data. 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, that likely is not enough.

Speaker 3

If you look at the pivotal trial for Tyvaso in PAH, that was over 200, I think it was 230 or so patients to show a statistically significant benefit. So we see the improvement in the blended population. We don't know who's on active and who's not, but we're pleased with it. It's a good number and there are patients who are clearly improving and we'll just have to wait to see the unblinded data.

Speaker 6

Great. Appreciate the answers.

Speaker 8

And that concludes our Q and A session for today. I would like to hand back to management for closing remarks.

Speaker 2

Thanks very much everyone for joining us today.

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